TAP Vol 1 Issue 1 by Harborside Press LLC

Health-care reform and oncology 4, 65–67

PARP inhibitors in breast ca 12

Understanding proteomics 24

VOLUME 1, ISSUE 1

JUNE 2010 ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

Cover Feature

Radioimmunotherapy Is Safe and Effective in Follicular Lymphoma after 8 Years of Follow-up

Introducing The ASCO Post

By Alice Goodman ature follow-up data of a multicenter phase II study demonstrate that six cycles of cyclophosphamide, vincristine, and prednisone (CVP) followed by one cycle of tositumomab and 131I-tositumomab (Bexxar) therapy achieved high remission rates with adequate safety and durable remissions in patients with newly diagnosed advanced follicular lymphoma (FL).1 “These 8-year follow-up data show that CVP followed by radioimmunotherapy is a highly active first-line therapy for follicular non-Hodgkin lymphoma (NHL),” stated senior author John P. Leonard, MD, Center for Lymphoma and Myeloma at Weill Medical College of Cornell University in New York City. “These results are the first description of sequentially combining 131I radioimmunotherapy following CVP—the second most common chemotherapy backbone choice for FL in the United States. Use of the nonanthracycline regimen is important because roughly two-thirds of patients with FL in the United States are currently managed without

By James O. Armitage, MD, Editor-in-Chief

1.00

Survival Probability

0.75

0.50

0.25

Progression-free survival Overall survival

Time Since Start of CVP (years) Fig. 1: Kaplan-Meier estimates for progression-free survival and overall survival. CVP = cyclophosphamide, vincristine, and prednisone. Copyright © 2010, American Society of Clinical Oncology.

anthracyclines at the time of diagnosis,” he added. Although this was a small study of 30 patients with newly diagnosed FL, Dr. Leonard said, results are encouraging because all patients responded to the regimen. Approximately 53% achieved a complete response continued on page 10

Clinical Trials

Institute of Medicine Recommends 12 Sweeping Changes to NCI’s Clinical Trials Cooperative Group Program By Barbara Boughton

or the past 50 years, the National Cancer Institute’s Clinical Trials Cooperative Group Program has played a key role in developing new and improved cancer therapies and preventive strategies. NCI-sponsored trials have studied distinct cancer subpopulations and those with rare cancers, elucidated the role of therapeutic and chemoprevention John Mendelsohn, MD agents such as tamoxifen

for breast cancer, and evaluated quality-of-life issues for patients with cancer. But a new report from the Institute of Medicine (IOM) of the National Academies concludes that the Clinical Trials Cooperative Group Program is in a “state of crisis.” The IOM report recommends 12 sweeping changes in the ways that their clinical trials are reviewed, prioritized, and funded— changes that are likely to affect players as diverse as NCI and the FDA, clinical research investigators, cancer patients, and even heath-care insurers and the pharmaceutical industry. More than 25,000 cancer patients, 3,100 institutions, and 14,000 investigators continued on page 17

ver the years I have become increasingly proud of the American Society of Clinical Oncology. I believe that ASCO is unique among specialty societies—at least in the various disciplines of oncology and hematology. Our Society is amazingly democratic (ie, with an independent nominating process and truly competitive elections), really “owned” by the members, and responsive to the members’ needs and desires. The current structure of the Annual Meeting, the other ASCO-sponsored meetings held throughout the year, the makeup of the Board of Directors, and the various ASCO publications all reflect efforts by the elected leadership to respond to members’ requirements. The ASCO Post (TAP) is the newest in a long series of innovations intended to make ASCO membership more valuable and rewarding. The ASCO Post will provide useful information covering a wide range of issues important to oncologists. The most important recent clinical research from the Journal of Clinical Oncology ( JCO), other major journals, and important meetings including our Annual Meeting will be summarized, and in many cases the views of the authors will be incorporated. These can provide quick updates in various aspects of oncology, or can provide the continued on page 71

MORE IN THIS ISSUE Direct from ASCO �� 27 Stereotactic body radiation therapy for inoperable lung cancer �� 52 FDA newly approved agents �� 69 Should oncologists participate in physician-assisted suicide? �� 73

What’s this? See page 72

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ASCOPost.com | JUNE 2010

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Editorial

Why The ASCO Post? Editorial Board James O. Armitage, MD Editor-in-Chief Professor, Internal Medicine Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska Associate Editors Douglas W. Blayney, MD University of Michigan Comprehensive Cancer Center Joseph S. Bailes, MD Texas Oncology Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA Houston, Texas Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

Robert W. Carlson, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Jay S. Cooper, MD Maimonides Medical Center

George W. Sledge, MD Indiana University

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Thomas J. Smith, MD Virginia Commonwealth University

George D. Demetri, MD Dana-Farber Cancer Institute

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida

Harborside Press Publishing Staff Conor Lynch Executive Editor Conor@harborsidepress.com

Wendy McGullam Director of Production Wendy@harborsidepress.com

Cara H. Glynn Director of Editorial Cara@harborsidepress.com

Leslie Dubin Vice-President, Director of Sales Leslie@harborsidepress.com

Andrew Nash Associate Director of Editorial Andrew@harborsidepress.com

Anthony Cutrone President Anthony@harborsidepress.com

Sarah McGullam Assistant Editor Sarah@harborsidepress.com

John A. Gentile, Jr. Chairman Jack@harborsidepress.com

Michael Buckley Graphic Designer Michael@harborsidepress.com

Contributing Writers

Charlotte Bath, Barbara Boughton, Jo Cavallo, Daniel Denvir, Alice Goodman, Caroline Helwick, Kathleen Louden, Larry Rosenberg, Matt Stenger, Leah Young, Patrick Young

Contributing Artists

Portraits by Keith Witmer, Keith Witmer Illustrations Artwork on page 24 by Alex and David Baker, DNA Illustrations Financial disclosure information available at ASCOPost.com.

Allen S. Lichter, MD Chief Executive Officer American Society of Clinical Oncology

t has been 5 years since ASCO has been part of a new publication, the last being the Journal of Oncology Practice ( JOP). As the ASCO Board and leadership evaluated the publication mix we recognized there was a gap that needed to be filled. The Journal of Clinical Oncology (JCO), now 25 years old, is the field’s flagship journal for presentation of clinical oncology research. JOP is making great strides to become the key journal for the complex issues involved in the actual practice of oncology. ASCO News and Forum, soon to morph into the ASCO Connection, speaks to our members about ASCO programs and issues. Finally, we communicate to the membership every other week though a comprehensive e-mail newsletter, the ASCO Express, which summarizes timely issues and announcements. There was healthy debate and controversy surrounding the creation of each of these publications. None of them was guaranteed success; their place in the world had to be earned. These publications are rigorously evaluated every few years to make sure they are upholding the standard the ASCO Board and leadership have set: to be associated with only the finest publications for our members. It was into that context that we began discussing an oncology newspaper.

A Publication for the Entire Oncology Community What we saw lacking was a publication targeted to the entire oncology community, covering broad areas of multidisciplinary oncology with thoughtful commentary from leaders in the field. While ASCO has over 28,000 members from over 100 countries, 23,000 of them physicians, the world of oncology is far larger. We believe that every oncology professional should be a member of ASCO, and, in a subsequent editorial, I will explain why. But until that happens, and as part of a strategy to facilitate that happening, ASCO

wants to add its name to a vehicle communicating to the field of oncology writ large. Enter The ASCO Post. The ASCO Post (TAP) will be published by our colleagues from Harborside Press. The team at Harborside Press brings years of experience as successful publishers in the field of oncology. Under their direction, and with the editorial leadership of former ASCO President, Dr. Jim Armitage, The Post will summarize and comment on the latest research findings, not only from ASCO’s meetings and journals, but from other venues as well. Policy and advocacy issues relevant to oncology will be highlighted in ways we have not been able to do so in ASCO publications. ASCO events as well as events from other organizations can be noted. We are confident that the readers of The ASCO Post will find this an engaging and informative publication. Plus, in each issue, selected pages will be dedicated to content that is “Direct from ASCO” (see pages 27 to 31 in this issue). The content on these pages will be provided by the Society and directed to ASCO members and other health-care professionals who may be interested in joining ASCO. In this issue the Direct from ASCO content explores a number of important ASCO initiatives and offers a close look at The ASCO Cancer Foundation and its role in supporting critical research, increasing cancer awareness, and offering hope to patients and their families. There are five other oncology “tabloid” newspapers publishing today, and we know there will be stiff competition for your attention and your eyes. The Board wants ASCO to be associated with the finest publication of its kind. We are determined that The ASCO Post will meet this challenge. We welcome your comments and feedback at any time. In the meantime, please enjoy reading the inaugural issue of The ASCO Post! —Allen S. Lichter, MD

The ASCO Post | JUNE 2010

PAGE 4

Expert’s Corner Health-care Reform

A Conversation with Joseph S. Bailes, MD How Health-care Reform Legislation Affects You and Your Patients By Jo Cavallo

fter a year of contentious debate— and decades of unsuccessful attempts—a comprehensive health-care reform bill was signed into law in March. Although some aspects of the law, including coverage of 32 million uninsured Americans, will be phased in over the next 4 years, some provisions in the law take effect within the next 6 months.

Another crucial component in the legislation, which ASCO championed for more than 20 years, is the inclusion of guaranteed insurance coverage for patients with cancer participating in clinical trials. The ASCO Post asked Joseph S. Bailes, MD, Chair of ASCO’s Government Relations

This law requires insurance companies to pay for routine costs in a clinical trial. That effectively means that an insurer cannot deny a patient coverage in a clinical trial by calling the trial ‘experimental’— it takes that word out of the lexicon. – Joseph S. Bailes, MD

For example, health insurers are now prohibited from denying coverage to children with preexisting conditions, and they can no longer place lifetime dollar limits on policy benefits and on “unreasonable annual limits”—an important change, especially for patients with cancer who need ongoing treatment. Also beneficial to patients with cancer is the elimination of copays for certain preventive health services, such as annual mammogram screenings, which takes effect in January 2011.

Committee, about how the new health-care reform legislation will impact oncologists and their patients.

Impact on Oncologists How will the health-care reform law affect oncologists both in the academic setting and in the private practice care setting? Dr. Bailes: Several important provisions in the health-care reform legislation will be positive for oncolo-

gists and our patients. For example, included in the law are various demonstration projects to determine how to achieve the best care and not just simply more care. One such project is the development of a center for Medicare and Medicaid innovation, and the purpose of that center is to conduct demonstration projects that not only help control costs but also enhance quality. There’s also a demonstration project for cancer treatment planning.

Patient Care How does the law help oncologists provide better care for their patients, and what’s the immediate effect of the law on the way they can treat their patients? Dr. Bailes: The elimination of preexisting conditions and lifetime caps takes away reasons to deny coverage, so that when an oncologist sees a patient, he or she will know that the appropriate therapy won’t have to be limited by payment considerations. I think that’s very important. Also, previously uninsured individuals will now have access to insurance, and we can avoid a lot of the delays that result from having to find financial resources to cover the costs of tests and therapy. The legislation requires that states set up insurance exchanges called American Health Benefit Exchanges, through which individuals can buy insurance. For individuals with preexisting conditions, coverage will be available in about 6 months. We hope that all of these changes will help individuals go to their oncologists and get care.

Clinical Trials What effect will the law have on encouraging patient participation in clinical trials? Dr. Bailes: It takes away the concern patients have about paying for routine medical costs associated with clinical trials. This law requires insurance companies to pay for routine costs in a clinical trial. That effectively means that an insurer cannot deny a patient coverage in a clinical trial by calling the trial “experimental”—it takes that word out of the lexicon. Coverage of routine care costs is going to be important because it’s been one of the barriers to participation in clinical trials, and this basically ensures that Americans get the care they’re supposed to get. Oncology is an evidence-based specialty driven by the results of clinical trials. The way we make progress is for individuals to participate in and get therapy through clinical trials. And to not have to argue about routine patient care costs with insurance companies, which goes on quite a bit, presents a very positive opportunity for oncologists to encourage patients to participate in clinical trials.

Impact on Outcomes Included in the law is the elimination of copays for certain preventive health services and screenings, including annual mammograms, starting in January. What impact will this have on cancer care outcomes and survival rates? Dr. Bailes: It will help improve survival rates not only in breast cancer, but if you look at colorectal cancer rates, prevention of the disease by screening, continued on page 14

The ASCO Post (ISSN 2154-3283) is published 12 times annually by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodical Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

Correspondence: Address general inquiries to Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com.

Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0905.

Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; email: leslie@harborsidepress.com.

Copyright ©2010 by Harborside Press, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Domestic: $75 for the print or online edition; $125 for both editions. International: $125 for print or online edition; $175 for both editions. Contact subscriptions@harborsidepress.com.

Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | JUNE 2010

PAGE 5

Editorial

ASCO as a Public Organization: No Longer Hiding Our Lamp under a Basket By George W. Sledge, Jr, MD

ike many professional organizations in the public sphere, ASCO regularly confronts policy issues. Because we are a large organization, and because we represent many constituencies, we are frequently called upon to offer our advice to the federal government. Our members must sometimes wonder where their Society stands on issues of interest to them, and whether the Society represents a strong voice supporting our common goals.

Developing Public Policy We develop public policy in many ways. First, we regularly task the Board of Directors with performing an “environmental scan”: What issues are bubbling up to the surface as important to our members? Where can we usefully intervene? Where should we allocate our (not infinite) resources to greatest effect? In addition, we regularly receive information from our members, often via our committees. For instance, our Clinical Practice Committee, representing our important state societies, serves as an invaluable source of in-

formation on the changing practice landscape (and many of our legislative efforts occur at the state level). Our Research Committee keeps the Board up to date on important federal initiatives affecting clinical research. And finally, ASCO staff members interact daily with the executive and legislative branches of government. We have been extremely fortunate to have colleagues such as Joseph S. Bailes, MD (the Board’s adviser on public policy) and Deborah Kamin, PhD (our Senior Director for Cancer Policy and Clinical Affairs) to help us navigate the sometimes treacherous Washington rapids. Much of this work comes together in our Government Relations Committee, which meets regularly to synthesize our responses on public policy initiatives. We also rely on our members for strategic intelligence. Many policy initiatives percolate through government advisory boards and legislative committees for months before entering public consciousness. Because ASCO members are often involved in the

public sphere, we sometimes receive a heads-up with sufficient time to prepare a measured and forceful response that clearly articulates our Society’s positions. We certainly appreciate, and indeed encourage, advance warnings from our members. Please don’t be bashful in contacting us if you think something important is coming down the pike in our direction. In the speedof-light Internet era, we need to be supple and rapid in our responses to emerging issues.

Political Outreach We comment on a broad array of issues, and just to list them would take far more space than I’ve been allotted. But several issues are key and serve as a focus for our efforts in both public and behind-the-scenes meetings and communications. First and foremost, we believe that the optimum care of patients with cancer requires a robust clinical infrastructure. We regularly interact with Congress in support of our clinical practitioners. Part of this is educational, explaining why the maintenance of our

George W. Sledge, Jr, MD ASCO President-Elect

clinical practice infrastructure is vital to the nation’s health and what ASCO is doing to ensure quality care. Equally important are our advocacy efforts: lawgivers are sensitive to public pressure, as they should be in a democracy. We often call upon our membership to contact their representatives on crucial votes, particularly those involving Medicare and Medicaid funding. The passage of the recent health-care reforms obviously poses both challenges and opportunities for cancer specialists, and we will continue to work with members of the executive branch (the Centers for Medicare & Medicaid Services, NCI, and FDA among others) to ensure that our voice is heard as new policy emerges from the mist. continued on page 11

Prostate Cancer

Sipuleucel-T Immunotherapy Approved for Metastatic Castrate-resistant Prostate Cancer By Larry J. Rosenberg, PhD ipuleucel-T (Provenge), a novel autologous cellular immunotherapy, was approved by the FDA on April 29 for treatment of men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). Dendreon Corporation, the manufacturer of sipuleucel-T, announced that this drug is the first therapeutic vaccine approved for the treatment of cancer, rather than its prevention. Sipuleucel-T vaccine therapy is developed by incubating autologous antigen-presenting cells (APCs), collected from each patient by leukapheresis, with a recombinant antigenic fusion protein containing prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. The antigen is taken up and processed by APCs, then presented on the cell surface. Following reinfusion into the patient, the activated APCs enhance antitumor immunity by

boosting the T-cell response against PAP-expressing prostate cancer cells.

100%–

IMPACT Trial Sipuleucel-T was approved based on results from the pivotal phase III IMPACT (Immunotherapy Prostate AdenoCarcinoma Treatment) trial that demonstrated significantly prolonged survival compared with placebo. Men with metastatic CRPC who were either asymptomatic or mildly symptomatic (N = 512) were randomized to treatment with sipuleucel-T (n = 341) or placebo (n = 171). Sipuleucel-T or placebo was administered every 2 weeks for three cycles. Patients were stratified by bisphosphonate use, primary Gleason score, and number of bone metastases. The primary endpoint was overall survival (OS). Updated results of the trial were presented at the 2010 Genitourinary Cancers Symposium by the lead continued on page 64

80%–

Overall Survival

60%–

Sipuleucel-T (n = 341) Median survival: 25.8 mo 36 mo survival: 32.1%

40%–

20%–

Placebo (n = 171)

Median survival: 21.7 mo 36 mo survival: 23.0% 0%

Time from Randomization (months) No. at Risk Sipuleucel-T Placebo

341 171

274 123

142 59

56 22

18 5

3 2

Fig. 1: IMPACT Overall Survival. Final analysis (349 events) with a median follow-up of 36.5 months. HR = 0.759 (95% CI = 0.606–0.951); P = .017 (Cox model); median survival benefit = 4.1 months. Courtesy of Philip Kantoff, MD.

ASCOPost.com | JUNE 2010

PAGE 9

News Prostate Cancer

Hormone Therapy plus Radiotherapy Produces Survival Benefit in Men with Intermediate-risk Prostate Cancer By Barbara Boughton

he landmark Radiation Therapy Oncology Group (RTOG) 94-08 clinical trial was the first to demonstrate definitively that the addition of short-term hormones to radiation therapy does not improve survival in men with low-risk prostate cancer. And while a new subgroup analysis of the trial, presented at the 2010 Genitourinary (GU) Cancers Symposium in San Francisco, showed that men with intermediate-risk prostate cancer obtained a significant survival benefit from hormone therapy, more study may be needed to truly judge the mer-

Advances since RTOG 94 -08 allow higher doses of radiation with better results... its of androgen deprivation therapy for this group of men, according to experts at the symposium. The 2010 GU Cancers Symposium was cosponsored by ASCO, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology. “There are still some questions about whether intermediate-risk patients will benefit from androgen

deprivation therapy, since modern advances in radiation therapy that have occurred since the RTOG 94-08 trial began in 1994 allow us to deliver higher doses of radiation with better results,” said Christopher Jones, MD, one of the study’s principal investigators and a partner at Radiological Associates of Sacramento in California.

RTOG 94-08: In Short ■■ The addition of hormone therapy to radiotherapy had most benefit for men with intermediate-risk prostate cancer.

■■ Androgen deprivation therapy did not improve survival for those with low-risk disease.

■■ More study is needed to determine if men with intermediate-risk disease will benefit from additional hormone therapy.

Key Data In the RTOG 94-08 trial, 1,979 patients with localized (mostly T1b-T2b) prostate cancer and a prostate-specific antigen (PSA) level ≤ 20 ng/mL were randomized to radiotherapy alone or to 4 months of flutamide at 250 mg three times a day, monthly goserelin (Zoladex) at 3.6 mg, or leuprolide at 7.5 mg starting 2 months before the initiation of radiotherapy. The dose of radiotherapy delivered to the prostate—66.6 Gy—was consistent with the standard of care in 1994. Median follow-up for patients in both arms was 8.4 years in the hormone-plus-radiotherapy arm and 8.1 years in the radiotherapy arm. Results indicated that for the overall study population, short-term hormone therapy given prior to and during radiation therapy increased a man’s chance of survival from 57% to 62%. The 10-year disease-specific survival also increased from 93% to 96% with the addition of

hormones. However, men with intermediate-risk prostate cancer seemed to benefit the most from hormone treatment. At 8 years, the overall survival for intermediate-risk patients treated with hormones plus radiotherapy was 72%, compared to 66% for those who received radiotherapy alone (HR = 1.23; 95% CI = 1.02-1.49). “It’s interesting to note that the actuarial death rate from intercurrent disease was similar in both arms, so there was no disadvantage to the addition of hormones,” said David McGowan, MD, of the Cross Cancer Institute in Edmonton, Alberta, Canada, another principal investigator for the study. The rates of gastrointestinal and genitourinary toxicities were similar in both arms, he added.

Results Not Definitive Dr. Jones noted that scientific evidence overwhelmingly supports the

Cabazitaxel Improves Survival in Patients with Castration-resistant Prostate Cancer

use of long-term androgen deprivation therapy in men with high-risk disease. He commented that although the results of the RTOG 94-08 study were not definitive for intermediate-risk patients, many clinicians still consider it wise to add hormonal therapy to radiotherapy for men in this risk group, particularly because hormones do not cause significant toxicity, he said. A newer trial, RTOG 08-15, will provide more evidence about the benefits of adding hormonal therapy to radiotherapy—at currently used doses—for those with intermediate-risk prostate cancer, he added. “RTOG 94-08 gives us level 1 data, and for the first time showed us that men with low-risk prostate cancer do not benefit from the addition of hormone therapy,” commented Deborah Kuban, MD, Professor in the Departcontinued on page 22

Prostate Cancer

By Barbara Boughton

en with castrate-resistant prostate cancer in whom docetaxel therapy fails may soon have a new treatment option, according to research presented at the 2010 Genitourinary Cancers Symposium in San Francisco, cosponsored by ASCO, the American Society for Therapeutic Radiology and Oncology, and the So-

ciety of Urologic Oncology. Results of the TROPIC trial, a double-blind, randomized phase III investigation of 755 men with castration-resistant prostate cancer whose disease progressed after treatment with a docetaxel-based regimen, indicated that the novel taxane cabazitaxel reduced the risk of death by 30% compared with mitoxantrone.

Cabazitaxel: In Short ■■ In the TROPIC trial, the investigational taxane agent cabazitaxel reduced

risk of death by 30% in men with metastatic castration-resistant prostate cancer compared to the currently FDA-approved agent mitoxantrone.

■■ Cabazitaxel represents an important new treatment option for men with advanced metastatic prostate cancer who have failed docetaxel.

“Cabazitaxel will represent a new therapeutic option for these very difficult-to-treat patients,” said lead researcher Oliver Sartor, MD, Piltz Professor for Cancer Research at Tulane Cancer Center in New Orleans. Dr. Sartor noted that treatments for men with metastatic prostate cancer who progress despite docetaxel are limited to supportive care, investigational agents, or hospice.

TROPIC Study The TROPIC study (Treatment of Hormone-refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-containing Regimen) is the first large randomized controlled trial to show an improvement in overall survival for men in whom docetaxel therapy fails.

Oliver Sartor, MD

In the trial, conducted at 132 centers in 26 countries, patients were randomized to either cabazitaxel at 25 mg/m2 or mitoxantrone at 12 mg/m2 once every three weeks, and both groups received 10 mg/d of prednisone. The median overall survival for men who received cabazitaxel was 15.1 months, compared to continued on page 23

The ASCO Post | JUNE 2010

PAGE 10

Cover Feature

Radioimmunotherapy continued from page 1

(CR) to CVP chemotherapy and 93% achieved a confirmed CR after radioimmunotherapy. “The 5-year outcomes were among the best reported for nonanthracycline regimens in unselected advanced FL patients,” he stated. The fact that 12 of 14 patients with bone marrow involvement and 14 of 15 patients with bulky disease achieved CR suggests the value of initial chemotherapy in clearing the bone marrow in these subsets of patients with See page 72 FL who would not otherwise be candidates for radioimmunotherapy, he added. Although these mature data are encouraging, a consideration is that

contemporary oncology practice now includes bolus IV cyclophosphamide instead of oral cyclophosphamide as used in the study and rituximab (Rituxan) is now commonly used to treat patients with FL. Dr. Leonard stated that he did not feel that the chemotherapy dosing (oral vs intravenous CVP) was a significant issue, but that the use of rituximab in a chemotherapy-plus-radioimmunotherapy regimen is one that warrants further study.

phosphamide po on days 1–5, 1.4 mg/ m2 up to 2 mg of vincristine IV on day 1, and 100 mg/m2 of prednisone po on days 1–5 of a 21-day cycle). Tositumo mab and 131I-tositumomab were initiated within 56 days after day 1 of the sixth cycle of CVP. All patients completed therapy as planned. Twenty-six patients received a 75-cGy total-body radiation dose, and four patients received a 65-cGy total-body radiation dose.

Study Details

Median follow-up of living patients was 8.4 years. After six cycles of CVP, the CR rate was 53% and the partial response (PR) rate was 47%. After completion of tositumomab/131I-tositumomab, the overall response rate (ORR) was 100%; 93% had CR (26 of 28 had confirmed CR). Median duration of response was not reached (range: 3–111+ months);

The study enrolled 30 patients at three sites in the United States between July 2000 and June 2001. All patients were over age 18 with CD20-positive untreated stage III/IV or bulky (tumor diameter ≥ 5 cm) stage II, low-grade FL. Patients were treated with six cycles of CVP chemotherapy (400 mg/m2 cyclo-

Efficacy

2- and 5-year progression-free survival rates were 76% and 56%, respectively; 2- and 5-year overall survival rates were 96% and 83%, respectively. Median overall survival was not reached. Six patients (17%) died of FL. In a univariate analysis, age > 60 years and stage III/IV at diagnosis were identified as significant predictors of duration of response. No significant predictors of CR or duration of response were identified on multivariate analysis.

Safety Therapy was well tolerated. During CVP chemotherapy, 15 patients required a dose reduction or delay or both, the majority for neutropenia. Two patients required infusion-rate adjustments during the administration of dosimetric and therapeutic tositumomab, and one continued on page 17

Is Radioimmunotherapy Underused in the Rituximab Era? By Alice Goodman

espite its proven success in treating non-Hodgkin lymphoma (NHL), radioimmunotherapy (RIT) has failed to gain wide clinical acceptance by the oncology community. In an opinion piece in the Journal of Clinical Oncology, Tom Illidge, MD, explored the underuse of targeted RIT for NHL, and in particular, for follicular lymphoma (FL). Dr. Illidge is Professor of Targeted Therapy and Oncology at the University of Manchester, United Kingdom

Contributing Factors “The reasons behind [the underuse of RIT] are many and complex, but they include uncertainty regarding the place of RIT in the management of follicular lymphoma, perceived complexity of the delivery and referral process, and concerns about late radiation toxicity. The issues regarding remuneration in the United States and elsewhere were slow to be addressed and may still provide barriers to the more widespread prescription of these drugs,” Dr. Illidge said. Another contributing factor is that many patients with FL are now successfully treated with the addition of rituximab (Rituxan) to chemotherapy, leading to the perception that RIT is not necessary to improve outcomes.

Available RIT Agents Two radioimmunoconjugates approved as front-line treatment by the FDA (tositumomab/131I-tositumomab [Bexxar] and 90Y-ibritumomab tiuxetan [Zevalin]) have unique, non–cross-reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab. “[The radioimmunoconjugates] are arguably the most active drug approaches ever developed for NHL,” Dr. Illidge stated. Over the past decade, RIT has achieved high response rates and durable remissions, with safe, predictable, and manageable toxicity in heavily pretreated patients with NHL. Even patients with poor prognostic features such as bone marrow involvement, bulky disease, and transformed histology have achieved good outcomes. RIT has also shown impressive results in both phase II and phase III studies as frontline therapy for previously untreated FL as consolidation therapy after initial chemotherapy. These studies report high rates of conversion from partial response (PR) to complete response (CR) with RIT, leading to impressive overall CR rates and progression-free survival, regardless of type of pretreatment chemotherapy. “This consistently high CR among all of the groups after 90Y-ibritumomab tiuxetan suggests that RIT was the

equalizer for less-active chemotherapy,” Dr. Illidge commented. In one phase III study, consolidation therapy with RIT improved the quality of response from PR to CR or unconfirmed CR in more than three-quarters of all patients.2 Moreover, RIT consolidation prolonged median progression-free survival by more than 2 years compared with no further treatment. Progression-free survival is now greater than 3 years in those who achieved a CR after initial chemotherapy. However, no overall survival advantage has been definitively seen with RIT in FL, he continued. The oncology community is skeptical about the efficacy of RIT consolidation therapy in the rituximab/chemotherapy (R-chemo) era, despite many patients failing to achieve a CR after induction therapy with Rchemo.

Rituximab plus Chemotherapy “In an era in which R-chemo has substantially improved outcome, it is easy to become complacent and think that an effective treatment approach such as RIT is not required in the treatment of follicular lymphoma,” Dr. Illidge said. Certain patients with FL who are at low risk, achieve a CR on R-chemo regimens, and enjoy prolonged progression-free survival may not derive further benefit from RIT. However, FL is a heterogeneous disease, he continued, and patients with

intermediate- or high-risk FL may develop recurrent and rapidly progressive disease. Standard approaches for these patients cause significant early and late toxicities that are much less of a problem with RIT. Patients with FL who are refractory to chemotherapy and rituximab are candidates for RIT, Dr. Illidge said. Compelling data suggest “RIT can play an important role in both chemotherapy- and rituximabrefractory disease, leading to high response rates with durable remissions.” The treating community may need to reexamine RIT in FL and “better define integration of this approach into the treatment algorithm for more patient groups with follicular lymphoma,” he stated. RIT should also be studied in transplant conditions and more aggressive lymphoma, he added. References 1. Illidge TM: Radioimmunotherapy of lymphoma: A treatment approach ahead of its time or past its sell-by date? J Clin Oncol. May 10, 2010 (early release online). 2. Morschhauser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156-5164, 2008.

ASCOPost.com | JUNE 2010

PAGE 11

Editorial

ASCO as a Public Organization continued from page 5

In an era when terms such as “comparative effectiveness research” and “quality initiatives” become increasingly important, we feel that our Society is in a strong position to educate

policy-makers and direct policy. Our Quality Oncology Practice Initiative (QOPI) and our new QOPI certification program serve to inform lawmakers and executive staff that for ASCO, quality care comes first. Our many practice guidelines, widely disseminated and influential, support

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL (dasatinib) in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: ≥10% – cough; 1%–<10% – lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular inflammation, muscular weakness, musculoskeletal stiffness; 0.1%–<1% – rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances, hyperuricemia; <0.1% – hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction; <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). DRUG INTERACTIONS Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information]. Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1) in Full Prescribing Information]. Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

our contention that evidence-based medicine is the best path to cost-efficient, high-quality care. And our Cancer.Net website, with its invaluable patient information, provides forceful evidence of our belief that well-educated patients make the most effective partners when confronting cancer.

H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL (dasatinib) therapy. Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and wellcontrolled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. Nursing Mothers It is unknown whether SPRYCEL is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established. Geriatric Use Of the 2182 patients in clinical studies of SPRYCEL, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. While the safety profile of SPRYCEL in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience fluid retention events and dyspnea. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment. Renal Impairment There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGE Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse Reactions], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2). SPRYCEL® is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1237674A6

DS-B0001A-06-09

Rev June 2009

Research Issues We also continue to represent a strong voice for cancer research. We regularly support increased funding for cancer research, for the simple reason that research cures cancer. In the past, we have supported what might be called “generic cancer research dollars” for NCI and the FDA. It has become clear that clinical cancer research has received insufficient federal stewardship. Our national cooperative oncology group system has suffered from years of neglect, coupled with increasing regulatory burdens. Part of the problem, I suspect, is that many view the cooperative groups as infrastructure. Infrastructure is never sexy: Bridges only attract interest when they collapse. The cooperative oncology group “bridge” is in danger of falling apart, even as the regulatory burden it bears has increased. This collapse would be a tragedy at a time when advances in biotechnology hold out so much promise. No other professional society cares as much about the cooperative group system, has such hands-on knowledge regarding clinical trials, or has as much at stake in its success. Because of this, ASCO supports a doubling in funding for the cooperative group system, and at the same time recognizes the need for increased efficiency in the clinical trials process (as outlined in a recent Institute of Medicine report, see page 1).

Communication Efforts Underlying all of the above initiatives is the need for improved communications. This communication must be two-way, both between the Society and its members, and between ASCO and the larger society. We are beefing up our communications efforts, and in particular are exploring new means by which our membership can communicate directly with the Board, and new ways of informing the public regarding our mission. In the past, we have often hidden our lamp under a basket. Health professionals are necessarily adverse to advertisement, and we all assumed that if we just did our jobs, that would be enough. We cannot afford this apparent quiescence in an era of rapid change. We have many great stories to tell on your behalf. Dr. Sledge is ASCO President-Elect. He will assume the role of ASCO President this month at the conclusion of the Annual Meeting.

