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Survivorship 2

AACR Cancer Progress Report 10

VOLUME 2, ISSUE 16

Prostate cancer and sexual functioning 34

NOVEMBER 1, 2011

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

2011 European Multidisciplinary Cancer Congress

Do We Need the USPSTF?

Everolimus Overcomes Resistance to Hormonal Therapy in Advanced Breast Cancer By Alice Goodman

“Everolimus is the first agent to enhance the clinidding everolimus (Afinitor) to exemestane in cal benefit of hormonal therapy in patients refracpostmenopausal women with advanced breast tory to hormonal therapy. This treatment represents cancer resistant to aromatase inhibitors significanta paradigm shift in the way we treat breast cancer,” ly improved outcomes, according to the phase III said lead investigator BOLERO-2 trial José Baselga, MD, reported at the [Everolimus] represents of Massachusetts 2011 European General Hospital Multidisciplinary a paradigm shift in and Harvard Medical Cancer Congress, the way we treat School in Boston. held September Fabrice Andre, 23–27 in Stockbreast cancer. MD, formal discusholm and spon—José Baselga, MD sant of the trial, called sored by the Eueverolimus “the most ropean Society for important advance in Medical Oncology, breast cancer since trastuzumab [Herceptin].” Dr. AnEuropean Cancer Organisation, and the European dre is at the Institut Gustave Roissy, Villejuif, France. Society for Radiotherapy and Oncology. The group Although hormonal therapy is a mainstay of treattreated with the combination of these two drugs had ment for estrogen receptor (ER)-positive patients, an improved progression-free survival of almost 7 nearly all patients who develop metastatic breast months and a 57% reduced risk of cancer progression continued on page 8 vs exemestane alone. Late-breaking Abstracts

NSCLC Studies: Bevacizumab/Pemetrexed Maintenance Improves Survival, KRAS Status Has No Impact on Outcomes with Sorafenib By Alice Goodman

aintenance therapy with bevacizumab (Avastin) plus pemetrexed (Alimta) showed a modest improvement in progression-free survival vs bevacizumab alone in patients with advanced non–small cell lung cancer (NSCLC), according to the final analysis

of the AVAPERL study. In a separate study, selecting patients according to KRAS status did not improve outcomes with sorafenib (Nexavar) in advanced NSCLC. Raising more SEE PAGE 33 questions than answers, acEMCC 2011: Non–Small Cell Lung Cancer Data cording to expert commentary, both studies were ■■ The phase III AVAPERL study showed that maintenance therapy with presented as late-breakbevacizumab plus pemetrexed achieved superior progression-free ing abstracts during the survival compared with bevacizumab alone. 2011 European Multidis■■ Critics note that combining two targeted therapies is a very expensive ciplinary Cancer Congress, strategy for a 4‑month gain in progression-free survival, and whether held recently in Stockholm pemetrexed alone could achieve the same results as the combination and sponsored by the Euneeds to be revisited with cost in mind. ropean Society for Medical ■■ A phase II study showed that selecting patients with KRAS mutations Oncology, European Candid not improve the performance of sorafenib.

By Derek Raghavan, MD, PhD

ike most of the folks reading this commentary, I’m a taxpayer. Although I sometimes become impatient with the strategic games on Capitol Hill, I basically appreciate that government helps many things to work, and some of them even work well. However, there are aspects of government function that do trouble me. I was more than a little perturbed when I had to deal with the extraordinary time-wasting nonsense that followed the encyclical from the U.S. Preventive Services Task Force (USPSTF) a couple of years ago, in which they unilaterally announced a change in recommendations on screening for breast cancer. It wasn’t that I was personally opposed to the specific recommendations, as I don’t specialize in the care of early breast cancer and didn’t know the data. But I was troubled that their constituency did not seem to include an expert specifically in breast cancer care, and more troubled that they felt it appropriate to issue their bulletin and press releases apparently continued on page 39

Dr. Raghavan is President, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.

MORE IN THIS ISSUE Oncology Meetings Coverage 53rd ASTRO Annual Meeting �� 3 2011 European Multidisciplinary Cancer Congress �� 4–9, 27 2011 Breast Cancer Symposium �� 32 Direct from ASCO �� 17 In the Clinic: Crizotinib �� 25

continued on page 5

November Is Lung Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | NOVEMBER 1, 2011

PAGE 2

Perspective

Helping Cancer Survivors Return to Work By Mary S. McCabe, RN, MA

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

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

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System 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

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD Stanford University Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

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

Stanley H. Winokur, MD Singer Island, Florida

Jay S. Cooper, MD Maimonides Medical Center

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

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 Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown 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

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Contributing Writers: Charlotte Bath, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Eileen O’Gara-Kurtis, Ronald Piana, Susan Reckling, Matthew Stenger, Marian Wiseman Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations Disclosure information available at ASCOPost.com.

or many of the 12 million cancer survivors throughout the United States, remaining in the workforce is an important expectation that requires the support and attention of the oncology community. And while continuing employment can be critically important for economic reasons (especially in the current financial climate), it is valued for reasons of fulfillment and self-worth as well.

Employment Obstacles and Facilitators Although survivors face a number of emotional and medical challenges after cancer treatment, studies show that the expectation to remain in the workforce is not just a wish, but rather, a realistic expectation. In fact, a recent

literature review found that, overall, 63.5% of cancer survivors returned to work after treatment.1 As clinicians trying to maximize the functioning of the cancer survivors in our care, we need to understand the factors that affect the ability of a patient with cancer to remain employed after treatment ends, in order to facilitate a return to work. There is no generic formula to offer all cancer survivors wishing to maintain employment. Rather, the workplace challenges depend on the cancer site, the treatment, the patient’s occupational status, and the roles of others, both at home and in the workplace. In particular, the impact of treatment on work and productivity in the job results from the effects of multimodality therapy on physical, cognitive, and psychosocial functioning, with fatigue and cognitive impairment being the most commonly reported obstacles to returning to a previous level of functioning on the job. The more prolonged and intense the treatment, the longer the absence from the workplace. But just as there are employment obstacles for cancer survivors who continued on page 13

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; Institutional 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 material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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53rd ASTRO Annual Meeting Thoracic Oncology

No Improvement in Survival with High-dose over Standard-dose Radiation for Stage III Non–Small Cell Lung Cancer By Susan Reckling

urprisingly, less may be more when it comes to radiation therapy with concurrent chemotherapy for patients with stage III non–small cell lung cancer (NSCLC), according to an interim analysis of the randomized phase III Radiation Therapy Oncology Group (RTOG) 0617 trial presented at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO).1 A higher dose of radiation (74 Gy) does not appear to improve overall survival for patients with unresectable NSCLC compared with the standard radiation dose (60 Gy). “Although the optimal radiation dose for lung cancer patients has not been tested in a randomized phase III trial for over 30 years, most [radiation oncologists] believed that higher doses of radiation cured more patients with lung

Radiation Dose for Stage III Non–Small Cell Lung Cancer ■■ A higher dose of radiation (74 Gy) did improve overall survival for patients with unresectable NSCLC compared with the standard radiation dose (60 Gy), in the RTOG 0617 trial.

