A Harborside Press® Publication

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

VOLUME 2, ISSUE 12

AUGUST 15, 2011

When I was first diagnosed with breast cancer in 1979 there was no global

movement to raise awareness of the disease, there were no pink ribbon pins to show sup-port, and there was no Internet with which to search for information. My doctor gave me the news on a Friday night, and the following Monday I had a mastectomy on my left breast. Everything was urgent. I had this cancer and it had to be treated right away. I was just 25 and I didn’t understand a lot of what was go-ing on, even though I was a nurse. I didn’t have anything about my diagnosis in writing, and I couldn’t find anyone my age to talk to about having breast cancer. I just acted on fear.

continued on page 4

continued on page 28

MORE IN THIS ISSUE

Oncology Meetings Coverage2011 ASCO Annual Meeting

Breast Cancer ..............................................3Multiple Myeloma .......................................6Ovarian Cancer ....................................... 10Prostate Cancer ........................................ 13Hepatocellular Carcinoma ...................... 14

Direct from ASCO .......................................20Psychosocial Oncology ............................... 31Integrative Oncology...................................39TAP Caucus .................................................. 42

Acting on Fear

continued on page 2

Ms. Stewart is a nurse and breast health educator at the Johns Hopkins Avon Foundation Breast Center in Baltimore.

The NCI-funded Na-tional Lung Screen-

ing Trial (NLST), pub-lished recently in The New England Journal of Medi-cine,1 was heralded as a landmark study in lung cancer detection. This study is the first compre-hensive clinical trial to find that screening high-risk individuals with low-dose CT reduces lung cancer deaths by 20% com-pared with chest x-ray. One of the trial’s co-leaders, Christine Berg, MD, spoke with The ASCO Post

about how the data answer critics of the study.

Early Thoughts on Lung Cancer Screening

The value of low-dose helical

By Deb Stewart, BSN, RN, CBCN, BPNC-ICAs told to Jo Cavallo

Expert’s Corner

Perspective

CT in lung cancer screening has been vigorously chal-lenged. What was your general sense of the issue going into the trial?

My history with this study dates back to the fall of 1998, when I learned of the discussion at the Varese Conference for lung cancer screening addressing the potential of low-dose helical CT for early detection. The preliminary information indicated that low-dose helical CT screening had

All parties—the government, payers, and con-sumers—agree that, left unchecked, rising

health-care costs will eventually hamstring vital por-tions of our delivery system. For example, Medicare, which covers more than 50% of the nation’s patients with cancer, is marching headlong toward insolvency. Largely due to sticker-shock prices of some newer therapeutics, oncology is in the spotlight of the health-care spending debate. In an occasional series of articles, The ASCO Post will look at oncology costs and how to reduce spending without hampering the quality of care.

Costs and ValuePut simply, health-care spending is calculated

as units of care multiplied by their respective costs. While numerous studies indicate that more services do not necessarily result in better outcomes, deter-mining the true clinical value of health services—es-pecially in a complex disease like cancer—is where much of today’s debate begins and ends.

While it is true that oncology costs are rising

at an unsustainable rate, it is important to weigh costs against outcomes. For instance, a study led by Aman Buzdar, MD, FACP, Professor of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, looked at survival data for nearly

57,000 patients with breast cancer from 1944 to 2004 and calculated 10-year survival rates. Dra-matic improvements were seen in local, regional, and metastatic disease. Among women with re-gional disease from 1944 to 1954, only 16.2% of women were still alive 10 years later, compared with 74% in the most recent decade analyzed, from 1995 to 2004.

Naturally, improvements over the past decades in breast cancer survival are due to a number of factors,

Rising Costs of Cancer Care: It’s More Than DrugsBy Ronald Piana

ASCO 2011 3, 6, 10, 13, 14 | FDA update 18, 19, 26, 27 | Suicide risk in patients with cancer 31

A Landmark Lung Screening Trial: What Does It Mean for Clinicians and Their Patients?By Ronald Piana

■ The NLST reported 20% fewer lung cancer deaths in those screened with low-dose helical CT compared with chest x-rays.

■ NLST participants included 53,454 individuals between 55 and 74 years at randomization with a history of at least 30 pack-years of cigarette smoking; if former smokers, participants had quit within the previous 15 years.

■ All-cause mortality (deaths due to any factor, including lung cancer) in the NLST was 7% lower in those screened with low-dose helical CT.

National Lung Screening Trial

SEE PAGE 45

Aman Buzdar, MD, FACP

PAGE 2 The ASCO Post | AUGUST 15, 2011

Patient’s Corner

Acting on Fearcontinued from page 1 After Cancer Treatment:

What’s Next?Once their treatment is over, cancer survivors should receive direction about specific follow-up plans, detailing how often they need to be seen by a physi-cian; for how long; and by whom. Questions for discussion include:

■ Should they continue to see their oncologist or should their primary care physician look after them?

■ What long-term treatment after effects should they expect, and what health screenings should they have and when?

■ If survivors are still having emotional difficulty coping with their cancer diagnosis, should they be referred to a support group and/or to a mental health professional for treatment?

Twenty years later, I had a second breast cancer diagnosis, but this time I was able to gather information. I took my time, I got a second opin-ion, and I weighed my options. I de-cided to have a mastectomy instead of a lumpectomy because I felt that having had cancer before and having it now, I would likely have it again. I took control.

What has been such a privilege for me as a patient navigator is to be able to interact with patients on a daily basis, to listen to their fears and as-sess their stress level. I can also relate to their emotional pain. I remember a patient saying to me, ‘You have no idea of what I’m going through.’ I ex-plained that even though everyone’s experience with cancer is different, I, too, am a breast cancer survivor and I understand what fear feels like. I understand what grief feels like and what it feels like to lose a breast and miss it. We were able to connect through our shared experiences of grief and loss.

Developing a Survivors’ Care Plan

In my professional experience the biggest fear that breast cancer survi-vors have is of recurrence, followed by uncertainty and death. They also have ongoing health concerns about the long-term side effects of treat-ment. Body image and sexual dys-function are another two big issues for breast cancer survivors, yet doc-tors rarely raise these problems with their patients, and many women are often reluctant to bring them up themselves. Encouraging women to be more open about their concerns and to ask questions would go a long way in alleviating some of the challenges associated with a cancer diagnosis.

Having a universally adopted sur-vivors’ care plan following cancer treatment would also greatly improve both the emotional and physical lives

of cancer survivors. After cancer treatment is completed, survivors should be given explicit information about their follow-up care (see box).

Loss and ChangeWhen I was recovering from

my first bout with breast cancer, I couldn’t stop thinking about what I went through, and then one day I woke up and I didn’t think about breast cancer until lunchtime and I thought, “This is a good day.”

In addition to fear, feelings of loss are always present in breast cancer survivors. It is not just the sense of loss over a missing breast, however, it’s a lot of things. It’s losing your self-identity and thinking you are no longer who you were. As medical professionals, we have to acknowl-edge the losses and changes patients face and guide them in their transi-tion through the stages of treatment and beyond. ■

Survivorship

ErratumMarvin J. Stone, MD, is Director of Oncology Medical Education, Quality & Safety, and Associate Director of the Baylor Charles A. Sammons Cancer Center, Dallas. In the July 1, 2011, issue of The ASCO Post, the affiliation pub-lished with Dr. Stone’s byline was incorrect. We apologize for this error. To view the full commentary by Dr. Stone, “On William Osler: the Old Art and the New Science,” visit http://www.ascopost.com/articles/july-1-2011/on-william-osler-the-old-art-and-the-new-science/.

James  O. Armitage, MD Editor-in-Chief

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

ASSOCIATE EDITORS

Joseph S. Bailes, MD Texas Oncology

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Douglas W. Blayney, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

Richard Boxer, MD University of Miami

Harold J. Burstein, MD Dana-Farber Cancer Institute

Robert W. Carlson, MD Stanford University Medical Center

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

Jay S. Cooper, MD Maimonides Medical Center

John Cox, DO Texas Oncology

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

George D. Demetri, MD Dana-Farber Cancer Institute

Paul F. Engstrom, MD Fox Chase Cancer Center

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Louis B. Harrison, MD Continuum Cancer Centers of New York

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Michael P. Link, MD Stanford University Medical CenterJohn L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

William T. McGivney, PhD National Comprehensive Cancer Network

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

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

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

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Virginia Commonwealth University

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

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

William C. Wood, MD Winship Cancer Institute, Emory University

INTERNATIONAL EDITORS

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Conor Lynch, Executive Editor Conor@harborsidepress.com

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

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Michael Buckley, Graphic Designer Michael@harborsidepress.com

Melanie Serge, Marketing Project Manager Melanie@harborsidepress.com

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

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

Anthony Cutrone, President Anthony@harborsidepress.com

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

Editorial Board

Harborside Press® Publishing Staff

Contributing Writers: Charlotte Bath, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Ronald Piana, Larry J. Rosenberg, PhD, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations

Disclosure information available at ASCOPost.com.

ASCOPost.com | AUGUST 15, 2011 PAGE 3

2011 ASCO Annual Meeting

Findings from a Canadian study presented at the 2011 ASCO An-

nual Meeting may expand the pool of patients with lymph node–positive breast cancer offered extended-field irradiation.1

“Results from MA.20 suggest that all women with node-positive disease following breast-conserving surgery be offered regional node irradiation provided they are made aware of the associated toxicities,” said Timothy Whelan, MD, of McMaster Univer-sity and the Juravinski Cancer Centre in Hamilton, Ontario.

Study RationaleAmerican Society for Radiation

Oncology (ASTRO) and ASCO guidelines recommend locoregional radiation following mastectomy for women with tumors > 5 cm or more than three positive axillary lymph nodes. The benefit in women with one to three positive nodes and in those treated with breast-conserving surgery has been unclear. Following breast-conserving surgery, women normally receive whole breast irra-diation, which may involve radiation to the lower axilla and some of the internal mammary nodes. Regional nodal irradiation to the internal mammary, supraclavicular, and high axillary lymph nodes may provide added benefits to whole breast irra-diation, but can be more toxic.

The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.20 trial evaluated the benefit of regional nodal irradia-tion in addition to whole breast irra-diation after breast-conserving sur-

gery for women with node-positive and high-risk node-negative breast cancer. The latter group included women with tumors ≥ 5 cm, and those with tumors ≥ 2 cm and fewer than 10 axillary nodes removed who were estrogen receptor–negative, had histologic grade 3 tumors, or had lymphovascular invasion.

The study accrued patients from March 2000 to March 2007. After the March 2011 interim analysis, the Data Safety and Monitoring Com-mittee recommended that the results be released.

The study randomly assigned 1,832 patients to receive whole breast irradiation (50 Gy in 25 frac-tions, with boost irradiation of 10 Gy in 5 fractions permitted) or whole breast plus regional nodal irradiation (45 Gy in 25 fractions).

Nearly a 6% Absolute Difference in Events

At a median follow-up of 62 months, the addition of regional nodal irradiation to whole breast ir-radiation significantly improved dis-ease-free survival, preventing both locoregional and distant recurrenc-es. There was also a trend toward improved overall survival, but this was not statistically significant, Dr. Whelan reported.

The 5-year disease-free survival rate was 84.0% in the whole breast ir-radiation arm and 89.7% in the whole breast/regional nodal irradiation arm, based on 144 and 102 events (recurrence, contralateral breast cancer, or breast cancer death), re-spectively. This represented a 33% reduction in events that was highly significant (P = .003).

Locoregional disease-free surviv-al was 94.5% with whole breast irra-diation and 96.8% with whole breast/regional nodal ir-radiation, for a 42% reduction in risk (P = .02). Two-thirds of regional re-currences were in the axillae.

More unexpected was the protec-tion achieved against distant recur-rences, with the distant disease-free survival rate being 87.0% with whole breast irradiation and 92.4% with whole breast/regional nodal irra-diation, a 36% reduction in risk (P = .002), he reported.

Five-year overall survival rates were 90.7% and 92.3%, respectively, based on 96 deaths in the whole breast irradi-ation arm and 74 in the whole breast/regional nodal irradiation arm—a 23% reduction in mortality (P = .07).

The trade-off for this disease-free survival improvement was more radia-tion dermatitis with the regional nodal irradiation addition (50% vs 40%; P < .001), pneumonitis (1.3% vs 0.2%; P = .01), and lymphedema (7% vs 4%; P = .004). While cosmetic outcomes were similar at 3 years, more of the regional nodal irradiation group con-sidered the outcome “fair or poor” at 5 years (36% vs 29%; P = .047). ■

Disclosure: Dr. Whelan reported no potential conflicts of interest.

Reference1. Whelan TJ, Olivotto I, Ackerman I,

et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. 2011 ASCO Annual Meet-ing. Abstract LBA1003. Presented June 6, 2011.

Expert Point of View

Thomas Buchholz, MD, of the University of Texas MD Anderson Cancer Center, Houston, commented that the “well conducted and analyzed”

MA.20 study addressed a “simple clinically relevant question,” and the findings “add to the conclusive evidence that radiation eradication of local-region-al microscopic disease reduces subsequent distant metastases and can improve survival.”

He said the locoregional results are not surpris-ing, as outcomes were consistent with expectations. “A 5.5% locoregional recurrence rate at 5 years is expected, and the 2.3% absolute improvement is reasonable,” he noted. “By itself, the locoregional benefit and risks are equal.”

But he found the 4.3% absolute reduction (from 12.7% to 8.4%) in distant metastases “surprising,” and suggested that based on these data, “the benefits now clearly outweigh the risks.” While surprising, there are a number of possible reasons why protection from distant metasta-ses was greater than for locoregional recurrences, but what seems certain is that lymph node risk is heterogeneous within the subset of patients with one to three positive nodes, Dr. Buchholz offered.

“I agree with the investigators’ conclusions,” he said. “We should offer regional nodal irradiation for higher-risk patients with one to three positive lymph nodes, but we should await additional data for low-risk patients with one to three positive nodes.” ■

Financial Disclosure: Dr. Buchholz reported no potential conflicts of interest.

Patients with Early Breast Cancer Benefit from Regional Nodal Irradiation Local and distant recurrences were significantly reduced.By Caroline Helwick

■ In the NCIC-CTG MA.20 trial, regional nodal irradiation, added to whole breast irradiation following breast-conserving surgery, improved disease-free survival, with a trend toward improved overall survival.

■ Locoregional recurrences were reduced by a relative 42%, and distant recurrences, by 36%.

■ The additional radiation was associated with more lymphedema, pneumonitis, and radiation dermatitis.

Regional Irradiation in Early Breast Cancer

SEE PAGE 45

Thomas Buchholz, MD

Timothy Whelan, MD

PAGE 4 The ASCO Post | AUGUST 15, 2011

Expert’s Corner

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, 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 Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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.

Copyright ©2011 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. Individual Domestic: $225; Individual International: $275; Institu-tional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

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.

Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@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 mate-rial 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.

A Clinician Weighs In on the National Lung Screening TrialBy Ramaswamy Govindan, MD

The results of the National Lung Screening Trial (NLST) will have important implications for

practicing oncologists if low-dose helical CT screen-ing is used routinely in the clinic.

First, we will begin to find many more small tumors than we do now. This will pose new sets of questions for research: What should be the op-timal strategy to manage these tumors? Should we be considering lesser resection for very small tu-mors instead of the conventional lobectomy? Will stereotactic radiotherapy be a preferable option to

surgery for these tumors? Second, are these small tumors detected through the CT screening process

in asymptomatic individuals biologically different from the tumors we cur-rently see when patients present with symptoms?

Fodder for Future ResearchNLST is just the beginning. There are 1 billion smokers (current and former)

in the world today. It is simply unrealistic to screen all smokers for lung cancer. The cost issues and logistics are not trivial. The important fact to keep in mind is that 1 in 10 smokers die of lung cancer. Is there a way to identify the population predisposed to developing lung cancer so that CT screening can focus on the really enriched population at risk? Recent advances in genomics give us hope that one day a simple and inexpensive molecular screening assay will identify the at-risk population for yearly CT screening. Like all good studies, NLST data not only advance the practice but also provide fodder for future research. ■

Disclosure: Dr. Govindan reported no potential conflicts of interest.

Dr. Govindan is Professor of Medicine, and Co-Director, Section of Medical Oncology, Washington University School of Medicine, St Louis.

Ramaswamy Govindan, MD

categorizing the severity of the ad-verse events. The Data and Safety Monitoring Board was regularly reviewing the data, and when we looked at the overall benefit for lung cancer mortality it included screen-

promise in terms of detecting more lung cancers than chest x-ray. Then Dr. Claudia Henschke’s major 1999 paper in The Lancet received posi-tive interest,2 and its report of earli-er-stage lung cancers detected with low-dose helical CT helped launch a vigorous debate as to next steps.

At the time, much of the debate centered on three opinions: One group thought that evidence for low-dose helical CT screening was so powerful that we didn’t need a trial and we should move forward with lung cancer screening. An-other opinion was that although the prelimi-nary information looked good, we have had many situations in oncology in which the first informa-tion was promising but a randomized, well-pow-ered trial ends up show-ing no benefit. Then there were the true skep-tics who thought this complex, aggressive disease could not be detected early enough to af-fect its dismal natural history. They reasoned that the positive benefits would not be offset by the compli-cations of surgery, radiation, and other interventions with risk.

The scientific community could not reach a consensus on this is-sue. However, the gold standard in answering clinical questions of this importance has been the random-ized controlled trial. So despite the many critics, conducting the NLST was the right decision. In fact, even

if the results had proved no ben-efit for low-dose helical CT, it still would have been an important out-come because we would have had to go back to the drawing board and ex-amine why this promising screening approach did not work. That’s how scientific discovery works.

Design and DataWhat gave this trial solid answers? The NCI-funded study was de-

signed and conducted by the Nation-al Lung Screening Trial Research Team, a joint effort of my group, the Lung Screening Study, under con-tract from the Division of Cancer

Prevention, and a group from the American Col-lege of Radiology Imag-ing Network (ACRIN), a Cooperative Group, funded by the Division of Cancer Treatment and Diagnosis. We enrolled 53,454 individuals who were at high risk but healthy enough to un-dergo surgery if needed.

So it was a very large sample of the high-risk population. If it had been a smaller study with a few thousand participants it would not have been statistically robust. NLST provided a valid scientific answer to the ques-tion we asked: Does screening with low-dose helical CT confer a signifi-cant reduction in lung cancer mor-tality compared with chest x-ray?

Have you looked at harms in rela-tion to benefits data?

Yes. In our primary manuscript, we produced data delineating and

National Lung Screening Trialcontinued from page 1

ing-associated harms. The overall assessment was a net benefit.

Where Do We Go From Here?Although NCI does not offer advice

Christine Berg, MD

continued on page 7

Cancer Screening

MG70618 0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.

Lilly Oncology believes that the future of cancer care relies on therapies and support programs that are tailored to the unique needs of your patients. That’s why we’re working with oncologists to fi nd new ways to help make a meaningful difference in the lives of patients. Tell us what your patients need—we’re listening.

Lilly Oncology Making science personal.

We’re listening.Your feedback inspires our actions.

48029_elonco_MG70618_ap6_fa.indd 1 5/16/11 10:44 AM

MG70618 0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.

Lilly Oncology believes that the future of cancer care relies on therapies and support programs that are tailored to the unique needs of your patients. That’s why we’re working with oncologists to fi nd new ways to help make a meaningful difference in the lives of patients. Tell us what your patients need—we’re listening.

Lilly Oncology Making science personal.

We’re listening.Your feedback inspires our actions.

48029_elonco_MG70618_ap6_fa.indd 1 5/16/11 10:44 AM

PAGE 6 The ASCO Post | AUGUST 15, 2011

2011 ASCO Annual Meeting

Three randomized controlled tri-als presented at the 2010 Annual

Meeting of the American Society of Hematology (ASH) suggested that treating multiple myeloma with le-nalidomide (Revlimid) increased the risk of second primary malignancies; of particular concern is transforma-tion to acute myeloid leukemia or myelodysplastic syndromes.1-3 At the ASCO Annual Meeting in June, ad-ditional studies that explored this is-sue suggested that the risk of second primary malignancies in this setting is low and the benefits of lenalidomide seem to outweigh the risks, but a num-ber of questions remain unresolved.

“Currently, we lack clear answers as to which patients will develop second primary malignancies after myeloma,” said Ola Landgren, MD, PhD, Chief

of the Multiple My-eloma Section at NCI and formal dis-cussant of the three papers at the ASCO meeting. “We lack clear answers due

to small numbers of patients in these studies and limitations of the study designs. We have to discuss benefits vs risks with patients, but there are no clear data to guide us at this time. A concerted effort is needed to char-acterize the molecular features of pa-tients who develop second primary malignancies after myeloma.”

MM-015 StudyMM-015 was one of the three stud-

ies at ASH raising concern about sec-ond primary malignancies.3 At ASCO, an updated analysis related to second

primary malignancies was presented. MM-015 enrolled 459 newly diag-nosed, transplant-ineligible patients with a median age of about 71 years at 82 centers in Europe, Australia, and Israel.4 Patients with newly diagnosed multiple myeloma were randomly as-signed to (1) melphalan/prednisone/lenalidomide followed by lenalido-mide maintenance, or (2) melphalan/prednisone/lenalidomide, or (3) mel-phalan/prednisone and treated until disease progression, at which point they all received lenalidomide plus dexamethasone.

The continuous lenalidomide arm (arm 1) achieved a significant and “unprecedented” improvement in pro-gression-free survival (median = 31 vs 13 months, respectively; 60% reduced risk of progression; P < .001). Progres-sion-free survival was even more im-pressive in patients aged 65 to 75 years (69% reduced risk of progression; P  <  .001). However, no difference in 5-year survival was seen among the three arms. Presenting author of this paper, Antonio Palumbo, MD, Uni-versity of Torino, Italy, said that with longer follow-up, a survival difference may emerge.

At a median follow-up of 30 months, the number of invasive sec-ond primary malignancies was 12 (7 hematologic malignancies, 5 solid tumors) in the lenalidomide mainte-nance arm of the trial, 9 (5 hematolog-ic malignancies, 4 solid tumors) in the melphalan/prednisone/lenalidomide arm, and 4 (1 hematologic malignan-cy, 3 solid tumors) in the melphalan/prednisone arm.

Dr. Palumbo emphasized that the risk of second primary malignancies, although increased by the concomi-tant use of lenalidomide and melpha-lan, is low and that the benefit-risk profile strongly favors the use of con-tinuous lenalidomide for newly diag-nosed patients.