The ASCO Post | JUNE 2010

PAGE 12

Feature Story Breast Cancer

PARP Inhibitors: Excitement Still Building By Caroline Helwick

t last year’s ASCO Annual Meeting, the class of agents capable of inhibiting poly (adenosine diphosphate-ribose) polymerase—ie, PARP inhibitors—was moved to the forefront in the minds of many oncologists. This occurred when investigators announced preliminary findings for two investigational compounds in triplenegative tumors and those deficient in the BRCA gene. The data prompted Eric Winer, MD, of Dana-Farber Cancer Institute, who served as a discussant on the topic at ASCO, to comment, “PARP inhibitors will likely be a major advance. When you go home [from ASCO], you can be really excited about this.” This month, as the ASCO 2010 Annual Meeting takes place, these drugs are on every clinician’s radar, the hope being that they will offer patients with

Eric Winer, MD

Joyce O’Shaughnessy, MD

icity. The findings came from further follow-up of a study of 120 patients with metastatic disease that she first reported at ASCO. “The results are spectacular,” commented Peter Ravdin, MD, of The University of Texas Health Science Center at San Antonio and a member of the symposium program. He

PARP Inhibitors: 2009-2010 Milestones ■■ The addition of BSI-201 to gemcitabine plus carboplatin almost

doubles the survival time in patients with triple-negative breast cancer.

■■ A phase III trial of BSI-201 rapidly completes enrollment. ■■ A phase II trial of olaparib is also underway. ■■ PARP is identified in all histologic types of breast cancer, not just uncommon forms.

■■ An international PARP 2010 Conference is scheduled, signaling the

importance bestowed upon this protein (Zurich, August 18-21, 2010).

triple-negative and BRCA-deficient breast cancer a real chance at prolonged survival. The ASCO Post followed up on the pivotal findings from 2009 to see how far this field has come in a year.

BSI-201 Findings ‘Spectacular’ PARP is important for DNA baseexcision repair. High expression of PARP has been found in DNA-unstable breast cancers, including BRCA1mutated and triple-negative tumors. BSI-201 (BiPar Sciences) is the first of the new class of PARP inhibitors. At the 2009 San Antonio Breast Cancer Symposium, Joyce O’Shaughnessy, MD, of US Oncology, Texas Oncology, and Baylor Sammons Cancer Center, Dallas, reported that triplenegative breast cancer patients receiving intravenous BSI-201 in addition to gemcitabine (Gemzar)/carboplatin had a median survival of 12.2 months compared with 7.7 months for chemotherapy alone, without additional tox-

pointed out that while response rates to chemotherapy were a predictable 16%, they jumped “strikingly” to 48% with the addition of the PARP inhibitor, and response duration doubled. Lee Schwartzberg, MD, of the West Clinic, Memphis, Tennessee, noted that the 50% reduction in mortality was especially striking since many patients crossed over to receive the investigational agent upon progression. “A significant number of patients are still alive 18 months after starting therapy,” he noted. “And surprisingly, the addition of BSI-201 had a negligible effect on toxicity. Obviously, it is of great interest to see substantial benefit with minimal incremental toxicity.” In an interview with The ASCO Post, Dr. O’Shaughnessy said a database lock on the phase II trial is in place for May/June, with a final analysis planned for soon thereafter. Data will not be presented at the ASCO Annual Meeting this year.

Gunter von Minckwitz, MD

A similarly designed phase III FDA registration trial of 420 patients was launched in July 2009 and has completed accrual, its primary endpoints being progression-free and overall survival. Dr. O’Shaughnessy commented that the study had an extremely fast enrollment, with 110 sites participating. “There was huge demand to be part of this trial,” she said.

Oral PARP Inhibitor: Olaparib Also hailed at ASCO 2009 was the oral PARP inhibitor olaparib (AstraZeneca). In an open-label dose-finding phase II trial of 60 advanced breast cancer patients with BRCA1 or BRCA2 mutations, all heavily pretreated, one-third of the women demonstrated tumor shrinkage, reported Andrew Tutt, MD, PhD, Director of the Breakthrough Breast Research Unit of Kings College in London. Median time to disease progression was 5.7 months in patients receiving 400 mg and 3.8 months in the 100-mg cohort. The estimated filing date for FDA approval is 2012, according to the company website. James Carmichael, BSc, MBChB, MD, Medical Science Director at AstraZeneca, said the company intends to start a phase III study in BRCA-

Lee Schwartzberg, MD

mutated breast cancer. In addition, he said that numerous randomized phase II studies are ongoing. “And at this year’s ASCO there will be a number of abstracts,” he said. These include an oral presentation based on translational research to assess the efficacy of single-agent olaparib in serous ovarian cancer [abstract 3002] and other reports from studies to define the optimal dose and schedule for olaparib in combination with chemotherapy [abstracts 1018, 3027, and 5041].

PARP Activity Not Limited to Uncommon Phenotypes Equally intriguing this year was news that broke during the European Breast Cancer Conference: PARP is not limited to patients with triplenegative or BRCA-deficient tumors. “PARP is present in all hormonereceptor and HER2 phenotypes,” according to Gunter von Minckwitz, MD, of the German Breast Group in Neu-Isenburg. In a retrospective analysis of tissue specimens obtained during a clinical trial of neoadjuvant chemotherapy, PARP levels predicted response to chemotherapy, with pathologic continued on page 15

Table 1: PARP Inhibitors in Clinical Development Compound

Company

Route

Dose/Schedule

Phase

AG014699

Pfizer

d1-5 q21d

I, II

AZD2281 (olaparib)

AstraZeneca/ KuDOS

Oral

400 mg po bid

I, II

ABT-888 (veliparib)

Abbott

Oral

TBD

I, II

BSI-201

BiPar/SanofiAventis

6.8 mg/kg IV on d1, 4, 8, 11 q21d

I, II, III

CEP-9722

Cephalon

Oral

TBD

MK4827

Merck

Oral

TBD

INO-1001

Inotek

TBD

TBD = to be determined.

43 00

1 Y S TH CO TAR RATE OO AS IMEN POC T B T PL O E SI A COMION T A VI R IPT FO CR BS SU

H NT MO 3-

RX ®*

O PR

In Previously Untreated Multiple Myeloma I M P O R TA N T 3 - Y E A R U P D AT E — S U S TA I N E D B E N E F I T UPDATED VISTA† OVERALL SURVIVAL (OS) ANALYSIS: VcMP‡ vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Patients Without Event

80 70 60 50 40 30 20 10

 VELCADE+MP (n=344)  MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Kaplan-Meier estimate.

Months

▼ Patients treated with VELCADE® (bortezomib) + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone ▼ The overall survival benefit was sustained despite subsequent treatments ▼ Median duration of VcMP treatment was 46 weeks/54 planned ▼ At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELCADE in combination with MP vs 15 months for MP alone (P=0.000002)

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page. VELCADE is indicated for the treatment of patients with multiple myeloma. *Subject to federal and state restrictions. EPOCRATES Rx Pro is a registered trademark of Epocrates, Inc. in the United States and other countries. All other trademarks referenced are those of their respective owners. †VISTA, a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. ‡VcMP=VELCADE + melphalan/prednisone (MP).

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit www.VELCADE.com.

The ASCO Post | JUNE 2010

PAGE 14

Expert’s Corner

Health-care 5:08 PM PageReform 2

4/14/10

continued from page 4

and the removal of potentially cancerous polyps during colonoscopies, it will also improve survival rates in that disease. Enhancing the ability of individuals to access screening programs translates to both survival and reduced chances of disease. And this will help

encourage individuals to get appropriate screenings.

Negative Potential Will the law have any negative impact on oncologists and the way they care for their patients? Dr. Bailes: In some instances, it’s too early to tell. For example, there’s

a provision that includes coverage expansion for people on Medicaid, but some studies have indicated that if you have Medicaid it’s only slightly better than being uninsured in some situations if you have cancer. A lot of it will depend on the type of coverage requirements that end up in the program and on what the appropriate

reimbursement is under Medicaid to make sure that services are covered. The Health Benefit Exchanges will have several different levels of plans, and it’s important for the oncology community to make certain that all levels include coverage for catastrophic care for diseases such as cancer. So there are concerns about how Medicaid and the insurance exchanges will play out in terms of coverage. Right now, Medicaid is not viewed as a very helpful type of coverage as far as cancer care is concerned.

ASCO’s Role

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V1238 03/10

What can ASCO do to ensure that patients get necessary cancer care? Dr. Bailes: A lot of the coverage requirements in the law will be done through regulation. In other words, the U.S. Department of Health and Human Services will write and propose regulations about what services are covered and what services are not. One thing ASCO will be doing is advocating enhancements in the coverage to make certain that cancer care is appropriately covered for these additional 32 million individuals who will have some type of health insurance coverage in 2014. Much of that is going to be done by the regulatory process.

Treatment Planning As part of the health-care law, a “patientcentered health research group” will provide physicians with more evidence-based information on the effectiveness of treatment for specific diseases. How will that affect treatment planning in cancer care? Dr. Bailes: The idea is to have patient-centered outcomes reported not just to individuals but to the medical community as well. My personal view is that the information can only help. The more data we have, the better we are able to care for our patients. I cannot see a downside to this.

Patient Perspective How do you think cancer patients generally will feel about the new law? Dr. Bailes: For individuals with cancer, passage of the health-care reform bill should be reassuring: It means that they will not face the inability to get insurance to cover cancer care, and they will not face financial ruin because of lifetime caps on policy benefits. More on health-care reform, see pages 65–67

ASCOPost.com | JUNE 2010

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Cover Feature Feature Story

continued from page 12

complete response rates increasing as PARP expression increased. Dr. von Minckwitz and colleagues rated 638 specimens as having low, medium, or high PARP expression. PARP expression was present regardless of hormone receptor or HER2 status. High cytoplasmic PARP expression correlated with aggressive tumor patterns like nonlobular histology, higher grade, and nodal involvement, whereas nuclear expression did not. Tumors with high cytoplasmic PARP expres-

I believe PARP inhibition fulfills the paradigm of personalized medicine. – Lee Schwartzberg, MD

sion had a much higher chance for a pathologic complete response than tumors with a low expression. Tumor grade virtually lost its significance in favor of PARP expression as an independent predictor of pathologic complete response, Dr. von Minckwitz noted. “We will present data on the prognostic value of PARP expression in terms of long-term outcome at this year’s ASCO Annual Meeting,” Dr. von Minckwitz offered. “It would be fair to say that PARP-positive breast cancer might become a new, clinically relevant entity, and we believe we may be on the verge of a major change in the way breast cancer is treated.” Dr. O’Shaughnessy commented on these findings. “This bolsters the idea that elevation of PARP expression is probably a marker for genomic instability in general, and PARP inhibitors need to be evaluated in other genomically unstable breast cancers. This is a big need, and multiple trials are planned.”

Looking Ahead The findings of the past year have led to robust clinical development, with at least seven PARP inhibitors now in development, according to Dr. Schwartzberg (Table 1 on page 12). “But there is no free lunch,” he acknowledged. It appears there may be secondary BRCA2 mutations that can restore BRCA expression and function, thus causing resistance to PARP inhibi-

tors. While this is a question to be explored down the road, he added, “the fact that we already know about this is favorable because we can start to design studies that exploit the mutation status.” Dr. Schwartzberg predicts that PARP inhibitors may have roles in additional settings and subsets of patients 37875-NIH CSSC ASCO Post Ad-v3 4/12/10

National Cancer Institute

PARP Inhibitors

since they enhance the activity of other DNA-damaging agents, ie, platinums, alkylators, and topoisomerase inhibitors. “There is reason to believe that PARP inhibition may be a broad, generalizable phenomenon that could add benefit to other drugs,” he said. Other questions to answer involve the optimal timing 11:43 AM Page 1 of PARP inhibition

relative to the cytotoxic agent, the optimal dose and schedule, and optimal duration of treatment. “Obviously, these are questions that will be answered once clinical utility is established,” Dr. Schwartzberg said. “Meanwhile, I am very excited. I believe PARP inhibition fulfills the paradigm of personalized medicine.”

Committed to Cancer Research

CCR Clinical Trials at NIH

re you looking for more CCR is currently conducting trials options for your patients? NCI’s for many types of cancer including: Center for Cancer Research •Prostate Cancer (CCR) conducts more than 150 •Lung Cancer/Thymoma clinical trials at the National •Lymphoma Institutes of Health (NIH) in •Pediatric Sarcoma Bethesda, Md. In the state-of-the•Kidney Cancer art NIH Clinical Center, the •Brain Cancer latest innovations in medicine are put into practice every day. To learn whether your patients may be eligible, visit

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Be Part of You know the vaLue of asCoâ&#x20AC;&#x2122;s Meetings. iMagine the vaLue MeMBershiP Brings. ASCO Members receive deep discounts on registration for all ASCO meetings, including the 2010 Annual Meeting. In fact, just by filling out a membership application to join ASCO, you can save an average of 50%* off the annual Meeting registration rate, even if youâ&#x20AC;&#x2122;ve already registered at the nonmember rate. Join today to experience these savings plus the benefit of being part of the only professional organization that represents all oncology disciplines. *Discount depends on membership category.

to become a member of asCo and to take advantage of these savings, simply: Mail or fax a completed application or visit one of our Member Services desks at the 2010 Annual Meeting. For personal service, please contact ASCO Member Services: Phone: 703-299-0158/888-282-2552 fax: 703-299-0255 e-mail: membermail@asco.org asCo Member services 2318 Mill road, suite 800 alexandria, va 22314

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ASCOPost.com | JUNE 2010

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Cover Feature

Radioimmunotherapy continued from page 10

patient required an infusion-rate adjustment during 131I-tositumomab. Of the 715 adverse events reported, 25% were grade 3 to 4 in severity. Fatigue (77%), alopecia (70%), and nausea (53%) were the most common nonhematologic toxicities after combination therapy. Sixteen patients developed an infection during CVP, and five developed an infection after tositumomab/131I-tositumomab. No grade 3 or 4 infusion-related adverse events or treatment-related deaths were reported. Grade 3 or higher common hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Five patients developed febrile neutropenia during CVP treatment, and none developed it after tositumomab/131Itositumomab therapy. Nineteen patients (63%) received growth factor support. Three patients (10%) received red blood cell and platelet transfusions after 131I-tositumomab therapy. No patient developed serum human antimouse antibody (HAMA) positivity after radioimmunotherapy. Over the long-term follow-up, one patient developed acute myeloid leukemia (AML) after 131I-tositumomab therapy (annualized incidence 0.4%). Other malignancies reported within 5 years of treat-

12 Sweeping Changes continued from page 1

from cancer centers and community oncology practices participate in Cooperative Group clinical trials each year—and they would all likely be affected by the IOM’s recommended changes. “Many people involved in the Cooperative Group clinical trials, including NCI and those doing research in the academic community and practice community, shared the same frustrations. The Cooperative Group trials system

ment were prostate cancer in 1 patient, basal cell carcinoma in 2 patients (one of them later developed squamous cell carcinoma), and myelodysplastic syndrome (MDS) in 1 patient. The current annualized incidence of MDS/AML in this study population is 1.4%.

Study Strengths The study had several strengths, including the prospective evaluation of a defined treatment regimen in a well-defined cohort of patients, and the 8-year follow-up of safety and efficacy in 100% of enrolled patients. However, the small size limits the power to estimate outcome measures precisely. “The combination of CVP and radioimmunotherapy should be among the regimens carefully tested for upfront therapy of FL, particularly in settings where avoidance of anthracycline is desired or necessary,” he stated. The investigation was funded by GlaxoSmithKline. Reference 1. Link BK, Martin P, Kaminski MS, et al: Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131–tositumomab in patients with untreated low-grade follicular lymphoma: Eight-year follow-up of a multicenter phase II study. J Clin Oncol. May 10, 2010 (early release online).

had become inefficient and slow, and we were not adequately funding and incentivizing people to participate— including patients and physicians,” said John Mendelsohn, MD, Chair of the IOM committee and President of The University of Texas M. D. Anderson Cancer Center. “There was too much recycling of efforts, and too much gathering of opinions and counteropinions to design the trials. Everything needed to be streamlined.” continued on page 18

In real dollars, total funding for cooperative clinical research is less today than a decade ago. While overall NCI funding has increased, funding for Cooperative Group trials has been virtually flat since 2002. – Douglas W. Blayney, MD

Expert Point of View Investigators recently reported that in patients with follicular lymphoma, complete response (CR) to therapy is associated with an improved outcome.1 Attainment of a CR is therefore a worthwhile goal in this population. Radioimmunotherapy (RIT) consolidation with either 131I-tositumomab (Bexxar) or 90 Y-ibritumomab tiuxetan (Zevalin) has been shown to be safe and the most effective singleagent strategy for converting a partial response Franck Morschhauser, MD (achieved with induction chemotherapy, with or without rituximab) to a CR.2 Indeed, CR rates achieved after first-line RIT consolidation are the highest reported to date for patients with follicular lymphoma, regardless of the type of induction therapy.

Promising Data The multicenter phase III randomized FIT trial (First-line Indolent Trial) compared consolidation with one administration of 90Y-ibritumomab tiuxetan vs no additional therapy after first remission following various induction regimens in 414 patients with advanced follicular lymphoma. The first report3 and the 1-year additional follow-up4 of the FIT trial have clearly established that 90Y-ibritumomab tiuxetan consolidation was safe and produced a consistent progression-free survival (PFS) benefit. Findings included a 2-year PFS advantage for patients with a PR after induction, a 3-year PFS advantage for patients with a CR or CRu (complete response uncertain) after induction, and a 2.5-year PFS advantage for patients who tested polymerase chain reaction (PCR)-positive after induction. Moreover, RIT consolidation did not rule out any subsequent therapeutic options including autologous stem cell transplantation. However, mature data on the proportion of patients who will enjoy a durable CR following first-line RIT consolidation and the incidence of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are still limited. In a recent update from a phase II trial of CVP (cyclophosphamide, vincristine, prednisone) followed by 131I-tositumomab, Link and colleagues reported a 56% 5-year progression-free survival and an annualized incidence of 1.4% for MDS/AML.4 These findings are truly promising, especially for frail patients who are unable to tolerate more aggressive chemotherapy. Mature safety and efficacy data from the large FIT trial, with a median followup of 5 years, should be available by the end of 2010. Hopefully, these results will help the medical community further integrate RIT consolidation into first-line therapy for follicular lymphoma. —Franck Morschhauser, MD Hospital Claude Huriez, CHU Lille, France References 1. Bachy E, Brice P, Delarue R, et al: Long-term follow-up of patients with newly diagnosed follicular lymphoma in the pre-rituximab era: Effect of response quality on survival—A study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 28:822-829, 2010. 2. Morschhauser F, Dreyling M, Rohatiner A, et al: Rationale for consolidation to improve progression-free survival in patients with non-Hodgkin’s lymphoma: A review of the evidence. Oncologist 14(suppl 2):17-29, 2009. 3. Morschhauser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:51565164, 2008. 4. Morschhauser F, Bischof-Delaloye A, Rohatiner AZS, et al: Extended followup of the international randomized phase 3 First-line Indolent Trial (FIT) shows durable benefit of 90Y-ibritumomab tiuxetan (Zevalin®) consolidation of first remission in advanced stage follicular non-Hodgkin’s lymphoma. Presented at an ASCOASH joint symposium, during the 50th Annual Meeting of the American Society of Hematology, San Francisco, 2008.

The ASCO Post | JUNE 2010

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Clinical Trials

12 Sweeping Changes continued from page 17

Streamlining Procedures The IOM report, developed at the request of NCI Director John Niederhuber, MD, aims to improve the current Cooperative Group program by recommending changes that would more rapidly translate scientific discoveries into public health benefits by increased collaboration among stakeholders. In addition, the IOM’s recommendations are intended to streamline planning and approval procedures and efficiently incorporate new technologies such as biomarkers and molecular imaging into cancer clinical trials. Research reviewed by the committee indicated that it takes an average of 2.5 years from the development of the concept to the beginning of a Cooperative Group clinical trial. As a result, such trials run the risk of being scientifically out-of-date before they start and See page 72 of losing the interest of both physicians and patients. In fact, long delays in designing and initiating trials—resulting from the repetitious applications required for approvals from academia, federal agencies, and institutional review—often lead directly to the slow accrual of patients, which can sound a death knell to a clinical trial. “Up to 40% of trials never accrue the adequate number of patients to achieve their goals and are not completed. That’s a very sad waste of time, talent, and resources, and it’s also unfair to the patients who participate in these trials,” Dr. Mendelsohn said.

and tweak a trial in ways that really don’t make a difference,” he said. The IOM report also found that both NCI and insurers are inadequately reimbursing patients and physicians for their participation. While the cost of a trial has been estimated at about $6,000 per case, NCI only funds about $2,000 of that amount, and the supplementary

care that patients in clinical trials often need—such as increased office visits— are not adequately reimbursed by many health insurers. As a solution, the IOM report advocated that NCI allocate a larger portion of its research funds to its Cooperative Group program, as well as increasing per-case reimbursement. However, if such changes could not be

put into action, and lack of funds remains a problem, the report indicates that only high-priority clinical trials with a good chance at completion should be funded. ”We hated to write that recommendation in the report, but if increased funding isn’t available we should at least do fewer trials so we can pay for them and get them completed,” Dr. Mendelsohn said.

In EGFR-Expressing Metastatic Colorectal Cancer...

Take Aim With ERBITUX+ Irinotecan

Inefficient Process “Part of the issue is that a significant amount of waste and non–value added activities have become part of the clinical trial approval process. My research indicates that 38 separate groups are involved in approving a clinical trial, and they all do it separately,” said David Dilts, PhD, systems engineer and a member of the IOM committee. Dr. Dilts is Director of Clinical Research for the Knight Cancer Institute and Professor of Health Care Management at Oregon Health & Science University. “These groups don’t coordinate or cooperate with each other. Because the Cooperative Group Trials Program has been going for 50 years or more, the system has accumulated a lot of barnacles that slow down any progress. People tend to tweak

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNING ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions

ASCOPost.com | JUNE 2010

PAGE 19

Clinical Trials

In a letter to NCI, ASCO President Douglas W. Blayney, MD, called on the federal agency to double its funding for cooperative clinical research by 2015. “In real dollars, total funding for cooperative clinical research is less today than a decade ago. While overall NCI funding has increased, funding for Cooperative Group trials has been virtually

flat since 2002,” Dr. Blayney wrote in his letter. Such increased funding would require internal reallocation from NCI as well as increased funding from the U.S. Congress—a goal that ASCO is working toward through advocacy efforts, Dr. Blayney said in an interview. A new survey by ASCO, published in the Journal of Oncology Practice in

May 2010, found that one-third of 509 U.S. and Canadian NCI-supported Cooperative Group sites plan to limit their participation in federally funded clinical trials due to inadequate per-case reimbursement. Nearly 40% of those sites planning to limit participation in NCI Cooperative Group trials reported plans to increase industry trial involve-

for IMPROVED RESPONSE Rechallenge First-Line Irinotecan Failures With ERBITUX + Irinotecan ■ ERBITUX is the only anti-EGFR monoclonal antibody with evidence to suggest that it restores chemosensitivity to irinotecan after progression on irinotecan1

Objective Response Rates in Second-Line Treatment and Beyond, All Patients (N=329)*2,3 23% ERBITUX + irinotecan (n=218)

11% ERBITUX alone (n=111)

95% CI: 18-29% P=0.007

95% CI: 6-18%

Median duration of response: 5.7 months Median time to progression†: 4.1 months

Median duration of response: 4.2 months Median time to progression†: 1.5 months

increase in response

CI=conﬁdence interval. * A multicenter, randomized (2:1), controlled clinical trial was conducted with ERBITUX + irinotecan vs ERBITUX alone.2 † Difference between groups (hazard ratio=0.54 [95% CI, 0.42-0.71]; P<0.001).1

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients2 ■ ERBITUX is a solution for intravenous infusion2

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneform rash (88%), asthenia/ malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%) EGFR=epidermal growth factor receptor.

Please see Important Safety Information including Boxed WARNINGS on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

ment. Anecdotal reports indicate that some sites see a need to increase industry trials in order to maintain the infrastructure, staffing, and equipment necessary to conduct clinical trials and remain compliant with rules and regulations, Dr. Blayney said. “Many investigators fear that subtle continued on page 20

The ASCO Post | JUNE 2010

PAGE 20

Clinical Trials

12 Sweeping Changes continued from page 19

biases are built into the construction of industry trials as opposed to Cooperative Group trials. In our survey, we received a good deal of anecdotal comments saying that Cooperative Group trials were a high priority for many sites, but they could no longer afford to do

them,” Dr. Blayney said. If Cooperative Group sites limit their participation in NCI-funded trials, the result could be decreasing innovation in cancer research, as well as a decline in comparative effectiveness research— which few pharmaceutical companies are motivated to do, Dr. Blayney said. “Our study demonstrated that many

sites are contemplating curtailing or abandoning their participation in Cooperative Group trials, and I think that’s a bad thing,” he said.

Funding the Best Trials The IOM report made recommendations aimed at ensuring that the best clinical trials are funded and eliminat-

ing redundancy among the 10 existing Cooperative Groups. Each would consist of multidisciplinary committees focused on particular disease sites (including statistical offices) that would generate trial concepts and provide leadership for those trials selected as high priorities. The NCI would evaluate each disease site multidisciplinary

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 —Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/ or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

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Clinical Trials

committee on the basis of peer review—with criteria that would range from the innovation of its clinical trials to its efficiency and speed in getting these trials up and running. Those that did well in review would be funded, whereas those that received poor ratings would not. The ultimate result would be that only the most innovative

and successful disease site committees would thrive and expand their membership—encouraging collaboration and merging of committees across the Cooperative Groups. These recommendations might also result in fewer Cooperative Groups, Dr. Mendelsohn said. “It might be better to have fewer Cooperative Groups, but the

main goal really is to have fewer trials that are also high priority, done in a timely way, and which ask the strongest scientific questions,” he said. “Potentially more competition would arise, but the idea would be to focus on the best concepts, and on drugs and studies that ask questions that matter,” said Michael Carducci,

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX (cetuximab) and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%) References: 1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345. 2. ERBITUX® (cetuximab) [package insert]. New York, NY and Princeton, NJ: ImClone Systems Incorporated and Bristol-Myers Squibb Company; March 2010. 3. US Food and Drug Administration, Center for Drug Evaluation and Research. Medical review of Erbitux (cetuximab) BLA. http://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/125084_ERBITUX_MEDR_P2.pdf. Accessed January 7, 2010.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

693US09AB24408

4/10

MD, AEGON Professor in Prostate Cancer Research of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. “You might have fewer Cooperative Groups, but you would also have more cooperation across groups and more timely better proposals,” he added. continued on page 72

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News

RTOG 94-08 Clinical Trial continued from page 9

ment of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center in Houston, and Chair of the GU Cancers Symposium.“But we don’t know if giving hormone therapy to intermediate-risk men in this trial simply made up for the lower doses of

radiation used at the time. We do know that androgen deprivation is a very potent and effective adjunct to radiation,” she said. “But going forward, we will need to know more about whether it is really necessary for men with intermediate-risk prostate cancer and subgroups of men with intermediate-risk cancers when higher doses of radiation

are given. It may be that intermediaterisk patients with less bulky tumors may not need hormone therapy,” she noted. For additional data on androgen deprivation plus radiotherapy in locally advanced prostate cancer, watch for abstracts CRA4504 and 4505, being presented June 6 at the ASCO Annual Meeting.

ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

Reference 1. McGowan D, Hunt D, Jones C, et al: Effect of short-term endocrine therapy prior to and during radiation therapy on overall survival in patients with T1b-T2b adenocarcinoma of the prostate and PSA equal to or less than 20: Initial results of RTOG 94-08. 2010 Genitourinary Cancers Symposium. Abstract 6. Presented March 5, 2010.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 2 Infusion Reaction 15 3 2 0 Infection 13 1 9 1 1 Chills 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 Alanine Transaminase, high3 43 2 21 1 Aspartate Transaminase, high3 38 1 24 1 Alkaline Phosphatase, high3 33 <1 24 0 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages Acneform Rash4 87 17 10 1 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

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Cabazitaxel continued from page 9

12.7 months for those who received mitoxantrone (HR = 0.70; 95% CI = 0.590.83; P ≤ .001). The median follow-up of patients was 12.8 months, although the trial lasted for 5 years. At the 2-year endpoint, cabazitaxel more than doubled survival compared to mitoxantrone.

Dr. Sartor pointed out that the patients enrolled in the trial had very advanced disease; more than half of patients had measurable disease, and almost 25% had visceral disease. The median time from their last docetaxel treatment to progression was less than 1 month, and patients had undergone a median number of 7.5 cycles of docetaxel.

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy Erbitux plus BSC BSC alone (n=288) (n=274) Body System Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 Body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 Mouth Dryness 11 0 4 0 Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis

Analysis of progression-free survival and response rates in both groups showed a significant advantage in the cabazitaxel arm. When the researchers looked at results in subgroups, such as patients who had been heavily treated with docetaxel or had progressed during their last docetaxel regimen, patients on cabazitaxel also survived longer.

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux (cetuximab) was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone Systems Incorporated. Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Rev March 2010

As expected, the major serious adverse event in the cabazitaxel arm was neutropenia; 81.7% of those on cabazitaxel experienced grade 3/4 neutropenia vs 58% in the mitoxantrone arm. Rates of grade 3/4 febrile neutropenia in the cabazitaxel arm were 7.5% for cabazitaxel recipients vs 1.3% for those on mitoxantrone. Although the most common reason for death in the study was progressive disease, 18 deaths in the cabazitaxel arm resulted from adverse events—most from neutropenia. “This is an adverse event that needs to be anticipated and

Expert Point of View “The TROPIC study shows that cabazitaxel represents a major clinical advance for patients who have failed docetaxel,” commented Nicholas Vogelzang, MD, Chair and Medical Drector of the Developmental Therapeutics Committee of US Oncology. The drug will give patients with metastatic castration-resistant prostate cancer an important new choice of therapies—and more importantly, can extend survival for these patients, Dr. Vogelzang added.

monitored carefully,” Dr. Sartor said. Besides neutropenia, the most common adverse events in patients receiving cabazitaxel were diarrhea, fatigue, and asthenia.

Major Clinical Advance Dr. Sartor noted that future clinical trials will be testing cabazitaxel in less advanced prostate cancers, and he anticipated that it may be investigated for other tumors as well. The findings from the TROPIC study will form the basis for submission to the FDA for approval of cabazitaxel, he added. For more information on cabazitaxel and presentation of the final results of the TROPIC trial, watch for abstract 4508 on June 6 at the 2010 Annual Meeting. Reference 1. Sartor AO, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castrationresistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). 2010 Genitourinary Cancers Symposium. Abstract 9. Presented March 5, 2010. Barbara Boughton is a freelance reporter based in the San Francisco area and coauthor of Reduce Your Cancer Risk.

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TAP on Technology

Proteomics, Cancer, and the Future of Tailored Therapy By Matthew Stenger

roteomics is the study of the identity, properties, and functions of proteins. A proteome is the total set of proteins in a cell or organism, for example, just as a genome is the total set of genes in a cell or organism. Proteomics is more complicated than its sister science of genomics for a number of reasons. Proteins are gene products that outnumber genes many-fold; in humans, for example, some 20,000 to 25,000 protein-coding genes may produce more than 1 million different protein species. Many genes can produce more than one version of the proteins they encode. And, unlike the genome of an organism, which remains relatively stable over time, the protein composition changes constantly through new production, elimination, and modification of proteins in response to internal and external stimuli. Thus, the proteome can vary widely among individuals based on such factors as age, gender, diet, exercise, and disease.

tein prostate-specific antigen (PSA). Relatively high rates of false-positive and/or false-negative results mark the use of these and other secreted single proteins as screening biomarkers. For example, elevated blood levels of CA-125 are found in only 50%

Key Techniques

rated according to mass and electric charge; those that are more common in samples from cancer patients are identified by enzyme-linked immunosorbent assay (ELISA), which uses antibodies to identify the proteins. A primary technology in pattern recognition studies is mass spectrometry (MS), which determines the masses and relative quantities of all proteins in a sample. The protein profiles or signatures produced by this technique can differentiate samples from patients with cancer from samples from those without cancer, but the technique does not identify the proteins constituting the signature. Chromatography plus tandem MS can be used to identify the individual proteins in an MS protein signature. Identifying the individual proteins is important to avoid incorrect characterization of a signature as intrinsically representing cancer-related differences, when it might actually reflect differences in the way cancer samples and noncancer samples are collected, stored, and processed.