■■ A radiation dose of 60 Gy, nonsquamous histology, and smaller gross Jeffrey Bradley, MD

cancer,” revealed presenting author of this study, Jeffrey Bradley, MD, a radiation oncologist at the Washington University School of Medicine in St. Louis. Although Dr. Bradley admits that many centers have been using the higher dose of radiation for these patients, he and his colleagues believe that the standard radiation dose should remain 60 Gy, based on these preliminary findings.

EXPERT POINT OF VIEW

urning up the “radiation dial” did not improve outcomes in the landmark RTOG 0617 study. Perhaps the real question, however, is why not, asked formal discussant of this trial Benjamin Movsas, MD, Chair of Radiation Oncology at Henry Ford Hospital, Detroit. Dr. Movsas offered several possible explanations. Important predictors of 5-year survival may include baseline comorbidities, quality of life, weight loss, and/or active smoking status. HisBenjamin Movsas, MD tology and technical factors may play a role as well. In terms of histology, the slightly higher rate of squamous histologies in the high-dose arm may be a small contributing factor to the poorer results, explained Dr. Movsas. Study presenter Jeffrey Bradley, MD, mentioned that nonsquamous histology is a factor that appears to be linked to improved survival. Moreover, Dr. Movsas suggested that differences in technique may play an important in terms of outcomes. Technical factors, such as the adequacy of the margins in light of tumor motion or the precise prescription isodose line chosen, could possibly account for some of the differences between the arms. “Technique, technique, technique: need I say more,” he declared. Indeed, the careful application of more precise techniques (such as stereotactic body radiation therapy as a boost) may improve results in the future. “We await further analysis of this study regarding the patterns of failure and technical considerations,” indicated Dr. Movsas. He concluded that “rather than simply turning up the ‘dial,’ we should turn up the ‘gain’ or biologic effectiveness of our strategies for our patients with lung cancer.”

■

Disclosure: Dr. Movsas serves as Chair of the RTOG Quality of Life subcommittee, but was not involved in this analysis.

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

tumor volumes were factors that appeared to be associated with improved survival.

■■ This study remains open to the standard-dose radiation arms, with chemotherapy with or without cetuximab.

Crossing the Futility Boundary Between November 2007 and April 2011, 426 patients with newly diagnosed stage III NSCLC took part in RTOG 0617, perhaps the largest study to date to ask the question of radiation dose in stage III lung cancer. Patients were randomized to one of four treatment arms: high-dose (74 Gy) radiation therapy vs standarddose (60 Gy) radiation therapy and concurrent chemotherapy with or without cetuximab (Erbitux). Concurrent chemotherapy included weekly paclitaxel and carboplatin. Two types of external-beam radiotherapy were used during the trial: three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). “This is the first phase III trial to allow IMRT in lung cancer,” declared Dr. Bradley. Preliminary study analysis showed that projected 12-month overall survival rates were higher with the standard 60-Gy radiation dose than with the higher 74-Gy dose (81% vs 74%), although Dr. Bradley acknowledged that the median follow-up was “rather short.” In addition, there did not appear to be a difference in outcomes based on which type of radiation therapy was used. (3D-CRT was used in 55% of patients, whereas IMRT was used in 45% of patients.) There appeared to be no statistical difference between the arms in terms of toxicity. After 90 events (deaths) had occurred, it was determined that the high-dose radiation arms had crossed the “futility boundary.” The high-dose

radiation arms were closed, and the study remains open to the standarddose radiation arms, with chemotherapy with or without cetuximab. Planned completion of the trial is expected later in the fall of 2011.

Predictors of Survival In an attempt to explain why the higher dose of radiation did not improve overall survival, the investigators are still carefully reviewing their data. Age, histology, gender, gross tumor volume, and total lung volume were considered as possible covariates predicting survival. However, according to Dr. Bradley, radiation technique and PET staging were not significant in predicting overall survival. The investigators concluded that radiation dose SEE PAGE 33 of 60 Gy, nonsquamous histology, and smaller gross tumor volumes were factors that appeared to be associated with improved survival.

■

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

Reference 1. Bradley JD, Paulus R, Komaki R, et al: Randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy ± cetuximab for stage IIIA/IIIB non-small cell lung cancer: Preliminary findings on radiation dose in RTOG 0617. 53rd ASTRO Annual Meeting. Abstract LBA2. Presented October 3, 2011.

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.

The ASCO Post | NOVEMBER 1, 2011

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European Multidisciplinary Cancer Congress 2011 EXPERT POINT OF VIEW

afal Dziadziuszko, MD, PhD, Medical University of Gdansk, Poland, and formal discussant at the EMCC meeting, pointed out that although the progression-free survival benefit of maintenance therapy with bevacizumab plus pemetrexed was impressive, the study population was restricted to patients who Rafal Dziadziuszko, had not experiMD, PhD enced disease progression on first-line therapy, enriching the population. On the heels of the positive PARAMOUNT study, where maintenance therapy with pemetrexed alone achieved a 38% reduction in risk of progression, Dr. Dziadziuszko took issue with the design of AVAPERL. He said that the appropriate question to ask was how much bevacizumab added to pemetrexed as maintenance therapy, “but AVAPERL asks the reverse question.” Weighing in on AVAPERL, Sunil Verma, MD, of Sunnybrook Hospital in Toronto, Canada, said that these results build on the PARAMOUNT study, showing that maintenance with pemetrexed is of value in this setting. But adding two expensive drugs together for ma i ntenan ce therapy may not Sunil Verma, MD be an option in the current health-care climate. “The cost-effectiveness of such a strategy needs to be evaluated and studied further,” Dr. Verma noted. Regarding the sorafenib study, Dr. Dziadziuszko said, “KRAS is the holy grail of targeted therapy for cancer. It is mutated in up to 30% of patients with non–small cell lung cancer, mostly those with adenocarcinoma who are heavy smokers. We are currently debating the prognostic and predictive role of KRAS mutations. When we compared results of this study with others of single-agent sorafenib in unselected patients, enrichment for KRAS mutations did not appear to improve outcomes. In fact, this study had the

lowest median progression-free survival, suggesting that KRAS mutations do not predict for sorafenib benefit.” “This study was of an unselected drug in a selected group of patients.

We need to understand the full spectrum of activity of sorafenib before using it in a selected group of patients. We need further biologic correlative work to determine who is most likely

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2011 10/11 08A11090A

to benefit,” Dr. Verma stated.

■

Disclosure: Dr. Dziadziuszko is a consultant for Roche (compensated). Dr. Verma has received research support from Roche and is on an advisory board for Roche and Lilly.

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European Multidisciplinary Cancer Congress 2011 NSCLC Studies continued from page 1

cer Organisation, and the European Society for Radiotherapy and Oncology.