BiRD StudyThe BiRD study also explored this

issue.5 BiRD was a small phase II trial involving 72 patients, median age 63 years, with newly diagnosed mul-

tiple myeloma. Patients were treated with lenalidomide, clarithromycin, and dexamethasone until progressive disease, stem cell transplantation, or unacceptable toxicity. At baseline, 8 patients had prior solid tumors, 2 had skin cancers, and 1 had lymphoma.

At a median follow-up of 6 years, median progression-free survival was 70.8 months and median 4-year over-all survival was 82.2%; median 5-year overall survival had not yet been reached. Follow-up at 5 years revealed five new primary solid tumors and no new hematologic malignancies.

Progression-free survival remains encouraging; frequency of second primary malignancies was low and similar to that reported in the Surveil-lance, Epidemiology, and End Results (SEER) database for people of similar age, said presenting author Adriana Rossi, MD, Weill-Cornell Medical College, New York. “Routine screen-ing and prevention measures should

Expert Point of ViewFormal discussant Ola Landgren, MD, PhD,

Chief of the Multiple Myeloma Section at NCI, had some additional comments about the 2011 ASCO presentations on second primary malignan-cies in lenalidomide-treated patients.1 He said that the reporting of second primaries has several limi-tations that patients and doctors need to be aware of. For example, these randomized studies were designed to evaluate responses and survival rates between the study arms. Thus, the sample sizes are too small to allow a careful characterization of the risk—and underlying mechanisms—of second primary malignancies. An al-ternative strategy to increase the sample size could be to pool several clinical studies and then do a retrospective collection of second primary malignan-cies. However, analysis-based retrospective data will inherently underesti-mate their true incidence.

On a general note, when interpreting data on second primary malignan-cies, and when comparing results from different studies, one has to be cau-tious. For example, differences in study design, including follow-up time, sam-ple size, controls, and quality of data, will always influence the results. Also, variations in survival differences between study arms play a role.

Most likely, several factors play a role in the development of second prima-ry malignancies, including host-related, treatment-related, myeloma-related, and behavioral factors. An important future research focus should be to de-termine the relative roles of each of these factors to elucidate the mechanisms involved, as well as to characterize the molecular features of patients who de-velop second malignancies following myeloma. ■

Financial Disclosure: Dr. Landgren reported no potential conflicts of interest.

Reference1. Landgren O: Secondary malignancies following multiple myeloma. 2011

ASCO Annual Meeting. Presented June 8, 2011.

Second Primary Malignancies Explored in Multiple Myeloma By Alice Goodman

Hematology

SEE PAGE 45Antonio Palumbo, MD

Ola Landgren, MD, PhD

■ Based on small numbers, an increase in second malignancies has been observed in the lenalidomide arm of randomized trials of multiple myeloma patients treated with maintenance lenalidomide; the evidence for causation is inconclusive.

■ Lenalidomide achieves statistically significantly longer progression-free survival, and one study has found a statistically significant overall survival benefit.

■ The benefits of treatment should be balanced against the risk of second primary malignancies and leukemic transformation.

■ Physicians need to discuss the risks with their patients, although the data are currently not clear.

■ More research is needed to characterize the molecular features of myeloma patients who develop second primary malignancies after treatment with lenalidomide.

Lenalidomide in Multiple Myeloma

ASCOPost.com | AUGUST 15, 2011 PAGE 7

2011 ASCO Annual Meeting

continue as medically indicated for each patient, including examination for skin cancer,” Dr. Rossi noted.

MM990/010 StudyMM990/010 was a pooled analysis

of two phase III studies with a total of 704 patients with relapsed/refractory multiple myeloma treated with lenalid-omide plus dexamethasone or placebo plus dexamethasone until disease pro-gression.6

During the active treatment phase, 8 invasive second primary malignancies developed in the lenalidomide arm vs 2 in the placebo arm; 11 noninvasive and 2 noninvasive second primaries developed in the two arms, respectively. Moreover, 3 of the 8 invasive malignan-cies occurred within the first 13 months of treatment.

“No clear pattern of invasive second primaries was seen. Nonmelanoma skin cancers developed in 11 patients on le-nalidomide plus dexamethasone and

2 patients on placebo,” said presenting author Ruben Niesvizky, MD, Weill-Cornell Medical College, New York.

The incidence of second primary malignancies was low and similar to the background incidence of similarly aged persons in the general population. However, overall survival was signifi-cantly longer in the group treated with lenalidomide plus dexamethasone, and improvement persisted with long-term follow-up. ■

Disclosure: Dr. Palumbo has served as a consultant for and received honoraria from Celgene and Janssen-Cilag, and has also received honoraria from Ortho Biotech. Dr. Rossi reported no potential conflicts of interest. Dr. Niesvizky has served as an advisor or consultant for Celgene, Millenium, and Onyx, has received honoraria from Celgene and Millenium, has received research funding from Proteolix, Seattle Genetics, Onyx, Millenium, and Celgene, has served on a data monitoring committee for Proteolix, and on an advisory committee/board of directors for Millenium and Celgene.

References1. Attal M, Laywers VC, Marit G, et

al: Maintenance treatment with lenalid-omide after transplantation for MYELO-MA: Final analysis of the IFM 2005-02. 52nd ASH Annual Meeting. Abstract 310. Presented December 6, 2010.

2. McCarthy PL, Owzar K, Anderson KC, et al: Phase III Intergroup study of lenalidomide versus placebo mainte-nance therapy following single autolo-gous hematopoietic stem cell transplant for multiple myeloma: CALGB 100104. 52nd ASH Annual Meeting. Abstract 37. Presented December 5, 2010.

3. Palumbo AP, Delforge M, Cata-lano J, et al: A phase 3 study evaluating the efficacy and safety of lenalidomide combining melphalan and prednisone in patients ≥ 65 year with newly diagnosed multiple myeloma (NDMM): Con-tinuous use of lenalidomide vs fixed-duration regimens. 52nd ASH Annual Meeting. Abstract 622. Presented De-cember 6, 2010.

4. Palumbo AP, Delforge M, Catalano J, et al: The incidence of second prima-ry malignancies (SPM) in melphalan-prednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) aged 65 or older. 2011 ASCO Annual Meeting. Abstract 8007. Presented June 5, 2011.

5. Rossi AC, Mark TM, Jayabalan D, et al: Incidence of second primary ma-lignancies (SPM) after 6-years follow-up of continuous lenalidomide in first-line treatment of multiple myeloma (MM). 2011 ASCO Annual Meeting. Abstract 8008. Presented June 5, 2011.

6. Dimoupoulos MA, Orlowski RZ, Niesvizky R, et al: Lenalidomide and dexamethasone (LEN plus DEX) treat-ment in relapsed refractory myeloma (RRMM) patients and risk of second primary malignancy (SPM): Analysis of MM-009/010. 2011 ASCO Annual Meeting. Abstract 8009. Presented June 5, 2011.

American Lung Association Reflects on the National Lung Screening Trial

The American Lung Association is optimistic about the promising re-sults of NCI’s National Lung Screening Trial, which indicate low-dose

CT scans can have significant impact on lung cancer mortality. This study is the first comprehensive clinical trial to find that screening high-risk in-dividuals with low-dose CT reduces lung cancer deaths by 20% compared with chest x-ray.

“Although the National Lung Screening Trial results are an important step forward in the fight against lung cancer, the single most important thing any smoker can do to reduce their chances of developing or dying from lung cancer is to quit smoking,” said Albert Rizzo, MD, American Lung Association Board Chair-Elect, and a pulmonary and critical care physician. “The Surgeon General’s 30th Report released in December confirmed that there is no safe level of exposure to tobacco  smoke, and the sooner someone quits smoking, the less likely he or she is to develop tobacco-related diseases.”

The American Lung Association is also convening an expert panel to re-view the National Lung Screening Trial study and to make policy recom-mendations.  This panel will be lead by Jonathan M. Samet, MD, MS, a lung health expert and a member of the American Lung Association’s Scien-tific Advisory Committee.

“If current or former smokers have questions regarding whether or not they should receive screening, the Lung Association recommends they speak with their health-care provider about the benefits and risks associated with screening,” said Dr. Rizzo. ■

to clinicians, shouldn’t this trial initi-ate a serious discussion about how we proceed with lung cancer screening?

The discus-sion has already begun. The NCI results are clearly of importance to the population that we studied. What we are do-ing to further the discussion is working with the Cancer Interven-tion and Surveil-lance Modeling Network (CIS-NET), which conducts modeling of screening benefits for a variety of cancers. The modelers will validate that their models replicate our 20% mortality reduction from low-dose helical CT screening of a high-risk group as studied in the NLST. Then these modelers will introduce differ-ent parameters conferring lower risks of lung cancer, such as a younger age or lower pack-years of smoking, to determine a potential benefit-to-risk ratio. This information is important in dissemination of screening to a broader population. Additionally, CISNET will model the potential benefit of more rounds of screening or different frequencies.

Our colleagues in ACRIN are looking at costs related to the en-tire screening process, in terms of issues such as follow-up examina-tions to evaluate findings suspi-

cious for lung cancers and oth-er illnesses, sur-gery done to bi-opsy abnormal lesions, treat-ments delivered, etc. If lung can-cer screening is to be used, we need to under-stand not only the potential benefits but also the costs. All in-

terested parties should weigh in on this important issue.

Any last thoughts on lung cancer and its prevention?

It is vital that we do everything we can to help individuals in the United States and worldwide quit smoking or using other tobacco products. More important, it is up to us to intensify our efforts so that our youth never start smoking. ■

Disclosure: Dr. Berg reported no potential conflict of interest

References1. The National Lung Screening Trial

Research Team: Reduced lung-cancer

National Lung Screening Trialcontinued from page 4

It is vital that we do everything we can to help individuals

in the United States and worldwide quit smoking or

using other tobacco products.

Low-dose CT scans can have significant

impact on lung cancer mortality.

mortality with low-dose computed to-mographic screening. N Engl J Med 365:395-409, 2011.

2. Henschke CI, McCauley DI, Yan-

kelevitz DF, et al: Early Lung Cancer Action Project: Overall design and find-ings from baseline screening. Lancet 354:99-105, 1999.

ADVANCING SURVIVALHALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2011 Eisai Inc. All rights reserved. Printed in USA /May 2011 ERI 81

Please see accompanying brief summary of Halaven full Prescribing Information.

IndicationHalavenTM is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety InformationNeutropenia• Monitor complete blood counts prior to each dose, and

increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days

• Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels

• Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy• Patients should be monitored closely for signs of peripheral

motor and sensory neuropathy

• Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less

• Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed February 2, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for � rst-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano JA,Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923.

OVERALL SURVIVALDISCOVER

Included in the NCCN Guidelines1

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2

Halaven: Safety pro� le• Studied in the Phase III EMBRACE trial2

Most Common Adverse Reactions• Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%),

asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

• Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events had been observed, median OS with Halaven vs Control Arm

(Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2, 11

Halaven: The FIRST and ONLY third-line, single-agent therapy proven to signi� cantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10

CI=con� dence interval; HR=hazard ratio. *EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracycline, 10% other chemotherapy) and 3% hormonal therapy.2, 11

HalavenControl Arm

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 6 12 18 24 30 36

TIME (MONTHS)

PROP

ORTI

ON O

F PA

TIEN

TS A

LIVE

508 406 274 142 54 11 0254 178 106 61 26 5 0

HalavenTPC Arm

Number of patients at risk

UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2

TPC Arm (n=254)

10.6(9.2, 12.0)

203

13.2(12.1, 14.4)

386

Median OS (months [95% Cl])

Deaths

Halaven(n=508)

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Scan this code to visit www.halaven.com

or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered

to a pregnant woman and patients should be advised of these risks

QT Prolongation• In an uncontrolled ECG study in 26 patients, QT

prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities

• Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-

Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

ERIBPUS-3070_M03_Post_DDMAC_JournalAd_KING.indd 1 5/3/11 12:27 PM

ADVANCING SURVIVALHALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2011 Eisai Inc. All rights reserved. Printed in USA /May 2011 ERI 81

Please see accompanying brief summary of Halaven full Prescribing Information.

IndicationHalavenTM is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety InformationNeutropenia• Monitor complete blood counts prior to each dose, and

increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days

• Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels

• Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy• Patients should be monitored closely for signs of peripheral

motor and sensory neuropathy

• Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less

• Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed February 2, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for � rst-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano JA,Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923.

OVERALL SURVIVALDISCOVER

Included in the NCCN Guidelines1

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2

Halaven: Safety pro� le• Studied in the Phase III EMBRACE trial2

Most Common Adverse Reactions• Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%),

asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

• Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events had been observed, median OS with Halaven vs Control Arm

(Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2, 11

Halaven: The FIRST and ONLY third-line, single-agent therapy proven to signi� cantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10

CI=con� dence interval; HR=hazard ratio. *EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracycline, 10% other chemotherapy) and 3% hormonal therapy.2, 11

HalavenControl Arm

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 6 12 18 24 30 36

TIME (MONTHS)

PROP

ORTI

ON O

F PA

TIEN

TS A

LIVE

508 406 274 142 54 11 0254 178 106 61 26 5 0

HalavenTPC Arm

Number of patients at risk

UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2

TPC Arm (n=254)

10.6(9.2, 12.0)

203

13.2(12.1, 14.4)

386

Median OS (months [95% Cl])

Deaths

Halaven(n=508)

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Scan this code to visit www.halaven.com

or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered

to a pregnant woman and patients should be advised of these risks

QT Prolongation• In an uncontrolled ECG study in 26 patients, QT

prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities

• Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-

Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

ERIBPUS-3070_M03_Post_DDMAC_JournalAd_KING.indd 1 5/3/11 12:27 PM

PAGE 10 The ASCO Post | AUGUST 15, 2011

2011 ASCO Annual Meeting

Bevacizumab (Avastin) adminis-tered with chemotherapy and

continued after chemotherapy im-proves outcomes in ovarian cancer, according to two multicenter, random-

ized, double-blind phase III investiga-tions presented at the 2011 ASCO An-nual Meeting. The first study, ICON7, incorporated bevacizumab as part of first-line treatment with standard

chemotherapy,1 and the second study, OCEANS, used the monoclonal anti-body to treat platinum-sensitive, recur-rent ovarian, primary peritoneal, or fal-lopian tube cancer.2

ICON7 TrialEarlier results of ICON7 presented

at the 2010 European Society for Medi-cal Oncology (ESMO) meeting showed that combining bevacizumab with a platinum-containing doublet improved progression-free survival. Gunnar Kristensen, MD, a lead investigator of the study and Senior Consultant in the Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo, presented an updated progression-free survival analysis and an interim analysis of overall survival at the ASCO meet-ing. Mature overall survival results will be presented in 2013, he said.

The phase III study randomly as-signed 1,528 women with high-risk early-stage and advanced-stage ovarian cancer to 6 cycles of carboplatin plus paclitaxel every 3 weeks vs the same chemotherapy with bevacizumab at 7.5 mg/kg every 3 weeks continued for an additional 12 cycles. At baseline, medi-an age was 57 years, and 69% had serous histology.

The updated analysis showed a pro-longation of progression-free survival for the addition of bevacizumab, with a net gain of 2.4 months. Median pro-gression-free survival was 17.4 in the control arm vs 19.8 in the bevacizumab-containing arm (P = .039). At a median follow-up of 28 months, a trend toward prolonged overall survival with beva-cizumab was observed in the interim analysis, with median overall survival not yet reached (hazard ratio = 0.85; 95% confidence interval = 0.69–1.04).

Further analysis of overall survival showed that patients with a high risk of recurrence (ie, stage  III suboptimally debulked with > 1 cm tumor after sur-gery or stage  IV after surgery) derived greater benefit from bevacizumab than other patients. At a median follow-up of 28 months, 47% of high-risk controls were dead vs 34% of high-risk women treated with bevacizumab (P = .002).

Bevacizumab Makes Inroads against Ovarian CancerBy Alice Goodman

Gynecologic Cancer

Gunnar Kristensen, MD

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.Recommended dose delays• Do not administer HALAVEN on Day 1 or Day 8 for any of the following:

– ANC <1,000/mm3

– Platelets <75,000/mm3

– Grade 3 or 4 non-hematological toxicities• The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and

initiate the next cycle no sooner than 2 weeks later.Recommended dose reductions• If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN

at a reduced dose as set out in Table 1.• Do not re-escalate HALAVEN dose after it has been reduced.Table 1 Recommended Dose Reductions

Event Description Recommended HALAVEN Dose

Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following:

1.1 mg/m2

ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infectionPlatelets <25,000/mm3

Platelets <50,000/mm3 requiring transfusionNon-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicityOccurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2

Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.5.3 Embryo-Fetal ToxicityThere are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.5.4 QT ProlongationIn an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day  1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONSThe following adverse reactions are discussed in detail in other sections of the labeling:• Neutropenia • Peripheral neuropathy • QT interval prolongationThe most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1

MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)All Grades ≥ Grade 3 All Grades ≥ Grade 3

Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23%Anemia 58% 2% 55% 4%Nervous system disordersPeripheral neuropathyb 35% 8% 16% 2%Headache 19% <1% 12% <1%General disorders and administrative site conditionsAsthenia/Fatigue 54% 10% 40% 11%Mucosal inflammation 9% 1% 10% 2%Pyrexia 21% <1% 13% <1%Gastrointestinal disordersConstipation 25% 1% 21% 1%Diarrhea 18% 0 18% 0Nausea 35% 1% 28% 3%Vomiting 18% 1% 18% 1%Musculoskeletal and connective tissue disordersArthralgia/Myalgia 22% <1% 12% 1%Back pain 16% 1% 7% 2%Bone pain 12% 2% 9% 2%Pain in extremity 11% 1% 10% 1%InvestigationsWeight decreased 21% 1% 14% <1%Metabolism and nutrition disordersAnorexia 20% 1% 13% 1%

Table 2 (cont’d)

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth• General Disorders and Administration Site Conditions: peripheral edema• Infections and Infestations: upper respiratory tract infection• Metabolism and Nutrition Disorders: hypokalemia• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness• Nervous System Disorders: dysgeusia, dizziness• Psychiatric Disorders: insomnia, depression• Skin and Subcutaneous Tissue Disorders: rash8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Category DThere are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.8.3 Nursing MothersIt is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric UseThe safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.8.6 Hepatic ImpairmentA study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal ImpairmentNo formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose.12 CLINICAL PHARMACOLOGY 12.2 PharmacodynamicsCardiac ElectrophysiologyThe effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, mutagenesis, impairment of fertilityCarcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling• Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of

infection such as chills, cough, or burning or pain on urination.• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN.––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.© 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247)All Grades ≥ Grade 3 All Grades ≥ Grade 3

Respiratory, thoracic, and mediastinal disordersCough 14% 0 9% 0Dyspnea 16% 4% 13% 4%Skin and subcutaneous tissue disordersAlopecia 45% NAc 10% NAc

Infections and InfestationsUrinary Tract Infection 10% 1% 5% 0

aBased upon laboratory data.b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.

cNot applicable; (grading system does not specify > Grade 2 for alopecia).

ASCOPost.com | AUGUST 15, 2011 PAGE 11

2011 ASCO Annual MeetingGynecologic Cancer

“This represents a median gain in survival of about 8 months and a 36% reduction of risk of dying among high-risk patients,” Dr. Kristensen stated. Given the high cost of using bevacizum-ab and the fact that the high-risk group derived preferential benefit from front-line bevacizumab, Dr. Kristensen said that for now, he restricts the use of beva-cizumab to high-risk patients. “We need the final survival analysis,” he added.

OCEANS TrialOCEANS was a positive study

showing that bevacizumab added to carboplatin/gemcitabine followed by bevacizumab maintenance therapy pro-vided a clinically meaningful benefit in recurrent ovarian cancer, achieving

a 52% reduction in risk of progression and a median in-crease of 4 months in progression-free sur-vival compared with carboplatin/gem-

citabine alone. According to the inves-tigators, safety data were reassuring and consistent with the known side-effect profile of bevacizumab.

“Bevacizumab plus carboplatin/gemcitabine followed by bevacizum-ab maintenance should be consid-ered a new option for recurrent, plat-inum-sensitive ovarian cancer,” said

Carol Aghajanian, MD, of Memo-rial Sloan-Kettering Cancer Center in New York, who presented results at the Annual Meeting.

OCEANS randomly assigned 484 patients in a 1:1 ratio to receive either four cycles of carboplatin/gemcitabine plus placebo or the same regimen of carboplatin/gemcitabine plus bevaci-zumab at 15 mg/kg every 3 weeks con-tinued until disease progression. The primary endpoint of progression-free survival was met. At a median follow-up of 24 months, median progression-free survival was 8.4 months with stan-dard carboplatin/gemcitabine vs 12.4 months for the bevacizumab-contain-ing arm (P < .0001). Moreover, 79% of women who received bevacizumab had significant tumor shrinkage vs 57% in the carboplatin/gemcitabine–alone group. The curves separated between the two arms at 2 months and remained separate at 2.5 years of follow-up.

Dr. Aghajanian said that the next step is to evaluate the role of bevaci-zumab plus chemotherapy in plati-num-resistant ovarian cancer and to combine it with other emerging novel therapies.

Added PerspectiveAndrew Seidman, MD, Memo-

rial Sloan-Kettering Cancer Center, who moderated a press conference

where these data were released, noted that ICON7 and OCEANS show the benefit of antiangiogenic maintenance therapy at two different doses of beva-cizumab (7.5 and 15 mg). No head-to-head studies comparing the two doses have been performed.

“The data support a potential role for bevacizumab as the first biologic agent in ovarian cancer,” he stated.

Regarding the OCEANS results, he said: “A 52% improvement in progression-free survival with time away from cytotoxic chemotherapy

lets women live longer and have more active lives. It is reassuring that there were no new safety signals [with bev-acizumab] in this trial.” ■

Disclosure: Dr. Kristensen has been a consultant for Roche. Dr. Aghajanian has been a consultant for and has received research funding from Genentech. Dr. Seidman reported no potential conflicts of interest.

References1. Kristensen G, Perren T, Qian W, et al:

Result of interim analysis of overall survival in the GCIG ICON7 phase III randomised trial of bevacizumab in women with newly diagnosed ovarian cancer. 2011 ASCO An-nual Meeting. Abstract LBA5006. Present-ed June 4, 2011.

2. Aghajanian C, Finkler NJ, Ruther-ford T, et al: OCEANS: A randomized, double-blinded, placebo-contolled, phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with plati-num-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube can-cer. 2011 ASCO Annual Meeting. Abstract LBA5007. Presented June 4, 2011.