The two main approaches in identifying candidate proteins/signatures for use in cancer screening consist of protein identification and pattern recognition. Both require high-powered computing and bioinformatics sys-

Cancer cells can secrete specific proteins or protein fragments into the blood and other body fluids (urine, saliva, sweat). The hope for proteomics as it relates to cancer is to identify protein ‘signatures’—sets or patterns of proteins—in readily accessible fluids that can provide information about risk, presence, and disease progression. One hope is that assays based on protein signatures will be developed that allow screening for early detection of cancer or cancer risk. Another is that assays can be used to predict likelihood of response to particular treatments, detect response, anticipate adverse effects, and screen for early signs of disease recurrence. In short, success in some or all of these initiatives would greatly advance the ability to tailor cancer treatment to individual patients. (For more information on personalizing care through proteomics, see the Education Session, Proteomics Pathway Analysis for Tumor Classification and Therapy, being presented on June 8 at the 2010 ASCO Annual Meeting.) Monitoring for cancer-related proteins has been a part of clinical practice for some time—eg, in the form of screening for ovarian cancer using the protein CA-125 and screening for prostate cancer using the pro-

Protein Signatures

Fig. 1: Identification of proteins and signatures used in cancer screening requires highpowered computing and bioinformatives systems to analyze enormous amounts of data.

to 60% of women with early-stage ovarian cancer, but elevated levels are also found in noncancer conditions, such as pregnancy and endometriosis. (Watch for abstract 5061, being presented on June 5 at the ASCO Annual Meeting, for further information on the use of proteomics to diagnose ovarian cancer.) Similarly, only 25% to 30% of men with elevated PSA are found to have prostate cancer on biopsy, and 15% of men with PSA levels in the normal range are found to have prostate cancer. Evidence exists that using multiple proteins in protein signatures may greatly increase accuracy in cancer detection.

tems to process and analyze the enormous amount of data produced in proteomics studies (Fig. 1). Techniques for protein identification include the use of antibodies that bind to proteins thought or known to be overexpressed in particular cancers. Antibodies in microarray wells are exposed to fluid containing the proteins (eg, blood, urine). The proteins that bind to the antibodies can then be detected by fluorescence microscopy, with the amounts in samples from cancer patients being compared with amounts from samples from those without cancer. Another technique is gel electrophoresis, in which proteins are sepa-

Challenges to Proteomics Progress The latter problem highlights one of the many difficulties facing proteomics initiatives. Proteins are much more likely to be altered during isolation, storage, and handling than are DNA or other molecules of interest, jeopardizing the accuracy of findings and the conclusions based on them. In response to this problem, researchers and organizations are working to develop standards and best practice guidelines for collecting and processing patient samples. Another difficulty is the limited sensitivity of mass spectrometers. Although these devices can detect proteins that are 100 to 10,000 times less common than other proteins in a sample, proteins produced by cancer cells are often present in amounts that may evade detection by MS. Work is ongoing to improve MS sensitivity. In addition, the development of antibodies or other molecules (collectively, affinity reagents) that accurately identify proteins is an expensive and timeconsuming process that lags behind the detection of proteins and protein signatures used to differentiate cancer from noncancer specimens. continued on page 26

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VELCADE CRs Resulted in More Durable Responses MEDIAN DURATION OF RESPONSE IN PINNACLE† TRIAL (n=48/155) Complete responders (CR+CRu)

15.4 (95% CI, 13.4-15.4) (n=12)

All responders (CR+CRu+PR)

9.3 (95% CI, 5.4-13.8) (n=48)

5 6 7 8 Time (Months)

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▼ VELCADE® (bortezomib) is the only FDA-approved therapy for patients with relapsed MCL ▼ VELCADE delivers a 31% overall response rate, with 8% CR (CR+CRu)

MEDIAN DURATION OF RESPONSE IN PINNACLE TRIAL (n=48)

▼ Responding patients received a median of All responders 8 cycles of treatment with VELCADE 9.3 (CR+CRu+PR)

(95% CI, 5.4-13.8) safety profile ▼ VELCADE has a well-characterized (n=48)

Complete VELCADE Warnings, Precautions, and Adverse Events responders

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(CR+CRu) VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and (95% CI, 13.4-15.4) (n=12) Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral 0 1 2 3 4dose 5 modifi 6 7cations 8 9 or 10 11 12 13 14and 15 carefully 16 neuropathy, sometimes severe may occur—manage with discontinuation Time (Months) consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. *Subject to federal and state restrictions. EPOCRATES Rx Pro is a registered trademark of Epocrates, Inc. in the United States and other countries. All other trademarks referenced are those of their respective owners. PINNACLE, a single-arm, multicenter, phase 2 trial (N=155) evaluating the efﬁcacy and safety of VELCADE in mantle cell lymphoma (MCL) patients who have received at least 1 prior therapy.

†

For Patient Assistance Information or Reimbursement Assistance call 1-866-VELCADE (835-2233), OPTION 2, or visit www.VELCADE.com.

The ASCO Post | JUNE 2010

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TAP on Technology

Proteomics continued from page 24

Promising results have been achieved in identifying protein signatures for many cancers. Due in part to differences among laboratories in methods of processing specimens and analyzing proteins, many of these findings have been difficult to repli-

cate with currently available shared technology. Promising signatures must be validated in patient populations other than those in which they were initially derived and findings must be replicable by different laboratories before large-scale trials can accurately assess the potential clinical utility of these signatures.

NCI Initiatives The National Cancer Institute provides major support for proteomics and its potential to advance cancer research and treatment in the form of intramural and extramural initiatives (see box). The Antibody Characterization Program develops antibodies and other affinity reagents. The Clini-

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

Please see full Prescribing Information for VELCADE at www.VELCADE.com.

cal Proteomic Technologies for Cancer initiative comprises: the Clinical Proteomic Technology Assessment for Cancer program, a private/public collaboration assessing MS and affinity capture platforms; the Advanced Proteomic Platforms and Computational Sciences initiative, devoted to the development of new technologies and computational approaches for analysis and sharing of data; and the Proteomic Reagents and Resources Core, a source for affordable, wellcharacterized, and validated reagents. The Early Detection Research Network is an extensive collaboration of researchers developing and testing promising biomarkers/technologies for early detection of cancer. Proteomics-based research projects have produced a number of promising candidate markers for lung, pancreas, and prostate cancers. The Biomedical Proteomics Program is devoted to identification and characterization of protein signatures of cancer cells/tissues and the application of technologies directly to diagnosis, monitoring of side effects of treatment, and treatment improvements. Proteomics Information Resources National Cancer Institute NCI FactSheet: Proteomics and Cancer: http://www.cancer.gov/cancertopics/ factsheet/detection/proteomics Clinical Proteomic Technologies for Cancer (CPTC) initiative: http:// proteomics.cancer.gov and http:// proteomics.cancer.gov/library/primer.asp Clinical Proteomic Technology Assessment for Cancer (CPTAC) network: http://proteomics.cancer.gov/programs/ CPTAC/ Other Resources Yurong G, Fu Z, Van Eyk JE: A proteomic primer for the clinician. Proc Am Thorac Soc 4:9-17, 2007. Hanash SM, Pitteri SJ, Faca VM: Mining the plasma proteome for cancer biomarkers. Nature 452:571-579, 2008. Tonack S, Aspinall-O’Dea M, Neoptolemos JP, et al: Pancreatic cancer: Proteomic approaches to a challenging disease. Pancreatology 9:567-576, 2009. Wong SCC, Chan CML, Ma BBY, et al: Advanced proteomic technologies for cancer biomarker discovery. Exp Rev Proteomics 6:123-134, 2009. Larkin SET, Bashar Z, Taylor MG, et al: Proteomics in prostate cancer biomarker discovery. Exp Rev Proteomics 7:93-102, 2010. Gast M-CW, Schellens JHM, Beijnen JH: Clinical proteomics in breast cancer: A review. Breast Cancer Res Treat 116:1729, 2009.

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Direct from ASCO

Funding the Future The ASCO Cancer Foundation® looks forward after 10 successful years

unding research. Raising awareness. Bringing hope. These activities are the cornerstone of The ASCO Cancer Foundation®. The Foundation harnesses the knowledge of ASCO’s more than 28,000 oncologists and health-care providers to improve the treatment and survival of people living with cancer. The funding of breakthrough research, education, and quality improvement programs in cancer care gives patients and caregivers powerful resources to address the disease.

to improve cancer care,” Nancy R. Daly, MS, MPH, Executive Director of the Foundation, said. The success of the Foundation, and the opportunities it yields, keep hope alive for oncologists and their patients. “Every day when the Society’s members get up, they do so because they are devoting their creativity, understanding, and knowledge to bringing more sunrises to their patients,” Martin J. Murphy, PhD, DMedSc, Chair of the Foundation Board of Directors, said. “Charitable

The Foundation “provides a venue and a method for supporting cancer clinical research in an oncologist’s early, mid-, and even later career in an era when funding from other sources is decreasing. We fill, and thereby our members can help fill, a crucial need, which is to advance the treatment of cancer and care of our patients,” Joseph S. Bailes, MD, said. The Immediate Past Chair of the Foundation Board of Directors, Dr. Bailes oversaw the establishment

the Diversity in Oncology Initiative, the Study of Collaborative Practice Arrangements, the Study of Geographic Access to Oncology Care, the Breast Cancer Registry Pilot Program, Young Investigator Awards (YIAs), and the Improving Cancer Care Grant.

Furthering ASCO’s Public/ Societal Mission Providing up-to-date, oncologistapproved, unbiased cancer information to patients is a crucial part of

Fostering Crucial Programs ASCO’s primary goal is to provide critical programs and resources to its members. But the organization also has a broader, public/societal mission. “We feel that we, as cancer physicians, carry the public’s trust with us. There are things that we want to do that make the world a better place that are not strictly member benefits,” Allen S. Lichter, MD, ASCO CEO and the first Chair of the Foundation Board, said. Crucial programs such as investigator grants and awards cannot be supported by member dues alone; the Society relies on philanthropic gifts to make them possible. “Supporting public policy that affects patients with cancer and Americans in general, making sure that the public has an adequate supply of well-distributed oncology physicians, ensuring that the uninsured can receive the highest quality cancer care, reducing disparities in cancer outcomes, promoting the diversity of the oncology workforce: these are programs for which we need to raise funds. For ASCO to reach its full potential, to do as much good in the world as it possibly can, we are highly dependent on the success of the Foundation,” Dr. Lichter said. “Over the past 10 years, The ASCO Cancer Foundation has steadily grown through the dedicated support of our donors. We continue to increase our charitable activities in support of ASCO and the Foundation’s shared mission

Allen S. Lichter, MD

contributions to the Foundation are more than just charity—they are investments in the future of care for patients with cancer.”

Supporting Critical Research The Foundation is perhaps best known for its robust portfolio of grants and awards that support oncologists at all levels of their careers. In the past ten years, the Grants Program has grown exponentially. Since its inception, the program has awarded over 800 grants,

Martin J. Murphy, MD

Joseph S. Bailes, MD

of the Foundation’s Mission Endowment and the Susan G. Komen for the Cure®/ASCO Cancer Foundation Collaborative Commitment, both in 2008. The $12.1 million Endowment was created through support of four “Founding Donors” (Genentech BioOncology™, GlaxoSmithKline Oncology, Novartis Oncology, and sanofiaventis) and supplemented by two Sustaining Donors (Millennium: The Takeda Oncology Company and sanofi-aventis). The Mission

We believe that every oncology professional should be a member of ASCO. totaling more than $66 million, which have helped to transform the way cancer is prevented, detected, and treated. An article in the March 20, 2010 issue of Journal of Clinical Oncology details how the Grants Program has grown and evolved, and highlights how the program has launched the careers of multiple generations of physicianscientists.

Endowment’s unrestricted funds support a wide array of initiatives that are guided by “five pillars”: research, professional education, patient education and information, quality of and access to care, and international programs. The $10 million Komen/Foundation collaboration currently supports the Breast Cancer Symposium,

Nancy Daly, MS, MPH

the Foundation’s mission. For this reason, Cancer.Net, the Society’s patient information website, is supported by the Foundation. Cancer. Net is the first resource that many patients, friends, and family members turn to at the time of a cancer diagnosis, throughout treatment, and into survivorship. “Cancer is a catastrophic disease,” Dr. Murphy said. With Cancer.Net, the Foundation and ASCO “have an extraordinary opportunity to express their dedication to the people who need to know there is a Society that has their best interests at heart. And there is a need to express that to all the people who don’t know yet that ASCO is going to be important” when they or the people they love are affected by cancer. To increase awareness of cancer and of the resources that ASCO offers to patients and the public, the Foundation and Cancer.Net have reached out to serve as knowledge partners for athletic events and television programs including Skate America (see related story on page 31) and Kaleidoscope, a holiday continued on page 28

The ASCO Post | June 2010

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Direct from ASCO continued from page 27

entertainment variety special featuring Olympic skating champions and Grammy Award-winning music artists that aired on Fox Television last Thanksgiving Day. “We have to get the public involved to support ASCO, and help the public to understand that ASCO is fighting the battles that have significantly improved the survival and quality of life of our patients,” Michael B. Troner, MD, Past Chair of the Foundation Board of Directors, said. “The Foundation is a great way to make non-physicians aware of how we work.”

Leadership to Legacy Being a leader in the field of oncology means not only understanding and reacting to our pressing needs today, but also taking the actions necessary to allow the field to advance and thrive in the future. In oncology, as throughout medicine, clinical research is the keystone of progress in improving care. The ASCO Cancer Foundation is proud to have one of the strongest grants programs among professional societies. In order to continue to expand their efforts to fund the best and brightest in oncology research, the Foundation has launched its Leadership to Legacy annual campaign. This campaign is designed to give oncology professionals the opportunity to regularly support the

research that will ultimately build our professional legacy. Leadership to Legacy will be promoted to ASCO Members throughout the year, but during the ASCO Annual Meeting, all attendees are invited to participate and support research by donating at the Foundation’s Donor Lounge or in the boxes that are located throughout McCormick Place.

Looking to the Future The Foundation is not resting on the laurels of a successful decade. “We are proud of how far we’ve come in the last 10 years, and we are equally excited about the path that lies ahead of us,” said Ms. Daly. “We are steadfastly committed to growing and diversifying our sources of support, so that we can continue to provide unparalleled programs to oncologists, patients, and the community.” Until cancer is eradicated, the Board, member volunteers, and staff continue to find new methods and opportunities to contribute to the fight against the disease. The Foundation’s work is crucial, Dr. Murphy said, because “our job, our great honor, is to carry the message of ASCO’s dedication and to hold that torch aloft, because it is a beacon of hope for a better future for all patients with cancer.” Selected portions reprinted from ASCO News & Forum. © American Society of Clinical Oncology. (“Funding the Future.” ASCO News & Forum, January 2010: 12-17) All rights reserved.

Foundation Grants and Awards: Then and Now Each year, The ASCO Cancer Foundation offers increasing numbers of grants and awards to deserving oncology researchers and practitioners. Since 1999, the portfolio of available funding opportunities has grown considerably. 1999

2010*

Young Investigator Award (YIA)

Career Development Award (CDA)

*Numbers as of April 1, 2010.

Grants and Awards Opportunities ■■ Advanced Clinical Research Award (ACRA) ■■ Career Development Award (CDA) ■■ Clinical Trials Participation Award (CTPA) ■■ Community Oncology Research Grant (CORG) ■■ Comparative Effectiveness Research Professorship (CERP) ■■ The ASCO Cancer Foundation Improving Cancer Care Grant (ICCG), funded by Susan G. Komen for the Cure

■■ International Development and Education Award (IDEA) ■■ Long-term International Fellowship (LIFe) ■■ Merit Awards ■■ State Affiliate Grant ■■ Translational Research Professorship (TRP) ■■ Young Investigator Award (YIA) For the latest listing of and more information about the Foundation’s grants and awards, visit www.ascocancerfoundation.org.

Join ASCO’s Public Forum on Monday, June 7th Public education about cancer is not limited to the Internet. On Monday, June 7, immediately following the 2010 ASCO Annual Meeting, the Foundation will host “Answers to Cancer,” a new public forum with information on the most significant cancer advances to emerge from the Meeting presentations, geared to the layperson. This event will be presented free of charge and will focus on areas of greatest concern to patients, survivors, caregivers, and loved ones. A questionand-answer session will follow the panel presentation. The forum will take place from 6:30 to 9:00 PM at the Sheraton Hotel and Towers, Chicago, Illinois. Visit www.asco.org for more information about the public forum.

2010 Best of ASCO®: One Remarkable Program, Two Convenient Locations Unable to attend the ASCO Annual Meeting? This year, ASCO is offering two domestic Best of ASCO® Meetings:

July 16-17 The Palace Hotel San Francisco, CA

July 23-24 Renaissance Boston Waterfront Hotel Boston, MA

The top abstracts from the 2010 ASCO Annual Meeting will be presented at each Meeting, along with expert commentary on how the science may best be applied in practice. Register and make housing reservations online at www.asco.org/boa2010.

Housing Reservation and Early Registration Deadline: June 16, 2010, 11:59 PM (EDT)

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Direct from ASCO

Stephen Cannistra to Succeed Daniel Haller as Editor-in-Chief, Journal of Clinical Oncology Dr. Cannistra content with a simplified lifestyle. “I still cut my own grass and do all of my own gardening. I don’t own a Blackberry or GPS unit and have never missed a meeting or gotten lost,” he said.

Had Dr. Cannistra missed his calling as an oncologist, the science buff says he would most likely be a physicist or astronomer, and has invested a good deal of time into astrophotography, a technically challenging hobby that combines his

passion for astronomy and his love of pictures. “It’s the perfect combination of left and right brain activities,” he said. Sciences aside, Cannistra loves the American west and has hiked in continued on page 31

Stephen A. Cannistra, MD

n the last two decades, Stephen A. Cannistra, MD, has become an increasingly integral member of Journal of Clinical Oncology ( JCO), serving as a reviewer, associate editor, consultant editor, and editorial board member. In May 2011, he will replace Daniel G. Haller, MD, as editor-inChief. The Boston-based oncologist received his Bachelor of Science and Medical degrees from Brown Universit. Following internship and residency training in medicine at Johns Hopkins Hospital, Dr. Cannistra completed his fellowship training in medical oncology at the Dana-Farber Cancer Institute. He currently works at the Dana-Farber/Harvard Cancer Center, Beth Israel-Deaconess Medical Center, and Harvard Medical School. Dr. Canninstra’s investigator-initiated clinical trials include studies of combination chemotherapy in ovarian cancer and the role of oral antiangiogenesis agents in treating early relapse in patients with ovarian cancer. Through his basic research efforts Dr. Cannistra identified novel adhesion molecules in ovarian cancer cell metastasis and defects in the apoptotic pathway contributing to ovarian cancer drug resistance.

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY INCLUSION CRITERIA* PRIMARY ENDPOINT • Advanced NSCLC

• Overall survival

• Receiving 1st-line chemotherapy

SECONDARY ENDPOINTS

• Hemoglobin (Hb) ≤ 11 g/dL

• Progression-free survival • Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

2:1 Randomization (darbepoetin alfa: placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Shoot for the Moon With so many obligations, Dr. Cannistra spends the majority of his time focused on oncology. When he does get a rare break, he turns to astronomy for peace of mind. “I’ve always marveled at the night sky—not only is it beautiful, but once you understand how large the universe is, how small we are, and how we are most definitely not the center, it helps to place everything else into proper perspective.” It is this perspective that has kept-

Darbepoetin alfa 500 mcg Q3W

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria can be found in the protocol.

For more information, please visit www.782study.com or call 1-866-965-0782 (US and Canada only).

MC45038-D-6

04-10

The ASCO Post | June 2010

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Direct from ASCO

Journal of Oncology Practice Now Available in PubMed Central

ournal of Oncology Practice ( JOP) is now fully searchable online in PubMed Central, four months after each issue’s publication date, thus having its material accessible by an even wider audience. PubMed Central is a free digital archive of journal literature developed and operated by the National Center for Biotechnology Information (NCBI), a division of the National Library of Medicine (NLM) at the U.S. National Institutes of Health (NIH). In addition to articles, it also contains author manuscripts of selected articles written by NIH-funded researchers from several thousand journals not archived in PubMed. The goals of PubMed, as stated within the NLM’s Congressional mandate, are to: 1) permanently preserve digital journal literature in the life sciences, and 2) improve access to biomedical information for health professionals, researchers, and the public.

Full Content of JOP Available JOP is committed to a fullparticipation agreement with PubMed Central. More specifically, the complete contents of all future editions of JOP will be deposited to

the database, as well as archival content of the first five years. In addition to its presence on PubMed Central, JOP is indexed in EBSCOhost, CINAHL, and Embase, and is also easily identified with Google Scholar. The January 2010 issue of JOP was the first issue to be included in the database. “We’re excited because it means that authors who submit their work and are published in the JOP will be able to find [more] readers, and readers who are looking for their work will be able to find it most easily,” said Editor-in-Chief John V. Cox, DO, MBA. “I view that as a success for JOP because our work is [now] more accessible—and hopefully we’ll find a wider audience and [put the publication to] more use, and that’s exactly what JOP is all about.” The PubMed Central National Advisory Committee, established in 1999, provides independent advice on the content and operation of PubMed Central. Accordingly, PubMed Central does not include any unreviewed research articles. The Committee is responsible for establishing criteria for groups submitting material to the system, and ensuring

that PubMed Central remains responsive to the needs of researchers, publishers, librarians, and the general public. Members of the Committee are appointed by the Director of NIH from the biomedical and information communities, as well as the general public.

The enhanced accessibility of work published by JOP reinforces the value of the Journal to practicing doctors.

Qualifications: Scientific and Editorial Quality Only material that meets the NLM’s standards for the archive can be accepted. A journal must qualify on two levels: the scientific and editorial quality of its content, and the technical quality of its digital files. PubMed Central contains nearly two million articles, most of which have a corresponding entry in its counterpart, PubMed. PubMed is a free search engine for accessing the MEDLINE database of citations, abstracts, and some full-text articles; it also provides access to additional relevant websites, and links to the other NCBI molecular biology resources. As part of the new agreement between JOP and PubMed Central, JOP metadata will be entered into PubMed’s database when content goes live on PubMed Central—mak-

– John V. Cox, MD

ing JOP material discoverable in PubMed for the first time. “The editorial staff at JOP is proud of the fact that work published in JOP is searchable by interested readers via so many resources,” Dr. Cox said. “The enhanced accessibility of work published by JOP reinforces the value of the Journal to practicing doctors. This increase in visibility also enhances the value of the Journal to authors who wish their work widely available.” Originally printed in ASCO News & Forum © American Society of Clinical Oncology. (ASCO News & Forum, April 2010: 38) All rights reserved.

Enhancing Doctor-Patient Communications ASCO’s Patient Information Program

ell-informed patients are their own best advocates and invaluable partners for physicians. As you help patients understand their diagnosis and treatment, remember that the American Society of Clinical Oncology (ASCO) is here to help you. ASCO offers a comprehensive patient information program so that oncologists can feel confident that they are offering their patients the best possible educational resources. This program is designed to provide patients with timely, oncologist-approved information to help them make informed health-care decisions.

Cancer.Net: ASCO’s 24/7 Resource for Patients The program’s centerpiece is Cancer.Net (www.Cancer.Net), ASCO’s free patient information website. The site offers information on more than

120 types of cancer and cancer-related syndromes, clinical trials, managing side effects, caregiving, survivorship, and much more. It also contains comprehensive information about how to cope with the emotional and social effects of living with cancer, whether the reader is the person with cancer, a caregiver, family member, or friend. Content is written in easy-tounderstand language and vetted by the Cancer.Net Editorial Board. This advisory board is composed of more than 150 medical, surgical, radiation, and pediatric oncologists, other doctors, oncology nurses, social workers, and patient advocates. This combined effort makes Cancer.Net the most up-to-date and trusted resource for cancer information on the Internet. ASCO is the voice of the world’s cancer physicians — and Cancer.Net brings the expertise and resources

Fig. 1: Cancer.Net free resource for patient information.

of ASCO to people with cancer, as well as to those who care for and care about them. “Cancer.Net is the premier source of information for patients, for all different kinds of cancer,” said ASCO

Past President Larry Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs, and Medical Director, Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center. “I have found it in-

ASCOPost.com | JUNE 2010

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Direct from ASCO credibly useful to be able to refer my patients to Cancer.Net, so that they can get up-to-date information that is accurate and spend time with it. They can get the information they need to ask me the appropriate questions. Cancer.Net has proven to be invaluable for that purpose.”

information regarding tobacco, with additional content planned.

Printed Materials Offer Easy Portability In addition to its online information, ASCO offers a wide array of printed cancer information, in-

Cancer.Net is the premier source of information for patients, for all different kinds of cancer. – Larry Norton, MD

This website can be a valuable resource throughout your patient’s cancer journey. It is updated constantly with new information, including breaking research news that is summarized to highlight what each study means for patients. There are always new articles, videos, and audio podcasts exploring practical subjects, as well as answers to common questions on such topics as: the cost of cancer care, health disparities, prevention, and policy issues about cancer.

Cancer.Net en Español: Serving the SpanishSpeaking Community A growing amount of Cancer. Net’s information is being translated into Spanish, found under Cancer. Net En Español (www.cancer.net/ espanol). This section now offers detailed information on the most common cancer types among Hispanics/Latinos in the United States. Other translations include What to Know: ASCO’s Guidelines (based on clinical practice guidelines for physicians), information on managing side effects, an introduction to clinical trials, and cancer prevention continued from page 29

several places, including the Grand Canyon, the Grand Tetons, Zion, Yellowstone, and Glacier National Park. “There is something very special and transcendent about seeing the sunrise over the Grand Canyon on a clear, crisp morning,” he said.

cluding ASCO Answers fact sheets, guides to cancer, research news summaries, and booklets, including the Managing the Cost of Cancer Care guide. These materials offer portable cancer information that is written in the same patient-friendly language as the website. Several titles are now available in Spanish. There are also free Cancer.Net promotional materials available for display in your waiting room or office. To order any of these materials, visit www.Cancer. Net/ordermaterials.

Patient Advocacy Efforts Important Part of Outreach ASCO offers a range of programs to engage and partner with the patient-advocate community. This includes events and services at ASCO’s scientific meetings, including the association’s Annual Meeting where there is a special patient-advocacy booth, research review sessions, and much more. To learn about ASCO’s patient advocacy programs, visit www.Cancer.Net/advocacy. © 2010. American Society Oncology. All Rights Reserved.

Clinical

“I’m a New Englander through and through, even though I’ve never become used to the winters. But when I retire, I’m going to Arizona.” Until then, Dr. Cannistra will continue to make his mark in the oncology world. © 2010. American Society of Clinical Oncology. All Rights Reserved.

ASCO Raises Cancer Awareness through Figure Skating Events

hile ASCO’s commitment to advancing high-quality cancer care is well known in the cancer community, it is also important to convey this mission to the general public. Over the past several years, ASCO has worked with other organizations to raise awareness of issues in cancer and promote the comprehensive, oncologist-approved cancer information available on ASCO’s patient website, Cancer.Net (www.cancer. net). ASCO is participating in a yearlong partnership with U.S. Figure Skating, making the fight against all cancers an official cause of the organization. “Just as skaters rely on their coaches for advice and guidance, people with cancer can rely on Cancer.Net to get the most trusted, doctor-approved information to guide them through their diagnosis, treatment, and survivorship,” ASCO CEO Allen S. Lichter, MD, said. “ASCO is pleased to partner with U.S. Figure Skating to bring this valuable information to people everywhere.”

Why Figure Skating? Many prominent figure skaters have faced cancer publicly. For example, former U.S. and Olympic champions Scott Hamilton, Peggy Fleming, and Dorothy Hamill are cancer survivors, and current skater Rena Inoue was successfully treated for lung cancer before winning two U.S. pairs titles with her partner John Baldwin in 2004 and 2006. Figure skating is also the most-watched Olympic sport and is widely viewed by women, according to U.S. Figure Skating, the sport’s national governing body. Furthermore, women are the key group making health-care decisions for their families, according to the U.S. Department of Labor.

2009 Cancer.Net Skate America and Kaleidoscope ASCO and Cancer.Net had a unique opportunity to reach a broad audience through two widely publicized figure skating events in November: Skate America and Kaleidoscope. These events helped raise awareness about cancer and educate people about the resources available

to patients and their families to the audience who most seeks accurate health information from a trusted source. Cancer.Net was the title sponsor for Skate America, U.S. Figure Skating’s premier annual international competition. This competition was held last fall in Lake Placid, New York, and was featured prominently in national advertising and promotions. To further increase awareness of issues surrounding women and cancer, ASCO continued its involvement with Kaleidoscope (formerly known as Frosted Pink with a Twist), established in 2008. Cancer.Net again served as the official clinical cancer information resource for the event that was broadcast on FOX on Thanksgiving Day, 2009. In addition, more than 15,000 cancer survivors attended the taping of Kaleidoscope in Washington, DC. The event marked Mr. Hamilton’s and Ms. Hamill’s return to the ice as they performed to the live music of fellow cancer survivor Olivia Newton-John and 14-time Grammy Award winner David Foster. Olympic gold medalist Kristi Yamaguchi and two-time Olympic medalist Nancy Kerrigan also performed. Selected portions reprinted from ASCO News & Forum. © American Society of Clinical Oncology. (“ASCO Raises Cancer Awareness through Figure Skating Events.” ASCO News & Forum, January 2010: 26-27) All rights reserved.

what is

MBC

References: 1. Horner MJ, Ries LAG, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2006. Bethesda, MD: National Cancer Institute; 2008. http://seer.cancer.gov/csr/1975_2006/. Published 2009. Accessed April 7, 2010. 2. American Cancer Society. Cancer Facts and Figures 2009. Atlanta, GA: American Cancer Society; 2009. http://www.cancer.org/downloads/STT/500809web.pdf. Accessed April 7, 2010. 3. Oâ&#x20AC;&#x2122;Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005;10(suppl 3):20-29. 4. Mayer M, Grober SE. Silent Voices: Advanced Breast Cancer Needs Assessment Survey Report. Haverford, PA: Living Beyond Breast Cancer; 2006. http://www.lbbc.org/data/news/LBBCsilentvoices.pdf. Accessed April 7, 2010. 5. MBC Advocacy Working Group. Bridging gaps, expanding outreach: Metastatic Breast Cancer Advocacy Working Group Consensus Report. Breast. 2009;18:273-275. 6. Orlando L, Colleoni M, Fedele P, et al. Management of advanced breast cancer. Ann Oncol. 2007;18:vi74-vi76. 7. Andreetta C, Minisini AM, Miscoria M,

MBC has no Cure Millions of women currently living in the United States have a history of breast cancer, and nearly 200,000 new cases were reported in 2009.1,2 Few patients are initially diagnosed with metastatic breast cancer (MBC), but approximately 30% of those diagnosed with earlier stages of breast cancer will eventually develop metastatic disease.3 Advances in the treatment of MBC are helping patients live longer and healthier lives, but the 5-year survival rate is only 27%.2,3 MBC patients faCe Challenges Patients with MBC face different challenges than patients with earlier stage breast cancer.4 Because MBC therapy is not curative and appropriate treatment decisions are not always clear, patients may be at high risk for clinical depression and/or anxiety disorders.4 MBC patients may feel isolated from the rest of the breast cancer community because their specific needs are often not addressed.4,5 Additionally, patients who have progressed to MBC have lived with the rigors of their disease and its treatment for a longer period of time. This can increase their sensitivity to the common physical and social side effects of therapy and tumor-related symptoms.4 MBC has no estaBlished standard of Care

therapy Missing?

Due to the chronic nature of MBC, the goal of treatment is to provide significant clinical benefit to patients.6,7 Because multiple patient factors related to treatment history and tumor classification must be considered for an individualized therapeutic approach, no single drug or regimen can be considered the standard of care for MBC patients.3 Compounding these challenges, it is unclear which clinical endpoint is the most appropriate measure for evaluating MBC treatment. MBC trials differ with regard to CliniCal endpoints In a recent study, 88% of patients described prolonged survival as the primary goal of MBC treatment; however, when asked to choose the most important clinical endpoint in MBC, physicians were split between overall survival (OS) and progression-free survival (PFS).8 Over the last decade, no single-agent MBC therapy has been FDA-approved based on significantly improved OS.9-15

Join the ongoing discussion about the challenges of MBC by visiting www.mbcdiscussion.com.

In recent years, the FDA has approved new cancer therapies based on a variety of endpoints. These include OS, PFS, time to tumor progression (TTP), and overall response rate (ORR). Each of these endpoints provides important clinical information, but research has yet to establish a standard in clinical trial endpoints.