Maintenance Therapy AVAPERL is a randomized, multicenter, open-label phase III study

of 376 patients with advanced, metastatic, or recurrent NSCLC. The study enrolled patients who had achieved disease control (complete or partial remission or stable disease) after one line of bevacizumab/ cisplatin/pemetrexed. They were randomly assigned to maintenance

therapy with either bevacizumab alone or bevacizumab/pemetrexed and treated until disease progression. The combination of bevacizumab/pemetrexed as maintenance therapy added 4 months to progression-free survival vs bevacizumab alone, and reduced the risk

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

ORAL THERAPY

Mechanism of action Abiraterone is an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17 -hydroxylase/C17,20-lyase) — Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue Androgen biosynthesis inhibition with ZYTIGA® results in decreased levels of serum testosterone and other androgens At the interim analysis of the pivotal phase 3 study, ZYTIGA® + prednisone showed a statistically significant improvement in median overall survival (OS) compared with the control arm* — Median OS: 14.8 months vs 10.9 months (hazard ratio = 0.646; 95% confidence interval: 0.543, 0.768, P < 0.0001)

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time

AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a Phase 3, randomized, double-blind, placebocontrolled, multicenter study in patients with metastatic castration-resistant prostate cancer (mCRPC who had r e c e i ve d p rior c h e m oth e rapy c o nt aining do c e t a xe l (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

of progression by 50%. At a median follow-up of 11 months, median progression-free survival was 10.2 months for the combination vs 6.6 months with bevacizumab alone (P < .001), and all subgroups benefitted from the combination vs continued on page 6

The ASCO Post | NOVEMBER 1, 2011

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European Multidisciplinary Cancer Congress 2011 NSCLC Studies continued from page 5

bevacizumab alone. Median overall survival had not yet been reached in the combination arm and was 15.7 months in the bevacizumab arm. Median duration of disease control favored

the combination arm: 7.8 vs 4.9 months (P < .001). Treatment was well tolerated. Lead author Fabrice Barlesi, MD, University of MediterraneeAssistance Publique Hopitaux de Marseille, Marseille, France, said, “Overall, one line of treatment with

cisplatin/pemetrexed/bevacizumab followed by continuation maintenance with bevacizumab/pemetrexed is well tolerated and results in the most pronounced reduction in risk of progression in this setting of patients with NSCLC who achieved disease control. Although the num-

ZYTIGA™ (abiraterone acetate) Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. 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. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be

ber might be viewed as low, 4 months represents a great improvement in the setting of metastatic lung cancer.”

Sorafenib and KRAS Status In a phase II study of 59 patients with locally advanced NSCLC who experienced disease progression on

ZYTIGA™ (abiraterone acetate) directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders 4.2 23.4 4.1 Joint swelling/discomfort2 29.5 26.2 3.0 23.1 2.3 Muscle discomfort3 General disorders 26.7 1.9 18.3 0.8 Edema4 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Cardiac disorders 7.2 1.1 4.6 1.0 Arrhythmia5 Chest pain or 3.8 0.5 2.8 0 chest discomfort 6 2.3 1.9 1.0 0.3 Cardiac failure7 1 2 3 4 5

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

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PAGE 7

European Multidisciplinary Cancer Congress 2011 a previous platinum-containing regimen, and who had KRAS mutation– positive tumors, sorafenib showed some clinical activity. Although the primary endpoint of the study was met (nonprogression rate > 52%), the progression-free survival data are disappointing, with some patients

showing rapid progression. However, some heavily treated patients had prolonged benefit from sorafenib. “Although further study of sorafenib is warranted, we need to identify the subgroups of patients with KRAS mutations who are most likely to benefit. A randomized phase

II study should be conduted to investigate whether sorafenib is more active than standard chemotherapy in patients with KRAS-mutated NSCLC,” stated lead author A.M. Dingemans, MD, Maastricht University Hospital, The Netherlands.

■

Disclosure: Dr. Barlesi has disclosed

ZYTIGA™ (abiraterone acetate)

Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no speciﬁc antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations]. Manufactured by: Patheon Inc. Toronto, Canada

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelﬁnavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. 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 and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA.

a relationship with Roche and Lilly. Dr. Dingemans received an unrestricted grant from Bayer.

References 1. Barlesi F, de Castro J, Dvornichenko V, et al: AVAPERL (MO22089): Final efficacy outcomes for patients with advanced non-squamous non-small cell lung cancer (nsNSCLC) randomised to continuation maintenance (mtc) with bevacizumab (bev) or bev+pemetrexed (pem) after first-line (1L) bev-cisplatin (cis)-pem treatment (Tx). 2011 European Multidisciplinary Cancer Congress. Abstract 34LBA. Presented September 24, 2011. 2. Dingemans AM, Mellema WW, Groen HJM, et al: A phase II study of sorafenib in patients with locally advanced and/or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) with a K-Ras Mutation. 2011 European Multidisciplinary Cancer Congress. Abstract 27LBA. Presented September 24, 2011.

November Is

Lung Cancer Awareness Month.

Manufactured for: Centocor Ortho Biotech Inc. Horsham, PA 19044 Issued: April 2011 08Z11008

See pages 3, 25, and 26 for lung cancer news in The ASCO Post.

The ASCO Post | NOVEMBER 1, 2011

PAGE 8

European Multidisciplinary Cancer Congress 2011 Advanced Breast Cancer continued from page 1

cancer become resistant to hormonal therapy. The results with everolimus in this group of patients are particularly important, because the benefits from any secondary therapy are typically limited, Dr. Baselga explained. Everolimus inhibits the mTOR protein in cancer cells, which acts as an important regulator of tumor cell division, blood vessel growth, and cell metabolism. “The rationale for the combination therapy in this trial rests on the crosstalk between estrogen re-

ceptor and mTOR signaling. Synergy has been shown in a number of models and in a pilot phase II study,” Dr. Baselga told listeners. BOLERO-2 enrolled 724 patients with ER-positive advanced breast cancer refractory to either letrozole or anastrozole (aromatase inhibitors). Patients were randomly assigned to treatment with exemestane or exemestane plus everolimus until disease progression or unacceptable toxicity. Crossover to the unassigned therapy was not allowed in this trial. Dr. Baselga presented results from

EXPERT POINT OF VIEW

Photo: A. Cheron

he goal of this study was to reverse the resistance to endocrine therapy and delay time to chemotherapy, explained Fabrice Andre, MD, Institut Gustave Roissy, Villejuif, France. “The control group is appropriate because we have no better endocrine therapy than exemestane. Progression-free survival is a good endpoint, and there is no major bias in this trial to influence results.” This is the third trial to consistently report the benefits of everolimus plus hormonal therapy in imFabrice Andre, MD proving progression-free survival, he continued. “The hazard ratio for everolimus is consistent with that of other major molecular targeted agents, including gefitinib, imatinib, trastuzumab, and sunitinib,” he noted. “These findings show that the first-in-class targeted agent is highly effective. Everolimus not only improves outcomes [in patients with hormone-refractory metastatic breast cancer] but also open the door to study this drug in combination with other drugs to avoid resistance that develops via compensatory pathways once mTOR is inhibited. It will require sequential biopsies to understand and reverse mechanisms of resistance,” he told listeners.