Expert Point of View

Formal discussant, Anil Sood, MD, The Uni-versity of Texas MD Anderson Cancer Cen-

ter, Houston, said that both studies presented im-portant information, but several issues should be considered, including the best combination with bevacizumab, whether the benefits accrue from bevacizumab alone or chemotherapy plus bevaci-zumab, the optimal dose of bevacizumab, how long to continue treatment, and the true role of bevaci-zumab in platinum-sensitive disease.

“The gains in progression-free survival [with bevacizumab] are relatively modest. This raises questions about the best che-motherapy partners and the bevacizumab dose. When you stop giving beva-cizumab, there is a falling off of benefit. We don’t know how long to continue treatment. Also cost is a factor…. Bevacizumab costs about $100,000 per year,” Dr. Sood said.

“We are not necessarily curing patients [with bevacizumab]. They may de-velop adaptive-evasive responses. Much more work needs to be done to iden-tify and develop more effective therapies,” he commented. ■

Financial Disclosure: Dr. Sood reported no potential conflicts of interest.

Anil Sood, MD

Andrew Seidman, MD

SEE PAGE 45

■ The ICON7 trial showed that front-line bevacizumab added to platinum-containing chemotherapy and continued as maintenance therapy extended progression-free survival in high-risk early-stage or advanced ovarian cancer by a median of 2.4 months.

■ The OCEANS trial showed that platinum-based chemotherapy plus bevacizumab, with bevacizumab continued until disease progression, improved median progression-free survival by about 4 months in women with recurrent ovarian cancer.

■ These trials raise questions about optimal timing and dose of bevacizumab, best chemotherapy combinations, and which patients to treat in the absence of biomarkers, given the high cost of the drug and modest improvements in progression-free survival.

High-risk and Recurrent Ovarian Cancer

Contact The ASCO PostEDITOR I A L COR R ESPONDENCE

James O. Armitage, MD Editor-in-Chief

email: Editor@ASCOPost.com

Cara H. Glynn Director of Editorial

email: Cara@harborsidepress.com

Phone: 631.935.7654

Andrew Nash Assoc. Director of Editorial

email: Andrew@harborsidepress.com

Phone: 631.935.7657

EDITOR I A L OFFICEHarborside Press

37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805

ASCOPost.com HarborsidePress.com

R IGHTS A ND PER MISSIONSemail: Permissions@harborsidepress.com

A DV ERTISING Rates, reprints, or supplements

Leslie Dubin

email: Leslie@harborsidepress.com Phone: 631.935.7660

C O M I N G S O O N

CRI00127B/280523 © 2011 Pfizer Inc. All rights reserved. August 2011

ASCOPost.com | AUGUST 15, 2011 PAGE 13

2011 ASCO Annual Meeting

Men with prostate cancer who receive intermittent courses of

androgen-suppressing therapy can live as long as those who are treated with continuous therapy, according to re-sults of a recently concluded study. Until now, standard treatment has con-sisted of continuous therapy, but this is expected to change as a result of these findings. Juanita Crook, MD, FRCPC,

of the University of British Columbia, presented the results of the phase  IIII randomized trial conducted by the Na-Na-tional Cancer Institute of Canada Clin- Clin-ical Trials Group (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK In-tercontinental Trial CRUKE/01/013), at the 2011 ASCO Annual Meeting.1

Conventional radiation therapy for localized prostate cancer is associated with a >30% incidence of prostate-specific antigen (PSA) failure, which is typically treated with hormonal thera-py. Intermittent androgen suppression for PSA recurrence following surgical or radiation treatment for prostate cancer can delay hormone resistance

and improve qual-ity of life, but it was not known if this approach could pro-long survival. This open-label, noninfe-riority randomized

trial compared intermittent androgen suppression and continuous androgen deprivation to evaluate effects on sur-vival and quality of life.

Study DesignPatients eligible for enrollment had

rising PSA levels >  3.0 ng/mL more

than 1 year post-radiotherapy and may have had up to 1 year of neoadjuvant or adjuvant androgen-deprivation thera-py for localized prostate cancer. Strati-fication factors consisted of time since radiotherapy (> 1–3 vs > 3 years), ini-tial PSA (<  15 vs >  15 ng/mL), and prior radical prostatectomy or andro-gen-deprivation therapy. Intermittent androgen suppression cycles consisted of 8 months of treatment with PSA-determined off-treatment periods. The primary endpoint was overall survival; secondary endpoints were hormone resistance, cholesterol/HDL/LDL, length of nontreatment periods, tes-tosterone level, quality of life, and po-tency recovery.

Men who enrolled in this clinical trial had initially undergone defin-itive radiotherapy for their prostate cancer, either as primary treatment or as salvage for recurrence after radical prostatectomy, but subsequently de-veloped elevated levels of PSA, indi-cating relapse. Nearly 1,400 men par-

ticipated in the trial, which recruited patients from 1999 until 2005. Most enrolled patients were from Canada, but others were from the United States and United Kingdom.

Patients randomly assigned to the control group (n = 696) received con-696) received con- received con-con-tinuous injections of a slow-release luteinizing hormone–releasing hor-uteinizing hormone–releasing hor-mone (LHRH) blocker, usually at 3-month intervals. Those in the ex-perimental group (n = 690) received the same drug but in 8-month treat-ment cycles, which were interrupted

for extended “drug holidays” last-ing several months to years. Patients were monitored for PSA levels every 2 months. When PSA levels rose to >  10 ng/mL while off treatment, LHRH blocker therapy was resumed for another 8-month cycle.

Major ResultsThe trial follow-up period was

stopped early (median follow-up, 6.9 years) because a planned interim analysis, reviewed by an independent data and safety monitoring committee, unequivocally demonstrated no differ-ence in survival outcome between the two treatment groups. Median overall survival was 8.8 years on intermittent androgen suppression vs 9.1 years on continuous androgen deprivation (HR = 1.02; 95% CI = 0.86–1.21; P = .009 for noninferiority [HR ≥ 1.25 for intermittent androgen suppression vs continuous androgen deprivation]). Patients on the intermittent androgen suppression arm had more disease-

related deaths (122 vs 97) and fewer disease-unrelated deaths (134 vs 146).

Patients receiving intermittent androgen suppression therapy had a reduced incidence of hot flashes, but rates of other adverse events, including myocardial events and osteoporotic fractures, were similar between the two groups. Full testosterone recovery was noted in 35% of men on the in-termittent androgen suppression arm. Those receiving intermittent courses of the testosterone-suppressing drug reported better quality of life because

of fewer or less intense side effects. Us-Us-ing a 10-point change from baseline score as a clinically meaningful crite-rion for quality-of-life change, inter-mittent androgen suppression patients had significant improvements in physi-cal function, fatigue, urinary problems, hot flashes, desire for sexual activity, and erectile function compared with men on the continuous androgen de-privation arm (all P ≤ .01).

Other Implications“These important findings also have

significant economic and quality-of-life implications,” noted Dr. Crook. Pa-tients on the intermittent therapy used only one-third the amount of drug as compared with continuous therapy, re-ducing both cost and toxicity. Adverse effects associated with androgen-sup-pressing therapy include hot flashes, sexual impotence, growth of breast tis-sue, insomnia, weight gain, worsening of diabetes, loss of muscle mass, and osteoporosis.

According to Dr. Crook, “For PSA recurrence after definitive radiation therapy, intermittent androgen sup-pression given as per the PR.7 algo-rithm is not inferior to continuous androgen deprivation with respect to overall survival.

“Intermittent androgen suppres-sion should be the standard of care for most men with PSA recurrence after definitive radiotherapy—ei-ther primary or salvage post–radical prostatectomy—who are initiating androgen-deprivation therapy,” she concluded. ■

Disclosure: Dr. Crook has received honoraria and research funding from Abbott, AstraZeneca, and sanofi-aventis.

Reference1. Crook JM, O’Callaghan CJ, Ding

K, et al: A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after rad-ical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013). 2011 ASCO An-nual Meeting. Abstract 4514. Presented June 6, 2011.

Intermittent or Continuous Androgen Suppression Produces Comparable Survival after Radical Therapy in Prostate CancerBy Larry J. Rosenberg, PhD

■ In men with PSA recurrence following definitive radiotherapy for prostate cancer, intermittent androgen-suppressing therapy produces survival equivalent to continuous therapy.

■ Intermittent androgen suppression was associated with improved quality of life compared with continuous androgen deprivation.

■ The results suggest intermittent therapy should be the standard of care for most patients who experience PSA recurrence after definitive radiotherapy and are initiating androgen-deprivation therapy.

Intermittent vs Continuous Androgen Suppression for Prostate Cancer

Juanita Crook, MD, FRCPC

SEE PAGE 45

Genitourinary Cancer

C O M I N G S O O N

CRI00127B/280523 © 2011 Pfizer Inc. All rights reserved. August 2011

PAGE 14 The ASCO Post | AUGUST 15, 2011

2011 ASCO Annual Meeting

Patients with hepatocellular car-cinoma and moderate liver dys-

function can derive benefit from, and be treated safely with, sorafenib (Nexavar), according to the second interim analysis of the GIDEON trial,

presented at the 2011 ASCO Annual Meeting by Jorge A. Marrero, MD, of the University of Michigan in Ann Arbor.1

Real-life Practice SettingsGIDEON (Global Investigation of

Therapeutic Decisions in Hepatocel-lular Carcinoma and of Its Treatment

with Sorafenib) is an ongoing, global, prospective study of sorafenib in real-life practice. It is evaluating the drug in diverse settings and patient subgroups

Sorafenib Acceptable in Child-Pugh B Patients with Hepatocellular Carcinoma But should not be routinely prescribed, yetBy Caroline Helwick

Expert Point of View

The GIDEON trial “can provide us with important information

on safety and single-arm efficacy in the Child-Pugh B population,” said Bert H. O’Neil, MD, of the Univer-sity of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“The results suggest that safety is similar between Child-Pugh A and Child-Pugh B patients; how-ever, the duration of therapy for the Child-Pugh B population was exceedingly short, 8.5 weeks. This suggests that equivalent numbers of adverse events occur in a shorter pe-riod of time,” Dr. O’Neill said. “The low number of dose reductions in the Child-Pugh B population is also interesting, but is also affected by the short treatment duration.” Tak-en together, these findings suggest that sorafenib can be started at full doses in future studies of the Child-Pugh B population, he said.

Dr. O’Neil cautioned against extrapolating these results to cur-rent clinical practice at this time, concluding that sorafenib should re-main investigational in Child-Pugh B patients, for whom the “the stan-dard of care remains best supportive care.” Sorafenib should probably not be used at all in the Child-Pugh C cirrhotic population, he added. ■

Disclosure: Dr. O’Neil reported having a consultant or advisory role for Amgen and Bayer-Onyx and receiving honoraria from Amgen.

Bert H. O’Neil, MD

Gastrointestinal Cancer

693US11AB05808 TRIM 7.625" x 10.5" Publication:

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Select ERBITUX + RT

ERBITUX Indications� ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or

regionally advanced squamous cell carcinoma of the head and neck

� 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

ERBITUX Boxed WARNINGS� 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

� 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

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

for Increased OVERALL SURVIVALERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT

ERBITUX + RT (n=211) vs RT alone (n=213)

Median overall survival49.0 months vs 29.3 months HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate55% vs 45%P=0.05

Survival in Combination With RT*1,2

22%improvement†

19.7month

improvement

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confi dence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2

† Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

� Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information� The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

� ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck. 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

� Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The followingsites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

693US11AB05808_HN_LRD_7625x105.indd 1-2 7/8/11 5:12 PM

ASCOPost.com | AUGUST 15, 2011 PAGE 15

2011 ASCO Annual Meeting

where data are limited, such as for pa-tients with Child-Pugh B disease, who are generally excluded from liver can-cer trials.

Approximately half of the 3,322 patients enrolled were eligible for the second interim safety analysis, 957 of whom were classified Child-Pugh

Child-Pugh Score

The Child-Pugh score, a prognostic measure used in pa-tients with chronic liver disease, is determined by five

clinical measures, including total bilirubin level; serum albu-min level; prothrombin time expressed by international nor-malized ratio (INR), presence of ascites (none, mild, severe);

and presence of hepatic encephalopathy (none; grade I-II; grade III-IV). Each clinical measure is assigned 1 to 3 points ranging from least severe (1 point) to most severe (3 points).  A total score based on the five clinical measures is used to de-termine Child-Pugh class of disease (A, B, or C). ■

continued on page 16

693US11AB05808 TRIM 7.625" x 10.5" Publication:

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Select ERBITUX + RT

ERBITUX Indications� ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or

regionally advanced squamous cell carcinoma of the head and neck

� 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

ERBITUX Boxed WARNINGS� 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

� 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

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

for Increased OVERALL SURVIVALERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT

ERBITUX + RT (n=211) vs RT alone (n=213)

Median overall survival49.0 months vs 29.3 months HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year survival rate55% vs 45%P=0.05

Survival in Combination With RT*1,2

22%improvement†

19.7month

improvement

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confi dence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2

† Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

� Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information� The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

� ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck. 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

� Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The followingsites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

693US11AB05808_HN_LRD_7625x105.indd 1-2 7/8/11 5:12 PM

PAGE 16 The ASCO Post | AUGUST 15, 2011

2011 ASCO Annual Meeting

A, 367 were Child-Pugh B, and 35 were Child-Pugh C patients. Adverse events were similar among the arms but serious events occurred in 56% of Child-Pugh B and 63% of Child-Pugh C patients, vs 29% of Child-Pugh A patients. Drug-related serious

adverse events were seen in 15%, 6%, and 8%, respectively, and events re-sulting in permanent discontinuation of sorafenib were observed in 38% of Child-Pugh B, 51% of Child-Pugh C, and 24% of Child-Pugh A patients.

“Compared with Child-Pugh A pa-tients, Child-Pugh B patients did not have a higher incidence of drug-re-

lated adverse events but had a higher incidence of liver-associated events. Also, as liver function worsened, there was a significant increase in the death rate,” he added, noting that most deaths were due to tumor progression or underlying liver disorders.

“Our preliminary interim analysis of results indicates that the sorafenib

safety profile is generally similar in the Child-Pugh B and Child-Pugh A pa-tients,” Dr. Marrero concluded.

Survival DataWhile median overall survival

reached 10.3 months for Child-Pugh A patients, it was 4.8 months for Child-Pugh B and just 2.0 months for

Hepatocellular Carcinomacontinued from page 15

693US11AB05808 TRIM 7.625" x 10.5" Publication:

Electrolyte Depletion� Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX (cetuximab) 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

Late Radiation Toxicities� The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation

therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively— The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone

and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing� In women of childbearing potential, appropriate contraceptive measures must be used during treatment

with ERBITUX 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 all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, 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 carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

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

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 fi rst 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

Cardiopulmonary Arrest� Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell

carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, 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 the 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 therapy

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 acneiform rash, skin drying and fi ssuring,

paronychial infl ammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients— Acneiform 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

ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck

— 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© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB05808 5/11

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014

693US11AB05808_HN_LRD_7625x105.indd 3-4 7/8/11 5:12 PM

ASCOPost.com | AUGUST 15, 2011 PAGE 17

2011 ASCO Annual Meeting

Child-Pugh C patients. However, time to progression was similar for Child-Pugh B and Child-Pugh A: 3.6 and 4.2 months, respectively, vs 2.1 months for Child-Pugh C.

“The shorter median overall surviv-al in the Child-Pugh B patients most likely reflects the poorer prognosis and natural history of liver disease in

this population,” he suggested. “Con-sistent with previously reported stud-ies, these preliminary data indicate that Child-Pugh status appears to be a useful prognostic factor for overall survival.”

Mean daily dose was 630 mg, which was similar among the groups, and, somewhat surprisingly, dose in-

terruptions and modifications were also comparable. Median duration of treatment, however, was significantly shorter for Child-Pugh B: 9 weeks vs 12 weeks for Child-Pugh A, and only 4 weeks for Child-Pugh C. ■

Disclosure: Dr. Marrero reported receiving honoraria from Bayer and Onyx and research funding from Bayer.

Reference1. Marrero JA, Lencloni R, Kudo M, et

al: Global Investigation of Therapeutic Deci-sions in Hepatocellular Carcinoma and of Its Treatment with Sorafenib (GIDEON) sec-ond interim analysis in more than 1,500 pa-tients: Clinical findings in patients with liver dysfunction. 2011 ASCO Annual Meeting. Abstract 4001. Presented June 7, 2011.

693US11AB05808 TRIM 7.625" x 10.5" Publication:

Electrolyte Depletion� Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX (cetuximab) 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

Late Radiation Toxicities� The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation

therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively— The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone

and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing� In women of childbearing potential, appropriate contraceptive measures must be used during treatment

with ERBITUX 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 all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, 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 carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

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

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 fi rst 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

Cardiopulmonary Arrest� Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell

carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, 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 the 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 therapy

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 acneiform rash, skin drying and fi ssuring,

paronychial infl ammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients— Acneiform 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

ERBITUX Plus Radiation Therapy 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 squamous cell carcinoma of the head and neck

— 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© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB05808 5/11

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014

693US11AB05808_HN_LRD_7625x105.indd 3-4 7/8/11 5:12 PM

PAGE 18 The ASCO Post | AUGUST 15, 2011

FDA Update

The FDA issued a new draft guidance to facilitate the de-

velopment and review of “compan-ion diagnostics”—tests used to help health-care professionals determine whether a patient with a particular disease or condition should receive

a particular drug therapy or how much of the drug to give. The draft document is intended to provide companies with guid-ance on the agency’s policy for reviewing a companion

diagnostic and the corresponding therapy.

One common type of companion diagnostic looks for whether a pa-tient has a specific gene

amplification or protein overex-

pression that could predict whether a drug might benefit the patient or lead to harm. For example, trastu-zumab (Herceptin) was approved with a companion test, and testing is routinely performed on women diagnosed with breast cancer to

FDA Issues Guidance for Diagnostic Tests Used with Targeted Therapies

693US11AB05808 TRIM 7.625" x 10.5" Publication:

eRbITUx® (cetuximab)injection, for intravenous infusionBrief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONs AND UsAGesquamous Cell Carcinoma of the Head and Neck (sCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressingmetastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a singleagent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who areintolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warningsand Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith 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 treatmentbenefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is notrecommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) andClinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONsNone.

WARNINGs AND PReCAUTIONsInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux,included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred 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 withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See BoxedWarning and Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, 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 andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis,cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88%of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17%of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious 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 pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary.

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADveRse ReACTIONsThe 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, dermatologictoxicity 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 experienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor 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 3and 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 in1–4% 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 Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (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 AdvancedsCCHN

erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

body system Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of Patientsbody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4skin/AppendagesAcneiform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 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”.

3 Based on laboratory measurements, not on reported adverse events, the number of subjects with testedsamples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

4 Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustularrash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), 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 toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]

Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended 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 AdvancedColorectal Carcinoma1 Treated with erbitux Monotherapy

erbitux plus bsC bsC alone(n=288) (n=274)

body system Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <1

1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.2 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 infusion-related.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiformrash (14%).

ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable 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 beinfluenced 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 antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experienceThe following adverse reaction has been identified during post-approval use of Erbitux. Because this reactionwas reported from a population of uncertain size, it was not always possible to reliably estimate its frequency orestablish a causal relationship to drug exposure.

• Aseptic meningitis

DRUG INTeRACTIONsA drug interaction study was performed in which Erbitux was administered in combination with irinotecan. Therewas no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

Use IN sPeCIFIC POPULATIONsPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly 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 ofcetuximab (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 fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).

Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue 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 UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab betweenthe two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distributionappeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single doseof 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group(1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OveRDOsAGeThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOxICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly 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 controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared 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 weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATIONAdvise 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 adequatecontraception 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 doseof Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA

Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A8 ER-B0001A-03-11 Rev March 2011

693US11AB05808_HN_LRD_7625x105.indd 5-6 7/8/11 5:13 PM

ASCOPost.com | AUGUST 15, 2011 PAGE 19

FDA Update

help determine whether the patient should receive the drug.

“These proposed guidelines sup-port the development of innovative new targeted medicines and their corresponding diagnostic tests and are intended to provide manufac-turers with greater predictability,” said Jeffrey Shuren, MD, Direc-

tor of the FDA’s Center for Devices and Radiological Health. “It is the agency’s goal to help stimulate early collaborations between drug and device makers so they can develop the best medical products for treat-ing patients.”

The draft guidance also clarifies the FDA’s definition of a compan-

ion diagnostic, recommends early engagement between the FDA and manufacturers, highlights the FDA’s intention to conduct simultane-ous reviews of a drug or biologic therapy and its corresponding com-panion diagnostic, and identifies in-stances where the FDA may approve a targeted medicine in the absence

of a cleared or approved companion diagnostic.

The FDA is seeking public input on the draft guidance. Comments can be submitted onlin e or in writ-ing to: Division of Dockets Manage-ment (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852. ■ODAC Recommends Accelerated Approval for Brentuximab

Seattle Genetics, Inc, announced that the FDA’s Oncologic Drugs

Advisory Committee (ODAC) voted 10-0 to recommend that the agency grant accelerated approval of brentux-imab vedotin (ADCETRIS) for the treatment of patients with Hodgkin lymphoma who relapse after autolo-gous stem cell transplant (ASCT). In addition, ODAC voted 10-0 to rec-ommend that the FDA grant acceler-ated approval of brentuximab for the treatment of patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). The FDA is expected to act on the two Biologics License Applications (BLAs) for bren-tuximab by August 30, 2011, under the Prescription Drug User Fee Act.

Brentuximab is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of Hodgkin lym-phoma and ALCL. The ADCETRIS BLAs were based primarily on data from a pivotal trial in relapsed or re-fractory Hodgkin lymphoma that was conducted under a Special Protocol Assessment with the FDA and from a phase II trial in relapsed or refractory systemic ALCL. ■

Send Us Your News

Send your news of new appointments, awards,

or significant events to The ASCO Post. Write to editor@ ASCOPost.com.

All submissions will be considered for publication.

693US11AB05808 TRIM 7.625" x 10.5" Publication:

eRbITUx® (cetuximab)injection, for intravenous infusionBrief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONs AND UsAGesquamous Cell Carcinoma of the Head and Neck (sCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressingmetastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a singleagent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who areintolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warningsand Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith 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 treatmentbenefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is notrecommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) andClinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONsNone.

WARNINGs AND PReCAUTIONsInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux,included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred 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 withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See BoxedWarning and Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, 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 andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis,cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88%of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17%of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious 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 pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary.

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADveRse ReACTIONsThe 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, dermatologictoxicity 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 experienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor 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 3and 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 in1–4% 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 Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (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 AdvancedsCCHN

erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

body system Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of Patientsbody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4skin/AppendagesAcneiform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 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”.