Puglisi F. First-line chemotherapy with or without biologic agents for metastatic breast cancer. Crit Rev Oncol Hematol. In press. 8. Sheik-Yousouf A, Gandhi S, Dukhovny S, Verma S. A comparison of physician and patient perceptions of clinically important endpoints in the treatment of metastatic breast cancer (MBC). Eur J Cancer Suppl. 2010;8:77. 9. Abraxane [package insert]. Bridgewater, NJ: Abraxis Bioscience, LLC; 2009. 10. Gemzar [package insert]. Indianapolis, IN: Eli Lilly and Company; 2006. 11. Ixempra [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009. 12. Taxol [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. 13. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2008. 14. Food and Drug Administration. Accelerated approval for Taxotere for the treatment of patients with locally advanced or metastatic breast cancer. Published June 22, 1998. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20449_ltr.pdf. Accessed April 8, 2010. 15. Xeloda [package insert]. Nutley, NJ: Roche Laboratories Inc; 2006. ÂŠ2010 Eisai Inc.

ERI 24A

The ASCO Post | JUNE 2010

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Spotlight on Chicago

Academic Cancer Centers Achieve Many Oncology ‘Firsts’ Chicago, Illinois, host city for the ASCO Annual Meeting for the next 10 years, has a proud history in oncology. By Kathleen Louden

weet Home Chicago is home not just to the ASCO Annual Meeting but also five medical school–affiliated cancer centers that have accomplished many breakthroughs in the treatment and understanding of cancer. “We don’t get the press here in Chicago that other regions do, but that doesn’t mean we don’t do innovative things,” said Patrick Stiff, MD, Professor of Oncology at Loyola Uni-

Patrick Stiff, MD

In testing nitrogen mustard in patients with lymphoma in 1943, Dr. Jacobson showed for arguably the first time (researchers at Yale University, New Haven, Connecticut, also are considered pioneers of chemotherapy) that chemotherapy worked in humans. According to Dr. Schilsky, Dr. Huggins “essentially opened up the field of hormone research” by showing in 1941 that prostate tumors

Richard L. Schilsky, MD

versity Stritch School of Medicine and Director of Loyola’s Cardinal Bernardin Cancer Center, located just outside Chicago in Maywood, Illinois. Loyola and Chicago’s other academic cancer centers—Northwestern University, Rush University, University of Chicago, and University of Illinois at Chicago—have helped advance oncology in many ways. From the University of Chicago alone, researchers have included one of the fathers of chemotherapy (the late Leon O. Jacobson, MD), one of the fathers of hormone therapy (the late Charles B. Huggins, MD), and the discoverer of chromosomal translocations in cancer ( Janet Rowley, MD, Professor of Medicine, Molecular Genetics, and Cell Biology). “It’s hard to think of one institution with three faculty members who had such an impact on cancer,” said Richard L. Schilsky, MD, Professor of Medicine and Deputy Director of the University of Chicago Comprehensive Cancer Center. “Their work has manifested itself in many breakthroughs in cancer treatment.”

Steven T. Rosen, MD

regressed after castration; he won a Nobel Prize for his work. In 1972 Dr. Rowley identified chromosome abnormalities in chronic myelogenous leukemia followed by the discovery of other chromosomal abnormalities in acute myeloid leukemias. “She turned around the thinking of cancer to be a fundamentally genetic problem. In many ways, Dr. Rowley’s work provided the basis for targeted therapy,” Dr. Schilsky commented. Many of the cancer advances achieved in Chicago have been in treating breast, lung, and hematologic cancers, and more specifically, in bone marrow transplants.

Breast Cancer The discovery of the estrogen receptor in 1958 by University of Chicago researcher Elwood Jensen, PhD, revolutionized the treatment of breast cancer, many believe. His finding made it possible to measure whether a woman’s breast cancer was estrogenreceptor positive and would respond to hormonal therapy. “Until then, we removed everyone’s

ovaries if they were premenopausal and had metastatic disease,” said Janet Wolter, MD, Professor Emeritus of Internal Medicine with Rush University Medical Center. (Dr. Wolter, a pioneer in breast cancer treatment, is profiled on the following page.)

Lung Cancer In the early 1980s, Rush University Medical Center was one of the original centers to use combined radiation therapy and chemotherapy before lung resection for treatment of stage III non–small cell lung cancer, said L. Penfield Faber, MD, Rush University Surgery Professor and Vice Chairman, Department of Cardiovascular-Thoracic Surgery. Initial studies showed this approach might improve survival. Since then, this combined-modality therapy has doubled the 5-year survival rate compared with other treatments, studies show. “Now for patients with advanced lung cancer, we can give them some hope,” Dr. Faber said. With his partner, the late Robert J. Jensik, MD, Dr. Faber was one of the earliest U.S. advocates for doing tissue-sparing sleeve lobectomy, which was invented in England. The proce-

of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “The use of chemoimmunotherapy for non-Hodgkin lymphoma and chronic lymphocytic leukemia has improved cure rates without a significant increase in toxicity,” Dr. Rosen said. University investigators also participated in pioneering studies of the treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (Leustatin), which can induce long-term remission, according to Dr. Rosen. “We have probably made the greatest impact [in oncology by testing] drugs that became standard treatments, which have improved quality of life and prolonged survival,” he added. As examples, he cited medications to treat cutaneous T-cell lymphoma, including alemtuzumab (Campath), denileukin diftitox (Ontak), and vorinostat (Zolinza).

Bone Marrow Transplants Both Northwestern and Loyola reportedly have among the largest stem cell transplant programs in Illinois, annually helping hundreds patients with hematologic cancers and other lifethreatening diseases.

Chicago’s five medical school–affiliated cancer centers have accomplished many breakthroughs in the treatment and understanding of cancer. dure uses anastomoses, after removal of a cancerous lobe of the lung, to reconnect the remaining lobe and bronchial segment.

Hematologic Cancers Among the most important advances in treating cancers of the blood are targeted therapies, including monoclonal antibodies. Northwestern University conducted proof-of-concept clinical trials of monoclonal antibodies in the 1980s, said Steven T. Rosen, MD, Professor of Medicine and Director

Researchers at Loyola’s cancer center in March 2000 became the first to successfully transplant bone marrow cells grown outside the body, Dr. Stiff said. “From as little as a tablespoon of bone marrow, we were able to do an entire transplant,” he said. Loyola, according to Dr. Stiff, is a leader in nonembryonic stem cell research using umbilical cord blood. The research team is trying to magnify the number of umbilical cord stem cells grown in vitro, because the number of these cells is limited in cord blood.

ASCOPost.com | JUNE 2010

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Spotlight on Chicago

The advantage of cord blood stem cells is that human leukocyte antigens (HLA) do not need to match a patient as closely as donated bone marrow. Thanks to cord blood transplants and creation of the National Marrow Donor Program’s unrelated donor registry, Dr. Stiff said it is possible to cure many patients who could not otherwise find a suitable donor. “If you had leukemia in 1985 and needed a bone marrow transplant, the

forward. They continue to perform important clinical and basic science studies that they hope will improve cancer care. Two of the centers, Northwestern and University of Chicago, have the state’s only National Cancer Institute–designated comprehensive cancer research centers. Besides doing their own research, the five cancer centers often collaborate with each other through regional oncology consortia.

Pioneering Cancer Physician Recalls Half-Century of Healing By Kathleen Louden

In her early days of treating breast cancer, “it was a surgeon’s disease, and the internist was not involved,” Dr. Wolter recalled. “Now we are giving chemotherapy before surgery, so everything’s come around 180 degrees.”

Cancer Advances in Chicago

Janet Wolter, MD

W Discovered the estrogen receptor, now used to guide breast cancer treatment (University of Chicago)

Was the first to successfully grow bone marrow cells outside the body, making it possible to manufacture large numbers of stem cells for transplant in adults (Loyola University)

Performed one of the first phase II clinical trials of neoadjuvant therapy in advanced lung cancer, combining radiation therapy and chemotherapy before lung resection, which improved survival (Rush University)

Conducted among the first clinical trials in the country of monoclonal antibodies, a targeted immunotherapy, for lymphoma (Northwestern University)

First demonstrated in primates that azacytidine can modulate gene expression by blocking DNA methylation; this approach is now an important component of treatment of myelodysplastic syndrome (University of Illinois at Chicago)

Sources: University of Chicago Medical Center, Loyola University Cardinal Bernardin Cancer Center, Rush University Medical Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Illinois Medical Center.

chance of coming to transplant was one in three,” Dr. Stiff said. “Now we can find a donor for 90% of patients. It may be a cord blood donor. We’ve come a long way.”

Current Efforts Chicago’s cancer centers have helped the field of oncology move

Dr. Stiff said, “We work together on research, we collaborate on the phone, and we refer patients to each other. We would rather work together to improve outcomes than fight about who’s better.” ASCO has committed to host the Annual Meeting in Chicago for the next 10 years.

hen the poliovirus vaccine put polio specialist Janet Wolter, MD, “out of business” in 1963, she began looking for a new job. She found one—and a new specialty—at Presbyterian-St. Luke’s Hospital in Chicago, Illinois, which later became Rush University Medical Center. Dr. Wolter worked with endocrinologist Samuel G. Taylor III, MD, who was interested in hormonal treatment of breast and prostate cancers. At first she told him, “I would be crazy to go from polio to cancer.” After a brief stint at data analysis, however, she was eager to see patients again and began treating and studying people with cancer. Her oncology career lasted until she retired from Rush in fall 2009 as a professor of internal medicine. Over the course of 5 decades, Dr. Wolter enrolled more than 800 patients in clinical trials that helped define which breast cancer treatments worked, codeveloped the first multidisciplinary comprehensive breast cancer center in the Midwest, and was a pioneer in using nurse specialists to work in tandem with oncologists. Rather than focusing on her own achievements, she praised Dr. Taylor. “We’re lucky that people like Dr. Taylor recognized the potential for hormone therapy,” Dr. Wolter said, noting the lives these medications have saved. “A patient of mine with breast cancer was on tamoxifen for 22 years [before] she had a recurrence. Then I put her on an aromatase inhibitor. She’s still alive.”

Learned as Specialty Developed As chemotherapy drugs became available and as she tested hormonal treatments, Dr. Wolter said she learned medical oncology “from the ground up.” That learning curve included giving high doses of testosterone to women with breast cancer—an unsuccessful strategy that proved to have some undesirable side effects. Dr. Wolter’s work also included many successes. For instance, she began testing tamoxifen in the early 1980s, first for treatment of advanced breast cancer and, when that proved effective, for treating earlystage breast cancer and eventually for prevention. She conducted those studies through the cooperative work of the National Cancer Institute’s National Surgical Adjuvant Breast and Bowel Program (NSABP). Dr. Wolter considers her longtime work with the NSABP her most important contribution to oncology. Besides serving on the NSABP executive committee and board of directors, she was Rush’s principal investigator for many of the program’s multicenter studies. These studies included finding effective combinations of chemotherapy as well as the landmark clinical trials that led to the establishment of lumpectomy plus radiation therapy as the standard surgical treatment over mastectomy. The latter, she said, was the only time she experienced difficulty recruiting women to participate in clinical trials. “Patients had to agree that, when they woke up from surgery, they may continued on page 64

Help Deliver

in Chronic Phase Ph+ CML After Gleevec

ÂŽ

(imatinib mesylate) tablets

WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. ADVERSE REACTIONS: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. TASIGNA (nilotinib) capsules is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosomeâ&#x20AC;&#x201C;positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on following pages.

TASIGNA delivers cytogenetic response in the chronic phase after Gleevec1 40% of patients achieved an unconfirmed major cytogenetic response (MCyR) (95% CI: 33-46)1 28% of patients achieved an unconfirmed complete cytogenetic response (CCyR) (95% CI: 22-34)1 12% of patients achieved an unconfirmed partial cytogenetic response (PCyR) (95% CI: 8-16)1 Rapid responses: 2.8 months median time to MCyR2

Important study design information1 A single, open-label, multicenter study was conducted to evaluate efficacy and safety in patients with Ph+ CML in the chronic phase with resistance or intolerance to Gleevec. At the time of data cutoff, 280 patients with a minimum follow-up of 6 months were enrolled Of the 280 patients, 232 were evaluable for efficacy. The efficacy end point was unconfirmed MCyR, which included CCyR and PCyR CyR criteria: CCyR (0% Ph+ metaphases) or PCyR (1%-35%). Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample

Prescribe TASIGNA for your patients in the chronic phase who are no longer responding or are intolerant to Gleevec1 Patients who are not meeting minimum treatment goals: Complete hematologic response (CHR) at 3 months, CyR at 6 months, or MCyR at 12 months Patients who lose HR or CyR at any time Patients who cannot tolerate Gleevec

References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Aug 2009. 2. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540-3546.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

10/09

C-AM7-100019

TASIGNAÂŽ (NILOTINIB) CAPSULES IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE TASIGNA (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. WARNINGS AND PRECAUTIONS Myelosuppression Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction. QT Prolongation TASIGNA prolongs the QT interval. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically. Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Sudden Deaths There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence. Elevated Serum Lipase Caution is recommended in patients with a history of pancreatitis. Check serum lipase levels monthly or as clinically indicated. Hepatotoxicity Serum bilirubin and hepatic transaminases The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated. Electrolyte Abnormalities TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor periodically during therapy. Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely. Drug Interactions The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA. Concomitant strong CYP3A4 inhibitors The concomitant use of strong CYP3A4 inhibitors or antiarrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to Â˝ the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided. Concomitant strong CYP3A4 inducers The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone,

phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St Johnâ&#x20AC;&#x2122;s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of TASIGNA may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the TASIGNA dose should be reduced to the indicated TASIGNA dose. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein. If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised. Food Effects Food increases blood levels of TASIGNA. Patients should avoid food 2 hours before and at 1 hour after the dose is taken. Lactose Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption. Use in Pregnancy There are no adequate and well controlled studies of TASIGNA in pregnant women. However, TASIGNA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. ADVERSE REACTIONS In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia,

febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%). DOSE ADJUSTMENTS OR MODIFICATIONS TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of TASIGNA may need to be increased, depending on patient tolerability. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Hepatic impairment If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (ChildPugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered. OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

Tasigna® (nilotinib) Capsules

Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE Tasigna (nilotinib) is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. [See Clinical Studies (14) in the full prescribing information]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily. [See Clinical Pharmacology (12.3) in the full prescribing information]. Treatment should continue as long as the patient does not show evidence of progression or unacceptable toxicity. Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken. [See Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) and Clinical Studies (14) in the full prescribing information]. If a dose is missed, the patient should not take a make-up dose, but should resume taking the next prescribed daily dose. Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated. 2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1. Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec 1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline. 3. If QTcF is between 450 msec and 480 msec after 2 weeks reduce the dose to 400 mg once daily. 4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued. 5. An ECG should be repeated approximately 7 days after any dose adjustment. Myelosuppression: Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2). Table 2. Dose Adjustments for Neutropenia and Thrombocytopenia 1. Stop Tasigna, and monitor blood counts Chronic Phase or ANC* <1.0 x 109/L Accelerated Phase and/or platelet counts 2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L CML at 400 mg <50 x 109/L and platelets >50 x 109/L twice daily 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily *ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases. [See Adverse Reactions (6.1)]. Table 3. Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase 1. Withhold Tasigna, and monitor serum lipase or amylase or amylase ≥Grade 3 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1 Elevated bilirubin 1. Withhold Tasigna, and monitor bilirubin ≥Grade 3 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1 Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities: If other clinically significant moderate or severe non-hematologic toxicity develops, dosing should be withheld, and may be resumed at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 400 mg twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Serum lipase levels should be tested monthly or as clinically indicated. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Bilirubin and hepatic transaminases levels should be tested monthly or as clinically indicated. [See Warnings and Precautions (5) and Use in Specific Populations (8) in the full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, 400 mg once daily (a dose reduction to 1/2 of the original daily dose) is predicted to adjust the nilotinib AUC to the AUC observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. [See Boxed Warning, Warnings and Precautions (5.2 and 5.7) and Drug Interactions (7.2) in the full prescribing information]. Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St. John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued the nilotinib dose should be reduced to the indicated dose. [See Drug Interactions (7.2) in the full prescribing information].

Hepatic Impairment: If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, the following dose reduction should be considered: For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered. [See Boxed Warning, Warnings and Precautions (5.9) and Use in Specific Populations (8.7) in the full prescribing information]. 3 DOSAGE FORMS AND STRENGTHS 200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. [See Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna (nilotinib) can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. [See Dosage and Administration (2)]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner. [See Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. [See Drug Interactions (5.7) and Food Effects (5.8)]. The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. [See Electrolyte Abnormalities (5.6), Monitoring Laboratory Tests (5.12), and Warnings and Precautions (5.8)]. 5.3 Sudden Deaths There were five sudden deaths reported in patients receiving nilotinib in an on-going study (n=867; 0.6%). A similar incidence was also reported in the expanded access program. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase levels should be tested monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. [See Boxed Warning, Dosage and Administration (2), and Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided. [See Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely. [See Boxed Warning, Dosage and Administration (2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption. 5.11 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in laboratory animals at maternal exposures that were lower than the expected human exposure at the recommended dose of 400 mg BID. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do. [See Use in Specific Populations (8.1) in the full prescribing information]. 5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments. [See Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert. [See Boxed Warning and Warnings and Precautions (5)]. QT prolongation and Sudden Deaths [See Boxed Warning, Warnings and Precautions (5.2, 5.3)] Myelosuppression [See Warnings and Precautions (5.1)] Elevated serum lipase [See Warnings and Precautions (5.4)] Hepatotoxicity [See Warnings and Precautions (5.5)] Electrolyte abnormalities [See Boxed Warning and Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318; CML-AP=120). The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145-1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1-163). In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drugrelated adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. [See Boxed Warning and Warnings and Precautions (5.2 and 5.3)]. Discontinuation for drug-related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients. Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of patients who received at least one dose of Tasigna are listed. Table 4. Treatment-Emergent Adverse Reactions Reported in ≥10% of Patients in the Clinical Studya CML-CP CML-AP N=318 N=120 Body System and Preferred Term All Grades CTC Gradesb All Grades CTC Gradesb (%) 3/4 (%) (%) 3/4 (%) Skin and subcutaneous Rash 33 2 28 0 tissue disorders Pruritus 29 1 20 0 Gastrointestinal disorders Nausea 31 1 18 <1 Diarrhea 22 3 19 2 Constipation 21 <1 18 0 Vomiting 21 <1 10 0 Abdominal pain 11 1 13 3 Nervous system disorders Headache 31 3 21 2 General disorders and Fatigue 28 1 16 <1 administration site conditions Pyrexia 14 1 24 2 Asthenia 14 0 12 2 Edema, peripheral 11 0 11 0 Musculoskeletal and Arthralgia 18 2 16 0 connective tissue disorders Myalgia 14 2 14 <1 Pain in extremity 13 1 16 2 Bone pain 11 <1 13 <1 Muscle spasms 11 <1 14 0 Back pain 10 <1 12 <1 Respiratory, thoracic and Cough 17 <1 13 0 mediastinal disorders Dyspnea 11 1 8 3 Infections and infestations Nasopharyngitis 16 <1 11 0 a Excluding laboratory abnormalities b NCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna. Table 5. Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities CML-CP CML-AP N=318 N=120 Grades 3/4* Grades 3/4* Hematologic Parameters 37%2 Thrombocytopenia 28%1 Neutropenia2 28% 37%3 Anemia 8% 23% Biochemistry Parameters Elevated lipase 15% 17% Hyperglycemia 11% 4% Hypophosphatemia 10% 10% Elevated bilirubin (total) 9% 10% Elevated SGPT (ALT) 4% 2% Hyperkalemia 4% 3% Hyponatremia 3% 3% Hypokalemia 1% 5% Elevated SGOT (AST) 1% 1% Decreased albumin 1% 1% Hypocalcemia 1% 4% Elevated alkaline phosphatase 1% 3% Elevated creatinine <1% 0% *NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4 2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4 3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4 6.2 Additional Data from Clinical Trials The following drug-related adverse reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), and uncommon (0.1%-1%) adverse reactions single events are captured as unknown frequency. For laboratory abnormalities, very common events (≥1/10) not included in Table 4 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis. Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia. Unknown frequency: thrombocytosis, leukocytosis. Endocrine Disorders: Uncommon: hyperthyroidism. Unknown frequency: hypothyroidism, thyroiditis. Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia.

Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite, increased appetite. Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia. Psychiatric Disorders: Common: Insomnia. Uncommon: depression, anxiety. Unknown frequency: disorientation, confusional state. Nervous System Disorders: Common: dizziness, paresthesia. Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia. Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy. Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye irritation, dry eye. Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain. Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension. Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence. Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus. Hepatobiliary Disorders: Uncommon: hepatitis. Unknown frequency: hepatotoxicity, hepatomegaly, jaundice. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin. Uncommon: exfoliative rash, ecchymosis, swelling face. Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity. Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain. Uncommon: muscular weakness. Unknown frequency: arthritis, joint swelling. Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria. Unknown frequency: renal failure, hematuria, urinary incontinence. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. General Disorders and Administration Site Conditions: Common: pyrexia. Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise. Investigations: Very common: lipase increased. Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased. Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased. 10 OVERDOSAGE No cases of overdose have been reported. In the event of overdose, the patient should be observed and appropriate supportive treatment given. 16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs. Carton of 4 blister packs of (4x28)...............................................................................NDC 0078-0526-87 Blisters of 28 capsules .................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period. Tasigna (nilotinib) Capsules, 200 mg, should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Rev: August 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

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The ASCO Post | JUNE 2010

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News Renal Cell Cancer

RFA Shows Promise as Treatment Alternative in Selected Patients with Renal Cell Cancer By Barbara Boughton

adiofrequency ablation (RFA) may be an effective treatment option for select patients with small renal cancer masses, such as those who are elderly, have comorbidities, or have other active malignancies, according to a study presented at the 2010 Genitourinary (GU) Cancers Symposium in San Francisco.1 However, RFA needs to be applied very carefully; and for those patients whose tumors do not involute, it’s advisable to perform follow-up biopsies, according to researchers at The University of Texas M. D. Anderson Cancer Center. “You can’t rely on CT or MRI to claim success based on lack of enhancement,” said senior author Surena Matin, MD, Associate Professor of Urology at M. D. Anderson. The Symposium was cosponsored by ASCO,

the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology.

Survival Rates In the single-institution study at M. D. Anderson, the cases of 124 patients who did not qualify or were unable to undergo surgery and who received RFA were retrospectively reviewed. The median age of patients was 70, and the median tumor size was 2.8 cm. The 1- and 3-year local recurrence-free survival rates were 99% and 94.6%, and the 1-, 3-, and 5-year overall survival rates were 92.4%, 84.5%, and 70.8%, respectively. Two patients had incomplete ablation and their tumors were reablated. In 29 patients, however, the tumors failed to involute, and biopsies were performed at a median

RFA for RCC: In Short ■■ A new study of 124 patients at The University of Texas M. D. Anderson

Cancer Center showed that radiofrequency ablation may be a feasible and safe alternative to partial nephrectomy in select patients with small renal cancer masses—particularly those who are elderly, have comorbidities, or have other active malignancies.

■■ Careful consideration should be given to percutaneous core biopsy of any noninvoluting zones of ablation after RFA, even when no enhancement is evident on imaging.

Jose Karam, MD

time of 23 months postablation. Three of these patients had residual disease, although they showed no tumor enhancement on imaging, and they were retreated with either RFA or partial nephrectomy. Complications such as gross hematuria, acute hypertension, and pneumothorax affected 21 patients. Those with larger tumors were more likely to suffer complications, according to lead author Jose Karam, MD, a Urologic Oncology Fellow at M. D. Anderson. “Radiofrequency ablation is a feasible and safe alternative to surgery that we can offer those who cannot undergo or tolerate surgery—but is not something we would offer to young, healthy patients,” Dr. Karam said.

Need for Follow-up Biopsies While other researchers have found that RFA can result in up to a 30% to

Targeted Therapy Rarely Effective for Primary Tumors in Metastatic Renal Cell Cancer

40% rate of residual disease, the M. D. Anderson data indicated a far higher success rate, noted Dr. Matin. These data, however, support the need for follow-up biopsies in patients whose tumors do not involute—and the importance of careful patient selection, he added. Biopsies should be considered in patients whose tumors do not involute 6 months or later after treatment, he said. “For those with underlying medical conditions or who are too sick for surgery, radiofrequency ablation may be the preferred approach,” commented Nicholas Vogelzang, MD, Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology, and Vice Chair of the genitourinary committee of the Southwest Oncology Group. “It’s an evolving technology, but people need to be aware that you can’t always expect complete eradication of the tumor, and these patients need to be watched quite carefully,” he said. Reference 1. Karam JA, Ahar K, Jonasch E, et al: Radiofrequency ablation (RFA) of renal tumors: Clinical, radiographic and pathologic results from a tertiary care center. 2010 Genitourinary Cancers Symposium. Abstract 316. Presented March 7, 2010. Renal Cell Cancer

By Barbara Boughton

lthough the efficacy of targeted therapy for metastatic renal cell cancer is well established when prior nephrectomy is performed, research reports on the effectiveness of targeted therapy for treatment of the primary tumor have largely been anecdotal. Some case reports, however, have shown a dramatic response when tar-

E. Jason Abel, MD

geted therapy is used prior to nephrectomy in bulky primary tumors. Yet the largest study to date of targeted therapy in metastatic renal cell cancer shows that such dramatic responses occur very rarely, according to research presented at the 2010 Genitourinary Cancers Symposium in San Francisco. 1

Low Partial Response Rate In the study of 143 patients with metastatic renal cell cancer, only 5.6% had a primary tumor partial response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) after a median follow-up of 1 year. However, 35% of patients experienced 11% to 30% shrinkage of their tumor, and only 7% experienced an increase in tumor size of greater than 11%.

Targeting Renal Cell Cancer: In Short ■■ The largest study to date on use of targeted therapies in metastatic

r enal cell cancer with the primary tumor in place showed that only 5% of patients achieved a partial response as defined by RECIST criteria, and 35% experienced 11% to 30% shrinkage in their tumors.

■■ The study showed that patients who experience greater than a 10% response within the first 90 days are more likely to achieve a large maximal response.

“Patients with big complex tumors who do not undergo an upfront cytoreductive nephrectomy may have a meaningful response in the primary tumor, but it’s unlikely to be a dramatic response,” said lead researcher E. Jason Abel, MD, a Clinical Fellow in Urologic Oncology at The Univer-

sity of Texas M. D. Anderson Cancer Center. “It’s important to be realistic about your expectations,” he added. Dr. Abel noted that in the study, patients who did best on targeted therapy experienced an early response—within the first 90 days. Those who had a continued on page 46

The ASCO Post | JUNE 2010

PAGE 44

News Lymphoma

Evolving Questions in Follicular Lymphoma Highlighted at International Hematology Meeting By Alice Goodman

ptimal first-line therapy and the role of postremission/maintenance therapy are evolving challenges in the management of follicular lymphoma. The impact of recent studies on these issues was explored at a session on clinical management of common lymphomas during the recent 14th Annual International Congress on Hematologic Malignancies in Whistler, British Columbia, Canada.

Optimal First-line Therapy: New Standard Emerging? R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) is standard firstline therapy for follicular (indolent) lymphoma in most countries, but this regimen has not been proven to be the best treatment, said session moderator Andrew Zelenetz, MD. Dr. Zelenetz is Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York. Michael Williams, MD, the Byrd S. Leavell Professor of Medicine and Pathology at the University of Virginia in Charlottesville, discussed his approach to follicular lymphoma. The discussion of first-line therapy centered on a potentially practice-changing study presented at the Annual Meeting of the American Society of Hematology in December 2009. That study, presented by Matthias J. Rummel, MD, on behalf of the German Study Group on Indolent Lymphoma (StiL), found that first-line

therapy with bendamustine (Treanda) plus rituximab was superior to CHOP plus rituximab (CHOP-R) in follicular lymphoma. Not only was bendamustine/rituximab better tolerated than CHOP-R, but it also clearly resulted in a significantly superior progression-free survival (PFS). The study included 549 patients who were symptomatic with a large tumor burden and had a protocol-specified indication for therapy in line with criteria recommended by GELF (Groupe d’Etude des Lymphomes Folliculaires). Significantly lower rates of grade 3 and 4 hematologic toxicity (including leukocytopenia and neutropenia) occurred with bendamustine/rituximab vs CHOP-R (P < .0001). The incidence of nonhematologic toxicities was also much lower in the group receiving the experimental treatment. Overall response rates were similar in the two arms. Complete response rates were 39.6% for the experimental arm vs 30% for CHOP-R, translating to a significantly better PFS—a median of 54.9 vs 34.8 months, respectively (P = .00012). “This study raises the important question of how influential these findings should be. In our discussion of follicular lymphoma at the meeting in Whistler, this trial came up over and over again,” Dr. Zelenetz said. He added, “A confirmatory study is ongoing in the United States, Canada, and Australia. Nonetheless, anecdotal evidence

suggests that this regimen is being adopted for selected patients.”

Postremission Therapy Another controversial topic explored by Dr. Williams was the role of postremission therapy in follicular lymphoma. Dr. Zelenetz said that currently three options are available for maintenance therapy in follicular lymphoma once remission has been achieved: observation; consolidation with radioimmunotherapy; or maintenance rituximab (see Table 1). Speakers at the Whistler meeting also discussed the benefit of maintenance therapy with rituximab in follicular lymphoma. Although rituximab maintenance therapy is often given to patients who respond to first-line rituximab-containing regimens, randomized controlled trials have not reported any overall survival benefit. Two separate randomized controlled trials in relapsed/refractory patients with follicular lymphoma have shown that maintenance rituximab significantly prolonged PFS. In one study, following R-CHOP, patients were randomized to receive either maintenance rituximab or no treatment.1 In the second trial, following R-FMC (rituximab, fludarabine, mitoxantrone, cyclophosphamide), patients were also randomized to maintenance rituximab vs no treatment.2 A recent meta-analysis of randomized trials suggested an overall survival

Table 1: Consolidation in Postremission Follicular Lymphoma Options

Pros

Cons

■■ Overall survival benefit of alternatives not (yet) established

Observation

■■ Rituximab retreatment is an option ■■ Diminished risk of late toxicity (especially

■■ Shorter PFS

pan-hypogammaglobulinemia)

Rituximab maintenance

■■ Superior PFS compared to maintenance

Radioimmunotherapy

■■ Superior PFS compared to observation ■■ Brief therapy ■■ Limited resistance to anti-CD20 therapy ■■ Approved by FDA

FIT = First-line Indolent Trial; OS = overall survival; PFS = progression-free survival.■ Courtesy of Andrew Zelenetz, MD, PhD.

■■ Hypogammaglobulinemia ■■ No OS benefit (to date) ■■ May result in resistance to rituximab ■■ Potential for late toxicity (appears to be low after initial therapy)

■■ No OS benefit (to date) ■■ FIT trial has limited number of

rituximab/chemotherapy patients

advantage for maintenance rituximab in previously treated relapsed/refractory follicular lymphoma.3 However, the meta-analysis was difficult to interpret, Dr. Zelenetz said, because the induction therapy prior to maintenance therapy varied and included different regimens. “Unfortunately, no trial has directly addressed the role of maintenance

An impact on overall survival in the PRIMA trial would be practicechanging. – Andrew Zelenetz, MD

rituximab as remission therapy after front-line chemotherapy,” he stated. With the two randomized controlled trials mentioned above as background, results of the Primary Rituximab and Maintenance (PRIMA) trial are eagerly awaited, Dr. Zelenetz continued. In this European trial, maintenance rituximab was given following three different rituximab-containing regimens: FMCR, CVP (cyclophosphamide, vincristine, prednisone)-R, and CHOP-R. “PRIMA explores the question of whether there is a benefit in patients who respond to first-line rituximabcontaining regimens,” Dr. Zelenetz explained. “Although the primary endpoint of PFS is of interest, an impact on overall survival would be practicechanging.” The final results of PRIMA will be presented at the ASCO Annual Meeting this June.

Radioimmunotherapy Radioimmunotherapy is the only FDA-approved postremission therapy for follicular lymphoma. An international, randomized phase III trial showed that consolidation therapy with yttrium-90–ibritumomab tiuxetan (Zevalin) after first remission prolonged PFS by 2 years compared with no consolidation therapy in patients with advanced follicular lymphoma.4 Dr. Zelenetz said that as both singlecontinued on page 47

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News

Targeted Therapy in Renal Cell Carcinoma continued from page 42

greater than 10% response within the first 90 days, or about one-third of patients, had a maximum response of 24%. By contrast, patients without an early response, or about two-thirds of patients, had a maximum response of

only 10%, Dr. Abel said. “If you don’t get more than a 10% response in the first 90 days, the chances decrease for having a dramatic response,” Dr. Abel said.