■

Everolimus/Exemestane in Refractory Advanced Breast Cancer ■■ Everolimus added to exemestane improved progression-free survival

in postmenopausal women with advanced breast cancer who became refractory to hormonal therapy.

■■ The phase III BOLERO-2 trial results are considered practice-changing.

the first interim analysis, when the study was stopped in light of the superiority of the combination arm. At the time of data cut-off, 47% in the combination arm and 29% in the exemestane arm were on therapy.

Key Results The trial met its primary endpoint, showing that the addition of everolimus to exemestane improved median progression-free survival from 2.8 months with exemestane alone to 6.9 months with the combination (P < .0001), according to investigator assessment. According to central radiologic review, everolimus extended progression-free survival from 4.1 months with exemestane alone to 10.6 months (P < .0001). This improvement was consistent across all subgroups, including number of prior therapies, presence of visceral metastases, bone metastases, and prior use of chemotherapy. Response rates were significantly higher in the combination arm—9.5% vs 0.4%, respectively (P < .0001)—and the rate of clinical benefit was also significantly higher in those treated with

the combination: 33.4% vs 18%, respectively (P < .0001). Overall survival data are not yet mature, Dr. Baselga noted. Side effects were consistent with those reported for everolimus, with the most SEE PAGE 33 common grade 3/4 adverse events including stomatitis (7.7%), anemia (5.8%), dyspnea (3.9%), hyperglycemia (4.3%), fatigue (3.7%), noninfectious pneumonitis (3.1%), and elevated liver enzymes (3.1%).

■

Disclosure: Dr. Baselga is a consultant for Novartis Pharmaceuticals. Dr. Andre has received a research grant from Novartis and is a speaker for and on the advisory board for Novartis.

Reference 1. Baselga J, Campone M, Sahmoud T, et al: Everolimus in combination with exemestane for postmenopausal women with advanced breast cancer who are refractory to letrozole or anastrozole: Results of the BOLERO-2 phase IIII trial. 2011 European Multidisciplinary Cancer Congress. Abstract 9LBA. Presented September 26, 2011.

T-DM1: Antibody Drug Conjugate Outperforms Standard Anti‑HER2 Therapy in Metastatic HER2-positive Breast Cancer By Alice Goodman

he investigational antibody-drug conjugate T-DM1 improved progression-free survival over standard chemotherapy with docetaxel plus trastuzumab (Herceptin) when given as first-line treatment of HER2-positive metastatic breast cancer, according to an open-label phase II study reported

at the 2011 European Multidisciplinary Cancer Congress.1 In addition, T-DM1 was associated with much lower rates of neutropenia and alopecia, which are troubling side effects of standard docetaxel/trastuzumab. T-DM1 is a unique agent that combines the monoclonal antibody trastu-

T-DM1 for HER2-positive Breast Cancer ■■ An antibody drug conjugate that combines trastuzumab with potent

cytotoxic chemotherapy achieved superior progression-free survival vs standard trastuzumab plus chemotherapy in HER2-positive breast cancer.

■■ T-DM1 is associated with much lower rates of alopecia and neutropenia than are seen with standard trastuzumab/docetaxel.

■■ Phase III trials are needed to confirm these results.

zumab with a potent cytotoxic chemotherapy (a derivative of maytansine) through a stable linker. When trastuzumab binds to extracellular HER2, the trastuzumab exerts its antitumor benefits and then the entire T-DM1 molecule is taken up into the cell, where the linker releases the potent chemotherapy. To give some idea of its potency, emtansine is 100 times more potent than vincristine in vitro. “The stable linker is the magic. I tell my patients that trastuzumab is like a well-aimed gun, and the bullet is the chemotherapy attached,” said Sara Hurvitz, MD, Director of Breast Oncology at the University of California, Los Angeles. Progression-free survival was sig-

Sara Hurvitz, MD

nificantly improved by T-DM1: a median of 14.2 months vs 9.2 months for standard chemotherapy (P = .0353). “Patients with metastatic breast cancer who received T-DM1 had a 41% improvement in the time they lived with no worsening of disease

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PAGE 9

European Multidisciplinary Cancer Congress 2011 compared with standard chemotherapy plus trastuzumab. These provocative data illustrate that first-line treatment with T-DM1 extends time living without cancer with far fewer side effects than standard chemotherapy plus trastuzumab,” Dr. Hurvitz commented.

Unique Agent “I believe that this is the magic and clever drug we have been waiting for, but we will need validation in a large randomized trial,” said formal discussant Martine Piccart, MD, Institut Jules Bordet, Brussels, Belgium, and President-Elect of the European Society for Medical Oncology. The study enrolled 137 patients with HER2-positive advanced breast cancer and randomly assigned them to trastuzumab/docetaxel vs T-DM1.

Crossover from the control arm to the T-DM1 arm was allowed at disease progression, but the data Dr. Hurvitz presented were pre-crossover. Overall survival data are not mature and will be presented in 2012, and quality-oflife data from the study will be presented at the San Antonio Breast Cancer Symposium in December.

Toxicities and Responses At the time of data cutoff, 43.3% of patients in the T-DM1 arm and 21% of controls were on therapy. Median duration of treatment was 10 months with T-DM1 vs 5.5 months for docetaxel. Dr. Hurvitz suggested that the ability to stay on T-DM1 longer may be related to its more favorable toxicity profile. Grades 3 and 4 adverse events were reported in 46% of T-DM1 patients

EXPERT POINT OF VIEW: European Perspective

artine Piccart, MD, of the Institut Jules Bordet, Brussels, Belgium, and PresidentElect of the European Society for Medical Oncology, was highly enthusiastic about the findings of the phase II T-DM1 study, but said, “We have to remember this is an open-label trial, and in a study like this, events may be attributed to disease progression although they are not truly progression.” She also said that only 25% of patients in the phase II trial were previously exposed to adjuvant Martine Piccart, MD trastuzumab, and the situation is different now, when HER2-positive patients routinely get trastuzumab. She cited the large difference in adverse events as the major factor in the ability to continue on treatment with T-DM1 vs standard chemotherapy. However, “the control arm in this trial seems to do a little less well than in other trials reported in the literature.” “We look forward to validation in a comprehensive phase III trial. Then T-DM1 will be available to patients in the not-too-distant future,” Dr. Piccart stated.

■

Disclosure: Dr. Piccart receives consultancy fees from Roche, and her institute receives research grants from Roche.

COVERAGE OF MORE THAN

from

EXPERT POINT OF VIEW: U.S. Perspective

“T

his is an exciting drug,” said Hope Rugo, MD, Professor of Medicine at University of California, San Francisco. “It is highly effective and extremely well tolerated, with no hair loss, which is very important to patients. It also enables using a lower dose of trastuzumab.” Dr. Rugo cited these outstanding questions: What is the efficacy of T-DM1 in trastuzumab-resistant patient? What is the toxicity after therapy is Hope Rugo, MD stopped? In the study reported at the 2011 European Multidisciplinary Cancer Congress, patients were treated until disease progression. She said T-DM1 will probably be studied in the adjuvant and neoadjuvant setting. “We have to wait for results of EMILIA to validate this phase II study,” she commented.