3 Based on laboratory measurements, not on reported adverse events, the number of subjects with testedsamples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

4 Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustularrash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), 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 toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]

Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended 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 AdvancedColorectal Carcinoma1 Treated with erbitux Monotherapy

erbitux plus bsC bsC alone(n=288) (n=274)

body system Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <1

1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.2 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 infusion-related.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiformrash (14%).

ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable 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 beinfluenced 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 antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experienceThe following adverse reaction has been identified during post-approval use of Erbitux. Because this reactionwas reported from a population of uncertain size, it was not always possible to reliably estimate its frequency orestablish a causal relationship to drug exposure.

• Aseptic meningitis

DRUG INTeRACTIONsA drug interaction study was performed in which Erbitux was administered in combination with irinotecan. Therewas no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

Use IN sPeCIFIC POPULATIONsPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly 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 ofcetuximab (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 fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).

Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue 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 UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab betweenthe two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distributionappeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single doseof 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group(1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OveRDOsAGeThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOxICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly 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 controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared 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 weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATIONAdvise 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 adequatecontraception 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 doseof Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA

Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2011 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A8 ER-B0001A-03-11 Rev March 2011

693US11AB05808_HN_LRD_7625x105.indd 5-6 7/8/11 5:13 PM

PAGE 20 The ASCO Post | AUGUST 15, 2011

Direct from ASCO

Imagine just four oncologists at-tempting to provide care for a

population of 82 million people liv-ing in a country covering twice the territory of Texas. That’s the state of cancer care in Ethiopia.

And imagine a country of more than 90 million people—more than twice the population of California—where the lion’s share of people with cancer don’t know they have cancer and thus don’t seek medical atten-tion until their disease is advanced. This is Vietnam.

Epidemiologists estimate that a majority of the world’s new cases of cancer are in low- and middle-income countries like Ethiopia and Vietnam. The situation is dire.

That’s why the International Can-cer Corps (ICC)—which ASCO launched with the international medical education organization Health Volunteers Overseas (HVO) in Honduras in 2010—has just ex-panded to Ethiopia and Vietnam. The purpose: to help bring care to underserved populations by assist-ing with the training of oncologists and others involved with the treat-ment of cancer patients.

Priorities Targeted to Each Country’s Needs

In the coming months, ASCO member volunteers will begin pack-ing up and heading to the two new sites, singly or in teams, staying for 1 to 4 weeks, with other health pro-fessionals going

over 3 to 4 times a year, said Quyen D. Chu, MD, HVO Program Direc-tor for Vietnam. Dr. Chu is Albert Sklar Endowed Pro-fessor of Surgery and Director of the Peri-toneal Surface Ma-lignancies Program at the Feist-Weiller Cancer Center at Louisiana State University Health Sciences Center in Shreveport.

Through the new HVO/ICC partnership with Vietnam’s Univer-sity of Hue, vol-unteers will help develop curricula, lead workshops in treatment ar-eas that have the greatest need, and provide side-by-side clinical instruction. “The point is to assist with building infrastructure, enhancing what they already have and helping them keep abreast of the latest technology,” said Dr. Chu, who conducted a needs assessment in Vietnam for the new ICC program and volunteered there in 2010.

Because the lack of a national screening program in Vietnam con-tributes to a significant number of patients presenting only after their disease is advanced, developing a more robust palliative care program

is a priority there.In Ethiopia, the HVO/

ICC’s major objective will be addressing the shortage of oncologists. Volunteers will help establish a 3-year residency program in clini-cal oncology at Tikur An-bessa (Black Lion) Hos-pital in Addis Ababa, the only hospital in Ethiopia that sees cancer patients. In addition, HVO/ICC volunteers will provide training to residents en-rolled in the hospital’s internal medicine train-ing program, and more specialized oncologic

training to surgeons, radiotherapy specialists, nurses, pathologists, and other health-care professionals who

provide cancer

care at Black Lion. Volun-teers will also help develop a national cancer plan and education in cancer prevention measures. Assignments will range from 2 to 4 weeks.

The HVO Program Director for Ethiopia is Kenneth D. Miller, MD, Director of the Adult Cancer Sur-vivorship Program at Dana-Farber Cancer Institute.

Honduras Focus Has Been on Training Providers

ASCO and HVO chose Honduras as their first location for collaboration,

because Honduras has fewer than 20 oncologists to serve a population of 8  million, and just one public hospi-tal where cancer care is available. The Honduras HVO/ICC program focus-es on three hospitals in the capital city of Tegucigalpa, with special attention given to the surgical oncology residen-cy program there, which has just two residents at any one time.

Linus Chuang, MD, volunteered in Honduras in May and November 2010. What impressed him most about the HVO/ICC program was its focus on capacity building. Dr. Chuang, Associate Professor of the Division of Gynecologic Oncology and Co-Director of the Minimally Invasive Surgery Department of Ob-stetrics, Gynecology, and Reproduc-tive Science at Mount Sinai School of Medicine, said that other humanitar-ian efforts he’s been involved with fo-cused primarily on caring for patients in immediate need. In contrast, this program’s value is in sharing clinical knowledge and skills with interna-tional colleagues, helping residents, fellows, and doctors already on the ground enhance the way they manage cancer patients.

“These young doctors will go and work in little villages, and in their lifetimes they will help countless pa-

tients—not just the 20 people I could help during my short time there,” said Dr. Chuang, adding that his volunteer work through HVO/ICC was one of the most edifying things he’s ever done.

For additional in-formation about the International Cancer Corps program with HVO and to learn how to volunteer in Hondu-ras, Ethiopia, or Viet-nam, send an email to ASCO at internation-al@asco.org or to HVO

at d.stonehirsch@hvousa.org. ■© 2011. American Society of Clinical Oncology. All rights reserved.

ASCO’s International Cancer Corps Launches Initiatives in Ethiopia and VietnamVolunteers sought to help build cancer care infrastructure.

Vietnam: Quyen Chu, MD, right, performing a mastectomy at

Hue College of Medicine and Pharmacy in Vietnam.

Ethiopia: (left to right) Kenneth D. Miller, MD, and Bogale Solomon Desalegne, MD, MSc, Head of the Radiotherapy Center at Addis Ababa University and Director of the Cancer Center at Tikur Anbessa Hospital in October 2010.

Honduras: (left to right) Linus T. Chuang, MD, Jose Angel Sanchez, MD, the on-site coordinator for the volunteer oncology program (adult cancers), and Frederic V. Price, MD, FACS, in May 2010.

ASCOPost.com | AUGUST 15, 2011 PAGE 21

Direct from ASCODirect from ASCO

ASCO and seven other oncology organizations held a Capitol

Hill briefing in July and explained to nearly 200 members of Congress and their staffs how widespread can-cer drug shortages are creating “a crisis in care.”

According to the University of Utah Drug Information Service, the number of drug shortages has tripled between January 2006 and Decem-ber 2010. Last year there were over 211 medications in short supply af-fecting numerous classes, including chemotherapy drugs, antibiotics, and anesthetic drugs.

Dire ConsequencesAt the briefing, ASCO President

Michael P. Link MD, explained how 2011 could be the worst year since the problem has been tracked. “Through the middle of June, there are already 156 new drug shortages. If this trend holds through the rest of the year we must brace ourselves for more than 300 new cases.”

Dr. Link outlined the many con-sequences shortages have on cancer patients and oncology practices in-cluding treatment delays, less effec-tive or no workaround therapies, patient anxiety, the time and expense practices waste on finding supply, the adverse effect on ongoing clinical tri-als, and a price markup that increases the cost of care.

Congressional BillsMany in the oncology commu-

nity, including ASCO, are backing two Congressional bills introduced this year for provisions that are im-portant first steps in addressing this complex issue.

The Preserving Access to Life-Saving Medications Act, intro-duced in February by Senators Amy Klobuchar (D-Minn) and Robert Casey (D-Pa), contains some of the recommendations from the Novem-ber 2010 Drug Shortages Summit co-convened by ASCO.

In June, Representatives Tom Rooney (R-Fla) and Diana DeGette (D-Colo) introduced HR 2245, which provides the FDA with enhanced au-thority to require notification from manufacturers expecting a disruption in their usual supply of drugs.

Briefing participants included ASCO, Association of Community Cancer Centers, Association of Oncol-ogy Social Work, American Society of

Health System Pharmacists, Commu-nity Oncology Alliance, Leukemia & Lymphoma Society, Oncology Nurs-ing Society, Children’s Cause for Can-

cer Advocacy, and US Oncology. ■© 2011. American Society of Clinical On-cology. All rights reserved.

Oncology Community Briefs Members of Congress and Calls for Action

PAGE 22 The ASCO Post | AUGUST 15, 2011

Direct from ASCO

ASCO’s Oncology Slide Li-brary—which allows ASCO

meeting attendees to upload and share their ASCO meeting presen-tation slides with slide-library sub-scribers—may only be a year old, but participation is already very high. This year’s Annual Meeting in June marked the first time ASCO gave each speaker the opportunity to have his or her presentation slides included in the library, and just over two-thirds said yes.

Benjamin Levy, MD, Head of the ASCO Integrated Media and Technology Committee (IMTC) planning group for the slide library, is excited about this, saying that the nascent library is a truly collaborative way for all ASCO members to stay up to date on fast-moving research.

“Oncology has become an ex-tremely complicated field as new data emerges in different tumor types,” said Dr. Levy, Assistant Pro-fessor at Albert Einstein College of

Medicine and Director of Thoracic Medical Oncology at Beth Israel Hospital. “This includes preclinical data, such as the discovery of a new molecular pathway, as well as the clinical trials involving new drugs that target these pathways. Recog-nizing this complexity, there exists a need to simplify, explain, and share the groundswell of information that we are faced with every day as physi-cians. I think the ASCO slide library will help achieve this goal and meet the needs of ASCO members, who for a long time have been asking for a service like this.”

What’s in the Slide Library?Currently in the Oncology Slide

Library are 2,371 slide or poster presentations uploaded by ASCO meeting presenters and 899 individ-ual slides or presentations owned by ASCO. Most were uploaded during ASCO’s Annual Meeting this sum-mer, but some are from the 2011 Gastrointestinal Cancers Sympo-sium and the 2011 Genitourinary Cancers Symposium. The highest areas of use thus far have been in breast cancer and gastrointestinal cancers.

All presenters at all meetings as-sociated with ASCO will now be asked whether they’d like to add their slides to the library, which is hosted on the ASCO University website. A large influx of slides is ex-

ASCO’s Oncology Slide Library Functions as a Share-and-Exchange Forum More then two-thirds of those asked shared their slides at the Annual Meeting.

Volume 29, Issue 15 May 20, 2011

www.jco.org

JOURNAL OF CLINICAL ONCOLOGYOfficial Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al

Coalesced Multicentric Analysis of Patients With Myelodysplastic Syn-dromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg

Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarci-noma. J.R. Hecht et al. Editorial: A.F. Sobrero et al

Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al

Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico

ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

What’s Hot in

JCOTop 10 most-accessed articles recently published in Journal of Clinical Oncology

1. Impact of KRAS and BRAF Gene Mutations on Targeted Therapies in Colorectal CancerAdam Bass29(19): 2728

2. Breast Cancer Tumor Size, Nodal Status, and Prognosis: Biology Trumps AnatomyElizabeth A. Comen, et al 29(19): 2610

3. Palliative Care and the Quality of LifeDiane E. Meier, et al29(20): 2750

4. Anti–Vascular Endothelial Growth Factor Therapy for Breast Cancer: Can We Pick the Winners?Bryan P. Schneider, et al 29(18): 2444

5. The Paradox of Positive ThinkingEliezer M. Van Allen29(19): 2730

6. New Initiatives at Journal of Clinical OncologyStephen A. Cannistra29(19): 2609

7. Rectal Cancer Trials: No MovementMartin R. Weiser29(20): 2746

8. Expanding Our Therapeutic Options: Beta Blockers for Breast Cancer?Patricia A. Ganz, et al29(19): 2612

9. Stat5: From Breast Development to Cancer Prognosis, Prediction, and ProgressionDavid Tweardy, et al 29(18): 2443

10. Newly Diagnosed Acute Promyelocytic Leukemia: Arsenic Moves Front and CenterElihu H. Estey29(20): 2743

JCO.org

pected after the Breast Cancer Sym-posium in September.

To make sure nothing inaccurate winds up in the library, Dr. Levy said IMTC members closely oversee the content as it comes in. They also watch closely for material uploaded by individuals who don’t hold the copyright to it.

How Can the Slides Be Used?Anyone who has an ASCO ac-

count can subscribe and download content from the slide library for educational purposes. The cost is $50 per year. Nonsubscribers can browse the slides but not down-load them. User-uploaded slides are marked as hailing from an external source and are downloadable as

PowerPoint files. The ASCO slides, marked as copyrighted by ASCO, can also be downloaded. Neither can be altered once uploaded.

In addition, users can create and save personalized slide sets right on the website.

Stephanie Williams, MD, Presi-dent of Hematology-Oncology As-sociates of Illinois and Professor of Clinical Medicine at Northwestern Feinberg School of Medicine, used the slide library just after ASCO’s Annual Meeting this summer, when she was asked to deliver an update on the lymphoma abstracts pre-sented at the meeting to fellow phy-sicians back home in the Chicago area. Dr. Williams said she loved the library’s ease of use, and that it

Benjamin Levy, MD

Because the cost of cancer care can be high, it is important for your

patients to understand what to expect before starting treatment so that they can manage the financial effect of can-cer in the most effective way possible. To that end, Cancer.Net, ASCO’s patient information website, offers a guide designed to help patients talk with the health-care team about these issues (www.cancer.net/managing-

Help Your Patients Manage the Cost of Cancer Care

costofcare). It outlines what costs to expect, types of insurance, how insur-ance rules are changing under the 2010 health reform law, financial resources, tips to organize financial paperwork, and more. Free printed copies are available through ASCO’s bookstore (www.cancer.net/eStore). ■

© 2011. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | AUGUST 15, 2011 PAGE 23

Direct from ASCODirect from ASCO

1. Genomic Testing and Therapies for Breast Cancer in Clinical PracticeJennifer S. Haas, et al7(3S): e1s

2. Health Technology Assessment and Private Payers’ Coverage of Personalized MedicineJulia R. Trosman, et al7(3S): 18s

3. Characterizing Medical Care by Disease Phase in Metastatic Colorectal CancerXue Song, et al7(3S): 25s

4. Advancing Performance Measurement in Oncology: Quality Oncology Practice Initiative Participation and Quality OutcomesFrancis X. Campion, et al7(3S): 31s

5. Effect of the Pay-for-Performance Program for Breast Cancer Care in TaiwanRaymond N.C. Kuo, et al7(3S): e8s

Volume 7, Issue 3 May 2011

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al

Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al

Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

Journal of oncology Practice

www.jop.ascopubs.org

What’s Hot in JOP Top 5 most-accessed articles recently published in Journal of Oncology Practice

jop.ascopubs.org

allowed her to quickly pull together slides from various presentations, which would have taken her much longer if she had to contact each of the presenters to obtain their slides and their permission.

Plus, she said, having such easy access to presentation slides can help oncologists stay boned up on what they learned at recent meetings.

“It’s a very good resource to have so you can go back over what you heard in the sessions,” said Dr. Williams, who added that she would continue to use the slide library to enhance and inform future talks she gives to residents, fellows, and other physicians.

Dr. Levy said the timing of the library couldn’t be better. “The last 5 years in cancer research have

Stephanie Williams, MD

been a very exciting time, but also very complex. The only way physi-cians will get a handle on all of it is through a sharing and exchange of information like this. The hope is to

level the playing field as more of us oncologists are exposed to all of the information out there. And patients are the ultimate winners.”

ASCO’s Oncology Slide Library

can be found here: www.university.asco.org/slides. ■© 2011. American Society of Clinical On-cology. All rights reserved.

ISTODAX® is now indicated for:• Treatment of peripheral T-cell lymphoma

(PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Introducing choice in treating PTCL

For more information: Please visit www.istodax.com

or call 1-888-423-5436

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation.©2011 Celgene Corporation 06/11 IST11004T

Right Hand Page2ej1 Q1 Q2Cosmos Communications 718.482.1800

19707a 06.29.11 133C M Y K

ASCO POST / HEM ONC TODAY

Important Safety InformationWARNINGS AND PRECAUTIONS:• Treatment with ISTODAX has been associated with

thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary

• Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy

• Electrocardiographic (ECG) changes have been observed with ISTODAX

• In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment

• Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration

• Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate

• Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

• ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives

ADVERSE REACTIONS:

Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS:• ISTODAX is metabolized by CYP3A4. Avoid concomitant use

with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible

• Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors

• Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives

USE IN SPECIFIC POPULATIONS:• Because many drugs are excreted in human milk and

because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

• Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Left Hand Page2ej1 Q1 Q2Cosmos Communications 718.482.1800

19707a 06.29.11 133C M Y K

ASCO POST / HEM ONC TODAY

ISTODAX® is now indicated for:• Treatment of peripheral T-cell lymphoma

(PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Introducing choice in treating PTCL

For more information: Please visit www.istodax.com

or call 1-888-423-5436

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation.©2011 Celgene Corporation 06/11 IST11004T

Right Hand Page2ej1 Q1 Q2Cosmos Communications 718.482.1800

19707a 06.29.11 133C M Y K

ASCO POST / HEM ONC TODAY

Important Safety InformationWARNINGS AND PRECAUTIONS:• Treatment with ISTODAX has been associated with

thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary

• Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy

• Electrocardiographic (ECG) changes have been observed with ISTODAX

• In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment

• Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration

• Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate

• Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

• ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives

ADVERSE REACTIONS:

Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS:• ISTODAX is metabolized by CYP3A4. Avoid concomitant use

with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible

• Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors

• Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives

USE IN SPECIFIC POPULATIONS:• Because many drugs are excreted in human milk and

because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

• Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Left Hand Page2ej1 Q1 Q2Cosmos Communications 718.482.1800

19707a 06.29.11 133C M Y K

ASCO POST / HEM ONC TODAY

PAGE 26 The ASCO Post | AUGUST 15, 2011

FDA Update

New Safety Information Reported for 5-alpha Reductase Inhibitors

The FDA announced that the Warnings and Precautions sec-

tion of the labels for the 5-alpha reduc-tase inhibitor class of drugs has been revised to include new safety informa-tion about the increased risk of being

diagnosed with high-grade prostate cancer. This risk appears to be low, but health-care professionals should be aware of this safety information, and weigh the known benefits against the potential risks when prescribing these

drugs, ie, finasteride (Propecia, Pros-car) and dutasteride (Avodart, and in combination with tamsulosin, Jalyn).

The new safety information is based on FDA’s review of two large, random-ized controlled trials that demon-

strated an overall reduction in prostate cancer diagnoses with finasteride and dutasteride treatment. However, this reduction was due to a decreased in-cidence of lower-risk forms of prostate cancer. ■

ISTODAX® (romidepsin) for injectionFor intravenous infusion only The following is a brief summary only; see full prescribing information forcomplete product information. 1 INDICATIONS AND USAGE

ISTODAX is indicated for:• Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have

received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have

received at least one prior therapy.These indications are based on response rate. Clinical benefit such asimprovement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information

The recommended dose of romidepsin is 14 mg/m2 administered intra -venously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cyclesshould be repeated every 28 days provided that the patient continues tobenefit from and tolerates the therapy.

2.2 Dose ModificationNonhematologic toxicities except alopecia• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until

toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin shouldbe delayed until toxicity returns to ≤Grade 1 or baseline and the doseshould be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicityreturns to ≤Grade 1 or baseline, then the dose should be permanentlyreduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur afterdose reduction.

Hematologic toxicities• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin

should be delayed until the specific cytopenia returns to ANC ≥1.5×109/Land/or platelet count ≥75×109/L or baseline, then therapy may be restartedat 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requiresplatelet transfusion: Treatment with romidepsin should be delayed untilthe specific cytopenia returns to ≤Grade 1 or baseline, and then the doseshould be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommendedsafe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic

Treatment with ISTODAX can cause thrombocytopenia, leukopenia(neutropenia and lymphopenia), and anemia; therefore, these hematologicalparameters should be monitored during treatment with ISTODAX, and thedose should be modified, as necessary [See Dosage and Administration(2.2) and Adverse Reactions (6)].

5.2 InfectionSerious and sometimes fatal infections, including pneumonia and sepsis,have been reported in clinical trials with ISTODAX. These can occur duringtreatment and within 30 days after treatment, and the risk of life threateninginfections may be higher in patients with a history of extensive or intensivechemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic ChangesSeveral treatment-emergent morphological changes in ECGs (including T-waveand ST-segment changes) have been reported in clinical studies. The clinicalsignificance of these changes is unknown [See Adverse Reactions (6)].In patients with congenital long QT syndrome, patients with a history ofsignificant cardiovascular disease, and patients taking anti-arrhythmicmedicines or medicinal products that lead to significant QT prolongation,appropriate cardiovascular monitoring precautions should be considered,such as the monitoring of electrolytes and ECGs at baseline and periodicallyduring treatment.Due to the risk of QT prolongation, potassium and magnesium should bewithin the normal range before administration of ISTODAX [See AdverseReactions (6)].

5.4 Tumor Lysis SyndromeTumor lysis syndrome (TLS) has been reported to occur in 1% of patientswith tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patientswith advanced stage disease and/or high tumor burden should be closelymonitored, appropriate precautions should be taken, and treatment shouldbe instituted as appropriate.