Sunitinib Produced Best Response In the study, patients were treated with a wide variety of targeted ther-

Why subscribe to Journal of Clinical Oncology?

apy agents. Those treated with sunitinib (Sutent) had the best overall response when compared to therapy with other agents—3 patients on sunitinib experienced a partial response, and 21 showed a 10% to 30% decrease in the size of their tumors. Dr. Abel noted that if newer-generation targeted therapies were more

Vol 27, No 21

J OURNAL O C LINICAL F O NCOLOGY

July 20, 20 09

Topoisomer CAF in HER ase IIα Amplific L.N. Harris 2-Amplified, Earlation Does Not Pred y et al. Edit orial: F.J. Breast Cancer: CALict Benefit From Elevated Esteva et Dose-Intens GB 8541/1 al Biomarke e 50013 Among Pati rs ents Withof Inflammation Are Breast Can Associated Adjuvant cer. B.L. Pier Wit Hor ce et al. Edit h Reduced Surv Breast Can monal Therapy ival orial: S.W Use Among cer. G. Kim . Cole mick Insu et red, Impact of al Low-Income Women Wit Endocrine Androgen Depriva h tion Outcomes. S.M.H. Alib Therapy on Bone, Dose-Modif hai et al. Editorial: Cardiovascular, and Hodgkin’s ied Oral Chemot W. Dale hera Lymphoma in East Afripy in the Treatme Prospectiv nt ca. W. Mw anda et al of AIDS-Related Non Alfa-2b Wite-Randomized Mul ticenter Adju Phase in h or Without a Mod Patients Wit ified High-Dvant Trial of Low h Lymph -Dose Inte Single-Agen Node–Nega ose Interferon rferon Alfa-2b tive Melano Characteriz t Bortezomib in ma. A. Hau Induction Prev schild et al Response ation of Peripheral iously Untreat ed Multiple and Neurop Neuropathy Mye athy. P.G. Dasatinib Richardson , and Molecular Cor loma: Efficacy, in the Trea et al relations The START tment of With A Trial. J.F. CML in Acc Apperley et elerated Japanese-U Phase Afte al r Imatinib NSCLC: A S Common Arm Failure: Ana Model for D.R. Gandara Assessing lysis of Paclitaxel Plus Populationet al Related PhaCarboplatin in Adv AMG 386 anc rma , ed cogenomic Solid Tum a Selective Angiopo s ors. R.S. Herb ietin Inhi bitor, in Adu st et al lt Patients With Adv Official Jour anced nal of the American Society of Clinical Onc ology www.jco.o rg

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active in primary tumors, it would be more promising for presurgical therapy. Patients who would benefit most from presurgical therapy would be those who have large tumors, tumors that are invasive into other organs, or a large volume of metastatic disease, he added. “The use of targeted therapies in metastatic renal cell cancer as a means to shrink the tumor is a hot topic today,” commented Nicholas Vogelzang, MD, Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology, and Vice Chair of the genitourinary committee of the Southwest Oncology Group. Dr. Vogelzang noted that most studies to date show the average shrinkage in tumor size varies from 12% to 22% in metastatic renal disease. “The data suggests that these therapies might be helpful for surgeons. At the same time, we have no prospective randomized studies that provide data on this approach yet—just level 2 evidence,” he noted. For further information on targeted therapy in metastatic renal cell carcinoma without cytoreductive nephrectomy, see abstract 4613, being presented June 7 at the ASCO Annual Meeting. Reference 1. Abel EJ, Tannir NM, Culp SH, et al: Does targeted therapy result in reliable and meaningful primary tumor downstaging in patients with metastatic renal cell carcinoma? 2010 Genitourinary Cancers Symposium. Abstract 318. Presented March 7, 2010. Barbara Boughton is a freelance reporter based in the San Francisco area and coauthor of Reduce Your Cancer Risk.

JCO.org: You will be able to access full-text articles including archival issues, browse JCO content by subject collection, and download figures into PowerPoint slides. Impact factor of 17.157: Of 141 oncology journals monitored worldwide, JCO ranks fourth in impact factor. In 2008, JCO’s published articles were cited a total of 97,639 times, accounting for fully 9.7% of all oncology journal citations. Expansive coverage on a range of cancer specialties: Topics covered include breast cancer Phase III clinical trials and clinical pharmacology, gastrointestinal cancer, lung cancer, and translational oncology.

More news from the 2010 Genitourinary (GU) Cancers Symposium, see pages 9, 22, and 23

ASCOPost.com | JUNE 2010

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News

Follicular Lymphoma continued from page 44

agent rituximab and radioimmunotherapy can be used at relapse, the compelling use of postremission therapy will occur if either strategy provides an overall survival advantage. Another twist in this evolving story is whether radioimmunotherapy can replace rituximab as upfront therapy. A separate trial called SWOG 0016 will evaluate radioimmunotherapy after CHOP vs rituximab upfront. This study is a direct comparison of R-CHOP vs CHOP followed by radioimmunotherapy (with tositumomab and iodine I-131 [Bexxar]). Results of this trial are anticipated in late 2010, according to lead investigator Oliver Press, MD. For additional information on rituximab immunotherapy, watch for abstract 8088 at the 2010 ASCO Annual Meeting. For more on radioimmunotherapy in FL, see pages 1, 10, and 17 in this issue.

outcome of relapsed/resistant follicular nonHodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295-3301, 2006. 2. Forstpointner R, Unterhalt M, Dreyling M, et al: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of ritux-

imab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108:4003-4008, 2006. 3. Vidal L, Gafter-Gvili A, Leibovici L, et al: Rituximab maintenance for the treatment of patients with follicular lym-

phoma: Systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 101:248-255, 2009. 4. Morschhausser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156-5164, 2008.

There are thousands of ways to show you care: working to improve health is one of them.

References 1. van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical

Progress Seen in War on Cancer, but Challenges Remain In the nearly 40 years since the 1971 National Cancer Act was signed into law, the so-called war on cancer has scored many achievements, including a decrease in the rate of new diagnoses and death, a commentary in the Journal of the American Medical Association noted.1 Susan M. Gapstur, PhD, MPH, and Michael J. Thun, MD, MS, of the American Cancer Society cited a series of national consensus reports that document a 15.8% decrease in the age-standardized death rate from all cancers combined between 1991 and 2006, and an almost 1% annual decrease in the rate of new diagnoses between 1999 and 2006. Nearly 40% of the decrease in the overall cancer death rate in men between 1990 and 2006 resulted from the decline in lung cancer mortality, largely attributed to primary prevention by reducing cigarette smoking. Reference 1. Gapstur SM, Thun MJ: Progress in the war on cancer. JAMA 303:10841085, 2010.

Sanofi-aventis U.S. is the U.S. affiliate of sanofi-aventis, a leading global pharmaceutical company that discovers, develops and distributes therapeutic solutions to help improve the lives of patients and their families. To find out more about our research, please visit www.sanofi-aventisoncology.com

The ASCO Post | JUNE 2010

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News Prostate Cancer

Novel Agents

Researchers Closing in on Identification of Prostate Cancer Subsets By Patrick Young

linical and laboratory investigations of castration-resistant prostate cancer indicate that researchers may be near to identifying subtypes of the disease. “Unlike many other cancers, we don’t yet have a clinically relevant scheme to subclassify our patients,” said Charles L. Sawyers, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC) at the 101st Annual Meeting of the American Association for Cancer Research (AACR), held April 17–21 in Washington, DC. “Are there different subtypes for prostate cancer? The precedent is clear in breast cancer, which is now divided into at least three major subgroups.” However, he noted, transcriptional studies in prostate cancer have yet to yield the robust findings seen in breast cancer.

Toward Subclassification Dr. Sawyers is co-inventor of MDV3100, Medivation, Inc’s oral androgen receptor antagonist. He fo-

cused much of his presentation on advances toward subclassification that have emerged from research on that drug, which could be a model for differentiating subtypes of the disease. Last year, Dr. Sawyers and colleagues reported that after conven-

HDAC inhibitors could block androgen receptor activity in castrate-resistant prostate cancer. tional hormonal treatments fail in prostate cancer, androgen receptor transcriptional activity remains crucial to tumor growth and survival. They also showed that histone deacetylase (HDAC) inhibitors, including vorinostat (Zolinza) and LBH589, now in clinical trials, could block an-

drogen receptor activity in castrationresistant prostate cancer models.1 More recently, his team has mapped DNA binding to androgen receptors across the genome, which revealed a reduced binding by about 1 log for MDV3100 compared to bicalutamide (Casodex), the standard treatment.

Key Clinical Trials Three days before Dr. Sawyers’ AACR presentation, The Lancet published online results of a dose-escalation phase I/II MDV3100 study, which showed positive results in patients with castration-resistant prostate cancer. Among 140 men—75 in whom chemotherapy failed and 65 chemotherapy-naive—researchers reported ≥ 50% reductions in PSA levels in 56% of the men. Median PSA responses lasted 41 weeks in chemonaive patients, 32 weeks for all participants, and 21 weeks for postchemotherapy patients.2 continued on page 50

Oncologists Scrutinize Marginal Benefits of Cancer Chemotherapy

Cost of Care

By Leah R. Young

ancer researchers who nourish ideas to fruition must start focusing on the clinical values of their discoveries and not just whether their ideas work, several experts said at a Special Session of the American Association of Cancer Research (AACR) Annual Meeting, held April 17–21 in Washington, DC.

Change in Cost vs Survival Between 1995 and 2007, “the cost of new prescription drugs for breast and colorectal cancer in clinical trials increased over 100 times, but the overall survival improvement in the new arm has stayed at less than 1%,” Thomas J. Smith, MD, Professor of Medicine and Palliative Care Research at the Massey Cancer Center, Virginia Commonwealth University Health System, told the AACR audience. Tito Fojo, MD, PhD, of the National Cancer Institute pointed to drugs like cetuximab (Erbitux), which can add $70,000 to patient medical costs but improve survival for only

1 month to 6 weeks, often at an additional cost of serious side effects. He also noted that adding bevacizumab (Avastin) to breast cancer treatment “improves progression-free survival but has yet to be shown to confer a significant survival advantage.” Dr. Fojo stressed that drug costs are only one part of the problem, noting that of equal concern is the possibility that the increasingly marginal benefits seen in clinical trials are in fact masking harmful effects in some patients. As an example, he cited the negative impact of cetuximab on progression-free survival when it is given to patients with colorectal cancer whose tumors harbor a KRAS mutation.1 In addition, he expressed concern that overall survival in some patients with breast cancer may be adversely impacted by singlenucleotide polymorphisms (SNPs) in the promoter region of the vascular endothelial growth factor (VEGF) receptor.2,3 Dr. Fojo concluded his presentation by urging audience members—

many of whom were investigators involved in basic research—to work to identify markers that predict response

Marginal benefits seen in clinical trials may be masking harmful effects in some patients. or the potential for harm before drugs reach clinical trials.

10 Cost-control Measures Dr. Smith, an oncologist, proposed “10 steps to bend the cancer cost curve.” He stated that the current double-digit rate of growth is simply not sustainable. The cost of insurance for a family of four has doubled from $6,000 to $12,000 in just 8 years, and continuation will have the consequence of continued on page 50

Researchers Unveil Promising Anticancer Drugs on the Horizon By Leah R. Young

esearchers at the 101st Annual Meeting of the American Association for Cancer Research (AACR) introduced four new drugs that appear to successfully fight tumors in preclinical trials. The clinical drug possibilities revealed at the AACR meeting, held April 17–21 in Washington, DC, include NMS-1116354, a Cdc7-kinase inhibitor; a two-inone antibody that targets EGFR and HER3; TAK-700, an inhibitor of 17,20-lyase; and NVP-BKM120, a selective inhibitor of type 1 PI3-kinases. AACR panel co-chair Matthew A. Marx, PhD, of Pfizer, Inc, San Diego, characterized the presentations as “the first disclosure of the structures of these new clinical candidates.”

NMS-1116354 Francesco Colotta, MD, PhD, of Nerviano Medical Sciences, Nerviano, Italy, described NMS-1116354 as a “potent and selective Cdc7LMW inhibitor” that “specifically induces phosphorylation of Mcm2 in Ser 40.” The compound, directed toward advanced metastatic solid tumors, is involved in DNA damage response and “activated by a still partially unknown mechanism.” It does not damage DNA in normal cells but induces apoptosis in solid tumor cancer cells by impairing DNA replication in those cells. The compound appears to be equally active in resistant cell lines that do not respond well to other cytotoxic agents, and in vivo it can be used in combination with widely approved anticancer drugs. NMS-1116354 appears more efficacious in tumors that are overexpressing MCL-1.

MEHD 7945A Gabriele M. Schaefer, PhD, of Genentech, Inc, South San Francisco, discussed MEHD 7945A, an antibody combination that blocks epidermal growth factor receptor (EGFR) and HER3 and results in a blockade of the major HER family signaling pairs. The compound has a higher potency compared to monospecific antibodies and inhibits EGFR and continued on page 50

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE THE 5-YEA R SU RVIVA L RATE IS 17 % FOR PAT IENTS W ITH METASTAT IC SOF T TISSU E SARCOMA, YET SIGNIF IC A NT TH ERA PEUTIC ADVANCE M ENTS A RE L A GGING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

The ASCO Post | JUNE 2010

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News

Prostate Cancer Subsets continued from page 48

The 1,200-patient AFFIRM trial—a randomized, double-blind, placebo-controlled phase III study of MDV3100—is underway in the United States, the United Kingdom, and 13 other countries.

Preclinical Findings Clues to distinguishing known cancer subsets have come from disease tissue. Prostate cancer poses an obstacle to this approach because advanced disease largely manifests as bone metastases, which are difficult to access. Dr. Sawyers’ laboratory has used preclinical models in efforts to identify subsets. He cited several recent findings from his team that might lead to differentiating types of prostate cancer: ■■ Researchers compared two genetically engineered mouse models. In one, the myc gene is expressed under control of the probasin promoter. Castration produced a

Marginal Benefits of Chemotherapy continued from page 48

fewer “haves” with coverage for anything, and many more “have-nots” without coverage for even the basics of curative and adjuvant care. Here are some of the points Dr. Smith made: ■■ “Expand use of biologic imaging (PET-CT), tumor markers, or circulating tumor cells to limit duration of ineffective therapies. At the same time, limit the use of ineffective tests such as blood tumor markers and CAT, PET, or bone scans in surveillance of breast cancer.” ■■ “For many cancer types, use sequential monotherapy for metastatic disease.” This approach results in less toxicity and is also less costly. ■■ “Provide tools to care providers to reset the patient’s unrealistic expectations of benefit” by discussing advance directives, prognosis, life planning, legacy, and legal issues, and by obtaining “truly informed consent.” Patients need answers to

partial response, but combining MDV3100 with castration yielded a dramatically stronger response. “This model is extremely sensitive,” Dr. Sawyers said. “In contrast, the Pten deletion model showed minimal response.” ■■ After restoring the damaged PI3K Chinese signaling pathway to baseline, mice treated with MDV3100 had dramatic disease regression— at least 80% in four of them. The finding indicates that loss of the pathway could serve as a biomarker for resistance and that restoring PI3K activity might restore androgen-sensitive dependence to such tumors. ■■ Alterations in DNA copy numbers potentially could provide useful predictive factors. In human experiments, the MSKCC team found high copy-number alterations in the NCAO2 gene, whose homolog is amplified in breast cancer. These changes occurred in

21% of primary tumors. Using this approach in human prostate tumors, Dr. Sawyers and his colleagues identified two patterns—cluster 2 with few alterations, and cluster 5 with many changes. They compared the two subsets by time to disease progression. “Cluster 2 did well out to almost 100 months, with 90% still in remission, vs cluster 5 doing very poorly,” he said. “If this can be consistently reproduced, there may be information in genome copy numbers in prostate cancer that can be prognostic.”

Promising Anticancer Drugs

References 1. Welsbie DS, Xu J, Chen Y, et al: Histone deacetylases are required for androgen receptor function in hormonesensitive and castration-resistant prostate cancer. Cancer Res 69:958-966, 2009. 2. Scher HI, Beer TM, Higano CS, et al: (2010). Antitumour activity of MDV3100 in castration-resistant prostate cancer: A phase 1–2 study. Lancet 375:1437-1446, 2010.

TAK-700

the question, “How long will I live with or without chemo, and what will that time be like?”

legged stool,” he said—better understanding of the biology of malignancy; development of targeted therapies; and creation of tools for biologic management of patients.

A Different Take But David R. Parkinson, MD, of Nodality, South San Francisco, has a different take on the dilemmas facing cancer researchers, providers, and patients. Dr. Parkinson believes that many of the inefficiencies in the system stem from a disconnect between the way we characterize patients and drug treatments. He maintains that truly personalized medicine, where biomarkers allow for targeted therapies that work on the patient’s particular malignancy, is the “missing piece for rational, efficient treatment.” Right now, he says, “we don’t have the tools for biologic management of patients.” But technologies are emerging that Dr. Parkinson believes will allow for the development of biologic tools so that clinical decisions can be based on individual biology. Rational, efficient treatment must be built on a “three-

References 1. Allegra CJ, Jessup JM, Somerfield MR, et al: American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti–epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091-2096, 2009. 2. Schneider BP, Wang M, Radovich M, et al: Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672-4678, 2008. 3. Gray R, Bhattacharya S, Bowden C, et al: Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 27:4966-4972, 2009.

continued from page 48

HER3/HER2–dependent signaling, producing a combined inhibition of MAPK and PI3K. MEHD 7945A demonstrates efficacy in vivo in a broad range of tumor types, including colon, head and neck, ovarian, breast, and pancreas. In studies using cynomolgus monkeys, the animals had delayed onset, lower incidence, and fewer skin lesions with MEHD 7945A than with cetuximab (Erbitux). Moreover, no new toxicities were reported. In his presentation on TAK-700, Masuo Yamaoka of Takeda Pharmaceuticals Co, Ltd, Osaka, Japan, explained that researchers used this nonsteroidal androgen synthesis inhibitor of the 17,20-lyase enzyme to treat castration-resistant prostate cancer. According to Dr. Yamaoka, preclinical studies showed that TAK700 binds to and inhibits 17,20-lyase in both the testes and adrenal glands. Phase I/II clinical trials have commenced to investigate the efficacy of TAK-700. A phase I study, with an enrollment of 26 patients, revealed that at doses of 300 mg twice per day, TAK-700 was well tolerated in patients with metastatic castrationresistant prostate cancer. Phase II enrollment is ongoing.

NVP-BKM120 William R. Sellers, MD, of Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, presented research on NVPBKM120, a selective type 1 PI3K inhibitor. In preclinical studies, NVP-BKM120 inhibited cell growth and induced apoptosis in a number of cell lines. Dr. Sellers indicated that NVP-BKM120 penetrates the blood–brain barrier, so it could be a drug suitable for glioblastoma and other tumors that have metastasized to the brain. In preliminary phase I data, 8 of 11 patients had metabolic partial responses.

Inside this issue of The ASCO Post News from these important oncology meetings:

■■ 2010 Genitourinary (GU) Cancers Symposium ■■ 101st Annual Meeting of the American Association of Clinical Research (AACR) ■■ 36th Annual National Meeting of the Association of Community Cancer Centers (ACCC)

■■ 14th Annual International Congress on ■ Hematologic Malignancies

■■ National Comprehensive Cancer Network ■ (NCCN) 15th Annual Conference

ASCOPost.com | JUNE 2010

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News Cost of Care

UnitedHealthcare Pilots Episode-based Care By Daniel Denvir

hen it comes to health care, the one matter on which bipartisan consensus exists is that costs are out of control. Just how to contain those costs is another matter. Many, including the Centers for Medicare & Medicaid Services, are looking to move away from the fee-for-service reimbursement model, which rewards care by volume rather than by quality. Currently, a number of demonstration projects are exploring bundled payments, including various takes on capitation.

Network (NCCN) Executive Vice President Patricia J. Goldsmith in a phone interview. She agrees that the incentive structure is broken, but is cautious nonetheless. “We now have a system where there’s an incentive to get the most ex-

pensive medicine and deliver the largest dollar amount to the practice; let’s not have the pendulum swing the other way and have the incentive be, ‘let’s get the cheapest medicine and deliver the largest dollar amount to the practice.’”

Dr. Newcomer said that data sharing across participating practices makes it impossible for providers to skimp on care. “The results will be measured and compared to their peers’,” he said. “Peo-

continued on page 54

Lee N. Newcomer, MD

UnitedHealthcare is piloting an episode-based payment system with six oncology practices, encouraging providers to identify the most effective treatment regimens and reimbursing them for “episodes” of care, defined as a treatment composed of a standard regimen over a determined period of time. The payment is made when a patient is identified. “Right now the system is turned upside down,” said Lee N. Newcomer, MD, UnitedHealthcare’s Senior Vice President for Oncology, at the 36th Annual National Meeting of the Association of Community Cancer Centers (ACCC), held recently in Baltimore, Maryland. “You have to get most of your income today from drug profit margins, so you have to pay attention to what drugs you select—and markups can make a difference.”

Managing Money vs Managing Care And while it is still too early to evaluate the pilot, other demonstrations around the country have shown decreased costs and improved patient outcomes. But bundled payments of any sort make some patient advocates and providers nervous. Experiments with capitation during the 1990s prompted a major backlash against managed care, with critics blaming payers for managing money instead of managing care. “The cheapest is not always best,” said National Comprehensive Cancer

Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11): 4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):64076415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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The ASCO Post | JUNE 2010

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News NSCLC

Stereotactic Body Radiation Therapy for Inoperable NSCLC Produces Higher Rates of Primary Tumor Control and Overall Survival By Charlotte Bath

tereotactic body radiation therapy (SBRT) produced high rates of primary tumor control (97.6%) and overall survival (55.8%) at 3 years among patients enrolled in the Radiation Therapy Oncology Group (RTOG) 0236 trial with early-stage but medically inoperable non–small cell lung cancer (NSCLC). SBRT “as delivered in RTOG 0236 provided more than double the rate of primary tumor control than previous reports describing conventional radiotherapy,” the investi-

Robert Timmerman, MD

gators wrote in the Journal of the American Medical Association (JAMA).1 The study included 55 patients with biopsy-proven peripheral T1-2 N0 M0 NSCLC tumors (44 with T1 tumors and 11 patients with T2). A previous study piloting dose levels used in this study found that patients with proximal tumors had higher rates of toxicity, including some toxic deaths, so patients with proximal tumors were excluded. The participating patients were unable to tolerate surgery because of comorbidities such as emphysema and heart disease. The prescribed SBRT dose was 18 Gy per fraction × 3 for a total of 54 Gy. “The main finding in this prospective study was the high rate of primary tumor control (97.6%),” the authors commented. “Primary tumor control is an essential requirement for the cure of lung cancer. Treatments applied for curative intent must be judged at least partly on their ability to control gross disease.” Tumor recurrence or progression at the primary site was documented in only one patient. Recurrence within the involved lobe was reported in three patients, resulting in a 3-year primary tumor and involved lobe (local) control rate of 90.6%. “Very few patients experienced treatment failures where we aimed our crosshairs, and very few had treatment failures elsewhere,” the trial’s lead inves-

tigator, Robert Timmerman, MD, of the University of Texas Southwestern Medical Center told The ASCO Post.

Survival Rates At 3 years, the disease-free survival rate was 48.3% and the overall survival rate was 55.8%. As noted in the JAMA article, conventional radiation treatment and observation generally offered to patients with inoperable early-stage lung cancer result in 2-year survival rates of less than 40%. The treatments were well tolerated despite the frailty and comorbidities of the study population. “Most published studies select patients who typically have a better prognosis, with good performance status, no weight loss, and reasonable life expectancy,” Dr. Timmerman said. “Our study was the exact opposite. If you had those good prognostic signs, then you couldn’t go on the trial. These people had lots of medical problems.” Each treatment took 20 to 60 minutes, and the entire course of treatment was completed in 1 to 2 weeks. The treatments were painless and required no sedation or anesthesia. According to Dr. Timmerman, patients appreciated that the treatments produced no immediate ill effects and allowed them to return to daily activities immediately. “The only invasive part of the treatment was the biopsy,” Dr. Timmerman said. “We required a biopsy because we wanted it to be clear that we were actually treating cancer.” For follow-up,

“we allowed biopsy but did not require it.” Patients were followed up every 3 months during the first 2 years after treatment and then every 6 months during the next 2 years, with CT performed at each visit to assess response and toxicity. If the CT scans revealed progressive soft-tissue abnormalities, PET scans were also required. These evaluation methods mean the study cannot be compared with surgical series relying on histologic confirmation, but Dr. Timmerman said such comparisons were never intended. When side effects did occur, they tended to do so 1 to 3 months after treatment. Protocol-specified treatment-related grade 3 adverse events were reported in seven patients (12.7%), and grade 4 adverse events occurred in two patients (3.6 %). No grade 5 treatment-related adverse events were reported.

trial, with a group of frail patients with multiple comorbidities, was nearly 56% at 3 years. “Medicare already pays for SBRT as a standard treatment,” Dr. Timmerman noted. He added that many private insur-

Standard of Care for Inoperable Patients?

ance companies agree there is enough evidence to support its use and will also pay for it as a standard treatment.

Should the SBRT regimen tested in RTOG 0236 be considered the standard of care for patients with NSCLC who are medically inoperable? Dr. Timmerman gave three reasons why it should: 1. Primary tumor control is dramatically better—not just a little better, but dramatically better—than anything else that has been published. 2. Treatment toxicity was within the realm of acceptability. 3. The survival rate of this prospective

‘Nihilistic Attitude’ Doesn’t Serve Patients Well Many people have had a “nihilistic attitude” toward patients with early-stage lung cancer and comorbidities that make them unable to tolerate surgical resection of their tumors, Robert Timmerman, MD, commented. “I’m using ‘nihilistic’ in the sense that these are patients with the worst consequences of their smoking habit,” he explained. “They have really bad emphysema, heart disease, and a history of TIAs or strokes. Many people have thought that lung cancer is the least of their problems. But I think that this study and others have shown that this type of attitude may not be serving patients very well. Some studies show that over half of these patients die of lung cancer. So even though they have numerous other health problems, they still are very much affected by their lung cancer,” he added. “Patients are coming to us with the expectation that we are going to cure their cancer. They don’t come to us and say, ‘Can you slow my tumor down until I die of something else?’ They say, ‘Can you cure my cancer?’ And if you can’t control a primary tumor, than you need to disclose that to the patient. Patients, at least in the United States, are interested in curative therapy when they have lung cancer.”

Most published studies select patients who typically have a better prognosis, with good performance status, no weight loss, and reasonable life expectancy. Our study was the exact opposite. – Robert Timmerman, MD

Refining the Dose RTOG is planning a head-to-head test of two less potent SBRT regimens, 12 Gy × 4 (popular in Japan) and 34 Gy × 1 (popular in Europe), Dr. Timmerman reported. The less toxic of these two regimens will then be compared in a phase III trial. Dr. Timmerman also announced that the National Institutes of Health recently accepted a proposal to test SBRT in patients with operable NSCLC. “A national trial in the United States will compare surgical resection using a sublobar resection (not the See page 72 full-lobe resection that is done in the healthiest patients) to SBRT—the exact regimen that we used in this study,” he said. The trial will include about 400 patients, and is being sponsored by the American College of Surgeons Oncology Group and the RTOG. Reference 1. Timmerman R, Paulus R, Galvin J, et al: Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303:1070-1076, 2010.

ca m w #1 B Vis nc ak rite 0 o o it 04 t er e a h pa a 3 tie dif wis t nt fer h o s. en an ce d fo r

Image: Colored scanning electron micrograph (SEM) of a lung cancer cell.

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The ASCO Post | JUNE 2010

PAGE 54

News

UnitedHealthcare continued from page 51

ple who withhold evidence-based care will be exposed.”

Keeping Physician Incomes Constant Under UnitedHealthcare’s episodebased care pilot, stronger incentive ex-

ists for doctors to schedule an office visit than a hospitalization, because office visits are still paid for on a fee-forservice basis. Drugs are paid for at the average sale price and are no longer the cornerstone of reimbursement. If payers decide to scale the model up, however, they will have to restructure how they make reimbursements.

Since UnitedHealthcare’s pilot only involves oncology providers, it is not subject to the logistic difficulty of distributing a single payment across many providers. “I don’t have any desire to reduce your incomes. I wanted to try and find a way to keep physician incomes constant,” said Dr. Newcomer. “At the same time, I

Call for Papers for State of Oncology Series American

Oncology f Clinical Society o

J O P

ournal of ncology ractice RITA THE AUTHO

VOLUME 6

RESOURCE

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ONCOLOGY

the Development of Filling the Gap: Practitioner Oncology Nurse increasing the Workforce care delivery by such as strategies for oncology ician practitioners, “Developing new g the roles of nonphys is critically numbers and expandin and physician assistants (PAs), ers (NPs) care needs of the nurse practition potential cancer the current and important to meet FAAN, et al US population.”

n, MSN, RN,

By Brenda Nevidjo

Cancer Care Ensuring Quality ology Through the Onc . . . are Workforce workforce. Health professionalsrapidly

in the oncology . . . because of the “There is a crisis t workforce shortages an aging oncology experiencing significan Americans requiring cancer care, n of workers. This misgrowing populatio of newly trained inadequate numbers cancer care could threaten patient workforce, and for supply and demand match between quality.” care, safety, and et al

By Laura Levit,

http:// jop.as

PRACTICES

010 JANUARY 2 oners ed Nurse Practiti Role of Advanc ts in and Physician Assistan Washington State By Jonathan C.

Britell, MD

Practical Model

for Psychosocial

Care

, PhD, et al

By Susan S. Hendrick

the t Perspective on Physician Assistan ing the rce Study Regard ASCO Workfo Assistants and Use of Physician Nurse Practitioners , MS, PA-C, et

By Maura Polansky

gy of Clinical Oncolo Georgia Society e Navigator Affiliat Forms a Patient g a Research Basic Steps to Buildin Program BSN, et al By Allison Baer,

RN,

JD,

copub s.org

Journal of Oncology Practice is accepting manuscripts for a Special Series focusing on issues changing the practice of oncology in the United States. This series will examine the effects of regulatory and payment policy on practice, especially with regard to how such pressures impact small practices disproportionately. Commentaries/ perspective pieces will be considered in all areas pertinent to changes in the daily workflow of oncology practices.

Suggested topics include: • Effects of changing reimbursement on delivery of care • Changes in reimbursement affecting access to and quality of care • Changing relationships between physicians, practices, hospitals and/or academic medical centers • Changes in practice that are viewed as positive • Changes in practice that are viewed as negative • Administrative burdens (e.g., complying with REMS, preauthorizations, pre-certifications, documentation required for off-label reimbursement by some CMS carriers/contractors) The editors are interested in manuscripts that elucidate specific events that are changing practices, as well as both successful and failed strategies to cope. Manuscripts written by patients and/or families will also be considered. Please submit your State of Oncology manuscript to JOP at jopsubmissions@asco.org by June 15.

For more information visit jop.ascopubs.org/misc/ifc.dtl, or contact the JOP editorial office at (703) 797-1900.

Deadline: June 15, 2010

do have a very strong desire to reduce your revenue, because if we’re seeking best practices, if we’re looking for ways to reduce cost, I need you to use your pen a lot more efficiently and with more attention to cost than you have in the past.”

Identifying Effective Regimens Like comparative effectiveness research (CER), UnitedHealthcare’s pilot requires providers to zero in on a set of effective treatment regimens. “How could we find out—of those 14 adjuvant therapies that are recommended by NCCN for breast cancer— which two we really ought to be using?” asked Dr. Newcomer. “And I mean that in terms of best relapse rates, best complication rates, and lowest cost.... In a world where we have literally hundreds of choices, how do we get to the two or three best practices?” An episode is defined according to condition. Stage III colon cancer, for example, would be set as a 6-month episode. Metastatic episodes would be 4 months, renewed until the patient died. Providers decide on the standard regimen they will follow for each episode, but once set it must be followed. If a particular patient requires treatment that deviates from the established regimen, doctors are free to provide the necessary care. UnitedHealthcare would only become concerned if compliance dropped below 85%. Once a year, each provider must meet with other groups taking part in the pilot and compare data. If doctors begin to “see an emergence of best practices,” Dr. Newcomer said, he expects them “to be migrating over to that best practice.”

Nationwide Trend Bundled payment pilots have taken off around the country, including the Medicare Acute Care Episode (ACE) demonstration. President Obama’s recent nomination of cost control advocate Dr. Donald Berwick indicates the Administration’s commitment to change the reimbursement model. In a 2008 Boston Globe column, Dr. Berwick and Dr. Joseph Dorsey wrote, “The closest you can come to heresy in today’s health-care policy debate is to suggest that managed care can help and that capitation is the best way to pay for it.... What a shame.” Health-care reform is now law, and payers are taking aim at cost. Fee-forservice may be on its way out. More on health-care reform, see pages 65–67

Identify/Screen for Psychosocial problems

ASCOPost.com | JUNE 2010

Treatment Plan LINK

SUPPORT

to Psychosocial Services

Psychosocial Oncology

PAGE 55

Expert’s Corner

• Give information • Identify needs

COORDINATE with Medical Care

• Emotional

The New Standard of Quality Cancer Care: Integrating the Psychosocial into Routine Care

• Help Manage illness/treatment

Follow-up

By Jimmie Holland, MD “To ignore these factors while we pour billions of dollars into new technologies is like spending all of one’s money on the latest model car and then not having the money left to buy gas to run the car” —Nancy Adler, PhD, Chair, IOM Committee, 2007

he Institute of Medicine (IOM) of the National Academy of Sciences published a report in 2007, “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs,” which proposed that the current evidence base supports the recommendation that “quality cancer care today must integrate the psychosocial domain in routine cancer treatment.”1 The Report noted that oncologic care in the United States is among the best in the world; however, attention to patients’ psychological and social concerns lags far behind the medical care. One must ask why this is the case when cancer carries a particularly frightening meaning to patients and when we know that unmet psychosocial needs negatively impact treatment adherence and outcome.