■

Disclosure: Dr. Rugo has received research funding from Genentech.

vs 89.4% of controls. Adverse events leading to discontinuation were: 7.2% vs 29%, respectively. More grade 3 or higher neutropenia (6% for T-DM1 vs 61% for controls) and hemorrhagic events (8% vs 17%, respectively) were reported with standard chemotherapy; more grade 1/2 thrombocytopenia occurred with T-DM1: 30% vs 6.1%, respectively. The rates of nonhematologic toxicities (alopecia, diarrhea, and peripheral edema) were much higher with standard chemotherapy. Only 4% of those who received T-DM1 had alopecia vs 67% of those on the control arm. No significant cardiac events were reported. Overall response rates were similar between the two arms: 64% for T-DM1 vs 58% for controls. Clinical benefit was reported in 75% of T-DM1 patients vs 81% of controls. The two treatments differed with respect to median duration of response: not yet reached for T-DM1 and 9.5 months for controls. T-DM1 is being studied in HER2-

50 KEY ABSTRACTS

Best of ASCO® Annual Meeting ’11 Don’t miss this special supplement to The ASCO Post, published with the October 15, 2011, issue. To view comprehensive reports on more than 50 key abstracts, go to ASCOPost.com. Featuring:

■■ Molecular Diversity in Metastatic Lung Cancer

■■ Locoregional Lung Cancer Management

■■ Breast Cancer Prevention and Treatment Strategies

■■ Colorectal Cancer Standards of Care ■■ Ovarian Cancer Screening and Outcomes ■■ Noncolorectal Gastrointestinal Cancers ■■ Novel Therapies for Metastatic ■■ Lymphoma Management Melanoma ■■ Research in Multiple Myeloma ■ ■ High-risk GIST and Soft-tissue Sarcoma ■■ Genitourinary Cancers: Prognostic Strategies and Novel Therapies ■■ Issues in Head and Neck Cancer

positive metastatic breast cancer in a comprehensive phase III program. The EMILIA study will compare T-DM1 vs lapatinib (Tykerb) plus capecitabine (Xeloda) in 980 patients; the MARIANNE study will compare docetaxel/ trastuzumab vs T-DM1 vs T-DM1 plus pertuzumab; and the TH3RESA study is comparing T-DM1 vs best supportive care in the salvage setting.

■

Disclosure: Dr. Hurvitz has received research grants from Genentech/Roche and a travel grant for symposium travel from Roche. Dr. Piccart receives consultancy fees from Roche, and her institute receives research grants from Roche.

Reference 1. Hurvitz S, Dirix L, Kocsis J, et al: Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel in previously untreated HER2-positive metastatic breast cancer: Primary results of a randomized, multicenter, open-label, phase II study (TDM4450g/BO21976). 2011 European Multidisciplinary Cancer Congress. Abstract 5001. Presented September 25, 2011.

The ASCO Post | NOVEMBER 1, 2011

PAGE 10

News Health-care Policy

AACR Issues Landmark Report on Cancer Progress By Ronald Piana

t a recent press conference in Washington, DC, the American Association for Cancer Research (AACR) assembled luminaries from the cancer research and care communities to discuss the salient points of the association’s newly released progress report on the current and future state of cancer research in the United States.1 During the opening remarks, AACR CEO Margaret Foti, PhD, MD (hc), noted that although much progress has been made since the National Cancer Act was signed into law (in 1971), the past several years of flat funding for the National Institutes of Health (NIH) and National Cancer Institute (NCI) may result in a slowing in the rate of future progress.

Call for a Renewed Commitment According to Dr. Foti, a central reason for developing the AACR Cancer Progress Report is to underscore the advances in cancer research that have benefitted patients and highlight the future challenges in cancer research that will require our nation’s policymakers to safeguard vital investments, such as the cancer research and biomedical science supported by the NIH and NCI. “Now is not the time to retreat from our mission, which is to prevent and cure cancer. We are here this afternoon to call for a renewed commitment to make the eradication of cancer at the earliest possible time a national priority,” said Dr. Foti. Dr. Foti acknowledged that the current U.S. economic malaise has had an across-the-board impact on research funding for cancer. However, policymakers need to understand that

well-spent research funding produces downstream treatments that ultimately reduce costs. She pointed out that in 2010—due to medical costs, premature deaths, and lost productivity—the NIH estimated that the total annual costs of cancer were $263.8 bil-

Judy Garber, MD, MPH

are related to tobacco and adult diet/obesity.

■■ Cancers due to five infections

(human papillomavirus, hepatitis B and C viruses, Helicobacter pylori, Epstein-Barr virus) correspond to 18% of total cancer incidence.

■■ Genomics and molecular biology are transforming patient care.

■■ Drug development is still a protracted process; more

James F. Holland, MD

lion. “But as the cancer research advocate Mary Lasker said, ‘if you think research is expensive, try disease.’ That simple phrase sums up why we should invest more in the research, which is the future of cost-effective health care,” said Dr. Foti. The next speaker at the press con-

Margaret Foti, PhD, MD

urges Congress to provide a sustained budget increase of at least 5% above the biomedical inflation rate. “This year marks the 40th anniversary of the signing of the National Cancer Act. It was historic legislation, and dramatic in its consequences because it focused the country’s attention on

In order to fulfill the extraordinary scientific and medical promise of cancer and biomedical research, the AACR respectfully recommends that Congress provide the NIH and NCI with annual budget increases of at least 5% above the biomedical inflation rate. —AACR Cancer Progress Report

ference was James F. Holland, MD, Mount Sinai Medical Center, who was AACR President in 1971, and was in attendance when President Richard Nixon signed the National Cancer Act

AACR Progress Report ■■ More than 50% of all U.S. cancers

into law. Dr. Holland gave an impassioned call for more funding, citing a litany of previous medical advances that have changed humankind for the better, but would not have been possible without dedicated scientific research. The AACR progress report

streamlined trials are needed.

■■ Drug resistance remains one of our greatest challenges.

■■ Cancer care disparities are still

problematic, largely due to lack of health-care access and low socioeconomic status.

■■ The future of cancer care rests

largely on the development of technologies such as whole-genome sequencing, nanotechnology, bioinformatics, and computational models.

the vital need to conquer this disease,” said the next speaker, 2009 Nobel Laureate and immediate AACR Past President Elizabeth H. Blackburn, PhD. Dr. Blackburn noted that many of the advances we have seen over the past 4 decades are due to research funded by the NIH and NCI. “We are on the cusp of being able to translate our current findings into therapies that will dramatically reduce the threat of cancer. But our ability to exploit these opportunities depends on a renewed commitment by Congress to provide NIH and NCI with the necessary funds,” said Dr. Blackburn.