5.5 Use in PregnancyThere are no adequate and well-controlled studies of ISTODAX in pregnantwomen. However, based on its mechanism of action, ISTODAX may causefetal harm when administered to a pregnant woman. A study in rats did notexpose pregnant animals to enough romidepsin to fully evaluate adverseoutcomes.If this drug is used during pregnancy, or if the patient becomes pregnantwhile taking ISTODAX, the patient should be apprised of the potentialhazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing PotentialAdvise women of childbearing potential that ISTODAX may reduce theeffectiveness of estrogen-containing contraceptives. An in vitro bindingassay determined that romidepsin competes with ß-estradiol for binding toestrogen receptors [See Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS 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 bedirectly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

Cutaneous T-Cell LymphomaThe safety of ISTODAX was evaluated in 185 patients with CTCL in 2 singlearm clinical studies in which patients received a starting dose of 14 mg/m2.The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).Common Adverse ReactionsTable 1 summarizes the most frequent adverse reactions (> 20%) regardlessof causality using the National Cancer Institute-Common Terminology Criteriafor Adverse Events (NCI-CTCAE, Version 3.0). Due to method ological differ -ences between the studies, the AE data are presented separately for Study 1and Study 2. Adverse reactions are ranked by their incidence in Study 1.Laboratory abnormalities commonly reported (> 20%) as adverse reactionsare included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185)

Study 1 Study 2(n=102) (n=83)

Grade 3 Grade 3Adverse Reactions n (%) All or 4 All or 4Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82)Nausea 57 (56) 3 (3) 71 (86) 5 (6)Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14)Infections 47 (46) 11 (11) 45 (54) 27 (33)Vomiting 35 (34) 1 (<1) 43 (52) 8 (10)Anorexia 23 (23) 1 (<1) 45 (54) 3 (4)Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1)Pyrexia 20 (20) 4 (4) 19 (23) 1 (1)Anemia 19 (19) 3 (3) 60 (72) 13 (16)Thrombocytopenia 17 (17) 0 54 (65) 12 (14)Dysgeusia 15 (15) 0 33 (40) 0Constipation 12 (12) 2 (2) 32 (39) 1 (1)Neutropenia 11 (11) 4 (4) 47 (57) 22 (27)Hypotension 7 (7) 3 (3) 19 (23) 3 (4)Pruritus 7 (7) 0 26 (31) 5 (6)Hypokalemia 6 (6) 0 17 (20) 2 (2)Dermatitis/Exfoliative

dermatitis 4 (4) 1 (<1) 22 (27) 7 (8)Hypocalcemia 4 (4) 0 43 (52) 5 (6)Leukopenia 4 (4) 0 38 (46) 18 (22)Lymphopenia 4 (4) 0 47 (57) 31 (37)Alanine aminotransferase

increased 3 (3) 0 18 (22) 2 (2)Aspartate aminotransferase

increased 3 (3) 0 23 (28) 3 (4)Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4)

(continued)

Only

C M Y K

Cosmos Communications 1

5ja

19707a1 07.05.11 133

Q1 Q2 Page 1

ASCOPost.com | AUGUST 15, 2011 PAGE 27

FDA Update

The FDA is seeking input on its proposed oversight approach

for mobile medical applications (“apps”) designed for use on smart-phones and other mobile computing devices. This approach encourages

the development of new apps, focuses only on a select group of applica-tions, and will not regu-late the sale or general consumer use of smartphones or tablets.

The agency’s draft guid-ance defines a small subset of mobile medical apps, in-cluding those that are used

as an accessory to medical devices al-ready regulated by the FDA, or that

transform a mobile communications device into a regulated medical device by using attachments, sensors, or other devices.

The FDA will update the guidance based on feedback received. ■

FDA Outlines Oversight of Mobile Medical Applications

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185)

Study 1 Study 2(n=102) (n=83)

Grade 3 Grade 3Adverse Reactions n (%) All or 4 All or 4Electrocardiogram

ST-T wave changes 2 (2) 0 52 (63) 0Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1)Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2)Hypermagnesemia 0 0 22 (27) 7 (8)Hypophosphatemia 0 0 22 (27) 8 (10)Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse ReactionsInfections were the most common type of SAE reported in both studies with8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing aserious infection. Serious adverse reactions reported in > 2% of patients inStudy 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactionsin > 2% of patients were fatigue (7%), supraventricular arrhythmia, centralline infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%),ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration,pyrexia, aspartate aminotransferase increased, sepsis, catheter relatedinfection, hypophosphatemia and dyspnea (4%).Most deaths were due to disease progression. In Study 1, there were twodeaths due to cardiopulmonary failure and acute renal failure. In Study 2,there were six deaths due to infection (4), myocardial ischemia, and acuterespiratory distress syndrome.DiscontinuationsDiscontinuation due to an adverse event occurred in 21% of patients inStudy 1 and 11% in Study 2. Discontinuations occurring in at least 2% ofpatients in either study included infection, fatigue, dyspnea, QT prolongation,and hypomagnesemia.

Peripheral T-Cell LymphomaThe safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study(Study 4) in which patients received a starting dose of 14 mg/m2. The meanduration of treatment and number of cycles in these studies were 5.6 monthsand 6 cycles. Common Adverse ReactionsTable 2 summarizes the most frequent adverse reactions (≥ 10%) regardlessof causality, using the NCI-CTCAE, Version 3.0. The AE data are presentedseparately for Study 3 and Study 4. Laboratory abnormalities commonlyreported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178)

Study 3 Study 4(N=131) (N=47)

Grade 3 Grade 3Adverse Reactions n (%) All or 4 All or 4Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85)Gastrointestinal disorders

Nausea 77 (59) 3 (2) 35 (75) 3 (6)Vomiting 51 (39) 6 (5) 19 (40) 4 (9)Diarrhea 47 (36) 3 (2) 17 (36) 1 (2)Constipation 39 (30) 1 (<1) 19 (40) 1 (2)Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2)Stomatitis 13 (10) 0 3 (6) 0

General disorders and administration site conditions

Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19)Pyrexia 46 (35) 7 (5) 22 (47) 8 (17)Chills 14 (11) 1 (<1) 8 (17) 0Edema peripheral 13 (10) 1 (<1) 3 (6) 0

Blood and lymphatic system disorders

Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36)Neutropenia 39 (30) 26 (20) 31 (66) 22 (47)Anemia 32 (24) 14 (11) 29 (62) 13 (28)Leukopenia 16 (12) 8 (6) 26 (55) 21 (45)

(continued)

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178)

Study 3 Study 4(N=131) (N=47)

Grade 3 Grade 3Adverse Reactions n (%) All or 4 All or 4Metabolism and nutrition disorders

Anorexia 37 (28) 2 (2) 21 (45) 1 (2)Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2)

Nervous system disordersDysgeusia 27 (21) 0 13 (28) 0Headache 19 (15) 0 16 (34) 1 (2)

Respiratory, thoracic and mediastinal disorders

Cough 23 (18) 0 10 (21) 0Dyspnea 17 (13) 3 (2) 10 (21) 2 (4)

InvestigationsWeight decreased 13 (10) 0 7 (15) 0

Cardiac disordersTachycardia 13 (10) 0 0 0

Serious Adverse ReactionsInfections were the most common type of SAE reported. In Study 3, 25patients (19%) experienced a serious infection, including 6 patients (5%)with serious treatment-related infections. In Study 4, 11 patients (23%)experienced a serious infection, including 8 patients (17%) with serioustreatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting(5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominalpain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, anddehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patientswere pyrexia (17%), aspartate aminotransferase increased, hypotension(13%), anemia, thrombocytopenia, alanine aminotransferase increased(11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia,hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia,leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheterrelated infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis,packed red blood cell transfusion, and platelet transfusion (4%).Deaths due to all causes within 30 days of the last dose of ISTODAXoccurred in 7% of patients in Study 3 and 17% of patients in Study 4. InStudy 3, there were 5 deaths unrelated to disease progression that weredue to infections, including multi-organ failure/sepsis, pneumonia, septicshock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, therewere 3 deaths unrelated to disease progression that were due to sepsis,aspartate aminotransferase elevation in the setting of Epstein Barr virusreactivation, and death of unknown cause.DiscontinuationsDiscontinuation due to an adverse event occurred in 19% of patients inStudy 3 and in 28% of patients in Study 4. In Study 3, thrombocytopeniaand pneumonia were the only events leading to treatment discontinuation inat least 2% of patients. In Study 4, events leading to treatment discontinuationin ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanineaminotransferase increased (4%).

6.2 Postmarketing ExperienceNo additional safety signals have been observed from postmarketingexperience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives

Prolongation of PT and elevation of INR were observed in a patient receivingISTODAX concomitantly with warfarin. Although the interaction potentialbetween ISTODAX and Coumadin or Coumadin derivatives has not beenformally studied, physicians should carefully monitor PT and INR inpatients concurrently administered ISTODAX and Coumadin or Coumadinderivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 EnzymesRomidepsin is metabolized by CYP3A4. Although there are no formal druginteraction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoco -nazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increaseconcentrations of romidepsin. Therefore, co-administration with strongCYP3A4 inhibitors should be avoided if possible. Caution should beexercised with concomitant use of moderate CYP3A4 inhibitors.Co-administration of potent CYP3A4 inducers (e.g., dexamethasone,carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

C M Y K

Cosmos Communications 1

5ja

19707a1 07.05.11 133

Q1 Q2 Page 2

PAGE 28 The ASCO Post | AUGUST 15, 2011

Perspective

We need to shift our payment incentives

toward cost containment and increase our focus

on evidence-based medicine. Doing that will

decrease incentives to overtreat.

–Peter B. Bach, MD, MAPP

including earlier diagnosis and better surgical techniques. However, increased use of expensive chemotherapies and biologics in the adjuvant and metastatic setting also play a role in increased sur-vival rates. Much lay press coverage on this subject gives particular attention

to high-priced agents, which obscures the discussion over rising costs. Policy-makers intent on reducing cancer care spending need a more nuanced appre-ciation of the clinical value of oncology treatments, from diagnosis to death.

The Gray Area of CostsThe ASCO Post asked health-care pol-

icy expert, Peter B. Bach, MD, MAPP, Director of the Center for Health Pol-icy and Outcomes at Memorial Sloan-Kettering, whether overutilization of services is a main driver of rising costs. “For obvious reasons, cancer spending gets singled out because the unit-of-care prices are so transparent. The challenge with aggregate data on the macro level is

that it is difficult to figure out which ser-vices are actually needed, which services are unnecessary, and which services we could pay less for,” said Dr. Bach.

He said that overutilization is one hy-pothesis for the upward spending trend. “But the cost issue is grayer than that. Of course we overuse services. The classic example is third- and fourth-line cancer agents in clinical scenarios where cure or even prolonging life is not viable,” said Dr. Bach. “But the unit pricing of our health care is also a factor. For example, we pay much more per unit of care, such as hospital days, than Western European countries, and in some regard with no better outcomes,” he added.

Shifting IncentivesDr. Bach stressed that constraining

oncology spending is a huge challenge, one that requires a multipronged ap-proach. “Among other things, we need to shift our payment incentives toward cost containment and increase our fo-cus on evidence-based medicine. Doing that will decrease incentives to over-treat,” said Dr. Bach.

According to Dr. Bach, a partial so-lution is to shift the incentives created by our current fee-for-service system, which reimburses each separate element of care, to an episode-based model that combines the collective costs of care into a single payment. Although Medicare has used episode-based payment models in a limited fashion, and the concept has been explored in certain chronic diseases such as diabetes, the complexity of can-cer presents difficult challenges.

Rising Costs of Cancer Carecontinued from page 1

may decrease concentrations of romidepsin and should be avoided ifpossible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport SystemsRomidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp,ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increasedconcentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

Pregnancy Category D [See Warnings and Precautions (5.5)].There are no adequate and well-controlled studies of ISTODAX in pregnantwomen. However, based on its mechanism of action, ISTODAX may causefetal harm when administered to a pregnant woman. A study in rats did notexpose pregnant animals to enough romidepsin to fully evaluate adversedevelopmental outcomes. If this drug is used during pregnancy, or if thepatient becomes pregnant while taking ISTODAX, the patient should beapprised of the potential harm to the fetus.In an animal reproductive study, pregnant rats received daily intravenousromidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day(0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% theestimated human daily dose based on body surface area and resulted in 5%reduction in fetal weight. Embryofetal toxicities associated with the use ofISTODAX were not adequately assessed in this study.

8.3 Nursing MothersIt is not known whether romidepsin is excreted in human milk. Becausemany drugs are excreted in human milk and because of the potential forserious adverse reactions in nursing infants from ISTODAX, a decisionshould be made whether to discontinue nursing or discontinue the drug,taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of ISTODAX in pediatric patients has not beenestablished.

8.5 Geriatric UseOf the approximately 300 patients with CTCL or PTCL in trials, about 25%were > 65 years old. No overall differences in safety or effectiveness wereobserved between these subjects and younger subjects; however, greatersensitivity of some older individuals cannot be ruled out.

8.6 Hepatic ImpairmentNo dedicated hepatic impairment study for ISTODAX has been conducted.Mild hepatic impairment does not alter pharmacokinetics of romidepsinbased on a population pharmacokinetic analysis. Patients with moderateand severe hepatic impairment should be treated with caution [See ClinicalPharmacology (12.3)].

8.7 Renal ImpairmentNo dedicated renal impairment study for ISTODAX has been conducted.Based upon the population pharmacokinetic analysis, renal impairment isnot expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied.Thus, patients with end-stage renal disease should be treated with caution[See Clinical Pharmacology (12.3)].

10 OVERDOSAGENo specific information is available on the treatment of overdosage of ISTODAX.Toxicities in a single-dose study in rats or dogs, at intravenous romidepsindoses up to 2.2 fold the recommended human dose based on the bodysurface area, included irregular respiration, irregular heart beat, staggeringgait, tremor, and tonic convulsions.In the event of an overdose, it is reasonable to employ the usual supportivemeasures, e.g., clinical monitoring and supportive therapy, if required.There is no known antidote for ISTODAX and it is not known if ISTODAX isdialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with romidepsin. Romidepsinwas not mutagenic in vitro in the bacterial reverse mutation assay (Amestest) or the mouse lymphoma assay. Romidepsin was not clastogenic in anin vivo rat bone marrow micronucleus assay when tested to the maximumtolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.Based on non-clinical findings, male and female fertility may be compromisedby treatment with ISTODAX. In a 26-week toxicology study, romidepsinadministration resulted in testicular degeneration in rats at 0.33 mg/kg/dose(2 mg/m2/dose) following the clinical dosing schedule. This dose resultedin AUC0-inf. values that were approximately 2% the exposure level in patientsreceiving the recommended dose of 14 mg/m2/dose. A similar effect wasseen in mice after 4 weeks of drug administration at higher doses. Seminal

vesicle and prostate organ weights were decreased in a separate study in ratsafter 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day),approximately 30% the estimated human daily dose based on body surfacearea. Romidepsin showed high affinity for binding to estrogen receptors inpharmacology studies. In a 26-week toxicology study in rats, atrophy wasseen in the ovary, uterus, vagina and mammary gland of females adminis -tered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following theclinical dosing schedule. This dose resulted in AUC0-inf. values that were0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.Maturation arrest of ovarian follicles and decreased weight of ovaries wereobserved in a separate study in rats after four weeks of daily drug adminis -tration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30%the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLINGKeep out of reach of children.Procedures for proper handling and disposal of anticancer drugs should beconsidered. Several guidelines on this subject have been published [SeeReferences (15)].

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling.

17.1 Instructions• Nausea and Vomiting

Nausea and vomiting are common following treatment with ISTODAX.Prophylactic antiemetics are recommended to be used in all patients.Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood CountsPatients should be informed that treatment with ISTODAX can cause lowblood counts and that frequent monitoring of hematologic parameters isrequired. Patients should be instructed to report fever or other signs ofinfection, significant fatigue, shortness of breath, or bleeding [SeeWarnings and Precautions (5.1)].

• InfectionsPatients should be informed that infections may occur during treatmentwith ISTODAX. Patients should be instructed to report fever, cough,shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [SeeWarnings and Precautions (5.2)].

• Tumor Lysis SyndromePatients at risk of tumor lysis syndrome (i.e, those with advanced stagedisease and/or high tumor burden) should be monitored closely for TLSand appropriate measures taken if symptoms are observed [See Warningsand Precautions (5.4)].

• Use in Women of Childbearing PotentialIf pregnancy occurs during treatment with ISTODAX, female patientsshould be advised to seek immediate medical advice and counseling.ISTODAX binds to estrogen receptors. Advise women of childbearingpotential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives [See Warnings and Precautions (5.6)].

• Patients should be instructed to read the patient insert carefully.

Manufactured for:Celgene CorporationSummit, NJ 07901Manufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146ISTODAX® is a registered trademark of Celgene CorporationU.S. Patents: 4,977,138; 7,608,280; 7,611,724ISTBVPI.002/PPI.002 06/11

C M Y K

Cosmos Communications 1

5ja

19707a1 07.05.11 133

Q1 Q2 Page 3

ASCOPost.com | AUGUST 15, 2011 PAGE 29

Perspective

In a recent paper published in Health Affairs,1 Dr. Bach and colleagues pro-posed an episode-based pilot for Medi-care using metastatic lung cancer as their model, proffering that oncology is compatible with episode-based pay-ments because it is evidence-based and employs updated guidelines in codify-ing standard care, providing opportuni-ties for both savings and quality control.

According to the proposal by Dr. Bach and coauthors, participating on-cologists would receive an episode-based payment for drugs and administration costs and would agree to use regimens accepted by the Centers for Medicare & Medicaid Services. The pilot would be divided into a traditional fee-for-service model followed by an episode-based phase. “Physicians would submit infor-mation from both phases. The first phase would document individual services; the second, a new claim code, would define the episode,” explained Dr. Bach.

Phase 1 fee-for-service claims would be used to determine the average cost of the episode of care, and Medicare would then shift to providing a single payment based on that average. A cen-tral feature of episode-based payment in this clinical scenario is the creation of incentives for oncologists to select lower-priced therapies from the choices judged equally appropriate.

Dr. Bach pointed out that along with the obvious savings associated with us-ing lower-cost regimens, adoption of an episode-based payment model could have the added fiscal benefit of pressuring drug manufacturers to reduce their prices, lowering costs within providers’ budgets. “We believe that our proposal has strong potential to serve as a stepping-off point toward comprehensive payment reform in oncology,” said Dr. Bach.

Burgeoning Cancer Population

Researchers at RTI International, Emory University in Atlanta, and the Centers for Disease Control and Preven-tion found that although over the past 2 decades medical costs for treating cancer have nearly doubled, the main driver for the increased costs is the growing num-ber of cancer cases, not treatment.2

“The number of cancer cases has increased proportionately more than medical expenditures, indicating that the increase in the cost of treating can-cer has been driven mainly by the in-crease in the number of cases and not by the cost per treated cancer case,” coauthor Justin Trogdon, PhD, told The ASCO Post. He added that early detection and enhanced prevention

are sound strategies for addressing the upcoming cancer population problem.

In an interview with The ASCO Post, Robin Yabroff, PhD, MBA, an epide-miologist in the Health Services and Economics Branch of NCI, concurred that our population was a major driver of cancer care spending. “The U.S. pop-ulation is aging and growing, which has a major influence on the rising costs of cancer care. A higher absolute number of newly diagnosed patients with cancer

along with longer survival rates is going to play a large role in cancer trends and their related costs,” said Dr. Yabroff.

Using linked SEER-Medicare data, Dr. Yabroff and colleagues have looked at cancer costs across three periods: the ini-tial phase, defined as the first 12 months after diagnosis; last-year-of-life phase, de-fined as the final 12 months of life; and continuing phase, defined as all months between the initial and last-year-of-life phases of care. Allowing for survival variations in certain cancers, the NCI re-searchers found that the costliest phases of care were the initial and last year of life.

Dr. Yabroff commented that parsing the exact drivers of costs is difficult. How-ever, her studies have shown that costs of hospitalizations and greater use of surgery and adjuvant therapy among the elderly

are also contributors. “The larger number of patients with cancer is a trend that we can comfortably predict as continuing and a future driver of cancer care costs. There’s more uncertainty about how treatment trends will impact the costs of care in the future,” said Dr. Yabroff.

ConclusionsIt is projected that in 2011, health-

care spending in the United States will cost approximately $2.7  trillion, ac-

counting for almost 18% of our gross domestic product (GDP). We spend more per person and a greater propor-tion of GDP on health care than any other country. Cancer care costs are about 5% of our total health-care spend-ing, and although we have seen major advances in treatments and survival rates over the past several decades, if the escalating growth in oncology spending remains unchecked, it will contribute to the greater ills and insolvency facing vi-tal parts of our delivery system.

Finding value within the multiple layers of our cancer care delivery system is an enormous challenge that requires honest examination of which therapeu-tic strategies provide the best, most cost-effective outcomes. Studies have shown that although the quantity and costs of services and drugs have increased at disquieting rates, it is the sheer number of new cases and longer survival rates of patients with cancer that are the main drivers of burgeoning spending.

Expenditures will be of even greater concern as the baby boomer popula-tion begins swelling the already finan-cially stressed Medicare program in 2011. Identifying and understanding the drivers of costs help policymakers and health-care experts wrestle with possible solutions. ■

Disclosure: Dr. Bach has received speaking fees from Genentech. Drs. Buzdar and Trogdon reported no potential conflicts of interest.

References1. Bach PB, Mirkin JN, Luke JJ: Ep-

isode-based payment for cancer care: A proposed pilot for Medicare. Health Af-fairs 30:500-509, 2011.

2. Tangka FK, Trogdon JG, Richard-son LC, et al: Cancer treatment cost in the United States: Has the burden shifted over time? Cancer 116:3477–3484, 2010.

The cost of treating cancer has been driven mainly by the increase in the number of cases and not by the cost per treated cancer case.

—Justin Trogdon, PhD

Visit The ASCO Post website at: ASCOPost.com

LEADERSHIP TO LEGACY ™

Together, anything is possible.

At the Conquer Cancer Foundation, our eyes are always on the places where

our researchers can make a real, tangible difference in the lives of patients.

Your gift to the 2011 Leadership to LegacyTM campaign will support the

Foundation’s Grants and Awards Program, focusing on researchers at the

dawn of their careers, building a pipeline of talent that will enrich cancer

care and research for years to come.

Join your colleagues.

Visit www.ConquerCancerFoundation.org/Legacy to make your gift today.

ASCOPost.com | AUGUST 15, 2011 PAGE 31

Psychosocial Oncology

The challenges of life-threatening physical illness can sometimes

lead to suicide. In fact, given the criti-cal stressors that a person with cancer faces, we might expect suicide to be a more common reaction. Patients with cancer are at increased risk of com-pleted suicide, though the prevalence

of suicidal ideation among these in-dividuals is equivalent to that seen in the general population.1 A review of Surveillance, Epidemiology, and End Results (SEER) data found 0.2% of pa-tients diagnosed with cancer commit-ted suicide, most within the first year after diagnosis. Suicidal risk appears to peak in the first month after diagnosis2 and may remain high for a few months thereafter.

Suicide is significantly increased in male patients with respiratory can-

Evaluating Risk for Suicide in People Diagnosed or Living with Cancer By Andrew J. Roth, MD

cers.3 Older adults have the highest rate of suicide compared with any other age group. Given the increasing numbers of older people being diagnosed with cancer, we are likely to see an upturn in those at risk for suicide. Several studies have shown that suicide among older patients with cancer is higher than in patients with other medical illnesses, after controlling for psychiatric illness and risk of dying within a year.4-7

The presence of a physical condi-tion is a risk factor for suicidal behav-ior even in the absence of mental disor-der or when controlling for depressive illness and alcohol use.8,9 The risk is increased with the number of physical ailments.