Attention to Psychological and Social Concerns Lags The reasons are several: (1) cancer care today is given largely in overworked outpatient clinics and offices where the fewest psychosocial resources are available; (2) patients with problems are reluctant to “bother” the doctor with emotional problems (they “don’t tell”) and doctors who are in a hurry “don’t ask”—our own oncologic “don’t ask/don’t tell” policy; (3) no mechanism exists for asking about psychosocial problems in routine care; (4) patients fear that if they bring up emotional problems they might be labeled a “psychiatric” case, which would be a second stigma

in addition to cancer; (5) the patient’s caregiver is often the neglected and unrecognized secondary patient; and (6) reimbursement for ambulatory psychological and social services is so low that professionals cannot independently earn their salaries from practice, and small oncology practices cannot provide sufficient salary support. The IOM panel explored the evidence base for psychosocial services and the barriers to delivery of services. It found strong evidence to support interventions for adequate communication between the patient and the oncologist or team, psychotherapy and counseling, psychopharmacologic medications, self-management (largely from diabetes literature), addressing adverse behaviors (eg, diet, smoking, alcohol), and support for the family caregiver. The multidisciplinary panel recognized that the key to implementation of the mandate lies in finding a rapid, simple way by which psychosocial needs can be assessed during routine visits.

Patient/ Family

The NCCN recommends the ‘distress thermometer,’ which is a 0-10 scale that looks like a thermometer and asks patients about their level of distress in the past week. – Jimmie Holland, MD

Medical Team

Identify/Screen for Psychosocial problems Treatment Plan LINK

SUPPORT

to Psychosocial Services

• Give information • Identify needs

COORDINATE with Medical Care

• Emotional • Help Manage illness/treatment

Follow-up

Fig. 1: Model for psychosocial services based on effective communication. Adapted from Adler and Page.1

During the past week, how distressed have you been?

Extreme Distress

Simple Model for Psychosocial Evaluation The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for management of distress, developed in 1997, had recommended a way to conduct such an assessment.2 To begin with, the guidelines addressed the stigma attached to any words implying a “psychological” problem. The term “distress” was chosen because it suggests a normal response, which can vary from a normal and expected level to a severe one (which we would identify as anxiety or depression). The IOM report follows the NCCN guidelines by stating that the oncologist should query all patients about their psychosocial

Patient-Clinician Partnership

Please indicate your level of distress on the thermometer and check the causes of your distress Practical problems

Physical problems

____Housing

____Pain

____Insurance

____Nausea

____Work/school

____Fatigue

____Transportation

____Sleep

____Child care

____Getting around

Family problems

____Bathing/dressing

____Partner ____Children Emotional problems ____Worry ____Sadness ____Depression ____Nervousness

No Distress

____Breathing ____Mouth sores ____Indigestion ____Constipation/diarrhea ____Bowel changes ____Changes in urination ____Fevers ____Skin dry/itchy

Spiritual/religious concerns

____Nose dry/congested

____Relating to God

____Tingling in hands/feet

____Loss of faith

____Feeling swollen

____Other problems

____Sexual problems

BRIEF SCREENING TOOL AND PROBLEM LIST

Fig. 2: Brief screening tool and problem list.

concerns within the first visit or two. Both NCCN and the IOM agreed that a simple, rapid screen or needs assessment would serve as a first phase, to red flag an individual for a second level of evaluation regarding a particular problem. The IOM developed a simple model that any office can implement without additional staff (Fig. 1). The model notes that adequate communication is the cornerstone of the relationship between the patient/ family and oncologist/team. A rapid screen for psychosocial needs, done during the initial or second visit, permits development of a psychosocial

treatment plan, which coordinates with the medical care, supports the patient, and links the patient to appropriate psychosocial services. Followup reassessment at clinically appropriate times should be based on illness and timing of visits.

Recognizing Distress The first step in the model is to identify or screen for patients’ psychosocial needs and problems. An increasing number of centers utilize electronic means to collect this information in the clinic waiting room (eg, continued on page 59

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ASCOPost.com | JUNE 2010

PAGE 57

In the News

Recent Reports Heighten Patient Concerns about Radiation Two New York Times articles raise questions about the safety of radiation therapy. By Charlotte Bath

In the News focuses on recent media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

wo articles published in The New York Times ( January 23 and 26, 2010) detailed the dangers of medical radiation when basic safety procedures aren’t followed. The articles described the decline and death of several patients. These included a 43-year-old man with cancer of the tongue who had received intensity-modulated radiation therapy (IMRT) to his entire neck because of an undetected computer error and a 32-year-old woman with breast cancer who, according to the Times, received more than three times the prescribed amount of radiation for breast cancer. She was left with a “gaping wound so painful that this mother of two young children considered suicide.” Another patient, a 76-year-old woman with breast cancer treated with high-dose radioactive seeds, did commit suicide after receiving twice her prescribed radiation dose on five separate occasions. The Times articles also described two men living with the consequences of radiation overdoses for prostate cancer.

The articles attributed the radiation errors to several factors, including the use of high-tech equipment before safety procedures were established and staff adequately trained, understaffing and lack of oversight at some hospitals, and software errors, which were often repeated and magnified because they are difficult to detect. In addition, errors often go unreported and uncorrected because of a patchwork of regulations and reporting requirements. In an interview with The ASCO Post, Anthony Zietman, MD, of Massachusetts General Hospital, shared some of what he told his patients who asked him about the dangers detailed in the Times articles and what quality assurance measures were in place at his institution to prevent excess radiation. As president of the American Society for Therapeutic Radiology and Oncology (ASTRO), Dr. Zietman also explained ASTRO’s six-point plan to improve radiation quality and safety and reduce the chances of medical radiation errors.

Looking for Patterns of Errors The New York Times articles singled out IMRT as a particular cause for concern. Dr. Zietman attributes this to the highly sophisticated nature of the machine, the reliance on computers with the inherent danger of “a software bug” that may not become apparent until the machine has been in use for a while, and the widespread acquisition of the units so that “it’s almost become the universal form of external-beam radiation for curative

You need to point out that your department is adequately staffed, that you have enough physicists, and that they are present every single hour that the patient is being treated, and that your machines shut down if anything is wrong. – Anthony Zietman, MD

Patients Are Frightened While the articles stressed that radiation is overall very safe and effective, “patients always were frightened of radiation therapy, as they can be from any cancer treatment, and temporarily they were more so,” Dr. Zietman said. “It is the responsibility of the treating physician to reassure patients.” After reading the articles, Dr. Zeitman reported that some patients specifically asked what quality assurance

Expect Questions The ASTRO website (www.astro.org) includes a wealth of information about radiation and radiation safety, including several lists of questions patients should ask their doctors.

■■ Who is involved in planning my radiation treatment? ■■ What procedures do you have in place so that the treatment team is able to treat me safely?

■■ How can I be assured that my treatment is being done correctly every day? ■■ What kind of safety checks do you perform each day? ■■ How often does the medical physicist check that the various machines involved in my treatment are working properly?

■■ If the equipment isn’t working and my treatment is delayed or post‑

poned, who checks that it is safe to use again? And will this delay affect my cancer?

■■ Will you take imaging scans regularly during my treatment? Who reviews those scans?

measures were in place. A reassuring response, he added, would be reporting that the treating institution had successfully completed an accreditation process. The accreditation system is currently conducted jointly by ASTRO and the American College of Radiology. “At the moment, it is voluntary,” Dr. Zietman said. “Only 11% of practices nationally have sought accreditation. I can tell you that since The New York Times articles, many more have been seeking it.”

Appropriate Training “Launching a significantly enhanced practice accreditation program and beginning the development of additional accreditation modules specifically addressing new, advanced technologies such as IMRT, SBRT [stereotactic body radiotherapy], and brachytherapy” is a priority of the ASTRO plan. “We don’t know whether this is going to become universal. It’s not yet mandated, but I think it may become necessary,” Dr. Zietman said, “We need some kind of accreditation system with teeth to assess an institution’s capacity to handle the modern technologies.” In several of the cases highlighted by The New York Times, a single therapist provided radiation therapy, with no one else checking. “Understaffing is an issue that needs to be addressed,” Dr. Zietman said. “You need to point out that your department is adequately staffed, that you have enough physicists, that they are present every single hour that the patient is being treated, and that your machines shut down if anything is wrong.”

cases.” In some cases, IMRT equipment may have been acquired to compete with nearby facilities. “This spirit of competition has its hazards: An institution that simply doesn’t have the manpower or sophistication to support it may purchase a prestige piece of equipment that will then cause trouble,” Dr. Zietman observed. “We need to identify these centers, look into the problem, and change or stop the practice.” To identify these unsafe practices, ASTRO advocated creating “a database for the reporting of linear accelerator– and computed tomography–based medical errors.” Dr. Zietman favors a “no-fault reporting system so that at least we can look for patterns.” It may be that a particular kind of machine, a particular type of facility, or certain staffing levels are associated with increased errors. “I don’t know what the patterns are,” he said, “but you collect the data and you see what patterns emerge. Then you act.” Another problem connected to the machines themselves is connectivity. “In radiation oncology or in continued on page 70

The ASCO Post | JUNE 2010

PAGE 58

In the Literature

Emerging Clinical Data HEMATOLOGIC MALIGNANCY

Bortezomib plus Melphalan/ Prednisone Benefits Patients with Multiple Myeloma The addition of bortezomib (Velcade) to melphalan (Alkeran) and prednisone (VMP) significantly improved overall survival (OS) in treatment-naive multiple myeloma patients ineligible for high-dose chemotherapy, according to the updated phase III VISTA trial. The trial was stopped early on the basis of significant prolongation of time to progression with the three-drug combination on interim analysis (median follow-up 16.3 months). Moreover, Mateos et al reported that initial VMP treatment did not appear to result in more-resistant relapse. The findings suggest that use of VMP as first-line treatment in myeloma patients ineligible for high-dose chemotherapy offers greater benefits than reserving bortezomib for use after relapse.

Key Findings Patients were randomly assigned to initial treatment with VMP (n = 344) or MP (n = 338). After a median follow-up of 36.7 months, VMP was associated with a 35% reduction in risk of death (HR = 0.65, P < .001) compared with MP. Median OS was not reached in the VMP group and was 43 months in the MP group, and 3-year OS rates were 68.5% and 54.0%, respectively. Among VMP patients (n = 178) vs MP patients (n = 233) receiving subsequent therapy, response rates were generally similar for those who later received treatment with thalidomide

(Thalomid)(41% vs 53%), lenalidomide (Revlimid)(59% vs 52%), or bortezomib (47% vs 59%). Median OS from the start of subsequent therapy was 30.2 months in the VMP group and 21.9 months in the MP group (P = NS). Median OS from the start of initial randomized treatment was not reached in the VMP group vs 45.0 months in the MP group (31% reduction in risk of death; HR = 0.688, P = .021), and 3-year OS rates were 67.9% vs 55.9%. The investigators found no significant difference in OS between VMP and MP groups from the start of subsequent treatment according to treatment with thalidomide-, lenalidomide-, or bortezomib-based regimens. However, they did observe a nonsignificant prolongation of survival with bortezomib-based treatment in the MP group (median not reached vs 27.8 months, P = .35). Mateos M-V, et al: J Clin Oncol April 19, 2010 (early release online).

LUNG CANCER

Sorafenib Added to Carboplatin/Paclitaxel Produces No Survival Benefit in Advanced NSCLC The addition of sorafenib (Nexavar), a multikinase inhibitor with activity including inhibition of vascular endothelial growth factor (VEGF), to carboplatin/paclitaxel in treatmentnaive patients with unresectable stage IIIB or IV non–small cell lung cancer (NSCLC) provided no apparent clinical benefit in first-line treatment, according to a recently reported phase III trial. The study was among several

recent studies that have assessed the potential for improving survival in advanced NSCLC by adding molecular targeted therapies to standard cytotoxic platinum-based doublets. Patients received carboplatin (area under the curve 6) and paclitaxel (200 mg/m2) on day 1 followed by either sorafenib at 400 mg bid (n = 464) or placebo (n = 462) on days 2 to 19 for up to six 21-day cycles. Maintenance treatment consisted of sorafenib at 400 mg bid or placebo. At a planned interim analysis (median duration of treatment 17–18 weeks), median overall survival (OS) was 10.7 months in the sorafenib arm and 10.6 months in the control arm (HR = 1.15, P = .915). The study was terminated due to the high improbability of demonstrating an advantage to the addition of sorafenib.

Squamous Cell Carcinoma Overall, 23% of patients in the sorafenib group and 25% in the control group had squamous cell histology. Among these patients, mortality was greater in the sorafenib group, which had a median OS of 8.9 months compared with 13.6 months in the control group (HR = 1.85, 95% confidence interval 1.22–2.81). This increased risk could not be attributed to an increase in adverse events. Another recent trial had shown a survival benefit with the addition of the VEGF inhibitor bevacizumab (Avastin) to carboplatin/paclitaxel in patients with nonsquamous advanced NSCLC. The prior observation of increased risk of fatal bleeding in patients with squamous cell carcinoma led to exclusion of these patients from phase III trials of bevacizumab in combination with chemotherapy. In the current sorafenib trial, squamous cell histology was associated with a greater risk of fatal bleeding events among all patients, but the investigators detected no notable difference in risk between the sorafenib and control subgroups in this regard.

Scagliotti G, et al: J Clin Oncol 28:18351842, 2010.

GASTROINTESTINAL CANCER

Older Patients with Colon Cancer Less Likely to Receive Adjuvant Chemotherapy

Older patients with stage III colon cancer are less likely to receive chemotherapy following surgical resection, according to an analysis of the use of

adjuvant chemotherapy and adverse events by age in a multiregional group of 675 patients. When they do receive chemotherapy, it is less toxic and of shorter duration than therapy that younger patients receive, and older individuals experience fewer adverse events. Overall, 513 patients (75%) received adjuvant chemotherapy, but this group included only 50% of patients aged 75 years and older compared with 87% of younger patients. Among patients receiving adjuvant chemotherapy, adjusted rates of late clinical adverse events were lower for patients 75 years and older than for younger patients. Patients aged 65 years and older were more likely than younger patients to discontinue chemotherapy at all follow-up times. Monitoring chemotherapy recipients for signs and symptoms, and providing interventions to evaluate and treat these indicators, could help patients meet evidencebased treatment goals, the investigators noted. Although doses and durations of chemotherapy were lower than recommended based on clinical trial data, further study is needed to determine the impact of this treatment on survival and recurrence rates, they added.

Kahn KL, et al: JAMA 303:1037-1045, 2010.

GENITOURINARY CANCER

Bevacizumab/Interferon Produces Similar Survival Results to Interferon Alone in Renal Cell Carcinoma The final analysis of the phase III AVOREN trial comparing bevacizumab (Avastin) plus interferon alfa-2α (Roferon A, IFN-α) (n = 327) with IFN-α alone (n = 322) in previously untreated patients with metastatic renal cell carcinoma showed no significant difference in overall survival between treatment arms. At an interim analysis, Escudier and colleagues had found significant improvements in progression-free survival (PFS; 10.2 vs 5.4 months, P < .001) and objective response rate (31% vs 13%, P < .001) in the bevacizumab arm. The trial was unblinded, and patients in the control arm were permitted to cross over to the bevacizumab arm. The PFS data were used to support regulatory applications, because overall survival (OS) analysis could have been confounded continued on page 60

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Expert’s Corner

Quality Cancer Care continued from page 55

West Clinic, Memphis; City of Hope, Duarte). Some offices use pencil and paper. The NCCN recommends the “distress thermometer,” which is a 0-10 scale that looks like a thermometer and asks patients about their level of distress in the past week. As validated in several studies, a mark of 4 or more cues the nurse or oncologist to follow-up with additional questions to evaluate the nature of the problem and to recommend appropriate referral.3 On the same page is a problem list, which specifies practical, emotional, physical, and spiritual problems that the patient may check off (Fig. 2). The value of these approaches is that for the first time, the examiner can rapidly integrate a psychosocial question into patient care with minimal effort and time. The Canadian Strategy for Cancer Control has taken a further step by making distress the sixth vital sign.4

2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Distress management. V.1.2010. Available at www. nccn.org. Accessed April 21, 2010. 3. Jacobsen PB, Donovan KA, Trask PC, et al: Screening for psychologic distress in ambulatory cancer patients. Can-

cer 103:1494-1502, 2005. 4. Bultz B, Holland J: Emotional distress in patients with cancer: The sixth vital sign. Commun Oncol 3:311-314, 2006. 5. Jacobsen PB: Promoting evidence based psychosocial care for cancer patients. Psychooncology 18:1893-1898, 2008.

Dr. Holland is Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center, New York. “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs” is available from the Institute of Medicine at http://tiny.cc/ f3n4x

One of the nation’s top cancer centers. One of America’s best hospitals. One unwavering focus.

Ensuring Implementation To ensure implementation of the IOM report, advocacy organizations and professional groups in cancer have formed an alliance with a dual purpose: to educate patients and their families that psychosocial concerns are a part of quality care today, and to urge our professional organizations to address these issues in all clinical practice guidelines, standards, and training programs. ASCO’s Quality Oncology Practice Initiative (QOPI) is a voluntary audit with which the oncologist can evaluate his or her own practice as to level of quality in several areas of care. This retrospective patient chart audit now includes a performance measure for the quality of psychosocial care.5 In summary, the IOM report of 2007 was a landmark for psychosocial care because it gave credibility to the field from a major independent national body that influences public and private health policy. The NIH will be able to use the recommendations about research and clinical practice guidelines. Accrediting bodies and training programs for oncologic professionals can use performance measures for quality of psychosocial care, which will bring positive changes in routine ambulatory cancer care. References 1. Adler NE, Page EK (eds): Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. Washington, DC, National Academies Press, 2007.

At Dana-Farber/Brigham and Women’s Cancer Center, everything we do is focused on defeating cancer. Our unique collaboration of two teaching affiliates of Harvard Medical School enables us to provide your patients with the latest and most innovative treatment. A leader in cancer research and care, we quickly translate the discoveries made in our labs to clinical practice. With more than 700 clinical trials underway, patients can take advantage of promising new therapies which may lead to advances in cancer treatment for all. And our multidisciplinary teams of specialists and subspecialists work together to provide personalized treatment plans. It’s more innovative care for your patients. And greater confidence for you. To make a referral, call 877-DFCI-BWH or visit www.dfbwcc.org for more information.

Focused on cancer. Focused on life.

The ASCO Post | JUNE 2010

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In the Literature

Bevacizumab/Interferon continued from page 58

by second-line or subsequent use of novel therapies that became available during the trial. In the final analysis, the investigators found no significant difference in OS between the bevacizumab group and the control group (23.3 vs 21.3

months; unstratified HR = 0.91, P = .336; HR stratified for risk and region 0.86, P = .129). A total of 13 control group patients crossed over to the bevacizumab arm after unblinding of the trial. When these patients were excluded from analysis, the reduction in risk of death in the bevacizumab arm increased to 16%, but the difference

remained nonsignificant (HR = 0.84, P = .076).

Potential Confounding Factor At least one postprotocol treatment (ie, treatment in patients who had progressive disease or discontinued study treatment) was administered to 55% of patients in the bevacizumab arm

and 63% of patients in the control arm. The tyrosine kinase inhibitors sunitinib (Sutent) and sorafenib (Nexavar) were the most common treatments, used by 35% of patients in the bevacizumab arm and 37% in the control arm. A post hoc analysis showed that among patients receiving postprotocol tyrosine kinase inhibitor treatment, risk of death was nonsignificantly decreased by 20% in the bevacizumab arm (median OS 38.6 vs 33.6 months, HR = 0.80, 95% confidence interval = 0.56–1.13). The authors concluded that bevacizumab plus IFN-α is active as first-line treatment in metastatic renal cell carcinoma. Given the typical use of multiple lines of therapy in this setting, benefit of treatment may be optimized by considering the overall sequence of therapy when selecting first-line treatment.

Escudier B, et al: J Clin Oncol 28:21442150, 2010.

Dutasteride Reduces Prostate Cancer Risk and Precursor Lesions

We are here, where you need us most We are committed to the discovery and development of innovative immunotherapeutic approaches aimed at helping patients fight cancers, such as advanced melanoma. Together, we can make a difference.

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study found that the dual 5α-reductase inhibitor dutasteride (Avodart) reduced the incidence of prostate cancer detected on biopsy among men with an increased risk of the disease. These men were considered to be at high risk because of their age (50–75), an elevated prostate-specific antigen (PSA) level (2.5–10 ng/mL), and a previous suspicion of prostate cancer that led to a biopsy. Eligible patients had had one negative biopsy within 6 months of enrollment.

Study Population Among 6,729 men who had a biopsy or prostate surgery during the 4 years of the study, cancer was detected in 659 (19.9%) of the 3,305 men who took daily dutasteride, compared with 858 (25.1%) of the 3,424 men in the placebo group. The investigators reported that this represents a relative risk reduction with dutasteride of 22.8% over the 4-year study period. Patients receiving dutasteride also showed a reduced risk of the progression of benign prostatic hyperplasia (BPH). At year 4, the investigators noted a 19.7% increase in mean prostate volume in the placebo group, compared with a 17.5% decrease in the dutasteride group (P < .001). Although more men in the placebo group than in the dutasteride group were receiving continued on page 70

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TAP on Policy

ASCO Adopts CMSS Code for Interactions with Industry By Jo Cavallo

n April, the 32 member organizations of the Council of Medical Specialty Societies (CMSS) voted to approve implementation of the CMSS Code for Interactions with Companies, a voluntary set of guidelines that encourage greater transparency in how the medical profession and industry conduct business. Development of the Code was first taken up 2 years ago when CMSS member organizations formed a task force to study conflict of interest policies among CMSS organizations and to make recommendations to clarify and standardize those policies without infringing on how individual medical societies operate.

Three Recommendations “The first task force came up with three recommendations, which were adopted at our annual meeting in the fall of 2008,” said Norman Kahn, MD, executive vice president and CEO of the Council of Medical Specialty Societies, a nonprofit organization devoted to medical professionalism and quality of patient care. “And those recommendations were, first, when specialty societies were creating their own conflict of inter-

est policies, there were 11 areas that they should consider including. The second recommendation was that specialty societies should consider disclosing on their websites the support they receive from companies. And, third, CMSS should consider developing templates of conflict of interest policies to help the member organizations.” The following year, the CEOs of CMSS’ member organizations, which represent more than 650,000 physicians nationwide, asked ASCO CEO Allen S. Lichter, MD, to chair a new task force to develop a voluntary code of conduct to “enhance professionalism and to disclose, manage, and resolve relationships with industry.” The outcome of that effort is the CMSS Code for Interactions with Companies, the first of its kind. “This Code represents the profession’s voluntary self-regulation in the area of conflict of interest,” said Dr. Kahn. “Prior to this Code, there was no code for specialty societies, so this fills a niche and serves as the standards and guidelines for the specialty societies in interacting with industry in a way that will make

This code represents the profession’s voluntary self‑regulation in the area of conflict of interest. – Norman Kahn, MD

sure that we fulfill our professional responsibilities. Those responsibilities include putting the needs of our patients first, voluntarily regulating ourselves, and being transparent.” The challenge for ASCO’s legal team, which was largely responsible for constructing the Code for Interactions with Companies, was to draft a set of guidelines that would clarify appropriate interactions between medical societies and the medical industry and reflect the experience and goals of the task force participants. “The Code had to be clear and relevant to a broad range of organizations in very different medical specialties,” said Dina L. Michels, ASCO’s vice president and general

counsel. “And one challenge was trying to write principles that are specific enough that they have a practical effect, but that are not so prescriptive they hamper CMSS members’ educational and scientific programs. Also, bear in mind that this is a voluntary code based on organizations deciding to come up with their own standards and monitor their own adherence with the standards. The Code is about recognizing best practices.” “We also tried to take stock of the external rules that societies have to comply with and to make sure that we weren’t layering on compliance obligations where we didn’t need to,” added Courtney D. Storm, ASCO’s associate counsel.

Q&A with Allen S. Lichter, MD, ASCO CEO

How the CMSS Code for Interactions with Companies Affects ASCO By Jo Cavallo

ow that the Council of Medical Specialty Societies Code for Interactions with Companies has been approved, we asked ASCO’s CEO Allen S. Lichter, MD, who chaired the task force charged with developing the Code, how the Code impacts ASCO’s relationships with the medical industry and what changes ASCO and its members can expect as a result. What was the impetus for developing the Code for Interactions with Companies? Dr. Lichter: There has been a lot of scrutiny over the last several years about the interactions between medical professional societies and industry, such as the device industry and the pharmaceutical industry, with concern over the fact that because our organizations receive funds from these com-

panies to sponsor events in education, the funding potentially grants influence that otherwise shouldn’t be granted. As organizations, we felt that we were doing things right, but there were no rules. And we thought we should get together and produce a code of conduct to say this is how we’re going to operate. Is this the first type of a universal code of conduct for medical societies? Dr. Lichter: It’s the first of its kind that we know about in medical professional societies, but it does echo what both PhRMA and AdvaMed did with their Codes of Ethics on Interactions with Health Care Professionals. While our Code for Interactions with Companies is the first of its kind for medical professional societies, it does in some respects follow on to the work

that’s been done by industry to say that they’re setting a code of conduct with us. And we noticed that it helped define for the device industry and the pharmaceutical industry the purpose of regulation and scrutiny, which spelled out the things we will do and the things we won’t do. It’s made things less confusing for them. Our sense is that things will be less confusing for us now. The other thing is that in the absence of us writing our own code, people were going to start writing codes for us. Our feeling was that it would be much better if we wrote our own code than if we had people who were not necessarily deeply inside our community write one for us. What will the Code accomplish? Dr. Lichter: First of all, it helps codify the parameters under which we

The CMSS Code for Interactions with Companies will be dis‑ cussed as part of an ethics ses‑ sion at the 2010 ASCO Annual Meeting, June 4 through 8, in Chicago. To view a copy of the Code, use your phone to follow the link in the barcode below.

See page 72

will interact with companies, including what we will accept and what we will not accept; how we will take funds; the need for specified written contracts, so that there is no suspicion about our continued on page 62

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TAP on Policy

Q&A continued from page 61

transactions; and that everything is disclosed. In fact, ASCO will be disclosing its sources of funds as part of signing on to this Code. And we very clearly state in the Code that supplying sponsorship support does not allow the sponsor to have any influence on

This is definitely a groundbreaking moment. This is the first time that medical professional societies have said, here’s how we will act, here are the rules of the road... the program, the speakers or the type of message; that our journals are following very rigorous rules; and that in every aspect of our interactions with commercial entities, we are taking as high an ethical road as we possibly can. This is definitely a groundbreaking moment. This is the first time that medical professional societies have said, here’s how we will act, here are the rules of the road, judge us by our adherence to this, and criticize us by our failure to adhere, or for what we left out of the code that should be present, or for parts of the code that should be more stringent. And we can deal with those critiques. What are some specific guidelines in the Code? Dr. Lichter: We emphasize that we’re an independent organization. The most valuable asset that ASCO has, or that any medical professional society has, is its integrity and the belief that when we give an opinion it represents the very highest level of ethics and science; that we’re truly doing what we believe is best for our patients; and that our actions are positively not influenced by anything other than how we read the science and how we see the care of our patients taking place. Preserving that integrity is the most important thing that we can do, and this Code underscores our independence and the transparency that we will use. The Code also details how we will run our meetings and our exhibits and how speakers will be chosen indepen-

dently, based on our regulations, and will not be influenced by industry. And that our journals and our advertisements in those journals will be as clear and as clean as we can possibly make them. It’s impossible for us to achieve perfection. Everybody is going to say that as long as our societies interact with the pharmaceutical and device industries, there is the opportunity for the appearance of influence. But we have stated in the Code the parameters under which we will operate, and I believe that the public and Congress and regulators can look at this Code and have great confidence that our integrity is preserved and enhanced.

I also want to say that we are very proud at ASCO that we were asked to lead this effort on behalf of our sister societies and that at least some of the impetus for doing it came from ASCO and the work that we’ve done. We have enjoyed a very solid reputation as an organization that has adopted conflict of interest policies early on and that has behaved in an ethical manner. How will the Code impact industry support at the ASCO Annual Meeting, in satellite symposia and sponsorship of educational programs? Dr. Lichter: Satellite symposia will now have to go through an ap-

The CMSS Code At-a-Glance The CMSS Code for Interactions with Companies strives to provide its mem‑ ber medical societies with guidelines to help them develop policies and pro‑ cedures that safeguard the independence of their programs, policies, and advocacy positions. The Code provides guidance in 10 specific areas:

1. 2. 3.

Independence

Acceptance of corporate sponsorships

Society meetings, including educational grants and society CME; CME-accredited

Transparency Acceptance of charitable contributions

How does the Code affect an oncologist’s day-to-day practice? Dr. Lichter: I don’t think an individual oncologist will notice much of a difference. Of course, with the additional transparency and disclosure, people will see more about us than they have in the past and we think that’s good. They will be able to see, for example, all the disclosures of interactions between our board members and industry that will be made available. I hope that oncologists have the confidence that their own professional society is in fact operating on a very high plane. I hope it will make our members even more confident that when we say something, when we publish articles in our journals, when we write a guideline or have an opinion, they won’t have to wonder if there is anything extraneous to the science that went into the information, because there won’t be any at all.

satellite symposia; non-CME informational/educational programs; and exhibits

6. Awarding of research grants 7. Clinical practice guidelines 8. Society journals 9. Standards for advertising 10. Standards for licensing proval process. This is something that ASCO has done for some time, but other organizations have not. Industry-sponsored symposia will have to be audited to verify that bias has not been introduced into discussion. In terms of educational activities, we work very hard to make sure that they are of the highest caliber. Our annual meeting has two parts: educational symposia, which are invited, and scientific papers, which are submitted and then judged and brought into the meeting based on merit. Having worked at ASCO as a volunteer for decades and now as a staff member, I can tell you that our programs are developed with the highest possible standards. And, hopefully, our willingness to voluntarily help put the Code together and to, along with our sister societies, voluntarily agree to abide by its guidelines, just reinforces that we take this responsibility very seriously.

Does the Code address the amount and value of industry gifts given away during ASCO’s annual meeting? Dr. Lichter: As I say, we’ve now become transparent in terms of where we get our funds, and we will disclose everything. So, yes, people who want to can go to our website (asco.org) and see that information, and we’ll publish it annually. The pharmaceutical industry has prohibited giving away little reminder items such as pens and notepads. But in exchange for sponsorship dollars, medical professional societies were still giving away those items—“brought to you by” such and such a company—and we thought that that was an end run on the intent of the PhRMA code. So now, for example, according to the guidelines in the CMSS Code, medical professional societies can’t do that either. Will that be noticeable? I don’t think people will miss the ballpoint pen or the notepad or the keycard, but they will notice that they have all disappeared. Will the Code help improve relationships between medical societies, especially ASCO, and industry? Dr. Lichter: Yes. I think the Code really creates a more level playing field in which both sides of the equation are operating from a well described, well thought out set of rules. Who has jurisdiction over compliance of the Code? Dr. Lichter: Jurisdiction to some extent will be from CMSS, but we do not intend to enforce the Code in some sort of punitive way. We’re taking our cue here from PhRMA, which basically relies on self-enforcement. We will do the same thing with the CMSS Code and would welcome hearing about instances where organizations that have agreed to abide by the Code are not. We will be the clearinghouse to feed that information back to those organizations and say we think you should look into this and either fix it if there’s a problem or explain to us that, in fact, somebody misinterpreted the guidelines.

In this Issue Important columns on health-care reform, see pages 65–67

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News

NCCN Clinical Practice Guidelines Important 2010 NCCN Updates You Need to Know By Caroline Helwick

he National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology have become the most widely used guidelines in oncology practice. The Guidelines cover 97% of all patients with cancer and are continually updated by expert panels. The following is a synopsis of the 2010 updates and key points made by panel representatives at the NCCN 15th Annual Conference. For the complete guidelines, visit NCCN at www.nccn.org.