Increased Funding Pays Dividends Continuing the call to increase research funding, current AACR President Judy Garber, MD, MPH, explained that we are in a defining mo-

ment in cancer research. “The value of biomedical research to the economic health and well-being of the nation cannot be overestimated. Decreased funding can have a dangerously chilling effect on our ability to recruit bright young researchers into the field. We cannot afford to lose them,” she warned. Dr. Garber said that we are at an inflection point, and it is urgent to increase scientific momentum. She also stressed that even during an economic downturn, it makes fiscal sense to spend dollars in biomedical research. “Scientific innovation not only saves and improves lives, but it also bolsters our competiveness in a global market and contributes to a more robust domestic economy by making medical investments in the future,” said Dr. Garber. Dr. Garber explained that more than 80% of the NIH budget is competitively awarded to research grants and institutions across the nation. “According to a 2008 study by Families USA, each dollar of NIH funding generates more than two times as much revenue in state economic output through the multiplier effect, adding an influx of jobs and capital in the communities where the research is conducted,” said Dr. Garber.

A Defining Moment Anna D. Barker, PhD, Director of Transformative Healthcare Networks at Arizona State University and Cochair of the AACR Progress Report said that the nation has reached a defining moment in the fight to conquer cancer. “We now see a future in which every patient with cancer can actually get his or her tumor sequenced and receive a therapy for a particular cancer, not every cancer. As we have come to realize, knowledge of your genome is power. For instance, very recently scientists used gene sequencing to identify a molecular defect in melanoma, in a gene we call BRAF,” said Dr. Barker. Dr. Barker said that the BRAF defect occurs in about 50% of melanoma patients. “This discovery is important because with this knowledge we were able to develop a drug targeting a particular group of patients. Testing in this cohort recently showed a significant increase in progression-free survival and actually demonstrated increased overall survival,” commented Dr. Barker. She added that although there are continued on page 13

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 1-year survival:

Percentage Surviving

100

51% vs 44%2

2-year survival:

23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication 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.

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

AVA0000400600

Printed in USA.

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2 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 Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/ embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) 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. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

(06/11)

www.avastin.com

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

AVASTIN® (bevacizumab) 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 Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • 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 Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound 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).] Hemorrhage The 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 Events The 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 Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of 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%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 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.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-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 Glioblastoma Avastin 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 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 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 Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 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 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3−4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. IFL + Placebo IFL + 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 (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).] NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).] Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy. 14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24-hour urine collection.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. NCI-CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued. System Organ Class/ IFN-α + Placebo IFN-α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5-FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin. Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under-estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) 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 Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine 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 Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose-related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital 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 Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated 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 with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one 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 neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 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 Avastin® (bevacizumab) compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma). 1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus South San Francisco, CA 94080-4990 ©2011 Genentech, Inc. Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

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Perspective

AACR Report

Cancer Survivors

continued from page 10

continued from page 2

other genetically targeted therapies, the impact of this discovery is gamechanging in that the defect is very specific. “The drug was developed and approved by FDA—simultaneously with the diagnostics and therapeutics—which really underpins the support for biomarker and drug development working in parallel. A huge step,” added Dr. Barker.

wish to return to work, there are imWhat the Oncology Team portant factors that can facilitate the Can Do process. Among the most important Although we think of workplace isof these positive influences, as idensues as being between survivors and tified by survivors themselves, are their employers, there are things we support from supervisors and occucan do to help. pational health First and foremost, professionals, the Guiding the survivor education is critipositive attitude cal. The survivor of coworkers, and to set reasonable often needs asworkplace accomexpectations for recovery sistance in undermodations. Restanding his/her cent studies have after treatment can as an emshown the survireduce stress and promote rights ployee under the vor’s perception of a successful dialogue with Americans with their employer’s Disabilities Act accommodation the employer. and may require for their cancer — Mary S. McCabe, RN, MA support in asking and its treatment for workplace acto be predictive commodat ions. of return to work. Guiding the survivor to set reasonable Flexible and/or reduced work hours expectations for recovery after treatduring treatment and a phased-in rement can reduce stress and promote a turn once treatment is completed are successful dialogue with the employer. key to formulating a successful plan In addition, communication beto assist survivors in their recovery

Embracing New Disciplines To date, more than 290 cancer genes have been identified, and the list continues to grow as advance technologies facilitate the generation of complete sequences of DNA from cancer cells. To ensure that progress does not stall, Dr. Barker stressed that we need to add more computational science into the mix, to manage and interpret our massive data sets. “To capitalize on the decades of progress that are documented in this report requires that we bring in new areas of science, especially computational scientists who can develop original analytical models and tools to help us

We are entering an era where cancer research is quickly moving to embrace multiple new disciplines. — Anna D. Barker, PhD

convert these data into usable information that will lead to the discovery of biomarkers and subsequently developed targeted agents,” said Dr. Barker. “We are entering an era where cancer research is quickly moving to embrace multiple new disciplines. The areas that we are looking to now, such as physics, mathematics, engineering, and integrating new technologies such as stem cell and nanotechnology will help us change the future of cancer in ways we can’t anticipate today. We are in a defining moment; it is up to us to seize it,” concluded Dr. Barker.

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Disclosure: Drs. Barker, Blackburn, Foti, Garber, and Holland reported no potential conflicts of interest.

Reference 1. American Association for Cancer Research: AACR Cancer Progress Report 2011: Transforming Patient Care Through Innovation. Available at www.cancerprogressreport.org. Accessed October 11, 2011.

and prevent a premature exit from the workforce.

tween the oncology team and the employer about the survivor’s recovery can go a long way toward dispelling misinformation and reduce the likelihood of unrealistic demands. Such conversations can also foster employer sensitivity and provide understanding about the rationale for work adjustments so a flexible plan can be developed for the individual employee. Finally, clear and factual information can play a key role in ensuring good relations between the returned worker and his or her coworkers—an important ingredient since colleagues play such an important role in productivity and job satisfaction.

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Disclosure: Ms. McCabe reported no potential conflicts of interest.

Reference 1. Mehnert A: Employment and workrelated issues in cancer survivors. Crit Rev Oncol Hematol 77:109-130, 2011. Ms. McCabe is Director of the Cancer Survivorship Initiative at Memorial Sloan-Kettering Cancer Center in New York.

National Organization Offers Guidance on Employment and Financial Issues for Patients with Cancer and Survivors By Caroline Helwick

he Cancer Legal Resource Center (CLRC) is a joint program of the Disability Rights Legal Center and Loyola Law School Los Angeles. This national organization provides free and confidential information on cancer-related financial and legal issues to cancer survivors, families, employers, health-care professionals, and others dealing with cancer. For oncology health-care professionals and all health providers with an interest in cancer, a resource

manual is available that provides answers to the various questions and issues often faced by patients with cancer and survivors. It also provides useful information about cancer-related legal issues, from diagnosis through survivorship, and can be downloaded at no cost through a grant from LIVESTRONG (see sidebar). The Resource Center provides advice on work-related and other issues ranging from insurance coverage and claims denials to workplace discrimi-

nation and estate planning. Staff at the Center can also answer questions about laws relevant to an individual’s personal situation and can direct patients with cancer and survivors to the appropriate resources as laws vary state by state. The CLRC recently hosted national Cancer Rights Conferences in Chicago (September 2011) and Ann Arbor (October 2011). For additional information, visit: www.CancerandCareers. org and www.cancerlegalresourcecenter.org