Suicidal IdeationSuicidal ideation is frightening and

upsetting for the patient, the fam-ily, and the oncology team members. Often suicidal thoughts may be con-sidered a potentially treatable coping response, but one that needs to be identified and addressed in a timely manner. Though suicidal ideation may be prevalent among patients with cancer,10 it is not usually a sign of im-minent harm. Understanding the iden-tifiable risk factors and interventions to prevent bad outcomes are impor-

tant for oncologists, oncology nurses, consultants, and ancillary services participating in oncology treatment, including social workers, physical and occupational therapists, and nutrition-ists.11

Some propose screening specifical-ly for suicidal ideation, as distinct from general depressive symptoms. Passive thoughts of wanting to die may occur quite frequently, particularly in the set-ting of advanced physical disease, and may serve as a mechanism of control over fears of an uncertain future of suf-fering based on worst case scenarios that come to mind when people think of cancer-related deaths. It is not un-usual for people to think in a condi-tional manner, especially when they are not very debilitated, “If the pain gets bad enough, I will end my life,” or “If I start to lose my faculties I would want to die.”

Suicidal statements may reflect an offhand comment resulting from frus-tration or disgust with a treatment course: “If I have to have one more MRI this year, I’ll kill myself.” Howev-er, an indication of significant despair may also be heard: “I can no longer bear what this disease is doing to all of us; I feel like such a burden. I think everyone would be better off without me.” Exploring the seriousness of the thoughts is imperative.

Table 1 lists questions for assessing suicidal ideation in patients with can-cer. It is important to ask if the patient has made a definite plan. Is the patient stockpiling medication? Does he or she own or have access to a weapon?

Risk FactorsThere are several important predic-

tors of suicide risk (Table 2), includ-ing psychological and medical vari-ables: history of a psychiatric disorder, particularly depression or substance abuse; recent bereavement; few social supports; poorly controlled pain; ad-vance stage of disease with debilita-tion; mild delirium with poor impulse control; and hopelessness or helpless-ness in the context of depression. Ad-dressing the medical and psychiatric variables with commitment to therapy may reduce suicidal ideation and risk. If the patient is actively suicidal, a 24-hour companion should monitor the patient’s behavior.

Bolund12 reports that fully half of all Swedish cancer suicides had previ-

ously conveyed suicidal thoughts or plans to their relatives. In addition, many of the completed cancer suicides had been preceded by an attempted suicide. This is consistent with the statistics for suicide in general, which show that a previous suicide attempt greatly increases the risk of completed suicide.13-15 A family history of suicide is of increasing relevance in assessing suicide risk.

Patients with advanced illness are at highest risk, perhaps because they are most likely to have such compli-cations as pain, major depression, de-lirium, and deficit symptoms. Suicidal ideation has also been reported as an uncomfortable activating, disinhibit-ing, or depressive side effect of medi-cations that may be prescribed for patients with cancer, including anti-depressants,16 steroids, opioids, ben-zodiazepines, asthma medications, in-terferon, and hypnotics. This does not mean we should limit the use of these medications, but we should provide appropriate information and follow up.

Psychiatric disorders are frequently present in hospitalized patients who are suicidal.17,18 Farberow and col-leagues19 reported that 86% of suicides occurred in the preterminal or ter-minal stages of illness, despite greatly reduced physical capacity. Poor prog-nosis and advanced illness usually go hand-in-hand. It is thus not surprising that in Sweden, those who were ex-pected to die within a matter of months were the most likely to commit suicide.

Uncontrolled pain in patients with cancer is a dramatically important

continued on page 34

Table 1: Questions for Assessing Suicide Risk in Patients with CancerAcknowledgement Open with the following statement (which does

not enhance risk):

■ Most patients with cancer have passing thoughts about suicide, such as “I might do something if it gets bad enough.”

■ Have you ever had thoughts like that?

■ Have you had any thoughts of not wanting to live or that it would be easier if you were to die?

Seriousness ■ Do you have thoughts of suicide?

■ Have you planned for it?

■ Have you thought about how you would do it?

Prior history ■ Have you ever been depressed or made a suicide attempt?

■ Have you ever been treated for other psychiatric problems?

■ Have you been psychiatrically hospitalized before being diagnosed with cancer?

Substance use ■ Have you ever had a problem with alcohol or drugs?

Bereavement ■ Have you lost anyone close to you recently (family, friends, or fellow patients)

Adapted from Roth AJ, Holland JC: Psychological Aspects of Hematologic Malignancies, in Wiernik PH, Goldman JM, Dutch JP, et al (eds): Neoplastic Diseases of the Blood, 4th edition, pp 1161. New York, Cambridge University Press, 2003.

Andrew J. Roth, MD

Table 2: Factors That May Identify a Higher Risk for Suicide

Medical History

■ Poorly controlled pain

■ Advanced stage of disease

■ Mild delirium/mental status changes with poor impulse control

Personal History

■ Prior psychiatric history/prior suicide attempts

■ Substance abuse

■ Recent bereavement

■ Few social supports

■ Hopelessness

■ Family history of suicide

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

Oncogenic BRAF: A new potential therapeutic target1,2

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4

Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially

result in tumorigenesis.1,2

The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2:

~50% of melanoma tumors4

~40% of papillary thyroid tumors4,5

~30% of serous ovarian tumors5

~10% of colorectal tumors6

~10% of prostate tumors6

In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2

Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

© 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

Oncogenic BRAF: A new potential therapeutic target1,2

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4

Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially

result in tumorigenesis.1,2

The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2:

~50% of melanoma tumors4

~40% of papillary thyroid tumors4,5

~30% of serous ovarian tumors5

~10% of colorectal tumors6

~10% of prostate tumors6

In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2

Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

© 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

PAGE 34 The ASCO Post | AUGUST 15, 2011

Psychosocial Oncology

risk factor for suicide. In several stud-ies, the vast majority of cancer-related suicides were committed by patients with severe pain, which was often in-adequately controlled and poorly tol-erated.12,20

DepressionDepression is a factor in 50% of

all suicides. Approximately 25% of all patients with cancer experience se-vere depressive symptoms, including major depression.21,22 Among those with advanced illness and progres-sively impaired physical function, symptoms of severe depression rise to 77%.23

Depression also appears to be important in terms of patient pref-erences for life-sustaining medical therapy. Ganzini et al24 reported that among elderly depressed patients, an increase in the desire for life-sus-taining medical therapies followed treatment of depression in subjects

who had been initially more severely depressed, more hopeless, and more likely to overestimate the risks and to underestimate the benefits of treat-ment. They found that patients with mild to moderate depression are un-likely to alter their decisions regard-ing life-sustaining medical treatment (despite treatment for their depres-sion). However, they concluded that severely depressed patients—particu-larly those who are hopeless—should be encouraged to defer advance treat-ment directives until after treatment of their depression.

HelplessnessA sense of helplessness in the face

of illness is an important factor in sui-cide vulnerability.25 Helplessness and a loss of control may be induced by symptoms or deficits due to the illness or its treatments, as well as the exces-sive need on the part of some patients to be in control of all aspects of living or dying. Being left to face illness alone may create a sense of isolation and abandonment that also leads to the de-velopment of hopelessness.

It is not uncommon for illness-related events to induce a great sense of helplessness even in those who are not typically controlling individu-als. Impairments or deficits induced by the patient’s illness or its treat-ments often include loss of mobility, paraplegia, loss of bowel and bladder function, amputation, aphonia, sen-sory loss, and inability to eat or swal-low. Most distressing to patients is the sense that they are losing control of their minds, especially when they are confused or sedated by medica-tions. The risk of suicide is increased in patients with such physical impair-ments, especially when accompanied by psychological distress and dis-turbed interpersonal relationships due to these deficits.20

ManagementThe management of a patient with

cancer who is suicidal is based on the following goals: developing and main-taining a supportive relationship and trustworthy communication; assessing the risk and status of suicidal ideation,

intent, and plan to hurt oneself; and offering the patient a sense of control by helping him or her to focus on that which can be controlled. Moreover, it is essential to convey the attitude that much can be done to improve the qual-ity, if not the quantity, of life. Thus, it is important to actively treat the symp-toms of pain, nausea, insomnia, anxi-ety or restlessness, depression, confu-sion, and fatigue. ■

Disclosure: Dr. Roth reported no potential conflicts of interest.

References1. Robson A, Scrutton F, Wilkinson L,

et al: The risk of suicide in cancer patients: A review of the literature. Psychooncology 19:1250-1258, 2010.

2. Johnson TV, Garlow SJ, Brawley OW, et al: Peak window of suicides oc-curs within the first month of diagnosis: Implications for clinical oncology. Psy-chooncology. January 24, 2011 (early re-lease online).

3. Hem E, Loge J, Haldorsen T, et al: Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol 22:4209-4216, 2004.

4. Chochinov HMC, Wilson KG, Enns M, et al: Desire for death in the terminally ill. Am J Psychiatry 152:1185-1191, 1995.

5. Breitbart W, Rosenfeld B, Pessin H, et al: Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA 284:2907-2911, 2000.

6. Rosenfeld B, Breitbart W, Stein K, et al: Measuring desire for death among patients with HIV/AIDS: The schedule of attitudes toward hastened death. Am J Psy-chiatry 156:94-100, 1999.

7. Rosenfeld B, Breitbart W, Galietta M, et al: The schedule of attitudes toward hastened death: Measuring desire for has-tened death in terminally ill cancer pa-tients. Cancer 88:2868-2875, 2000.

8. Scott KM, Hwang I, Chiu WT, et al: Chronic physical conditions and their association with first onset of suicidal be-havior in the world mental health surveys. Psychosom Med 72:712-719, 2010.

9. Druss B, Pincus H: Suicidal ideation and suicide attempts in general medical ill-nesses. Arch Intern Med 160:1522-1526, 2000.

10. Walker J, Waters RA, Murray G, et al: Better off dead: Suicidal thoughts in cancer patients. J Clin Oncol 26:4725-4730, 2008.

11. Valente SM: Oncology nurses’

Suicide Risk in Patients with Cancercontinued from page 31

knowledge of suicide evaluation and pre-vention. Cancer Nurs 33:290-295, 2010.

12. Bolund C: Suicide and cancer: II. Medical and care factors in suicide by can-cer patients in Sweden. 1973-1976. J Psy-1973-1976. J Psy-chosoc Onc 3:17-30, 1985.

13. Zweig R, Hinrichsen G: Factors associated with suicide attempts by de-pressed older adults: A prospective study. Am J Psychiatry 150:1687-1692, 1993.

14. Dubovsky SL: Averting suicide in terminally ill patients. Psychosomatics 19:113-115, 1978.

15. Murphy GE: Suicide and attempted suicide. Hosp Pract 12:78-81, 1977.

16. Nishida T, Wada M, Wada M, et al: Activation syndrome caused by paroxetine in a cancer patient. Palliat Support Care 6:183-185, 2008.

17. Breitbart W: Cancer pain and sui-cide, in Foley K, Bonica JJ, Ventafridda V (eds): Advances in Pain Research and Therapy, vol 16, pp 399-412. New York, Raven Press, 1990.

18. Breitbart W: Suicide in cancer pa-tients. Oncology 1(2):49-55, 1987.

19. Farberow NL, Schneidman ES, Leonard CV: Suicide among general medical and surgical hospital patients with malignant neoplasms. Medical Bulletin 9; Washington, DC; U.S. Veterans Adminis-tration; 1963.

20. Farberow NL, Ganzler S, Cuter F, et al: An eight year survey of hospital suicides. Suicide Life Threat Behav 1:184-201, 1971.

21. Chochinov HMC, Wilson K, Enns M, et al: Prevalence of depression in the terminally ill: effects of diagnostic criteria and symptom threshold judgments. Am J Psychiatry 151:537-540, 1994.

22. Massie MJ, Holland JC, Straker N: Psychotherapeutic interventions, in: Hol-land JC, Rowland JH (eds): Handbook of Psychooncology: Psychological Care of the Patient with Cancer, pp 455-469. New York, Oxford University Press. 1989.

23. Breitbart W, Jaramillo JR, Cho-chinov HM: Palliative and terminal care, in Holland JC, Breitbart W, Jacobsen PB, et al (eds): Psycho-oncology, pp 437-449. New York, Oxford University Press. 1998.

24. Ganzini L, Lec MA, Heintz RT, et al: The effect of depression treatment on elderly patients’ preferences for life-sustaining medical therapy. Am J Psych 151:1613-1616, 1994.

25. Chochinov HM, Wilson KG, Enns M, et al: Depression, hopelessness, and suicidal ideation in the terminally ill. Psy-chosomatics 39:366-370, 1998.

Jimmie Holland, MD, Guest Editor

Providing care beyond medical treatment, the multidisciplinary field of psychosocial oncology addresses the psychological, so-cial, and emotional health of the patient with cancer. On an oc-casional basis, The ASCO Post will explore the realm of psycho-social oncology with a column guest edited by Jimmie Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Me-morial Sloan-Kettering Cancer Center, New York.

ASCOPost.com | AUGUST 15, 2011 PAGE 35

JCO Spotlight

Final results of an international phase II trial of first-line treatment

for primary testicular diffuse large B-cell lymphoma show that using a combined treatment strategy includ-ing chemotherapy and central nervous system and testicular prophlaxis “was associated with a good outcome.” The results were reported in the Journal of Clinical Oncology.1 Radiotherapy pre-vented contralateral testis relapses, but central nervous system prophylaxis “deserves further investigation,” the in-vestigators stated.

Conducted by the International Extranodal Lym-phoma Study Group (IELSG) and the Italian Lymphoma

Foundation, the trial (IELSG-10) in-volved 53 patients, aged 22 to 79, with untreated stage I or II primary testicu-lar diffuse large B-cell lymphoma. The treatment plan consisted of six to eight courses of R-CHOP (rituximab [Ritux-an] added to cyclophosphamide, doxo-rubicin, vincristine, and prednisone) every 21 days (R-CHOP21), CNS pro-phylaxis with four doses of intrathecal methotrexate, and radiotherapy to the contralateral testis (30 Gy) for all pa-tients and to regional lymph nodes (30 to 36 Gy) for stage II disease.

Patient OutcomesOne patient experienced progressive

disease at nodal and extranodal sites dur-ing treatment and died. All the others achieved a complete response. At a me-dian follow-up of 65 months, the 5-year progression-free survival rate was 74% and overall survival rate was 85%. Nine patients relapsed; five of those patients died of lymphoma and the other four had salvage therapy. The 5-year cumula-tive incidence of central nervous system relapse was 6%, and no contralateral testis relapses occurred. A total of 10 pa-tients died, none from toxicities, which were mild during the R-CHOP21 treat-ment. Grade 3/4 toxicities included he-matologic effects (28%), neurologic ef-fects (13%), and infections (2%).

The investigators concluded that combined treatment with R-CHOP21 plus central nervous system and testicu-lar prophylaxis is a promising approach for primary testicular diffuse large B-cell lymphoma, achieving an effective

Combined Therapy Produces Good Outcomes in Primary Testicular Diffuse Large B-cell LymphomaBy Charlotte Bath

systemic control of the disease with no contralateral testis relapses and a low incidence of central nervous system relapse. They added that the accept-

able toxicity profile of treatment seen in their trial was remarkable considering that, as usual for this disease, half the patients were over age 65. ■

Reference1. Vitolo U, et al: J Clin Oncol 29:2766-

2772, 2011.

Hematology

SEE PAGE 45

Despite advances in targeted cancer therapy,

an important escape pathway remains: METAlthough advanced antitumor therapies have become available, many tumor types continue to evade treatment.1 Research has identified the MET pathway as one of the most critical escape pathways utilized by tumors. In most normal tissues, MET and its only known ligand, hepatocyte growth factor (HGF), are found in low levels. But in a range of malignancies—including thyroid, prostate, ovarian, lung, and breast cancers—MET is upregulated and drives more invasive and aggressive behavior of tumor cells, resulting in metastasis.2-7 Recent evidence also shows that inhibition of angiogenesis creates hypoxic conditions in the tumor that may further upregulate MET and ultimately promote disease progression.5,7

Exelixis is fully devoted to shutting down MET-driven escape in cancer. Therefore, we are investigating the dual targeting of the MET and VEGF pathways to simultaneously inhibit metastasis and angiogenesis in several cancers.

Visit www.METinhibition.com to learn moreabout the role of MET in tumor escape.

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. http://seer.cancer.gov/csr/1975_2008/. Accessed May 10, 2011. 2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth [draft manuscript]. 2011. Data on file, Exelixis, Inc. 3. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 4. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109:863-867. 5. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347-361. 6. Capdevila J, Argiles G, Rodriguez-Frexinos V, Nuñez I, Tabernero J. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med. 2010;9:153-162. 7. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207-2214.

© 2011 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 06/11

M8

LS 1

Q1

Q2

Cosmos Com

munications 718.482.1800

19651a06.21.11

133C

MY

K

B:11.25 in

B:8.625 in

T:10.5 in

T:7.625 in

S:9.75 in

S:6.75 in

JOB#: 10157PROOF#: 1CLIENT: ExelixisDESC: AdvertorialColor: 4CAD: TBrancaccioTRAFFIC: EAnonuevoOPERATOR: mdGALLEY#: 1DATE: 2011/06/21 - 16:50CREATED: 6/20/11 - 10:14 AMFONTS: Neo Sans Pro Medium, Neo Sans Pro Bold, Neo Sans Pro Regular, Helvetica Neue LT Std 77 Bold Condensed, Helvetica Neue LT Std 47 Light Condensed, Helvetica Neue LT Std 47 Light Condensed ObliqueIMAGES: Exelixis_KO.eps, 10157_JA_twk.tifCOLORS: C=24 M=0 Y=98 K=8, C=0 M=7 Y=80 K=0, PaperNOTES: DOC PATH: EXL_XLX_Q10157:EXL_XLX_Q10157_JA_D01.inddDOC SIZE: 10” X 13”PRINT SCALE: 100%

PAGE 36 The ASCO Post | AUGUST 15, 2011

In the News

Newer drugs, including sipuleucel-T (Provenge), cabazitaxel (Jevtana),

and abiraterone (Zytiga), can extend survival modestly and ease symptoms for men with advanced prostate can-cer. Maximizing the benefit to patients will require shifting the focus from de-veloping individual drugs to develop-ing integrated therapies, according to Christopher J. Logothetis, MD, Chair of the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

“There are multiple new drugs avail-able to patients with advanced prostate cancer. While each drug works indi-vidually, we believe developing opti-mal combinations and sequences with these drugs is the key to further im-proving therapy,” Dr. Logothetis said.

“By developing a manual on how to use prostate cancer drugs in opti-mal combinations and sequences, we will be able to design therapies that are greater than the sum of the individual drugs,” Dr. Logothetis explained in an interview with The ASCO Post.

Unique Opportunity“When you look at other cancer types,

the greatest clinical benefit has come from using drugs at the right time during the course of the disease and in the right com-binations. What is unique about prostate cancer, however, is that the disease is rela-tively slower-growing and less threatening in the immediate term than other cancer types. This creates an opportunity for clinical research with drug combinations that will actually help the patient being treated in the study and not just create knowledge for the next generation of patients. If drug development is moving quickly enough and the disease is grow-ing slowly enough, the patient can choose to participate in research for both altruis-tic and pragmatic reasons. In essence, we are prescribing research to help him.”

Optimizing Treatment for Advanced Prostate Cancer Requires Shifting Focus from Individual Drugs to Integrated Therapies By Charlotte Bath

In the News focuses on media re-ports that your patients may have questions about at their next visit. This continuing column will pro-vide summaries of articles in the popular press that may prompt such questions, as well as com-ments from colleagues in the field.

Developing a manual for using pros-tate cancer drugs “is both straightfor-ward and difficult,” Dr. Logothetis said. “The task is straightforward in the sense that different individual drug compa-nies appreciate it is in their best interests to collaborate and design trials that op-timize the most effective drug combina-tions. It is clear a shared clinical research platform needs to develop very quickly.”

More complex and difficult may be the job of designing trials in which data collected from one trial are interpreted not only in the context of that trial,

but also integrated with data sets from other trials. “What we are advocating is the creation of a new set of trial de-signs that allow us to look at the con-sequences of one therapy and how it impacts another,” Dr. Logothetis said. He also advocates “creating a new set of biomarkers that are specific to both the disease and the drug and integrate them to see if they change over time.”

Empiricism and BeyondChoosing which drug to administer

to a patient with prostate cancer is cur-

rently based on “empirically derived gen-eral rules that have not always been criti-cally tested,” Dr. Logothetis said. “For example, one general rule is that patients who have disease with symptoms or the impending likelihood of symptoms should receive chemotherapy, while pa-tients with less symptomatic, lower-vol-ume disease should initially receive less toxic therapies like immunotherapies.” While this seems logical, there is little evidence to back it up, he said.

With sipuleucel-T, an immunother-

Expect Questions from Your Patients

Drugs for the treatment of prostate cancer have been in the news be-

cause of recent approvals by the FDA, the costs connected with their use, and associated improvements in survival.1 More recently reported was the decision to allow Medicare coverage of sipuleucel-T treatment for men who met the FDA approval criteria. The following informa-tion may be helpful for physicians fielding questions from patients who have read or heard about these new drugs and want to know if the drugs are right for them.

What is the FDA-approved use for sipuleucel-T?

Sipuleucel-T (Provenge) was ap-proved in April 2010 for the treatment of v or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer. A cellular immunother-apy, sipuleucel-T consists of autologous peripheral blood mononuclear cells acti-vated with a recombinant human protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colo-ny-stimulating factor (PAP–GM-CSF). Common adverse reactions reported in safety evaluations were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

What is the FDA-approved use for cabazitaxel?

Cabazitaxel (Jevtana), a taxane, was approved in June 2010 for use in combination with prednisone to treat metastatic, hormone-refractory prostate cancer previously treated with a docetax-el-containing regimen. In clinical trials, the most common grade 3/4 adverse

reactions were neutropenia, leukopenia, anemia, diarrhea, fatigue, and asthenia.

What is the FDA-approved use for abiraterone?

Abiraterone (Zytiga) was approved in May 2011 for the treatment of men with metastatic, castrate-resistant pros-tate cancer who are no longer respond-ing to docetaxel. According to the NCI, “abiraterone is the first in an approach-ing wave of new agents for prostate cancer that, directly or indirectly, target testosterone.”2

Abiraterone “can also be considered in patients who have symptomatic disease who are not good candidates for chemo-therapy” and might be used before che-motherapy, noted Christopher J. Logo-thetis, MD, of The University of Texas MD Anderson Cancer Center. “The study of abiraterone in patients who have not yet received docetaxel-based chemo-therapy has completed accrual, and the results will hopefully be available this year. The results from that study will provide insights into optimizing the sequence of abiraterone and chemotherapy.”