Breast Cancer “A positive PET scan in a woman with localized breast cancer is as likely to be a false positive as a true positive, and as likely to lead to an incorrect treatment decision as a correct one.” Robert W. Carlson, MD, Stanford Cancer Center, Palo Alto, California ■■ Sentinel node biopsy is recommended as the standard of care for nodal evaluation, with axillary dissection reserved for positive findings, in most cases. ■■ PET and PET/CT scans should not be used for the initial staging of early breast cancer, or for monitoring metastatic cancer in most patients. They may be useful for locally advanced disease. ■■ Paclitaxel should be administered every 2 weeks or weekly, but not every 3 weeks.

Colorectal Cancer “The panel wrestled with whether MSI testing should always be done” in patients with stage II colorectal cancer, and reached consensus that it should be recommended for patients ≤ 50 years of age.” Paul F. Engstrom, MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania ■■ Bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix), and irinotecan should not be used in the adjuvant setting for patients with stage II or III disease, outside of a clinical trial. ■■ Testing for microsatellite instability (MSI), or mismatch repair gene status, is recommended for patients with stage II colorectal cancer ≤ 50 years of age. ■■ Testing for BRAF mutations

should be considered for KRAS wild-type tumors. ■■ Chemotherapy-free intervals should be avoided in the metastatic colorectal cancer setting. ■■ The use of transanal resection in rectal cancer should be limited.

Gastrointestinal Stromal Tumor

■■ “Patients with a low risk of recurrence who have no mitotic activity might not need adjuvant imatinib (Gleevec), even for a reasonably sized GIST.” George D. Demetri, MD, Dana-Farber Cancer Institute, Boston, Massachusetts ■■ An entirely new page of recommendations for managing patients with very small gastric GISTs (< 2 cm) has been added. ■■ To assess response to therapy, CT is the sole recommendation, and PET is no longer included. ■■ Two new pages provide principles of pathologic assessment and principles of surgery for GIST. ■■ Adjuvant imatinib should be considered in patients with intermediate- to high-risk GIST but may not be required for patients with a low risk of recurrence and no mitotic activity.

Esophageal Cancer “Our recommendations are to try to use new techniques, and to use uniform staging and long-term follow-up to make sure that additional treatment can actually benefit these patients.” Jaffer A. Ajani, MD, The University of Texas M. D. Anderson Cancer Center, Houston ■■ The updated guidelines advocate for precise staging of patients. ■■ The initial workup should include esophagogastroduodenoscopy and multidisciplinary team collaboration; endoscopic ultrasound is a minimum requirement. ■■ Tis and T1a tumors are potentially curable with endoscopic mucosal resection, as an alternative to esophagectomy. ■■ For T1b and higher, the primary treatment is definitive chemoradiation, preoperative chemotherapy, or preoperative chemoradiation before esophagectomy.

Multiple Myeloma “The old regimens are no longer acceptable first-line options.” George Somlo, MD, City of Hope Comprehensive Cancer Center, Duarte, California ■■ Initial treatment is important: induction chemotherapy, followed by autologous stem cell transplant, followed by maintenance therapy is the new standard. ■■ For induction therapy, triple regimens that include novel agents are superior to standard doublets. ■■ Maintenance therapy with lenalidomide (Revlimid) is the most important addition to the guidelines.

Prostate Cancer “The NCCN Panel on Prostate Cancer is the first cancer-treatment panel to recommend not treating cancer.” James L. Mohler, MD, Roswell Park Cancer Institute, Buffalo, New York ■■ Annual prostate-specific antigen (PSA) screening is recommended only for men at high risk according to family history, African-American race, and PSA > 1 ng/mL. ■■ A new risk category was defined: very-low-risk prostate cancer. ■■ Active surveillance is now the only recommendation for men with low-risk cancer and life expectancy < 10 years, and very-lowrisk cancer and life expectancy < 20 years.

■■ Active surveillance is more fully described in the guidelines. ■■ Daily image-guided radiation therapy (IGRT) is required for high-dose radiotherapy (≥ 78 Gy). ■■ External-beam radiation therapy (EBRT) failure workup and treatment is clarified. ■■ Chemotherapy algorithms have been simplified. ■■ Docetaxel is the only recommended first-line chemotherapy regimen, and there is no best secondline regimen.

Acute Myeloid Leukemia “Over the past 7 to 10 years, several new molecular markers have emerged that appear to offer more prognostic information for patients with AML…it is important to think about testing for these mutations at the time of diagnosis.” Douglas Smith, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland ■■ Bone marrow with cytogenetics is a mandatory part of the workup for acute myeloid leukemia (AML) and is the gold standard of outcome predictors. ■■ Not all mutations confer a poor prognosis: “good” mutations are NPM1 and CEBPA, and a “bad” mutation is FLT3/ITD. ■■ The revised Guidelines have add-

continued on page 71

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Novel Agents

Sipuleucel-T Immunotherapy Approved for CRPC continued from page 5

investigator, Dr. Philip Kantoff, of the Dana-Farber Cancer Institute.1 With an estimated median follow-up time of 34.1 months, patients in the sipuleucel-T arm had a significantly greater median OS compared with those in the control arm (25.8 vs 21.7 months; HR = 0.775, 95% CI = 0.614–0.979; P = .032). Median 3-year survival rates were 31.7% and 23.0%, respectively. Results were similar across patient subgroups. In an updated analysis with 349 events and an estimated median followup of 36.5 months, sipuleucel-T treatment was associated with a 4.1-month median survival benefit (HR = 0.759, 95% CI = 0.606–0.951; P = .017; see Figure 1). Median time to objective disease progression, however, did not differ between the two groups (14.6 vs 14.4 weeks; HR = 0.951, 95% CI = 0.77–1.17; P = .628). This discrepancy between OS and objective disease progression highlights the difficulty of

accurately measuring the latter endpoint in advanced prostate cancer and the limitations of using standard endpoints such as objective disease progression in assessing response to immunotherapy, given the fact that antitumor responses may be slower than with chemotherapy. According to Dr. Kantoff, “Patients and physicians need to understand that little change in response or time to progression occur over the 4 weeks when this therapy is administered, and that benefits are long-term, that is, improved survival.” Sipuleucel-T therapy was generally well tolerated in the IMPACT trial. Adverse events (AEs) reported more commonly in patients who received sipuleucel-T included chills (54.1%), pyrexia (29.3%), headache (16.0%), flu-like symptoms (9.8%), myalgia (9.8%), hypertension (7.4%), hyperhidrosis (5.3%), and groin pain (5.0%). Most AEs were mild in severity, and the frequency of serious AEs with sipuleucel-T was no different from the control group.

Long Road to Approval The approval of sipuleucel-T marks an achievement for Dendreon, especially in light of the vaccine’s long road to approval. Dendreon attempted to have sipuleucel-T approved in 2007 based on results from two previous randomized phase III trials in CRPC. In these earlier studies, a small survival benefit was achieved, but the trials did not meet the primary endpoint of improved progression-free survival, and the FDA did not approve the drug at that time. Several factors may limit the use of sipuleucel-T, at least over the short term. A complete course of therapy (three infusions over a 1-month period) will cost an estimated $93,000, which may pose reimbursement issues. The pricing is based in part on Dendreon’s assumption that patients are willing to pay around $23,000 for each additional month of life gained, similar to other anticancer therapies (with sipuleucel-T providing an estimated 4-month increase in survival). The higher cost of sipuleucel-T may be

offset by the lower toxicity and reduced costs of supportive care (including hospitalization) that are often needed with chemotherapy. Manufacturing capability may also be a limiting factor. In contrast with chemotherapy and many biologics, sipuleucel-T must be customized for each patient, resulting in slower production. Dendreon projects that enough drug will be available to treat only about 2,000 patients in the first year; production is expected to scale up to full manufacturing capacity by mid-2011. In Dr. Kantoff’s opinion, “These results generate hope among cancer patients that this form of therapy will open up new potential treatments and that more investigators will move into the field of immunotherapy and continue to improve on this first step.” Reference 1. Kantoff P, Higano CS, Berger ER, et al: Updated survival results of the IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer (CRPC). 2010 Genitourinary Cancers Symposium (abstract 8).

Pioneering Cancer Physician continued from page 35

or may not still have their breast,” Dr. Wolter commented.

Team Approach Begins With the development of more treatment options for breast cancer, Dr. Wolter said it became clear to her and her colleagues that the surgeon, medical oncologist, and radiation oncologist should see the patient together. “Two or three radiation oncologists, a couple of surgeons, and a few of us internists said, ‘Let’s have a meeting and discuss the patients’ cases,’” she said. That informal collaboration led to the creation in 1985 of what Rush calls “the first comprehensive breast center in the Midwest.” In what is now a common model, all cancer specialists see the patient on the same day, meet together to agree on treatment options, and then present the options to the patient. In the mid-1970s, Dr. Wolter established another multidisciplinary service, the Rush Pigmented Lesion Clinic, reportedly one of only about 15 programs in the United States that offers photodocumentation of dysplastic nevi and diagnosis of skin cancers. The idea came to her, she said, after signing “a lot of death certificates” for patients with melanoma.

“I thought, this is crazy—we ought to be able to save these patients,” said Dr. Wolter, who patterned the clinic after one in Philadelphia. Dr. Wolter also was an early user of advanced practice nurses in oncology, said Rush Director of HematologyOncology Philip Bonomi, MD. In the early 1970s, patients needing radiation therapy were admitted to the hospital, creating large inpatient populations. Dr. Wolter and other oncologists trained nurses to go on rounds with them and evaluate some of the patients. “In a sense, they became nurse practitioners on the job. They couldn’t write prescriptions, but they could do patient encounters,” Dr. Wolter said. “It was a good system, and pretty soon we all had joint practice nurses.”

Special Celebration And for Janet Wolter it was a good career—one that Rush University Medical Center honored with a special celebration on February 27. Dr. Bonomi, who trained with her as an oncology fellow, said, “The things we’ve learned from her will continue to help us in taking care of patients, doing clinical research, and maintaining the highest standard of integrity.”

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PAGE 65

Health-care Reform

Comprehensive Health-care Legislation Brings Potential for Major Changes in Oncology Practice

Health-care Reform: Dealing with Reality By Richard Boxer, MD, FACS

By Nora Janjan, MD, MPSA, MBA

T T

his inaugural issue of The ASCO Post follows an intense year of debate about the American health-care system. The themes of the health-care debate on both sides were distilled down to two issues: (1) concerns about access to quality health care, and (2) the personal, private sector, and public costs of health care. Driving these two issues were the appropriateness—and the costs—of current medical practice patterns. A year ago, the evaluation of current medical practice by comparative effectiveness research (CER) was codified in the American Recovery and Reinvestment Act (ARRA). The ARRA created an interagency infrastructure, the Federal Coordinating Council for CER, within the Department of Health and Human Services. To accelerate CER, this infrastructure received $1.1 billion in appropriations. The passage of the Patient Protection and Affordable Care Act (PPACA) 2010, in title VI, part III, subtitle D, section 6302, subsequently ordered the indefinite insertion and funding of the Federal Coordinating Council for CER within title XI of the Social Security Act, in addition to the creation of multiple other agencies for the evaluation of medical practice.

Targeted Areas of Research Quickly fulfilling its charge to prioritize topics for CER of medical practice, the Institute of Medicine under ARRA targeted high-volume and high-cost areas in oncology for the first quartile of the program. Among the topics in oncology targeted for the first quartile of CER were the “effectiveness of management strategies,” including watchful waiting for ductal breast carcinoma in situ and localized prostate cancer, the use of imaging technologies in every aspect of cancer diagnosis and care, and the use of genetic and biomarker testing. These oncology topics have also been recently addressed by the U.S. Preventive Services Task

Force, the Medicare Coverage Advisory Committee, the Medicare Payment Advisory Commission (MedPAC), and the Institute of Clinical and Economic Review.

Reducing Medicare Spending The Congressional Budget Office estimated that the impact of a Federal Center for Comparative Effectiveness Research on total health-care spending would be five times the cost of funding the center. It was estimated that CER could reduce Medicare and Medicaid spending by $1.3 billion between the years 2008 and 2017. This is particularly important given the approximate $500 billion cuts in Medicare reimbursement budgeted within the PPACA. With a $75 billion appropriation, the PPACA mandates that the Administrator of the Centers for Medicare & Medicaid Services develop quality measures for medical practice between 2010 and 2014, with an additional $20 billion dollars appropriated for periodic review. These measures will be used to report performance information to the public, and for all public and private health-care programs. The Social Security Act will be amended by the PPACA to include an Authorization of Adjustment for Cancer Hospitals. In this authorization, the Secretary will conduct a study to determine if the costs incurred by cancer hospitals “exceed...costs incurred by other hospitals furnishing services under this subsection with respect to ambulatory payment classification groups,” taking into account the cost of drugs and biologicals. However, this provision allows the Secretary to “provide for an appropriate adjustment... to reflect those higher costs effective for services furnished on or after January 1, 2011.” Both children’s and free-standing cancer hospitals remain excluded from the Medicare prospective payment system (PPS). Quality reporting by PPS-exempt cancer hospitals is required in section 3005 of continued on page 66

he Patient Protection and Affordable Care Act (PPACA) became reality when President Obama signed the legislation with much fanfare on March 23, 2010. For nearly 75 years, our nation has been struggling with the fundamental issue of whether a more perfect union should have health care as a right or as a privilege. Although health-care reform will take years to complete (regulators will need to define hundreds of decision points), the election of 2008 brought forth the majority in Congress who voted for a different approach to insuring Americans. Simply stated, elections matter.

Partisan Debate The PPACA is the most sweeping social legislation since 1965—and the most partisan. The debate has stirred emotional, social, and philosophical upheaval. Critics from the right railed about process, affordability, government takeover of medicine, forced participation, privacy, federal authority over medical decisions, raising taxes, cuts in Medicare, an Independent Payment Advisory Board (thus Congress abrogates its oversight responsibility), and greater regulation of health insurance. Critics on the left wanted a public option and mandates. But we must start somewhere. Congress decided that the perfect should not be the enemy of the good. Health professionals will be in the center of making the “good” better. Our health-care system has eight core problems (see sidebar). The question is: Will the PPACA fundamentally alter the system? Millions of Americans will have improved access to health care; 32 million Americans who are presently without insurance will be insured; millions will no longer lose their insurance when they either lose or change jobs (portability); millions will no longer be concerned about preexisting conditions (guarantee issue), discontinuation of insurance during an illness, bankruptcy due to illness, or maximum lifetime benefits

running out; millions of young adults up to age 26 will be eligible for coverage under their parents’ policies. But the system will not be fundamentally changed unless the incentives are changed. When outcomes are the goal; when payment is not

Eight Core Problems ■■ Far fewer people pay for

health care than consume it.

■■ Doctors and hospitals are

paid to provide health care, not to prevent illness.

■■ Perverse incentives

encourage more care, not smarter or better care.

■■ The consumer does not have

incentives (third-party payers are responsible for the vast majority of the costs) or sufficient knowledge to use health care wisely.

■■ Health care is inefficiently

distributed, and costs are out of control.

■■ The legal tort system incents doctors to order more tests than may be medically essential.

■■ 47 million Americans have no coverage and millions more are underinsured

■■ Transparency is missing

in care, costs, quality, and complications.

based on individual testing and treatments, but based on diagnoses and results; when the small minority of health delivery motivated by greed is eliminated—we all know it exists— and the vast majority unencumbered by avarice takes a stand against it, then the fundamentals will change and real health-care reform will occur. And these changes must come from health professionals, not government.

Incentives for Change Only when all in the health-care industry are incentivized to give efcontinued on page 67

The ASCO Post | JUNE 2010

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Health-care Reform

Health-care Legislation continued from page 65

the PPACA and must be published by October 2012.

Programs of Importance to Oncology Oncology is included within the PPACA’s provision for tax credits and

grants for therapeutic discovery projects. Qualifying therapeutic discovery projects must show reasonable potential to (1) produce new therapies that treat areas of unmet medical need, by preventing, detecting, or treating chronic or acute diseases; (2) reduce long-term health-care costs; or (3) “significantly advance the goal of curing cancer with-

in the 30-year period.” Moreover, consideration will be given to projects with the greatest potential to (directly or indirectly) create and sustain high-quality, high-paying jobs in the United States, and to advance U.S. competitiveness in the fields of life, biologic, and medical sciences. In addition, the PPACA addresses initiatives for the diagnosis of

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oral cancer and colorectal cancer. Also important to oncology is the Community-Based Care Transitions Program in section 3026 of the PPACA, which “provides funding to eligible entities that furnish improved care transition services to high-risk Medicare beneficiaries.” A high-risk Medicare beneficiary is defined by a “hierarchical condition category score, as determined by the Secretary, based on a diagnosis of multiple chronic conditions or other risk factors associated with hospital readmission,” which may include cognitive impairment, depression, a history of multiple readmissions, or “any other chronic disease or risk factor as determined by the Secretary.” Additionally, the Secretary “may expand the duration and the scope of the program...if the Secretary determines...that such expansion would reduce spending under this title without reducing quality.” This CommunityBased Care Transitions Program will be funded by $500 billion from Medicare.

Hospice Reform In concert with the CommunityBased Care Transitions Program, section 3132 (entitled Hospice Reform) mandates that “the Secretary shall collect additional data and information... appropriate to revise payments for hospice care” by no later than January 1, 2011. The data may include but are not limited to (1) charges and payments, (2) the number of days of hospice care attributable to individuals enrolled for benefits, (3) the number of days of hospice care attributable to each type of service, (4) charitable contributions and other revenue, (5) the number of hospice visits, (6) the type of practitioner providing the visit, and (7) the length of the visit and “other basic information with respect to the visit” that can include but is not limited to the cost of the type of service and the amount of payment for the type of service. Adjustments in per diem payments “will reflect changes in resource intensity in providing...care and services during the course of the entire episode of hospice care.” The legislation also adopts MedPAC hospice program recertification recommendations.

In Conclusion The sweeping health-care legislation passed over the past year will impact oncology practice through increased regulatory intervention and justification of continued on page 71

ASCOPost.com | JUNE 2010

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Health-care Reform

Health-care Reform and Cancer: Beginning of the End or a New Beginning? By John L. Marshall, MD

s a resident Washington, DC, oncologist, I thought it was my obligation to read the entire health-care reform bill, H.R. 3200. Expecting 2,600 pages, I was relieved to find there were only 1,050 pages as I set out to read the bill this past spring. What I found was that our new law, intended to completely change our lives for the better, is written in a foreign language. Having a few connections in high places, I asked how best to approach this daunting task. Immediately I was told to avoid reading the entire bill and instead get hold of a summary, the CliffsNotes version of H.R. 3200. It turns out the bill itself refers to past bills and laws, none of which I would understand without first retrieving those earlier documents and poring through them.

A Lot of Listening I likened the experience to that when our patients cite the medical literature to us but invariably misinterpret the data. We exhale, roll our eyes, and caution our patients against ever reading the medical literature again. I now know how they feel. To assess the health-care reform bill, given the futility of reading the thing, I have resorted to doing a lot of listening.

Mad as Hell The loudest voices in the healthcare reform debate are those of the “screamers.” The screamers make it to

Dealing with Reality continued from page 65

ficient, quality, affordable health care that profits both the patient (with quality, efficiency, access, and affordabilty) and the provider (with financial and professional satisfaction) will the system become worthy of our great nation. American capitalism thrives on competition. Where it is lacking, no incentives for change exist. Thus, the only effective solution to a root cause

the evening news and the front pages of the newspapers. They are mad as hell and they are not going to take it anymore. They are afraid. They also have likely not read the bill (or the CliffsNotes) but are sure that it will turn our country into a communist, socialist, bronze medal country where a guy cannot even carry his gun into the local Starbucks. They are afraid that the bill will turn what is perceived to be the greatest health-care system in the world into some third world, Viagra-less society. They are so afraid and so sure that the bill is evil that they are storming the streets, shouting through bullhorns and holding angry

will improve our economy, lower our health-care expenditures, and improve and simplify our individual access to the health care of our choice; hope that health-care reform will reduce the threat of nuclear war, wipe out terrorism, and cure cancer.

Screamers 198, Hope 240 Then there are the rest of us—the quiet majority. We are listening, trying to learn what health-care reform is really all about. We are balancing the voices of fear and hope. We are both afraid and hopeful—afraid to lose what we have, but at the same time hopeful we can make it better.

Everyday, oncologists face all that is bad and good about our system. We enjoy access to the latest drugs, imaging when desired, and support systems to back us up when things get tricky. But we also have a dark side. signs, and threatening their elected officials with physical violence. If there is one major theme for the screamers, it is fear of change of any kind.

Hope Springs Eternal The next loudest voices come from the “change it now or never” gang. These folks conclude that health-care reform is critical to our future prosperity, that it will never happen unless we do it all at once, and, given our system of government, if we fail to do this now we will never get it done. Without reform, the country will quickly dissolve into a Wild West, dog-eat-dog, Starbucks Coffee and Gun Shop country. The reformers are full of hope: hope that controlling health-care costs of the health-care crisis is real economic competition, tort reform, and physicians controlling the overutilization of health expenditures.

Other Measures The creation of American Health Benefit Exchanges and Small Business Health Options Programs will expand risk pools that may cross state lines to make them as large as possible and will rationalize health insurance. Economies of scale and spread-

Everyday, oncologists face all that is bad and good about our system. We enjoy access to the latest drugs, imaging when desired, and support systems to back us up when things get tricky. But we also have a dark side: expensive, toxic drugs with limited benefit on which our business model is based; high copays that severely limit patient access to truly spectacular medicines; and incredibly complicated clinical research requirements. Unfortunately, we also know that too many uninsured patients will never make it to our office doors until it is too late. And I wish that I did not have to ask my patients “how do you pay for your drugs” before I made a treatment decision. ing risk as well as community rating do not reduce quality; they improve efficiencies and thus control costs. Tort reform must be enacted. Because doctors and hospitals are vulnerable to lawsuits, “defensive medicine” has been estimated to waste over $100 billion each year (ie, tests are performed that may not be beneficial for diagnosis or treatment but are obtained to protect against a lawsuit). There are methods of resolving disputes using health courts or

We already have a system of “haves” and “have-nots.” Should we cling to what we have or let it all loose and hope it comes together for the better?

To Which Group Do You Belong? Oncologists are fundamentally data-driven scientists who go to the evidence-based literature to learn what is fact. The health-care reform bill is too long; it’s akin to attempting to learn oncology by reading all of DeVita. What we could really use are some good CliffsNotes, ideally CliffsNotes that come with CME credits. We need some NCCN guidelines on healthcare reform, maybe even a throwaway journal on the subject. Maybe we could set up an on-label lecture series, “Coming soon to a Ruth’s Chris Steakhouse near you.” Clearly we are going to need help in understanding health-care reform, and I suggest we look to ASCO for guidance. It is ASCO’s mission to understand the interface between the complicated world of government and our world of cancer care. We should expect ASCO to provide guidance and to balance the interests of academics, private practitioners, cancer advocacy groups, industry, our country, and, most importantly, our patients. Hope is a core personality trait of all successful oncologists, and we share that hope with our patients everyday. We proceed, however, with the fear of all the bad things that can happen. What a perfect balance with which to move forward as we incorporate health-care reform into our lives. Dr. Marshall is Director, Ruesch Center for the Cure of GI Cancers at Georgetown University in Washington, DC.

mediation. The PPACA has provided for 5-year demonstration projects to states beginning in 2011. Although tort reform is essential, doctors must be proactive in reducing errors that lead to lawsuits. Care based upon outcomes research, electronic data management (electronic health records that are searchable), and reasonable protocols with physician input will reduce errors. Physicians must not abrogate that responsibility, continued on page 74

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FDA Update

The Past Year in FDA Drug Approvals New Cancer Drugs, Indications, and Label Changes, May 2009–May 2010 2010

■■ Sipuleucel-T (Provenge) approved for treatment of asymptomatic or minimally symptomatic prostate cancer that has metastasized and is resistant to standard hormone treatment (April 29, 2010). ■■ Erlotinib (Tarceva) approved for maintenance treatment of patients with locally advanced or metastatic non–small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy (April 16, 2010). ■■ Rituximab (Rituxan) approved for use in combination with fludarabine and cyclophosphamide

(FC), for the treatment of patients with chronic lymphocytic leukemia (February 18, 2010). ■■ Lapatinib (Tykerb) granted accelerated approval for use in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated ( January 29, 2010).

2009

■■ Romidepsin (Istodax) approved for the treatment of cutaneous Tcell lymphoma in patients who have received at least one prior systemic therapy (November 6, 2009).

■■ Ofatumumab (Arzerra) granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (Campath) (October 26, 2009). ■■ Pazopanib (Votrient) approved for the treatment of patients with advanced renal cell carcinoma (October 19, 2009). ■■ Pralatrexate (Folotyn) granted accelerated approval for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (September 24, 2009). ■■ Bevacizumab (Avastin) approved for use in combination with interferon alfa for the treatment of patients with metastatic renal cell

carcinoma ( July 31, 2009) ■■ Class labeling changes (regarding lack of efficacy in patients with KRAS mutations) implemented for anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix) ( July 17, 2009). ■■ Pemetrexed (Alimta) approved for maintenance treatment of locally advanced or metastatic nonsquamous non–small cell lung cancer patients with no disease progression after four cycles of platinum-based firstline chemotherapy ( July 2, 2009). ■■ Bevacizumab (Avastin) approved as a single agent for patients with glioblastoma, with progressive disease following prior therapy (May 5, 2009).

FDA Approves Risk Evaluation and Mitigation Strategy to Ensure Safe Use of Erythropoiesis-Stimulating Agents

he FDA recently approved a risk evaluation and mitigation strategy (REMS) to ensure the safe use of erythropoiesis-stimulating agents (ESAs). The medications included in the program are darbepoetin alfa (Aranesp) and epoetin alfa (Epogen, Procrit). FDA required Amgen, the manufacturer of these products, to develop the REMS based on studies demonstrating that use of ESAs can increase the risk of tumor growth and shorten survival in patients with cancer. Studies conducted in patients with cancer and in patients with renal failure also show that use of ESAs can increase the risk of myocardial infarction, congestive heart failure, stroke, and thrombotic events.

APPRISE Oncology Program Amgen, in collaboration with Centocor Ortho Biotech Products, was required to develop the ESA APPRISE Oncology program (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) for health-care professionals who prescribe ESAs to patients with cancer. Under the ESA APPRISE Oncology program, Amgen will ensure that only those hospitals and health-care

professionals who have enrolled and completed training in the program will prescribe and dispense ESAs to patients with cancer. Amgen is also required to oversee and monitor the program to ensure that hospitals and health-care professionals are fully compliant with all aspects of the program. The ESA APPRISE Oncology program requires that all health-care professionals who prescribe ESAs in patients with cancer do the following: ■■ Complete a training module that covers the use of ESAs for patients with cancer. Completion of the training module is required for enrollment in the ESA APPRISE Oncology program. ■■ Obtain a signed patient/healthcare professional acknowledgement form prior to initiating a new course of ESA therapy. The acknowledgement form attests that the health-care professional and patient have discussed the risks with using an ESA. ■■ Re-enroll in the ESA APPRISE Oncology program every 3 years. ■■ Health-care professionals not enrolled in the ESA APPRISE Oncology program will not be able to prescribe ESAs for use in patients with cancer.

As part of the enrollment in the ESA APPRISE Oncology program, health-care professionals must attest to understanding the following: ■■ ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non–small cell lung, head and neck, lymphoid, and cervical cancer. ■■ Health-care professionals not enrolled in the ESA APPRISE Oncology program will not be able to prescribe ESAs for use in patients with cancer. ■■ To decrease the risks of ESAs, the lowest dose of ESAs should be used to avoid red blood cell transfusion. ■■ Darbepoetin is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for red blood cell transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy. ■■ Epoetin alfa is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies

that have shown a reduction in the need for red blood cell transfusions in patients with metastatic, non myeloid malignancies receiving chemotherapy for a minimum of 2 months. ■■ ESAs are not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. ■■ ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. ■■ ESA use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being. ■■ ESAs should be discontinued following completion of a chemotherapy course of treatment. As part of the REMS, a Medication Guide explaining the risks and benefits of ESAs must be provided to all patients receiving ESAs. Additional information on the ESAs, this REMS and the ESA APPRISE Oncology Program is available at http://tiny.cc/7kw5b.

The ASCO Post | JUNE 2010

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In the News

Radiation Safety continued from page 57

medicine generally, you have different kinds of machines with different kinds of software that don’t necessarily talk to one another, or if they do, may have bugs below the level of detection,” Dr. Zietman said. “Some kind of universal standard needs to be established.” For the past 3 years, ASTRO has conducted Connect-A-Thons, bringing together vendors, software manufacturers, and their products. “We plug everything into everything else. If something works with everything else, we say it has passed the ASTRO

Connect-A-Thon test. We are trying to drive manufacturers toward universal connections by highlighting those that do. We are not endorsing their products,” he said, just pointing out what works together. “There has to be perfect communication” between the machines that provide the treatment and the planning software that designs the treatment, he added. “It gets very complicated, but it has to be sorted out.”

Opportunity to Improve Safety Culture “There is a safety culture,” Dr. Zietman said, “but we have to take that safety culture and tighten it up a notch.”

Dutasteride continued from page 60

an alpha-blocker (18.9% vs 12.7%, P < .001), patients in the dutasteride group with moderate or severe baseline symptoms of benign prostatic hyperplasia had a greater mean reduction in International Prostate Symptom Score than did men with similar symptoms in the placebo group (reduction of 3.9 vs 1.3 points)

Subsequent Increased Risk of High-grade Disease? The authors speculated that most tumors that were diagnosed during the trial were likely present at the time of randomization but had not been detected in the baseline biopsy. They concluded that their findings and other data support the hypothesis that dutasteride shrinks prostate tumors or inhibits their growth. Patrick C. Walsh, MD, echoed that point in an accompanying editorial (N Engl J Med 362:1237-1238, 2010). He noted that dutasteride and finasteride do not prevent prostate cancer but only temporarily shrink low-risk tumors, and that these drugs do not reduce the risk of a positive biopsy in patients with an elevated PSA level or an abnormal digital rectal examination. “Furthermore, the use of these drugs for prevention may be somewhat risky,” Dr. Walsh commented. “Because PSA levels are suppressed, men may have a false sense of security, and if prostate cancer ever develops, the diagnosis may be delayed until they have high-grade disease that may be difficult to cure.”

Andriole GL, et al: N Engl J Med 362:1192-1202, 2010.

BREAST CANCER

Neoadjuvant Trastuzumab plus Anthracycline/Taxane Chemotherapy Produces High Response Rate in Patients with HER2-positive Breast Cancer Untch and colleagues analyzed tumor response in patients with HER2-positive breast cancer receiving trastuzumab (Herceptin) in combination with anthracycline/taxane– based neoadjuvant therapy, finding a high pathologic complete response rate (pCR) without clinically relevant early toxicity. The results suggested that inclusion of trastuzumab in neoadjuvant treatment should be considered in patients with HER2-positive disease.

Treatment In the GeparQuattro study, patients with operable HER2-positive tumors received four cycles of preoperative epirubicin/cyclophosphamide followed by four cycles of docetaxel with or without capecitabine (Xeloda) and trastuzumab (6 mg/ kg after 8 mg/kg loading dose) every 3 weeks. Patients with HER2-negative tumors who received the same treatment without trastuzumab served as the reference group for comparison of rates of pCR, defined as no invasive or in situ residual tumors.

Higher pCR Rate in HER2-positive Tumors Of 1,509 patients in the study, 445 had HER2-positive tumors treated with trastuzumab and chemotherapy. The reference group consisted of

ASTRO’s quality and safety committee already “had all sorts of projects that were underway” when the articles appeared in The New York Times, Dr. Zietman said. The articles “provided us with the opportunity to put them all together and package them. It See page 72 gave us a platform to impress upon our members that this plan exists and say, ‘Let’s all get behind this,’” he added. “I think radiation oncology is intrinsically safe, but we can all be safer,” Dr. Zietman concluded. “I think we are

creating a safety culture in oncology that is going to be second to none. It really is going to be exemplary.” He expects that “radiation oncology centers have sharpened their practice just in response to patients asking questions” about the articles. For more information on ASTRO’s six-point patient protection plan to improve safety and quality and reduce the chances of medical errors, go to www.astro.org. To view the New York Times articles, “Radiation Offers New Cures, and Ways to Do Harm” (January 23, 2010) and “As Technology Surges, Radiation Safeguards Lag” (January 26, 2010), visit www.nytimes.com.