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The HCP Manual: A Legal Resource Guide for Oncology Health Care Professionals (2nd Edition - 2011)

his manual is a resource for health-care professionals (eg, doctors, nurses, social workers, psychosocial care providers, patient navigators, and advocates) on the various questions and issues often faced by patients coping with cancer, and provides valuable information about cancer-related legal issues, from diagnosis through survivorship. This manual is part of a project funded by LIVESTRONG to educate health-care professionals about cancer-related legal issues. For more information and to download the complete manual, visit http://bit.ly/jzIcCG

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June 1-5, 2012 | McCormick Place | Chicago, IL

ASCO Members ONLY

Housing and Early Registration for the 2012 ASCO Annual Meeting is Now Open ASCO members have an exclusive advanced window to secure hotel reservations and their first-choice of ticketed sessions for the 2012 Annual Meeting, to be held June 1-5 in Chicago, IL. Visit chicago2012.asco.org to make your hotel reservations, and register for the Meeting. Hotel reservations may be made without registering for the Meeting, but both processes are linked for your convenience. Know a colleague who does not belong to ASCO yet? Share this information on early Annual Meeting registration and housing advantages, available only to ASCO members.

Collaborating to Conquer Cancer

ASCOPost.com | NOVEMBER 1, 2011

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Expert’s Corner Pediatric Oncology

A Conversation with Richard J. Gilbertson, MD, PhD New Director of St. Jude Children’s Research Hospital By Ronald Piana

Richard J. Gilbertson, MD, PhD

t. Jude Children’s Research Hospital, Memphis, the country’s first and only NCI-designated Comprehensive Cancer Center devoted solely to children, recently appointed internationally regarded pediatric brain tumor researcher, Richard J. Gilbertson, MD, PhD, as its new Cancer Center Director. In a recent conversation with The ASCO Post, Dr. Gilbertson shed light on how his research background will help shape his goals at St. Jude.

Council grant. In August 2000, St. Jude recruited me as a new faculty in their neurobiology and brain tumor program in the Cancer Center. About 4 years ago, I became a leader of the neurobiology and brain tumor program. This has been a tremendous experience. The program includes more than 30 of the highestquality clinical and research faculty members. I have learned a great deal from my time as co-leader of the program. When I was asked recently to consider the position of Director of the Comprehensive Cancer Center, I was excited to take these lessons and

initiated by our own cancer center investigators. These children are our most precious charge. Ensuring that our research initiatives and clinical care are at the highest-level possible is my mission. Will your extensive background in childhood brain tumors affect the broader scope of your new position? From the beginning, St. Jude has challenged me to give back as much as the great opportunities it has afforded. I arrived here from England as a “wet behind the ears” researcher, but I had the very best of mentors in the likes of Tom Curran, Amar Gajjar, and Larry

As a foreigner, I have never ceased to be amazed by the generosity of the population of the United States and their recognition of St. Jude as a national resource for children with cancer. apply them across the other cancer disciplines at St Jude.

Career Path

Plans for the Future

In a nutshell, please describe your journey to the St. Jude directorship. I was born in England and, after graduating medical school in Newcastle upon Tyne, I trained in pediatrics, becoming a member of the Royal College of Pediatrics (this is equivalent to being board-certified in pediatrics) in 1995. I completed my PhD in molecular oncology in 1998 under a UK Medical Research

What is your vision for St. Jude moving forward? Basic and clinical research at St. Jude covers a multitude of disciplines. My overarching goal is to work with our faculty to marshal our very best science to improve care in the clinic. We see more than 450 children with newly diagnosed cancer each year, and 80% of those children are enrolled on trials that are

Kun. These folks taught me how to think about science and translational research in a way that’s meaningful for patient care. My approach to science and clinical research has certainly grown and been shaped by my work in brain tumors. In my new role, I am excited at the prospect of bringing these important lessons to the other programs. Historically, we’ve had a very good program in developmental therapeutics for solid malignancies; we now have the opportunity to take it to even greater heights under the co-leadership of Michael Dyer, PhD, a wonderful scientist, and Alberto Pappo, MD, one of our leading clinicians. We have similarly strong leadership, science, and clinical research in our hematologic malignancies, cancer prevention and control, and neurobiology and brain tumor programs. The basic science programs within the Cancer Center at St. Jude are also incredible; ensuring close interaction at all levels with the clinic in meaningful and productive ways will be key.

Current Challenges

Fig. 1: St. Jude Children’s Research Hospital is the only NCI-designated Comprehensive Cancer Center devoted to pediatric oncology. Photo courtesy of St. Jude.

Over the past few decades we’ve seen substantial advances in pediatric cancers. What current challenges keep you awake at night? Over the past 50 to 60 years, with

few exceptions, pediatric cancer mortality rates fell steadily—that is, until about 15 years ago. Since the mid-1990s this progress has stalled. This flattening of the curve represents hundreds of lost lives and devastated families: That keeps me awake. One likely reason for this plateau in survival rates is that standard chemotherapy, surgery, and radiation are now used to maximum efficacy. Further tweaking of these modalities is unlikely to bring more than very small returns in patient benefit. More than ever, our focus must be on understanding disease biology and exploiting this knowledge to develop innovative therapies. So, how do we best develop new therapies for children with cancer? One of the lessons I have learned from my own research is the great value of multidisciplinary teams. The combination of state-of-the-art technologies including genomics, stem cell biology, and animal modeling provides the opportunity to improve our understanding of disease biology at a pace that is not achievable when any one discipline operates in isolation. My own research is showing that childhood brain tumors previously regarded as single entities actually comprise distinct diseases or subtypes with different origins, mutations, and clinical outcomes. This knowledge brings both opportunities and challenges. In preclinical research, we now have the opportunity to model these subtypes of cancer with much greater accuracy, allowing for the development of new treatments tailored to specific tumor subtypes. Our clinical trial designs must become smarter. If we are to test drugs appropriately in the clinic, we must introduce better ways of matching the right patients to the right drug. This will demand the development of robust diagnostic tests that can accurately detect tumor subtype from routine clinical material. Also, since we are making rare diseases rarer through the discovery of subtypes, we must learn how to conduct multicenter and likely multinational trials. continued on page 16

The ASCO Post | NOVEMBER 1, 2011

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Expert’s Corner

Richard J. Gilbertson, MD, PhD continued from page 15

Cost of Care

Do the current economic woes and struggle to reign in health-care expenditures pose difficulties for the future research and clinical goals of St. Jude?

Fortunately not. The generosity of individuals around the nation who daily contribute to the mission of St. Jude through their giving is extremely humbling. As a foreigner, I have never ceased to be amazed by the generosity of the people of the United States and

their recognition of St. Jude as a national resource for children with cancer. Their donations make the work we do possible. Next year marks the 50th anniversary of the opening of St. Jude. Throughout this time, the institu-

Now Enrolling A Randomized Phase 3 Trial

tion has been responsible for countless key advances in the survival and quality of life of children with cancer. These achievements would not have been possible without those ongoing donations. Importantly, that generosity allows us to do the kind of cutting-edge work that also makes us extremely competitive for external peer-reviewed grant funding. Indeed, St. Jude remains one of the most competitive academic medical institutions. That combination of resources remains a robust recipe for success in the fight against childhood cancer.