What other new drugs are being used for patients with prostate cancer?

Denosumab (Xgeva) is a monoclonal antibody that was approved in June 2010 for the prevention of skeletal-related events in patients with metastases from solid tumors, including prostate can-cer. Denosumab can be used for “the relief and delay of bone symptoms” and “should be considered a supportive agent,” Dr. Logothetis said, but “does not impact survival.”

Cabozantinib (XL184) has not received FDA approval but has been shown in a phase I clinical trial to shrink prostate tumors or stop their growth and shrink bone metastases in most patients with prostate cancer. The FDA granted orphan drug designation to the agent in January 2011. Dr. Logothe-tis called cabozantinib a “very exciting drug” and said that this targeted therapy “may be particularly relevant because it blocks c-Met and VEGF, two pathways that are known to integrate with andro-gen signaling.” Cabozantinib has poten-tial toxicities, however, as evidenced by the deaths of six participants in the ran-domized discontinuation trial of cabo-zantinib, reported at the 2011 ASCO Annual Meeting. Studies are presently underway to identify the safest, most ef-fective dose of this drug in patients with advanced prostate cancer. ■References

1. Pollack A: New drugs fight prostate cancer, but a high cost. New York Times, June 27, 2011.

2. FDA approves abiraterone for ad-vanced prostate cancer. NCI Cancer Bulletin 8:9, May 3, 2011.

Christopher J. Logothetis, MD

continued on page 38

Genitourinary Cancer

INDICATION: Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS:

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen.

Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials– The utility of premedication in preventing the fi rst or subsequent

episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4)

– Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion– Immediately and permanently discontinue Vectibix® infusion in patients

experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion

reactions should be available during Vectibix® infusions

The case for Vectibix®

©2011 Amgen Inc. All rights reserved. 04-11 MC48257-B

Bleed: 10.75”Trim: 10.5”Live: 9.5”

Bleed

: 14.5”Trim

: 14”Live: 13”

1AMVX020_OncTimesAscoPost_JA_D01_P4CB.indd 1 4/20/11 10:26 PM

INDICATION: Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS:

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen.

Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials– The utility of premedication in preventing the fi rst or subsequent

episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4)

– Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion– Immediately and permanently discontinue Vectibix® infusion in patients

experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion

reactions should be available during Vectibix® infusions

The case for Vectibix®

©2011 Amgen Inc. All rights reserved. 04-11 MC48257-B

Bleed: 10.75”Trim: 10.5”Live: 9.5”

Bleed

: 14.5”Trim

: 14”Live: 13”

1AMVX020_OncTimesAscoPost_JA_D01_P4CB.indd 1 4/20/11 10:26 PM

INDICATION: Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS:

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Please see brief summary of Prescribing Information on next page. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen.

Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials– The utility of premedication in preventing the fi rst or subsequent

episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4)

– Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion– Immediately and permanently discontinue Vectibix® infusion in patients

experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion

reactions should be available during Vectibix® infusions

The case for Vectibix®

©2011 Amgen Inc. All rights reserved. 04-11 MC48257-B

Bleed: 10.75”Trim: 10.5”Live: 9.5”

Bleed

: 14.5”Trim

: 14”Live: 13”

1AMVX020_OncTimesAscoPost_JA_D01_P4CB.indd 1 4/20/11 10:26 PM

PAGE 38 The ASCO Post | AUGUST 15, 2011

In the News

Timing of Prostate Cancer Drugs: Earlier But Not Too Early?W hile sipuleucel-T, abi-

raterone, and cabazitaxel have been approved for patients with advanced disease, they might also be used in patients with ear-lier-stage disease, according to Christopher J. Logothetis, MD, of MD Anderson Cancer Center. “I think it is fair to say that they will be used better and more efficiently in a select group of patients early in the disease. There are already trials using abiraterone in the preopera-tive setting before radical prosta-tectomy and they show promise in what appears to be an enhanced effect on the tumor,” he reported.

“The unique problem with pros-tate cancer is that ‘earlier therapy’ can sometimes be too early,” Dr. Logothetis said. “If patients are only exposed to the drugs for 5 years, the side effects may be modest, but if patients live for an entire decade or more, continued exposure to thera-py may be significantly more toxic. The goal is to offer therapies after the cancer has demonstrated its po-tential to get aggressive, but before the cancer is visibly causing prob-lems. To do this, we need to develop better biomarkers that identify the transition to an aggressive cancer before it becomes obvious clini-cally,” he said ■

apy approved for patients with asymp-tomatic or minimally symptomatic met-astatic castrate-resistant prostate cancer, Dr. Logothetis and his colleagues at MD Anderson “generally treat patients who have progressive disease but are relatively

well and whose cancers are not likely to threaten them within the next 6 months with sipuleucel-T,” he explained. “In con-trast, patients with more advanced-stage disease who are more likely to develop symptoms receive chemotherapy.”

Ideally, in order to prolong patient sur-vival, the approach to administering pros-tate cancer drugs should “move beyond

empiricism to a rational process based on understanding the underlying biology of the pathways these drugs target,” Dr. Logothetis stated. “For example, I think there is a real sense of urgency to better understand precisely how immunothera-pies like sipuleucel-T interact with che-motherapy.” The critical question about how optimally to use immunotherapy

and cytotoxic therapy so they enhance rather than inhibit each other has not been addressed in clinical trials, he said.

“The current FDA-approved indica-tions for both abiraterone and cabazitaxel specify that these agents should be given after docetaxel,” Dr. Logothetis contin-ued, “but we are participating in clinical trials where these drugs are being used before docetaxel. If ever there was an an-ticipated interaction between agents that block pathways central to prostate cancer progression, it is with these drugs. We believe there is good reason to try these therapies in different sequences,” he ex-plained. “I think the results from these trials are going to rapidly produce major therapy advances that will prolong sur-vival in patients with advanced disease.” ■

Disclosure: Dr. Logothetis has received research support and honoraria from Pfizer, Johnson & Johnson, and Bristol-Myers Squibb.

Prostate Cancer Treatment Shiftcontinued from page 36

Vectibix® (panitumumab)Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONSDermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher)in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, andAdverse Reactions].Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurredin postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

INDICATIONS AND USAGEVectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC)with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) inFull Prescribing Information].The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-relatedsymptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefitfor Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancerwith these mutations. [see Clinical Studies (14) in Full Prescribing Information].DOSAGE AND ADMINISTRATIONRecommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusionover 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions]• Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction,permanently discontinue Vectibix.Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions]• Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade

2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of

Vectibix, treatment may be resumed at 50% of the original dose.– If toxicities recur, permanently discontinue Vectibix.– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the

recommended dose of 6 mg/kg is reached.Do not administer Vectibix as an intravenous push or bolus.CONTRAINDICATIONS: None.WARNINGS AND PRECAUTIONSDermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus,erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities,infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported.Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [seeBoxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix inapproximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusionreactions. [see Dosage and Administration].Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interimanalysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival andincreased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%),stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate inVectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicitiesexperienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of eachchemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with thoserandomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidenceof NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receivingVectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated withVectibix in combination with chemotherapy.Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following theinitial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, orpulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patientsis uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination withchemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized bycough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CTevidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonaryinfiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibixtherapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia(NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks orlonger after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should beperiodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenouselectrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sunexposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitorfor evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because theseare the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full PrescribingInformation]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression usingthe Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in thespecific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents,deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Referto the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible fortreatment with Vectibix and for full instructions on assay performance.ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions]• Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions]• Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions]• Pulmonary Fibrosis [see Warnings and Precautions]• Electrolyte Depletion/Monitoring [see Warnings and Precautions]• Photosensitivity [see Warnings and Precautions]The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominalpain, nausea, and diarrhea, including diarrhea resulting in dehydration.The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated byinfectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adversereactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trialsof a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Theadverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be relatedto drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent atthe recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial.The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had amedian age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1)

Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234)Grade*

Body System All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%)Body as a Whole Fatigue 26 4 15 3

General Deterioration 11 8 4 3Digestive Abdominal Pain 25 7 17 5

Nausea 23 1 16 < 1Diarrhea 21 2 11 0Constipation 21 3 9 1Vomiting 19 2 12 1Stomatitis 7 0 1 0Mucosal Inflammation 6 < 1 1 0

Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0Peripheral Edema 12 1 6 < 1

Respiratory Cough 14 < 1 7 0Skin/Appendages All Skin/Integument Toxicity 90 16 9 0

Skin 90 14 6 0Erythema 65 5 1 0Dermatitis Acneiform 57 7 1 0Pruritus 57 2 2 0Nail 29 2 0 0Paronychia 25 2 0 0Skin Exfoliation 25 2 0 0Rash 22 1 1 0Skin Fissures 20 1 < 1 0Eye 15 < 1 2 0Acne 13 1 0 0Dry Skin 10 0 0 0Other Nail Disorder 9 0 0 0Hair 9 0 1 0Growth of Eyelashes 6 0 0 0

*Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity wassevere (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to,conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) werereported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2%of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or oculartoxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix;and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications,including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergicreaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever,chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. Theuse of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes ofinfusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of whichapproximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction[see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated usingtwo different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbentassay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). Theincidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, anin vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%)with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of alteredpharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screeningimmunoassays and those who did not. 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, includingassay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisonof the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in apopulation of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)]• Skin and subcutaneous tissue disorders: Skin necrosis• Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)]• Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)]DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix.USE IN SPECIFIC POPULATIONSPregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 timesthe recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was notedin offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential riskto the fetus.Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation inthe developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developingfetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment areencouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Publisheddata suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excretedinto human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on themean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology(12.3) in Full Prescribing Information].Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix hasnot been studied in pediatric patients.Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not includea sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differencesin safety and effectiveness of Vectibix between these patients and younger patients.OVERDOSAGEDoses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration,and fatigue.PATIENT COUNSELING INFORMATIONAdvise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions],• Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration,

Warnings and Precautions and Adverse Reactions],• Diarrhea and dehydration [see Warnings and Precautions],• Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions],• Pregnancy or nursing [see Use in Specific Populations].Advise patients of the need for:• Periodic monitoring of electrolytes [see Warnings and Precautions],• Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy.

[see Warnings and Precautions],• Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy

[see Use in Specific Populations].This brief summary is based on the Vectibix® prescribing information v11, 3/2011Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending.©2006-2011 Amgen Inc. All rights reserved. MC46026-E

Trim: 10.75”

Live: 10”

Trim: 7.875”Live: 7”

1AMVX020_OncTimesAscoPost_PI_D01_BW.indd 1 4/20/11 10:24 PM

ASCOPost.com | AUGUST 15, 2011 PAGE 39

Expert’s Corner

Barrie R. Cassileth, PhD, Chief, Integrative Medicine Service

at Memorial Sloan-Kettering Can-cer Center (MSKCC) in New York, recently spoke with The ASCO Post about her quest to stamp out the il-legitimate use of alternative medicine in cancer care and the results from her latest research.

A researcher and educator about complementary practices for more than 30 years, Dr. Cassileth launched the Integrative Medicine Service at MSKCC 12 years ago to provide patients with integrative oncology care, to research the effectiveness of complementary therapies in improv-ing patients’ specific symptoms, and to investigate the potential adjunc-tive antitumor effects of botanical agents.

Role of Integrative OncologyWhat is the role of integrative medi-

cine in cancer care?Complementary interventions

in oncology are adjunctive. They are not substitutes for conventional cancer treatment. Integrative medi-cine offers something that is much needed in oncology: a greater focus on controlling the serious physi-cal and emotional symptoms that patients experience primarily as a consequence of today’s often ef-fective cancer treatments. There is substantial evidence that a range of complementary modalities can, in fact, relieve many common symp-toms, including pain, hot flashes, sexual dysfunction, urinary prob-lems, fatigue, xerostomia, anxiety, depression, stress, osteoarthritis, shortness of breath, neuropathy, and lymphedema.

A Conversation with Barrie R. Cassileth, PhDSeparating quackery from legitimate integrative oncology care practicesBy Jo Cavallo

What types of integrative therapies are used in cancer care?

We focus on six main categories of integrative care at MSKCC. These include acupuncture, massage thera-pies, and mind/body therapies, such as meditation and self-hypnosis. We also have a heavy emphasis on fitness and movement therapies because there is a survival advantage for many patients with cancer who engage in regular physical activity after diag-nosis. Music therapy is profoundly helpful, particularly for those who are noncommunicative or terminally ill. Not only does it relax patients and reduce stress and pain, music therapy also reduces mood disturbance. We showed that in a randomized clini-cal trial. Nutrition and supplement counseling is the sixth main area of our clinical and research focus.

We established the About Herbs website (mskcc.org/aboutherbs) be-cause it was clear that this kind of in-formation was sorely needed by both oncology professionals and patients. The site is free and now contains more than 250 continuously updated en-tries of evidence-based information. Judging by the number of hits and e-mails we receive, this award-winning website is clinically useful to oncol-ogy professionals from around the world. A second portal contains sim-plified information for patients. Any-one can enter either portal at no cost.

We have also been studying botan-icals, particularly medicinal mush-rooms. We are exploring whether their immune-enhancing ability makes them potentially useful as ad-juncts to mainstream cancer treat-ment. Many herbal compounds are used for medicinal purposes in areas of the world that rely on traditional medicines. In the developed world, they are often promoted and used in-appropriately.

Acceptance of Integrative Medicine

Are oncologists in the United States more receptive to the inclusion of integra-tive practices in traditional cancer thera-pies than oncologists in other parts of the world?

There’s no question about it. To-day, virtually every U.S. cancer pro-gram has an integrative medicine

service of some kind. It may be as small as a massage therapist a half-day a week or a music therapy pro-gram once a month, but most major cancer programs in North America have more substantial sets of activi-ties. They may not be as full-blown as ours in the sense that we cover every academic base: inpatient and outpatient care, research, education, and training.

I see the United States as about a decade ahead of other countries in this regard, but the rest of the world is catching up. Our department at MSKCC was consciously developed as a prototype that others could learn from and use parts of in their own hospitals. We have had the heads of hospitals from the U.S. and many

other countries come to visit seeking advice about developing their own integrative medicine program, and they leave with a plan to develop an integrative medicine unit at their in-stitutions.

Ongoing ResearchTalk about your research in botanicals

and herbs, as well as in other integrative disciplines in cancer care.

In general, I think the most im-portant issue concerning medicinal herbs, other botanical agents, and most dietary supplements is that they should be avoided by people on active cancer treatment. Herb-drug interactions represent a serious con-cern. Herbal remedies can prolong

Barrie R. Cassileth, PhD

Making Evidence-based Integrative Medicine Part of Mainstream Cancer CareDuring the 1960s and 1970s, the concept of a holistic approach to

treating disease that took into account the body, mind, and spirit grew in patient popularity and morphed into two basic categories: alterna-tive and complementary, which later became known by its acronym CAM (complementary and alternative medicine). However, because alternative therapy refers to unproven or disproven treatments that have no place in legitimate cancer care, integrative medicine experts, including Barrie R . Cassileth, PhD, Chief, Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center in New York, say the terminology is misleading and confusing and needs to be abandoned. Even the term “integrative medicine” can be misleading, said Dr. Cassileth, who instead uses a more accurate term to describe the practice of integrative oncology: evidence-based complementary medicine.

“Evidence-based complementary medicine refers to interventions that are rational and that have been found useful as adjuncts for purposes of symptom control,” said Dr. Cassileth in an interview with The ASCO Post. “These therapies are not said to cure cancer. And they are not offered, prom-ised, or sold as treatments to use instead of chemotherapy, radiation, or sur-gery. These therapies are meant to be used in combination with mainstream cancer treatment.”

Raising AwarenessBy making the term evidence-based complementary medicine more com-

monplace, Dr. Cassileth is hoping to educate both medical professionals and patients about the helpful, appropriate complementary therapies that are available, and distinguish them from the all-too-available questionable ap-proaches.

“If promoted techniques are found to be worthless or if they are patently absurd, such as homeopathy, they should be avoided. The medical world is in turmoil around these issues, and the public typically cannot tell the differ-ence between viable interventions and quackery. I spend half my time study-ing whether complementary approaches relieve patients’ specific physical and emotional symptoms and the other half trying to get rid of quackery. It’s not an easy task,” said Dr. Cassileth. ■

continued on page 41

Integrative Oncology

ASCOPost.com | AUGUST 15, 2011 PAGE 41

Expert’s Corner

First International Conference on Integrative CareLast March, nearly 250 oncology professionals and representatives of patient

organizations, insurance companies, and government agencies from 12 countries attended the First International Conference on Integrative Care for the Future held in Amsterdam. Barrie R. Cassileth, PhD, chaired the event. She ex-plained that the goals of the conference were to raise awareness of evidence-based research in complementary therapies that effectively reduce troubling side effects associated with cancer and cancer treatment, and to distinguish the legitimate practice of integrative oncology from the big business of bogus alternative cancer cure claims.

What was accomplished at the Conference on Integrative Care for the Future?Integrative medicine for cancer is in a peculiar position in the sense that

it gets attacked from both ends of the cancer care spectrum. It is criticized at times by mainstream oncology—more so in Europe than in the United States—as being quackery, which adamantly it is not. The complementary therapies that are being used and studied today in major academic centers are rational, evidence-based interventions. At the other end of the spectrum, in Europe and in other parts of the world, purveyors of bogus “treatments” have taken over the term “integrative medicine.” In Europe especially, integrative medicine and integrative oncology have become synonymous with quackery.

An important issue that emerged at this conference was the extent to which quackery is a huge problem throughout Europe and in other parts of the world. In the United States, where quackery has been prominent for many decades, it is a $40 billion-a-year business.

And that hinders the use of legitimate integrative care if patients are confused about the meaning of integrative medicine?

Absolutely. It also makes it very difficult for health-care professionals be-cause they’re not always sure what the terms integrative medicine and integra-tive oncology imply. Words have meaning, and they can have a detrimental as well as clarifying impact. We fought very hard to get away from the term “alternative therapy” because there are no viable alternatives to mainstream cancer care. We have to clarify the terminology, and I am now referring to complementary therapies as “evidence-based complementary medicine.” ■

bleeding and create other problems. There are a number of really good reasons not to use dietary supple-ments during cancer treatment. Avoiding them is MSKCC policy.

Our current research focuses on an extract from the maitake mushrooms, which has immune-enhancing potential. We have a study underway involving patients with myelodysplastic syndromes (MDS), to see whether the mushroom ex-tract makes a difference clinically. We know, for example, that the ex-tract increases neutrophil count and function in laboratory animals and in an early clinical study of patients with cancer. Our current phase II trial seeks to determine whether the extract enhances hematopoiesis in patients with MDS. Hopefully, we’ll find that neutrophil count and function are improved, and if that’s the case, we’ll move toward a larger study to look at survival and other responses. (For information about patient accrual, contact principal investigator Kathleen Wesa, MD, at 646-888-0845 or visit the Memorial Sloan-Kettering Cancer Center web-site at mskcc.org/mskcc/html/2270.cfm?IRBNO=09-094.)

We are also doing a very impor-tant study with vitamin D. Our ret-rospective analysis of banked sera

Barrie R. Cassileth, PhDcontinued from page 39

from patients with colorectal cancer showed a strong relationship be-tween length of survival and vitamin D levels. We’re now working on a similar study of data from patients with breast cancer and toward a pro-spective study to see whether replen-ishing patients’ vitamin D levels im-proves survival.

We are also enthusiastic about our acupuncture research program, and we’re about to complete a study of acupuncture treatment for lymph-edema. We first conducted a small pilot to make sure that acupunc-ture was safe. It was. The study had a stopping rule: achieving at least a 30% reduction in lymphedema in a minimum of 40% of patients. The study stopped very quickly. Now we are embarked on a larger pilot with a mechanism component.1 The regi-men is two acupuncture treatments a week for 4 weeks and then monthly follow-up phone calls to make sure that no adverse late events occur. These are important areas of re-search for us. ■

Disclosure: Dr. Cassileth reported no potential conflicts of interest.

Reference1. Cassileth BR, Van Zee KJ, Chan Y,

et al: A safety and efficacy pilot study of acupuncture for the treatment of chronic lymphoedema. Acupunct Med. June 18, 2011 (early release online).

The ASCO Post Wants to Hear from You

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800; Fax: 631.692.0805 www.ASCOPost.com

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com. All correspondence will be acknowledged and considered for publication in “Letters to the Editor.”

PAGE 42 The ASCO Post | AUGUST 15, 2011

TAP Caucus

Should Patients Over 70 Receive Aggressive Therapy for Acute Myeloid Leukemia?By Charles A. Schiffer, MD, and Farhad Ravandi, MD

continued on page 44

Over the past several decades, progress in the treatment of acute myeloid leukemia (AML)

in the older population (generally considered to be older than 60 years) has been limited (Fig. 1). In particular, the outcome of patients over age 70 has been poor, with few long-term survivors. Although AML is predominantly a disease of older adults, un-til recently many of the trials had been conducted in the younger population, and much of the available data was inapplicable to the elderly. This was largely attributable to reluctance (by both patients and phy-

sicians) to expose older patients to the toxic effects of “standard” chemotherapy. Furthermore, the few trials conducted specifically in the older population gen-erally excluded patients with poor performance status and comorbid medical conditions, again limiting their relevance to community practice.

However, several studies have clearly demonstrated the benefit of treatment, showing an improved response rate and survival when older patients with AML receive leukemia-specific therapy, and this is not at the expense of a worsened quality of life.1,2 Using data from the Swedish Leukemia Registry, investigators have reported that the outcome of patients with AML was better in regions where they were more likely to be offered intensive induction chemotherapy.3

In another study, U.S. investigators using data from Medicare administra-tive claims linked to 11 Surveillance, Epidemiology, and End Results (SEER) registries showed that only about 30% of patients older than 65 were treated with chemotherapy, and the median survival of the entire population was only 2 months.1 Among patients over 70, fewer than 20% received chemothera-py. In a separate analysis, they compared the outcomes of matched patients

treated or not treated with chemotherapy and reported approximately a three times higher median and 1-year survival in treated patients.

Patient SelectionSeveral studies have shown that conventional induction chemotherapy us-

ing the traditional cytarabine-plus-anthracycline regimens is only beneficial in a subset of patients in this population. Although response rates as high as 50% and 60% have been reported in such trials, the inclusion criteria for participation in these studies are generally very stringent, limiting the applicability of conclusions to only the healthiest and fittest patients, typically in the 60- to 70-year-old group.