1,050 patients with HER2-negative disease who received chemotherapy without trastuzumab. Rates of pCR were 31.7% in the HER2-positive group, compared with 15.7% in the HER2-negative group; 40% and 17.3% of patients, respectively, had no invasive residual tumor and no histologic nodal involvement. A high pCR rate of 16.6% was observed in HER2positive patients with no response to the first four cycles of epirubicin/ cyclophosphamide (3.3% among counterparts in the reference group). Breast conservation rates were 63.1% in the HER2-positive group and 64.7% in the reference group. Febrile neutropenia (9.9% vs 6.1%) and conjunctivitis (2.5% vs 0.9%) were significantly more common in patients receiving trastuzumab. Short-term cardiac toxicity profiles were similar, with congestive heart failure and cardiac ischemia each reported in two patients in each group. Five trastuzumab patients had left-ventricular ejection fraction (LVEF) decreases to < 45%, with two having a 10% decrease from baseline. LVEF remained below 50% in only one patient at the last measurement before surgery.

mastectomy (CPM), according to researchers at The University of Texas M. D. Anderson Cancer Center. Using SEER data to compare survival outcomes among women who had mastectomies and those who also had CPM, the investigators found that CPM was associated with a small improvement in 5-year breast cancer–specific survival, mainly in young women with early-stage estrogen receptor (ER)-negative breast cancer. They concluded that this finding is related to a higher risk of contralateral breast cancer at baseline.

Untch M, et al: J Clin Oncol 28:20242031, 2010.

Contralateral Prophylactic Mastectomy Improves Breast Cancer–specific Survival in Younger Women with ER-negative Disease Data from the Surveillance, Epidemiology, and End Results (SEER) program show that women with unilateral breast cancer are increasingly seeking contralateral prophylactic

SEER Data The SEER data identified 107,106 women aged 18 to 90 years with histologically confirmed breast cancer who had undergone mastectomy between 1998 and 2003, and a subset of 8,092 women (8.3%) who also had the uninvolved contralateral breast removed. For women aged 18 to 49 years with stage I–II ER-negative breast cancer, the 5-year adjusted breast cancer survival rate was 88.5% with CPM vs 83.7% without CPM— a difference of 4.8%. No reductions in breast cancer–related mortality were seen in younger women with early-stage ER-positive disease or in women over 60. Although the investigators accounted for a variety of potential influences on outcome in their analyses, they cautioned that a causal relationship between survival and CPM cannot be proved without a randomized controlled trial, which is unlikely to be conducted anytime soon. Bedrosian I, et al: J Natl Cancer Inst 102:401-409, 2010.

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News

2010 NCCN Updates continued from page 63

■■

■■ ■■

ed CEBPA mutations to the recommended markers. The treatment recommendations for acute promyelocytic leukemia (APL) now contain risk stratification based on white blood cell counts. Cytarabine plays a prominent role in the induction regimen for patients with APL. Performance status is now a criterion on which to base treatment recommendations for older patients with AML. Azacitidine (Vidaza), decitabine (Dacogen), and clofarabine (Clolar) are now category 2B recommendations for the treatment of older patients with AML.

more contemporary imaging are recommended additions to the FIGO staging system. ■■ MR and PET are useful methods of functional imaging for advanced cervical tumors ■■ Chemoradiation therapy may be more effective than radiation alone. ■■ Cisplatin/paclitaxel remains the standard treatment of recurrent or metastatic disease.

Non–Small Cell Lung Cancer

“Not much has changed over the past year or two regarding the treatment of cervical cancer.” Benjamin E. Greer, MD, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, Washington ■■ Few changes were made in the 2010 Guidelines, but major staging revisions are expected for endometrial cancer in the 2011 edition. ■■ Nodal information and the use of

“A significant revision is the inclusion of erlotinib (Tarceva) for patients with EGFR-positive disease across all levels of performance status. If you have the EGFR mutation, response rates are higher than 60%.” David S. Ettinger, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, Baltimore, Maryland ■■ Erlotinib is recommended as a firstline option for epidermal growth factor receptor (EGFR) mutation–positive disease. ■■ Pemetrexed (Alimta) and bevacizumab (Avastin) have emerged as treatment options for nonsquamous non–small cell lung cancer (NSCLC). ■■ There are many benefits to neoadjuvant therapy, but whether it prolongs

Health-care Legislation

Introducing The ASCO Post

continued from page 66

continued from page 1

therapeutic measures via comparative effectiveness research that incorporates patient-centered outcomes. Watchful waiting is now an accepted strategy in oncology. It is unknown whether the current strategies for locally advanced, metastatic, or other poor prognosis cancers will be influenced by CER, especially given the focus on hospice care within the PPACA. Time will tell how these legislative measures will influence the care of the cancer patient.

impetus to direct readers to the original articles.

■■

Cervical Cancer

Dr. Janjan is a consultant in health policy after retiring in 2008 as Professor of Radiation Oncology and Symptom Research at The University of Texas M. D. Anderson Cancer Center in Houston, Texas.

Enhanced Communication The ASCO Post will also provide an additional way for current ASCO leadership to communicate with members. This will be in the form of Letters from the President or other officers, committee updates, policy positions, and so forth. In this issue, ASCO President-Elect George Sledge elucidates his view of the direction ASCO should go (page 5), and ASCO CEO Allen Lichter comments on the reasons for developing The ASCO Post (page 3). We also hope that The ASCO Post

survival is uncertain. ■■ The issue of concurrent vs sequential chemoradiotherapy for unresectable stage III NSCLC continues to be debated.

Malignant Pleural Mesothelioma “There are limited data on the prognostic significance of serum markers and the best second-line treatment options. Therefore, the Panel found it challenging to arrive at a consensus regarding the best approach to managing patients with mesothelioma.” Lee M. Krug, MD, Memorial Sloan-Kettering Cancer Center, New York, New York ■■ Mesothelioma should be managed by a multidisciplinary team with experience in treating this rare cancer. ■■ CT of the chest with contrast is the recommended method for the initial workup. ■■ Patients with the epithelioid subtype are more likely to respond to chemotherapy. ■■ Because surgery alone may be an inadequate treatment, combinedmodality therapy is recommended for certain patients. ■■ The standard chemotherapy regimen is the combination of pemetrexed and cisplatin. will provide a forum for communication and debate among members. A variety of columnists will provide their opinions about important issues affecting oncology. In this issue, you will find columnists addressing health-care reform (pages 65-67) and issues regarding new standards for quality cancer care (page 55). In addition, we will pose questions regarding major controversies in our profession and have two members argue different sides of a question. We hope that this will be followed by a robust response from members to be published as Letters to the Editor, either in subsequent issues of The ASCO Post or online. In this issue, you will find the pros and cons of physicianassisted suicide in oncology. We are

Cancer of Unknown Primary “More effective therapies are emerging that produce a significantly good quality of life and long-term survival in patients with epithelial tumors. This makes it especially important to identify the specific tumor type.” David S. Ettinger, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland “The clinicians’ decisions can raise the cost of evaluation tenfold. We should think about the efficiency of care—not what we can do, but what we should do. Furthermore, the pathology evaluation is useless unless it is fully integrated with clinical management.” Charles Handorf, MD, PhD, University of Tennessee Cancer Institute, Memphis, Tennessee ■■ Most patients with cancer of unknown primary have metastases that limit life expectancy, but some have a treatable tumor that may respond well to treatment. ■■ The pathologic evaluation is critical to diagnosis, and is detailed in the updated guidelines. ■■ Guidelines recommend additional tests according to site of occurrence. ■■ Surgery should be considered for some lung nodules. extremely interested in your thoughts regarding this controversial, but very real, problem in caring for patients with incurable cancer. Send your comments to me c/o TAPCaucus@ ASCOPost.com. The ASCO Post will become the newspaper of our members. The content can and will adjust to the membership’s desires. It will be published initially at monthly intervals with the intention of eventually having two papers each month. We look forward to your feedback as to how The ASCO Post can better serve you. Dr. Armitage is Joe Shapiro Professor of Medicine and Professor and Chair of Oncology, University of Nebraska Medical School, Omaha.

The ASCO Post | JUNE 2010

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Clinical Trials

12 Sweeping Changes continued from page 21

Consolidating Administrative Functions The IOM committee also recommended administrative and organizational changes that would consolidate and streamline “back office” functions, including data collection and management, patient registration, audit functions, image storage and retrieval, drug distribution, and submission of case report forms across the Cooperative Groups. The IOM recommendations support the use of biorepositories and the development of novel trial designs, such as adaptive designs that assess response endpoints during trial accrual in real time. These measures would allow

clinical questions to be addressed more quickly and more efficiently. “More studies would incorporate not just the primary endpoint of survival, but would also ask questions about patient genetics that could make clear who did or did not benefit from a particular therapy,” Dr. Carducci said. The IOM report also made a case for uniform standards for imaging procedures, as well as a certification process for Cooperative Group investigators and staff, and an increased emphasis by academic medical centers on participation in Cooperative Group trials in promotion and tenure decisions.

Achievable Goals? The report also advocates a changing role for NCI—from oversight to support—except in cases where it holds the investigational new drug applica-

tion to the FDA, Dr. Mendelsohn said. In its grand vision for 2015, the IOM committee envisioned a future where insurers would adequately cover patient costs, participation in NCI-funded trials would be preferred by both oncologists and patients, and public-private partnerships could be forged with the pharmaceutical industry. Are these goals achievable? Dr. Mendelsohn noted that to some extent they are. The new health-care reform legislation passed by Congress would mandate that insurers controlled by the Employee Retirement Income Security Act (ERISA) would have to cover patient costs for clinical trials. And the pharmaceutical industry is much more likely to want to collaborate on NCI-sponsored trials once procedures are streamlined and trials can

be mounted and completed in a more timely fashion, he said. “The challenge is that when there’s a sharing of responsibility among the NCI, industry, and principal investigator, everyone has an opinion about what’s best. Everybody’s going to have to give a little bit to make collaboration happen,” he said. Whether the IOM committee’s vision for the Clinical Trials Cooperative Group Program will ultimately be fully realized is still an open question. All the recommendations in the report may not be put into effect, but significant improvements to the program are sure to be made, Dr. Mendelsohn said. “I think we can reorganize how we do things and achieve much of our vision. If people are convinced that this vision makes sense, much can be accomplished,” he added.

What Are Two-Dimensional Barcodes? two-dimensional (2D) barcode, also known as a matrix code, is a graphic image that contains information stored both horizontally (like the one-dimensional UPC used in supermarkets) and vertically. The added dimension in a 2D barcode enables the image to represent thousands of characters—essentially a portable database—compared with only 10 to 20 characters stored in the conventional unidimensional barcode. Given that added capacity, 2D barcodes are increasingly being used for fast data access in a variety of settings, and in documents from drivers’ licenses to tax returns.

Getting the application

Perhaps not surprisingly, the real boom in 2D barcode use has been in mobile marketing. Companies have developed technology that enables camera phones to scan matrix codes from a website, print publication, or poster. The consumer can then access content embedded in the code or be redirected to targeted content via the phone’s Web browser.

Scanning 2D codes

The 2D barcodes used in this issue of The ASCO Post will connect readers to further information about the articles they are reading. For instance, a report from the ASCO Annual Meeting may include a barcode that will connect readers online to the original abstract of the study discused. In this way, the editors of The ASCO Post hope to provide readers with further resources and validated information about the news in these pages. Find examples of 2D barcodes on the pages of this issue. Using the ScanLife application (see right), scan these codes with your camera phone, and see where they bring you. Watch for more barcodes in future issues of The ASCO Post.

There are 3 ways to download the ScanLife application. 1. Simply text the word “scan” to 43588. 2. Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”. 3. Visit the application store for your smartphone (such as the iTunes Store or the Android Market). The application is free, though standard data rates for your phone do apply.

When you see a code that you would like to scan, start the ScanLife application. The screen will look similar to camera mode. Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically. A short audio chime will indicate a successful scan and the phone will contact the server for further instructions. This may take up to a minute depending on data speeds and phone type.

What’s this?

ASCOPost.com | JUNE 2010

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TAP Caucus

Physician-assisted Suicide In Support of Physician-aided Dying By Nancy Crumpacker, MD

hy do I no longer use the phrase “physician-assisted suicide”? It is simply inaccurate. The phrase emerged to distinguish the practice from euthanasia, which suggests lack of choice on the part of the patient. But “physicianassisted suicide” has its own connotation problems. In Oregon and Washington, physician-aided dying is regulated by nearly identical Death with Dignity Acts (DWDA) that pertain specifically to Nancy Crumpacker, MD physician support in achieving a peaceful death. In both states, the DWDA does not regulate assisting in a suicide, because that is still a crime. We do not use the word “suicide” to describe similar medical practices like allowing patients to choose to withdraw or withhold medical treatment that will cause death. Current medical practice allows physicians to prescribe medication that sedates the patient into unconsciousness while food and hydration is withheld, thus hastening death.

Physician-assisted Suicide Is Unnecessary, Ineffective, and Increasingly Dangerous By Kevin Olson, MD

y opposition to physician-assisted suicide (PAS) stems less from purely ethical or religious ideology and more from pragmatic concerns about the delivery of this kind of care. My perspective comes as a full-time practicing hematology/ oncology physician for the past 16 years and as the leader of a group of 40 private practice oncologists for the past 10. The PAS challenge has had many beneficial consequences in Oregon including improved focus on palliative care at the end of life, Kevin Olson, MD improved hospice utilization (Oregon ranks among the nation’s leaders in this regard), improved training and expertise in the management of pain, and a reduced fear of painful death by those near the end of life—even for those who pursue a hastened death via PAS. However, three main issues drive my opposition to PAS: It is not needed, it is not always effective, and it is dangerous in an increasingly complex medical care delivery system.

Not Needed

I have prescribed medications under the DWDA for a few patients because I respect those who are dying and possibly experiencing suffering that I may not be able to ameliorate.

PAS is not needed for patients with cancer because it is rarely used. When asked about the frequency of requests for PAS, I use the “100-10-2-1” rule. That is, for every 100 individuals who ask about the option (often in the panic of being informed of a terminal diagnosis), only 10 begin to pursue the legal process of obtaining a prescription. Of those 10, only 2 follow through completely with the process and obtain a prescription (often because the dying process intervenes without the need for a hastened death). For the two who get prescriptions, one will actually use it.

More Than a Linguistic Distinction

For every 100 individuals who ask “about physician-assisted suicide,

The distinction is not just linguistic. The word “suicide” demeans people who wish a choice in the timing and manner of their imminent deaths. People using the DWDA and those who would commit suicide are opposites: ■■ The suicidal person is generally physically healthy but does not wish to live. The person who uses the DWDA is dying but wishes to live. ■■ Typical suicides bring shock and tragedy to loved ones. DWDA deaths bring closure and are supported by family and friends. ■■ Suicides are often impulsive and violent. Dying under our law allows planning for a peaceful death. ■■ Suicide is an expression of despair and futility. DWDA deaths are empowering acts. I have prescribed medications under the DWDA for a few of my patients. I did it because I respect those who are dying and possibly experiencing suffering that I may not be able to ameliorate. I watched as these patients gained a sense of control that had eluded them during months to years of terminal illness. I reminded myself that I am not able to fully understand how

Although a few of my patients have received a prescription as part of the PAS process, none has used it. Of the roughly 30,000 deaths that occur in Oregon each year, only 40 to 60 deaths occur as part of a PAS treatment. Most who participated in PAS over the past 2 years cite loss of autonomy and loss of dignity as their major motivation for the request. Fear of painful death was the primary concern in PAS patients in the early years of the program. Clearly, the healthcare system evolved to address and relieve these pain concerns, and it is possible

continued on page 74

only 10 pursue the legal process of obtaining a prescription, and only 2 of those 10 follow through and obtain a prescription.

The ASCO Post invites you to comment on the subject of physician-assisted suicide, or physican-aid‑ ed dying, a controversial, but very real issue in caring for patients with incurable cancer. Send your thoughts to Dr. James Armitage, c/o TAPCaucus@ASCOPost.com. Selected responses will be pub‑ lished online and in future issues of The ASCO Post.

The ASCO Post | JUNE 2010

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TAP Caucus

Physician-assisted Suicide Is Unnecessary

Support of Physician-aided Dying

continued from page 73

that similar improvements in autonomy and dignity issues can be achieved.

my patients experience suffering, and I accepted that I could relieve their suffering by assisting them in using the DWDA. I believe it is unethical and unprofessional to ignore my patients’ needs.

Not Effective The practice is not always effective. The law allows for patients to administer medication prescribed by a physician. In many cases, the rapid decline in performance status near the end of a terminal cancer illness makes the ability to swallow the medications difficult or impossible. One well-publicized case resulted in the patient lapsing into coma but not dying as a result of the prescription. (The patient died of other causes many days later.) Although some physicians have agreed to be present during the administration of medication, the law does not require this. Without a physician present, the patient or family may try to administer the drugs incorrectly.

Increasingly Dangerous As caregivers, we are asked to do more in an ever more complex healthcare system with significantly less financial support, the practice of PAS may be increasingly dangerous. In our own practice, we dealt with a patient referral that illustrates this potential problem. Already on hospice with a diagnosis of terminal lung cancer, the patient made a specific request to facilitate PAS, to hasten a death not coming fast enough for him. On further review and reevaluation, we found that he had an earlystage lung cancer, which was incorrectly interpreted by the referring physician as imminently terminal. He was taken off hospice, treated with curative intent, and lived for several more years before dying from causes unrelated to cancer. Some may argue that the law worked as intended in this situation. Yet it is reasonable to predict that health-care reform might create time pressures on physicians that could cause similar mistakes to go unnoticed. For these reasons I feel physicianassisted suicide is not a necessary component of care in patients with terminal cancer. Dr. Olson is President and Chief Medical Officer, Northwest Cancer Specialists, Portland, Oregon. Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®).

Listen to Your Patients’ Concerns What can you do for patients who ask you to control the timing of their death? First and foremost, respect them as you do all your patients by listening to their concerns. These patients will have symptoms that you may relieve with medications and hospice referral. Even if your patient requests your assis-

Dealing with Reality continued from page 67

or else the government will take the responsibility Nothing is more personal than one’s health and the freedom to choose a physician. Doctors understand the honor and responsibility that patients give to us. We are constantly mindful of the need to provide our patients with the best and most efficient care. We are all part of the solution to the health-care crisis in America. We all must continue to do our part. The best way to reduce health expenses is to prevent illness or cure disease without complications. These are the responsibilities of both doctors and patients.

tance in using physician-aided dying, a 90% likelihood exists that he or she will not complete the process.1 Sometimes repeated conversations are necessary to understand the meaning of the request. But what about suffering that cannot be addressed by these maneuvers? Even if you do not live in Oregon or Washington, you can offer the choice of voluntarily stopping eating and drinking. In a 2003 report by Ganzini and colleagues, hospice nurses rated these deaths. “On a scale from 0 (a very bad death) to 9 (a very good death), the median score for the quality of these deaths, as rated by the nurses, was 8.”2 For most patients, the chance to discuss their fears may be what they need most. For a valuable summary of the PPACA, I suggest reading “Summary of New Health Reform Law” by the Kaiser Family Foundation (available at http://www.kff.org/healthreform/8061.cfm). Dr. Boxer is Professor of Clinical Urology at the University of Miami. He is also Clinical Professor at the University of Wisconsin and the Medical College of Wisconsin. Dr. Boxer was a two-time finalist for U.S. Surgeon General (under both the William J. Clinton and George W. Bush administrations) and served on President Clinton’s Task Force on Health Reform. In addition, Dr. Boxer has served on the National Cancer Advisory Board, represented the United States at the World Health Organization, and was the Chair, National Health Policy Council.

References 1. Bascom PB, Tolle SW: Responding to requests for physician-assisted suicide: “These are uncharted waters for both of us....” JAMA 288:91-98, 2002. 2. Ganzini L, Goy ER, Miller LL, et al: Nurses’ experiences with hospice patients who refuse food and fluids to hasten death. N Engl J Med 349:359-365, 2003. Dr. Crumpacker is a retired oncologist living in Portland, Oregon. She is Medical Director of Compassion & Choices of Oregon and a past member of ASCO. Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®).

Editor’s Note As we went to press we learned that President Obama has announced his intention to appoint Harold Varmus, MD, to lead the National Cancer Institute. Dr. Varmus has served as the President of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City since January 2000. He is a former Director of the National Institutes of Health (NIH), co-recipient of the 1989 Nobel Prize in Physiology or Medicine for studies of the genetic basis of cancer, and recent co-chair of President Obama’s Council of Advisors on Science and Technology. Watch for comprehensive coverage of Dr. Varmus’s appointment in a future issue of The ASCO Post.

Coming in the July 2010 Issue of Comprehensive coverage of the 2010 ASCO Annual Meeting, including reports on this year’s plenary program:

■■ Abstract LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial

ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. Robert A Burger, MD, author/speaker.

■■ Abstract 2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in

patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC). Elisabeth A. Quoix, MD, author/speaker.

■■ Abstract 3: Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with nonsmall cell lung cancer (NSCLC). Yung-Jue Bang, MD, author/speaker.

■■ Abstract 4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma. Steven O’Day, MD, author/speaker

Plus much more from the Annual Meeting, along with New and Important Columns, Features, and Clinical Departments—don’t miss it!

Be sure to visit The ASCO Post online at www.ASCOPost.com.

AVASTINÂŽ (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTINÂŽ (bevacizumab) Suspend Avastin administration for â&#x2030;Ľ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in SpeciďŹ c Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: t Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] t 4VSHFSZ BOE 8PVOE )FBMJOH $PNQMJDBUJPOT [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] t )FNPSSIBHF [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] t /PO (BTUSPJOUFTUJOBM 'JTUVMB 'PSNBUJPO [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] t "SUFSJBM 5ISPNCPFNCPMJD &WFOUT [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] t )ZQFSUFOTJWF $SJTJT [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] t 3FWFSTJCMF 1PTUFSJPS -FVLPFODFQIBMPQBUIZ 4ZOESPNF [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] t 1SPUFJOVSJB [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound IFBMJOH BOE PS CMFFEJOH DPNQMJDBUJPOT PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP PG QBUJFOUT XIP SFDFJWFE CPMVT *'- BMPOF In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage 5IF JODJEFODF PG FQJTUBYJT XBT IJHIFS WT JO QBUJFOUT XJUI N$3$ SFDFJWJOH CPMVT *'- QMVT "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP "MM CVU POF PG UIFTF FWFOUT were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic FWFOUT XFSF NPSF GSFRVFOU JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO XIFO DPNQBSFE UP UIPTF SFDFJWJOH CPMVT *'- QMVT QMBDFCP BOE JODMVEFE HBTUSPJOUFTUJOBM IFNPSSIBHF WT NJOPS gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving DIFNPUIFSBQZ BMPOF *O 4UVEZ QBUJFOUT PO UIF CPMVT *'- QMVT "WBTUJO BSN BOE QBUJFOUT PO UIF CPMVT *'- QMVT QMBDFCP BSN SFDFJWFE GVMM EPTF XBSGBSJO GPMMPXJOH B venous thromboembolic event. Among these patients, an additional thromboembolic event PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE PG QBUJFOUT SFDFJWJOH CPMVT *'- BMPOF The overall incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events in Study 1 was 15.1% in patients SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP *O Study 1, the incidence of the following Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP QBUJFOUT SFDFJWJOH CPMVT *'- QMVT placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of (SBEF PS OFVUSPQFOJB XBT JODSFBTFE JO N$3$ QBUJFOUT SFDFJWJOH *'- QMVT "WBTUJO DPNQBSFE UP QBUJFOUT SFDFJWJOH *'- BMPOF *O 4UVEZ UIF JODJEFODF PG (SBEF neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH 1$ BMPOF 'FCSJMF OFVUSPQFOJB XBT also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade â&#x2030;Ľ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence PG (SBEF DPOHFTUJWF IFBSU GBJMVSF $)' XBT JODSFBTFE JO QBUJFOUT JO UIF "WBTUJO QMVT paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior BOUISBDZDMJOFT GPS .#$ UIF SBUF PG $)' XBT GPS QBUJFOUT SFDFJWJOH "WBTUJO BT DPNQBSFE to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3â&#x20AC;&#x201C;4 adverse events and selected Grade 1â&#x20AC;&#x201C;2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3â&#x20AC;&#x201C;4) adverse events, which occurred at a higher incidence (â&#x2030;Ľ 2%) in patients receiving CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP CPMVT *'- QMVT QMBDFCP BSF QSFTFOUFE JO 5BCMF

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracilâ&#x20AC;&#x201C;based chemotherapy. 1.2 Non-Squamous Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonâ&#x20AC;&#x201C;squamous nonâ&#x20AC;&#x201C;small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade â&#x2030;Ľ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in nonâ&#x20AC;&#x201C;small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%â&#x20AC;&#x201C;5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3â&#x20AC;&#x201C;4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of â&#x2030;Ľ1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was â&#x2030;¤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade â&#x2030;Ľ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in SpeciďŹ c Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3â&#x2C6;&#x2019;4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [â&#x2030;Ľ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. *'- 1MBDFCP *'- "WBTUJO Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).] NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms #PEZ BT B 8IPMF Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).] Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy. 14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick aCentral laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. reading should undergo further assessment with a 24-hour urine collection.

AVASTINÂŽ (bevacizumab) AVASTINÂŽ (bevacizumab) Grade 1â&#x20AC;&#x201C;4 adverse events which occurred at a higher incidence (â&#x2030;Ľ 5%) in patients receiving Table 4 CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP UIF CPMVT *'- QMVT QMBDFCP BSN BSF QSFTFOUFE JO 5BCMF NCI-CTC Grades 1â&#x2C6;&#x2019;5 Adverse Events in Study 9 Grade 1â&#x20AC;&#x201C;4 adverse events were collected for the first approximately 100 patients in each of 0DDVSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'/ Îą "WBTUJO WT *'/ Îą + Placebo) UIF UISFF USFBUNFOU BSNT XIP XFSF FOSPMMFE VOUJM FOSPMMNFOU JO "SN '6 -7 "WBTUJO was discontinued. 4ZTUFN 0SHBO $MBTT *'/ Îą 1MBDFCP *'/ Îą + Avastin Preferred term* (n = 304) (n = 337) Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% 0DDVSSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'- "WBTUJO WT *'-

General disorders and administration Arm 1 Arm 2 Arm 3 site conditions *'- 1MBDFCP *'- "WBTUJO '6 -7 "WBTUJO 'BUJHVF (n = 98) (n = 102) (n = 109) Investigations 8FJHIU EFDSFBTFE #PEZ BT B 8IPMF Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders 8FJHIU -PTT Hypertension 9% 28% Dry Mouth 2% 7% 4% *Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic 5IF GPMMPXJOH BEWFSTF FWFOUT XFSF SFQPSUFE BU B GPME HSFBUFS JODJEFODF JO UIF *'/ Îą plus Thrombocytopenia 0% 5% 5% "WBTUJO BSN DPNQBSFE UP *'/ Îą alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital BOE VOEFSMZJOH EJTFBTF 'PS UIFTF SFBTPOT DPNQBSJTPO PG UIF JODJEFODF PG BOUJCPEJFT UP "WBTUJO Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin. Only Grade 3-5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3â&#x20AC;&#x201C;5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events) occurring at a higher incidence drug exposure. Ăś JO QBUJFOUT SFDFJWJOH '0-'09 QMVT "WBTUJO DPNQBSFE UP QBUJFOUT SFDFJWJOH Body as a Whole: Polyserositis '0-'09 BMPOF XFSF GBUJHVF WT EJBSSIFB WT TFOTPSZ OFVSPQBUIZ Cardiovascular: Pulmonary hypertension, RPLS (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Hemic and lymphatic: Pancytopenia neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia in Study 2. 7 DRUG INTERACTIONS Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected A drug interaction study was performed in which irinotecan was administered as part of the in Study 4. Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events (occurring '0-'*3* SFHJNFO XJUI PS XJUIPVU "WBTUJO 5IF SFTVMUT EFNPOTUSBUFE OP TJHOJĂĽDBOU FGGFDU PG at a higher incidence (â&#x2030;Ľ2%) in 427 patients receiving PC plus Avastin compared with 441 patients bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), be a difference in the mean exposure of either carboplatin or paclitaxel when each was febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 administered alone or in combination with Avastin. However, 3 of the 8 patients receiving or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin (3% vs. 0%). without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. Metastatic Breast Cancer (MBC) In Study 9, there was no difference in the mean exposure of interferon alfa administered in Only Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events were collected in combination with Avastin when compared to interferon alfa alone. Study 5. Grade 3â&#x20AC;&#x201C;4 adverse events occurring at a higher incidence (â&#x2030;Ľ2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory 8 USE IN SPECIFIC POPULATIONS neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without 8.1 Pregnancy neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), Pregnancy Category C bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, (3% vs. 0.3%) and proteinuria (3% vs. 0%). including an increased incidence of speciďŹ c gross and skeletal fetal alterations. Adverse fetal outcomes Sensory neuropathy, hypertension, and fatigue were reported at a â&#x2030;Ľ 5% higher absolute incidence in were observed at all doses tested. Other observed effects included decreases in maternal and fetal the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] 'BUBM BEWFSTF SFBDUJPOT PDDVSSFE JO PG QBUJFOUT XIP SFDFJWFE QBDMJUBYFM QMVT "WBTUJO Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ from the mother to the developing fetus, and has the potential to cause fetal harm when abdominal, and pain/weakness/hypotension (2). administered to pregnant women. Because of the observed teratogenic effects of known inhibitors Avastin is not approved for use in combination with capecitabine or for use in second or third of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential line treatment of MBC. The data below are presented to provide information on the overall benefit to the pregnant woman justifies the potential risk to the fetus. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, 8.3 Nursing Mothers controlled study in which all adverse events were collected for all patients. All patients in It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in metastatic disease. Grade 1â&#x20AC;&#x201C; 4 events which occurred at a higher incidence (â&#x2030;Ľ5%) in patients substantial amounts. Because many drugs are secreted in human milk and because of the potential for receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to in Table 3. discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11â&#x20AC;&#x201C;50 days]) and the importance of the drug to the mother. [See Clinical Table 3 Pharmacology (12.3).] NCI-CTC Grade 1â&#x2C6;&#x2019;4 Adverse Events in Study 6 (Occurring at Higher 8.4 Pediatric Use Incidence [â&#x2030;Ľ5%] in Capecitabine + Avastin vs. Capecitabine Alone) The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Capecitabine been established. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Capecitabine + Avastin to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and (n = 215) (n = 229) exposure). The incidence and severity of physeal dysplasia were dose-related and were partially #PEZ BT B 8IPMF reversible upon cessation of treatment. Asthenia 47% 57% 8.5 Geriatric Use Headache 13% 33% In Study 1, severe adverse events that occurred at a higher incidence (â&#x2030;Ľ 2%) in patients aged â&#x2030;Ľ65 Pain 25% 31% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Cardiovascular hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Hypertension 2% 24% survival was similar in elderly patients as compared to younger patients. Digestive *O 4UVEZ QBUJFOUT BHFE Ăś ZFBST SFDFJWJOH "WBTUJO QMVT '0-'09 IBE B HSFBUFS SFMBUJWF SJTL Stomatitis 19% 25% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Metabolic/Nutrition In Study 4, patients aged â&#x2030;Ľ 65 years receiving carboplatin, paclitaxel, and Avastin had a 8FJHIU MPTT greater relative risk for proteinuria as compared to younger patients. [See Warnings and Musculoskeletal Precautions (5.8).] Myalgia 8% 14% In Study 5, there were insufficient numbers of patients â&#x2030;Ľ 65 years old to determine whether Respiratory the overall adverse events profile was different in the elderly as compared with younger patients. Dyspnea 18% 27% Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were Epistaxis 1% 16% captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any Skin/Appendages severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition Exfoliative dermatitis 75% 84% to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased Urogenital cough, and voice alteration. Albuminuria 7% 22% In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged â&#x2030;Ľ65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with Glioblastoma as compared to those receiving chemotherapy alone, regardless of age. However, All adverse events were collected in 163 patients enrolled in Study 7 who either received chemotherapy the increase in arterial thromboembolic events incidence was greater in patients aged â&#x2030;Ľ 65 years Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination (5.5).] with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated 10 OVERDOSAGE with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), 16 patients and with severe headache in three of 16 patients. epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade â&#x2030;Ľ3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1â&#x20AC;&#x201C; 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3â&#x20AC;&#x201C;5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3â&#x20AC;&#x201C;5 adverse events occurring at a IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH JOUFSGFSPO BMGB *'/ Îą) plus Avastin DPNQBSFE UP QBUJFOUT SFDFJWJOH *'/ Îą plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, 7453214 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Manufactured by: haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract Genentech, Inc. 4835706 hemorrhage, and traumatic hematoma). %/" 8BZ *OJUJBM 6 4 "QQSPWBM 'FCSVBSZ $PEF 3FWJTJPO %BUF +VMZ (SBEF o BEWFSTF FWFOUT PDDVSSJOH BU B IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH *'/ Îą plus 4PVUI 4BO 'SBODJTDP $" 94080-4990 ÂŠ 2009 Genentech, Inc "WBTUJO DPNQBSFE UP UIF *'/ Îą plus placebo arm are presented in Table 4.

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

9146401

(01/10)

Printed in USA.