A number of reports have examined the feasibility of intensive cytarabine-and-anthracycline–based strategies in the older AML population and have identified risk factors that predict a low response rate, a high induction mor-tality, and a low likelihood of 1-year survival.4 Among them, age remains an important predictor, with the outcome worse in patients over 70 and 80 years of age. Using such risk scores, it may be possible to better select patients for

The outcome of treatment of older adults with acute myeloid leukemia (AML) re-

mains unsatisfactory, although certainly not a to-tally futile exercise. Patients satisfying the entry criteria for cooperative group clinical trials can be expected to have complete remission rates of 50% to 55%, with remission durations of about 9 months, albeit with long-term survival rates of only about 10%. We have seen relatively little overall improvement in outcome for this popu-lation in recent decades. Nonetheless, these pa-

tients experience considerable benefit with complete remission, not the least of which is being at home for months with safe blood counts permit-ting normal activities.

Even so, many oncologists, including those who readily treat patients with advanced solid tumors and compromised performance status, are reluctant to offer potentially remission-inducing chemotherapy to older patients with AML. One consideration of course, is the need for 3 to 4 weeks of hospitaliza-tion with the possibility that the patient may not survive or ever leave the hos-pital. However, advances in supportive care—most notably the development

of highly effective antiemetics and replacement of the debilitating and neph-rotoxic amphotericin B with the more tolerable imidazoles—have permitted safer delivery of myelosuppressive chemotherapy, and the expected 30-day mortality is now approximately 10%.1

Inadequacy of Age CutoffsThe traditional breakpoint between younger and older (sometimes pe-

joratively termed “elderly”) patients,2 has been between 55 and 60 years of age, probably deriving from historical cutoffs for the application of al-logeneic transplantation. Although it is true that the frequency of poor prognostic factors (such as higher-risk cytogenetics, overexpression of multidrug resistance proteins, and AML evolving from prior myelodys-plasia) increases in older individuals, it is silly to assume that there are di-chotomous differences in leukemia biology according to discrete bound-aries in patient age.

In addition, age alone is not a reliable surrogate for the ability to toler-ate induction chemotherapy, and it is likely that subjective assessments of “performance” can be enhanced by the use of recently developed comor-bidity indices. Thus, for patients with adequate baseline medical status and organ function, almost irrespective of age, the first instinct should be to consider standard induction therapy or a well-conceived clinical trial (remembering that many clinical “trials” do not address important ques-tions or are not necessarily well conceived). Standard induction therapy should always be considered in the occasional older patient with “favor-able” karyotypes (core binding factor AML, t(8;21) or abn16q22) or nu-cleophosmin1 (NPM1) mutations).3

The real dilemma concerns patients who are truly “elderly,” regard-continued on page 43

Point of View

Several studies have clearly demonstrated the benefit of treatment, showing an improved response rate and survival when older patients

with AML receive leukemia-specific therapy, and this is not at the expense of a worsened

quality of life.

The real dilemma concerns patients who are truly ‘elderly,’ regardless of their exact age, as

evidenced by the presence of serious medical and/or cognitive comorbidities.

Charles A. Schiffer, MD Farhad Ravandi, MD

Hematology

ASCOPost.com | AUGUST 15, 2011 PAGE 43

TAP Caucus

less of their exact age, as evidenced by the presence of serious medical and/or cognitive comorbidities. Supportive approaches with trans-fusion and hydroxyurea are suitable for some of these patients. Many other older patients, however, who are otherwise reasonably well and functional, could benefit from ther-apies with the more modest aim of improvement in blood counts. The hypomethylating agents—azaciti-dine (Vidaza), decitabine (Daco-gen), and, particularly in Europe,4,5 low-dose cytarabine—are now used frequently in the outpatient setting. These agents produce very low rates of complete remission and variable rates of “hematologic improve-ment,” albeit with the potential for significant cytopenias and hospital-ization as well as the need for mul-tiple courses of therapy.5-8 No ran-domized trials have compared these putatively “gentler” approaches with standard anthracycline/cyta-rabine induction therapy.

Different AML TypesWhen considering treatment in this

population, it should be noted that AML in older patients can present in a couple of different “flavors”: ■ “proliferative” AML with hyper-

cellular marrows and rising levels of peripheral blasts

■ “MDSy” AML (with or without a prior diagnosis of myelodysplastic syndrome) with more than 20% to 30% blasts but with slowly pro-gressive cytopenias The former requires an almost im-

mediate decision about the suitability of intensive induction therapy, while many of the latter patients may not require any treatment, other than per-haps red blood cell transfusion, for long periods of time. It is likely that patients with more slowly proliferative disease are overrepresented in the tri-als using hypomethylating agents and low-dose cytarabine, and one should be cautious in extrapolating even these modest outcomes to the more gen-eral population of older patients with AML.5-7

Limits of BenefitThe treatment of less fit older

patients has become an active area of clinical research. Portrayed as an “unmet medical need” and a poten-tially easy target because of the his-

torically poor results, multiple phar-maceutical companies have designed small, sometimes phase II trials in an attempt to get new drugs approved without directly challenging the standard of anthracycline and cyta-rabine in a phase  III trial with sur-vival as an endpoint. In addition to problems in defining a population of

patients who cannot tolerate induc-tion chemotherapy, it has been dif-ficult to prove that the side effects of such treatment are less than what would be expected with “7+3” che-motherapy. This was the major prob-lem, as identified in an FDA review, with a phase  II study of clofarabine (Clolar), a drug with considerable

single-agent activity, but with dura-tions of marrow aplasia similar to what occurs after standard induction chemotherapy.8

ConclusionIt seems likely that the limits of the

benefit from chemotherapy have been

Charles A. Schiffer, MDcontinued from page 42

continued on page 44

MER110068_ANZ_Cancer_Care.indd 1 09.02.11 17:17

PAGE 44 The ASCO Post | AUGUST 15, 2011

TAP Caucus

defined, given the multiple mechanisms of resistance inherent in the stem cell origin of this group of leukemias. Real progress will be difficult but may depend on novel immunologic approaches and hopefully better understanding of stem cell biology. Until better science prevails, this complex decision in older patients is a reminder that there is still an “art” to medicine and that consultations with experienced leukemia centers are often advisable. ■

Disclosure: Dr. Schiffer has served as a consultant for Genzyme, Celgene, Ambit, and Ariad. He has received research grants from Ambit, Ariad, and Celgene.

Charles A. Schiffer, MDcontinued from page 43

References1. Lowenberg B, Ossenkoppele GJ, van

Putten W, et al: High-dose daunorubicin in older patients with acute myeloid leuke-mia. N Engl J Med 361:1235-1248, 2009.

2. Schiffer CA: “I am older, not elderly,” said the patient with acute myeloid leuke-mia. J Clin Oncol 28:521-523, 2010.

3. Becker H, Marcucci G, Maharry K, et al: Favorable prognostic impact of NPM1 muta-tions in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: A Cancer and Leukemia Group B study. J Clin Oncol 28:596-604, 2010.

4. Burnett AK, Milligan D, Prentice AG, et al: A comparison of low-dose cytarabine

and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109:1114-1124, 2007.

5. Fenaux P, Mufti GJ, Hellstrom-Lind-berg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009.

6. Blum W, Garzon R, Klisovic RB, et al: Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A 107:7473-7478, 2010.

7. Cashen AF, Schiller GJ, O’Donnell

MR, et al: Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leuke-mia. J Clin Oncol 28:556-561, 2009.

8. Kantarjian HM, Erba HP, Claxton D, et al: Phase II study of clofarabine mono-therapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin On-col 28:549-555, 2010.

Dr. Schiffer is Professor of Oncology and Medicine, Head of the Multidisciplinary Leu-kemia/Lymphoma Team, Division of Hema-tology/Oncology, Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit.

Farhad Ravandi, MDcontinued from page 42receiving conventional induction che-motherapy (typically those younger than 65).

Clearly, the rest of this population should be offered investigational, less intensive strategies in a clinical trial setting. With increased understanding of the biologic mechanisms of neoplas-tic transformation and with the identi-fication of the molecular events that lead to leukemogenesis, several new drugs with potential activity in AML have been developed. In many cases, these drugs are targeted at molecular events occurring in specific subgroups of patients, allowing the possibility of a personalized approach with specific drugs used for patients whose leuke-mia expresses the relevant target. With further advances in the field, more and more such agents will be available, and their use, either as single agents or in combination with other similar drugs, may provide us with more effective, less toxic strategies for treating the older, less fit population.

Risk-Benefit ExpectationsTherefore, a decision regarding the

best strategy should be based on ex-

pected outcomes. Perhaps those with the expectation of a low 8-week mor-tality, high complete response rate, and reasonable 3-year survival should be treated using conventional regimens, whereas those with a high expectation of initial mortality and low long-term survival should be offered investiga-tional agents. Arguments may be of-fered both for and against intensive chemotherapy for patients with risk-benefit expectations between these two groups.

Clearly, conventional cytarabine/anthracycline–based strategies are in-adequate in the majority of older pa-tients with AML, particularly in those over 70. For these patients, participa-tion in clinical studies of new agents with novel mechanisms of action is highly recommended. ■

Disclosure: Dr. Ravandi has received research funding from Sunesis, Bayer/Onyx, and Celgene. He has received honoraria from and served on the advisory board for Genzyme, Eisai, and Cephalon.

References1. Menzin J, Lang K, Earle CC, et al:

The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 162:1597-1603, 2002.

2. Juliusson G, Billstrom R, Gruber A,

Fig. 1: Limited progress in treatment of older patients with acute myeloid leukemia. Source: MD An-derson Cancer Center database.

Age ≥ 60 yr

P < .001

Treatment Era Total Died Median 5-yr< 1970

1970-19791980-19891990-19992000-2009

40170276572921

40169274541

70

0.9 mo1.6 mo3.7 mo5.5 mo7.4 mo

0%8%5%8%

10%

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 7 86

Surv

ival

pro

babi

lity

Years

et al: Attitude towards remission induc-tion for elderly patients with acute myeloid leukemia influences survival. Leukemia 20:42-47, 2006.

3. Juliusson G, Antunovic P, Derolf A, et al: Age and acute myeloid leukemia: Real world data on decision to treat and outcomes from the Swedish Acute Leu-kemia Registry. Blood 113:4179-4187, 2009.

4. Kantarjian H, O’Brien S, Cortes J,

et al: Results of intensive chemothera-py in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106:1090-1098, 2006.

Dr. Ravandi is Associate Professor of Medi-cine, Department of Leukemia, Univer-sity of Texas MD Anderson Cancer Center, Houston.

■ Important Oncology News from Meetings Worldwide

■ Original Columns and Perspectives from Oncology Leaders

■ Conversation with Experts About Issues in Cancer Care

■ Predicting Prognosis in Squamous Cell Head and Neck Cancer

Plus important columns, features, and clinical departments.

Visit The ASCO Post online at ASCOPost.com.

Coming in the September 2011 Issues of The ASCO Post

ASCOPost.com | AUGUST 15, 2011 PAGE 45

In the Literature

COLORECTAL CANCER

Venous Thromboembolism More Frequent after Open Colorectal Surgery than Post-laparoscopy

The risk of developing venous thromboembolism (VTE) may be nearly twice as high for patients un-dergoing open colorectal procedures as for those undergoing laparoscopic colorectal resections, according to a report in the Archives of Surgery. The authors also “identified malignancy, obesity, and congestive heart failure as statistically significant (P  < .05) risk factors for VTE” in association with open and laparoscopic colorectal surgery.

Researchers from the University of California–Irvine Medical Center, Or-ange, based their findings on National Inpatient Sample data for 149,304 pa-tients who underwent laparoscopic or

open colorectal procedures from 2002 to 2006. Laparoscopic surgeries were performed in 7,848, or 5.3% of the to-tal. While patients undergoing laparo-scopic procedures generally had fewer comorbidities than those who under-went open procedures, the most com-

mon pathologic condition overall was cancer of any type, with an incidence of 42.4%, the authors reported.

Data BreakdownOverall, VTE was diagnosed in

2,102 patients (1.4%). The investiga-

tors found that the incidence of VTE was significantly lower in the lapa-roscopic group (65 patients) than in the open procedure group (2,036 pa-tients)—0.8% vs 1.4%; P  < .001. By pathologic condition, patients with

Emerging Clinical Data on Cancer Management

Using QR Codes

The QR (Quick Response) codes found in this is-sue of The ASCO Post will connect readers to fur-ther information

about the articles they are reading.

These barcodes can be read by any mobile device with a camera, QR code–reading software, and Internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

Scanning the Codes

When you see a code that you would like to scan, start your code-reading application.

1

Position your device in front of the code so that it fills about half your screen.

2

The code will scan automatically.3

If the scan is successful, you will be rerouted to the targeted link.

4

continued on page 46

Cancer.Net’s Expressions of Hope Calendar, Now Accepting Artwork

Hope…for patients, by patients.

We invite anyone who has been affected by cancer — patients, friends, families, caregivers — to share their emotions through art and inspire hope in others.

Cancer.Net, the patient information website of The American Society of Clinical Oncology (ASCO), accepts artwork submissions year-round for its annual Expressions of Hope wall calendar.

Visit www.cancer.net/expressionsofhope

for more details and

submission information.

PAGE 46 The ASCO Post | AUGUST 15, 2011

In the Literature

inflammatory bowel disease had the highest incidence of VTE (1.4%), followed by cancer (1.3%) and diver-ticulitis (0.9%). By surgical resection site, rectal resection had the greatest incidence of VTE (2.8%), “which may be attributable to the extensive pelvic dissection required with resultant sur-rounding inflammatory involvement of the pelvic veins,” the authors stated.

Factors associated with an in-creased risk of VTE were limited to congestive heart failure, obesity, and malignancy in the laparoscopic group, but in the open procedure group also included chronic pulmonary disease, pulmonary circulation disorders, and inflammatory bowel disease. “Our findings, therefore, call into question whether we should be using the same risk factors and stratification for [lap-aroscopic] procedures as we do for [open] procedures because certain risk factors for VTE in a patient un-dergoing open colorectal surgery do not seem to portend an increased risk of VTE in the same patient undergo-ing laparoscopic colorectal surgery,” the authors noted.

“These study findings may be used by surgeons to more accurately assess a patient’s risk for perioperative VTE as well as to select appropriate throm-boprophylaxis in patients undergoing laparoscopic colorectal surgery,” they concluded.

Buchberg B, et al: Arch Surg 146:739-743, 2011.

Endoscopic Excision May Be Viable Alternative to Surgical Resection of Large Colorectal Polyps

A retrospective review of 104 con-secutive patients with large colorectal lesions, including 39 with carcinoma, found that “endoscopic excision of large colorectal polyps is a viable alternative to surgical resection in a select group of patients and can be performed safely with a good success rate.” The patients all had lesions “deemed not amenable to endoscopic resection at initial colo-noscopy,” most commonly performed for screening (51%) and positive fecal occult blood test results (24%), and had initially been referred for surgical resec-tion. In 68% of the patients the polyps were located in the colon, and the other 32% had rectal polyps. The results of the review were published in the Ar-chives of Surgery.

Among the 104 patients brought to the endoscopy suite for endoscopic excision, 98 had excisions, which were performed by two interventional en-doscopists. Most were complete exci-sions, although 20 patients had incom-plete excision with residual disease. Six patients did not have excisions and were referred back for surgical evaluation.

“We found that most patients (83%) could be successfully treated endo-scopically, with only a small number of patients (14%) requiring operative re-section to treat complications, incom-plete excision after index intervention, or long-term residual disease that could not be eradicated endoscopically,” the

authors commented. Endoscopic re-intervention was needed in 25 (27%) of 92 patients for reasons including re-sidual disease in 12 patients and recur-rence in 10 patients.

Reasons for Failure“Despite a high overall endoscopic

success rate in our group of patients, a diagnosis of carcinoma in situ or inva-sive carcinoma was associated with a lower success rate,” the authors noted. “Most of the lesions in our study were sessile. Although endoscopic polyp-ectomy may be a suitable option for many pedunculated malignant polyps, its role may be limited in sessile le-sions. This may be owing to technical factors, such as inability to safely ob-tain a deep margin, or because of the limitation of endoscopy in addressing the lymphatic spread in case of inva-sion. In our experience, the reasons for failure of endoscopic management of some of the cases harboring carcinoma were incomplete excision, long-term residual disease, and concern about the suitability of endoscopic excision in the setting of poor histologic fea-tures, such as lymphovascular inva-sion, or poor differentiation.”

The authors concluded that the involvement of surgeons is critical to determine which patients can ben-efit from endoscopic excision and which patients need surgical resec-tion. “When counseling patients who may benefit from endoscopic exci-sion, keep in mind that endoscopic reintervention or surgical resection is needed in approximately one-third of patients,” the authors cautioned. “Long-term surveillance is warranted for all lesions in view of the risk of re-

currence, especially for lesions located in the rectum.”

Kao KT, et al: Arch Surg 146:690-696, 2011.

BREAST CANCER

Higher Risk of Recurrence for Triple-negative Breast Cancer after Modified Radical Mastectomy without Radiation

“The paucity of therapeutic options” for women with triple-negative breast cancer “emphasizes the urgent need to optimize the current locoregional management of patients with [triple-negative breast cancer] and reduce their risk of locoregional recurrence,”

noted the authors of a Canadian study reported in the Journal of Clinical On-cology. The study, which involved 768 patients treated at a single cancer center and identified from the Alberta Can-cer Registry, found that women with T1-2N0 triple-negative breast cancer treated with modified radical mastecto-my without radiation had a significantly increased risk of locoregional recur-rence compared to women treated with breast-conservation therapy, consisting of lumpectomy and adjuvant radiation therapy. The median age of the women was 56, although the study included a high percentage of younger women, with 40% of the women younger than 50 years at time of diagnosis.

At a median follow-up of 7.2 years, 155 patients (20%) had disease progres-sion, 77 patients (10%) experienced locoregional recurrence, 103 (13%) developed distant metastases, and 123 (54 with locoregional recurrence and 69 with distant metastases) died as a result of disease progression. Univari-ate analysis revealed that patients who had breast-conservation therapy (319, or 42%), had a 5-year locoregional re-currence–free survival rate of 94%, compared to 85% for patients who had modified radical mastectomy (287, or 37%), and 87% for patients who had modified radical mastectomy plus ra-diotherapy (162, or 21%).

Independent Prognostic FactorMultivariate analysis comparing

modified radical mastectomy with breast-conservation therapy found that lymphovascular invasion and positive lymph nodes were associated with in-creased locoregional recurrence, and adjuvant chemotherapy was associated with decreased risk of locoregional re-currence. Modified radical mastectomy without radiotherapy was the only independent prognostic factor associ-ated with increased risk of locoregional recurrence compared with breast-con-servation therapy, the authors reported.

The authors noted that their study requires further validation from pro-spective clinical trials addressing the issue of locoregional management and risk of locoregional recurrence specifically in triple-negative breast cancer, which may lead to tailoring of locoregional treatment based on risk

of recurrence in this setting. ■

Abdulkarim BS, et al: J Clin Oncol. July 5, 2011 (early release online).

© Leo Cullum/The New Yorker Collection/www.cartoonbank.com

Emerging Clinical Datacontinued from page 45

SEE PAGE 45

SEE PAGE 45

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe 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 ComplicationsThe 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).]HemorrhageSevere 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).]

1 INDICATIONS AND USAGE1.1 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‑fluorouracil–based chemotherapy.1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC)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.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 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients 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 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious 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 ComplicationsAvastin 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 HemorrhageAvastin 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 ≥ 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 non–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%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]5.4 Non‑Gastrointestinal Fistula FormationSerious 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 ≤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 EventsSerious, 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 ≥ 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 Specific 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 HypertensionThe 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%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.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 reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 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 Specific 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 ReactionsInfusion 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 REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

• Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration

(2.4), Warnings and Precautions (5.7).]• Proteinuria [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 ExperienceBecause 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 ComplicationsThe 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 healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.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).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor 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 EventsThe incidence of Grade 3–4 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 chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients).Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was 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%.ProteinuriaGrade 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 FailureThe incidence of Grade ≥ 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 of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared 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 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central 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.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other 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 in Study 2.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone 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%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 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 1– 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 3–5 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 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α 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, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); 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) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8  patients receiving 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 without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

72229ha_c.indd 2 7/7/11 4:55 PM

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe 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 ComplicationsThe 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).]HemorrhageSevere 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).]

1 INDICATIONS AND USAGE1.1 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‑fluorouracil–based chemotherapy.1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC)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.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 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients 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 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious 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 ComplicationsAvastin 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 HemorrhageAvastin 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 ≥ 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 non–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%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]5.4 Non‑Gastrointestinal Fistula FormationSerious 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 ≤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 EventsSerious, 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 ≥ 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 Specific 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 HypertensionThe 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%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.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 reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 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 Specific 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 ReactionsInfusion 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 REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

• Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration

(2.4), Warnings and Precautions (5.7).]• Proteinuria [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 ExperienceBecause 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 ComplicationsThe 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 healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.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).]HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor 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 EventsThe incidence of Grade 3–4 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 chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients).Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was 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%.ProteinuriaGrade 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 FailureThe incidence of Grade ≥ 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 of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared 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 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central 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.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other 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 in Study 2.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone 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%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 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 1– 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 3–5 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 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α 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, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); 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) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8  patients receiving 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 without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

72229ha_c.indd 2 7/7/11 4:55 PM

0

20

40

60

80

100

Perc

enta

ge S

urvi

ving

OS (Months)6 12 18 24 30

First-line median OS:

20.3 vs 15.6 months(HR=0.66 [95% CI, 0.54–0.81],

P<0.001)

Avastin + IFL (n=402)Placebo + IFL (n=411)

In combination with IV 5-FU–containing chemotherapy in first- and second-line MCRC…

Because overall survival mattersThe only FDA-approved biologic with significant overall survival (OS) benefits in first- and second-line MCRC1-4

4.7-month increase in median OS with Avastin plus IFL in pivotal first-line Study 21072,4

Think Avastin

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; IFL=5-FU/leucovorin (LV)/irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

OS in second-line Study E3200:13.0 months with Avastin plus FOLFOX4 vs 10.8 months with FOLFOX4 alone (HR=0.75, [95% CI, 0.63–0.89] P=0.001)1,3

Indication 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

Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

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%)

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 accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. February 2011. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 4. Data on file. Genentech, Inc.

www.avastin.com©2011 Genentech USA, Inc. All rights reserved. AVA0000402600 Printed in USA. (05/11)

72229ha_c.indd 1 7/7/11 4:55 PM