Further Reflections Any last thoughts? I see a bright future for St. Jude and beyond. Every day, the Cancer Center is making new discoveries that hold great promise for clinical care. We’ve joined various new enterprises, such as the Pediatric Cancer Genome Project. This collaboration with the Washington University School of Medicine in St. Louis is assembling the whole genome sequence of 600 pediatric cancers. It is thrilling see these data coming through—the results are going to change the way we look at these diseases.

R A N D O M I Z E D

Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine

OS Primary endpoint

Ganitumab (AMG 479) is an investigational IGF1R inhibitor that has not been approved by the FDA.

KEY INCLUSION CRITERIA: • Histologically or cytologically conﬁrmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV) • Previously untreated with chemotherapy or radiation • ECOG Performance Status 0 or 1 For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20060540) • www.ClinicalTrials.gov (NCT01231347)

Oncology

As long as we keep a steady stream of invigorated young researchers coming into the labs and clinics, we’ll see real progress in treating childhood cancers. That’s one example that fuels my optimism. As long as we keep a steady stream of invigorated young researchers coming into the labs and clinics, we’ll see real progress in treating childhood cancers. Another source of optimism is the global collaborative spirit. There seems to be an encouraging new openness among researchers in pediatric oncology. If we build on this spirit, we’ll see much more rapid breakthroughs in our efforts to cure children with cancer.

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

ASCO 2011 Journal Ad_AMG479_090611.indd 1

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Direct from ASCO

Philanthropy Spotlight

Susan Halabi, PhD, Is Helping to Fund Future of Cancer Research Donates textbook profits to Conquer Cancer Foundation “I support the Conquer Cancer Foundation because its goals align with mine,” she says. “I’m more committed than ever to advancing cancer research, as is the Foundation.”

Advancing Knowledge through Donation of Book Proceeds

W M . K E V I N K ELLY, DO S U SA N H A L A BI, M D

Oncology Clinical Trials Shows You • • • •

A systematic guide to all aspects of the design, conduct, analysis and reporting of clinical trials in oncology Contributions from oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives Hot topics in oncology trials including: multi-arm trials, meta-analysis, and adaptive design , use of genomics, cost-effectiveness analysis Real-life examples from reported clinical trials included throughout

About the Editors:

William Kevin Kelly, DO, is Associate Professor of Medicine and Surgery, Yale School of Medicine, and Director, Clinical Research Service at the Yale Comprehensive Cancer Center, New Haven, Connecticut. Susan Halabi, PhD, is Associate Professor of Biostatistics and Bioinformatics, Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.

11 West 42nd Street New York, NY 10036-8002 www.demosmedpub.com

ONCOLOGY CLINICAL TRIALS

With chapters written by oncologists, researchers, biostatisticians, clinical research administrators, and industry and FDA representatives, Oncology Clinical Trials, provides a comprehensive guide for both early-career and senior oncology investigators into the successful design, conduct and analysis of an oncology clinical trial. Oncology Clinical Trials covers how to formulate a study question, selecting a study population, study design of Phase I, II, and III trials, toxicity monitoring, data analysis and reporting, use of genomics, cost-effectiveness analysis, systemic review and meta-analysis, and many other issues. Many examples of real-life flaws in clinical trials that have been reported in the literature are included throughout. The book discusses clinical trials from start to finish focusing on real-life examples in the development, design and analysis of clinical trials.

K ELLY H A L A BI

usan Halabi, PhD, thinks in terms of probabilities. Based at Duke University School of Medicine, where she is an Associate Professor of Biostatistics and Bioinformatics, Dr. Halabi specializes in the design and analysis of clinical trials, statistical analysis of biomarker and microarray data, and development and validation of prognostic models of clinical outcomes. She knows that realizing the Conquer Cancer Foundation’s vision—a world free from the ONCOLOGY fear of CLINICAL cancer—is ultimately a numTRIALS bers game. Successful Design, and Analysis who joins the EveryConduct, individual Conquer Cancer Foundation team— whether he or she dedicates time, creativity, and expertise to conduct or encourage cancer research; helps to raise funds to support research; or makes a direct financial contribution—brings us a step closer. “The value of human capital is enormous,” says Dr. Halabi. “Time is just as important as money. It’s not necessarily a matter of making large financial contributions. Volunteering—whether you’re giving time or money—makes a quantitative, effective, meaningful impact.”

Dr. Halabi has come up with an innovative way to contribute to the Conquer Cancer Foundation—one in which the vehicle for her philanthropy is in perfect alignment with the program it supports. She and her co-editor, Kevin Kelly, DO, are donating all proceeds of their book Oncology Clinical Trials: Successful Design, Conduct, and Analysis to the Foundation—with the gift earmarked specifically for use in funding its Young Investigator Awards.

W M . K E V I N K ELLY S U SA N H A L A BI

ONCOLOGY CLINICAL TRIALS Successful Design, Conduct, and Analysis

RECOMMENDED SHELVING CL A SSIFICATION : Oncology

“The book is intended to serve as a guide for junior faculty members who may be conducting their first—or one of their first—clinical trials,” Dr. Halabi

About the Young Investigator Awards Through its Young Investigator Awards, the Conquer Cancer Foundation has helped to launch the careers of more than 650 junior faculty working in virtually all areas of cancer research—providing vital early support that allows young researchers to gain the experience and establish the credentials they need to pursue further funding from government and private sources. The program is of career-defining benefit to the researchers who are honored with the Young Investigator Award. And its success in retaining and growing young talent will have a transformative impact on the future of cancer research. For more information about the Young Investigator Awards, please visit www.conquercancerfoundation.org/YIA.

says. “There’s a great synergy, in that both the book and the Young Investigator Awards support the work of our young colleagues as they embark on their careers.” “I know that my early career experiences really shaped my future,” she continues. “The importance of excellent mentors, institutional support— in terms of protecting research time for junior faculty—and the kind of early funding that we provide through the Young Investigator Awards cannot be overstated. It’s essential that we support and prepare the next generation of cancer researchers.”

Nurturing the Next Generation of Cancer Researchers Growing up in a family of engineers in Venezuela and Lebanon, Dr. Halabi’s aptitude for math—she was one of the first students in the undergraduate biostatistics program at the American University of Beirut—was complemented by an interest in medicine. “I liked math and I was interested in research,” she recalls. “And there are synergies. Both math and medicine are fields in which you need to be comfortable with uncertainty.” Dr. Halabi’s passion for cancer research took hold while she was completing her doctoral work at The University of Texas Health Sciences Center at Houston and collaborating on breast cancer and lung cancer studies with researchers at MD Anderson Cancer Center. During that time, her best friend was diagnosed with breast cancer that would eventually claim her life. She was the first of Dr. Halabi’s friends and colleagues to be affected by the disease—but not the last. “As I was growing older, I would encounter more and more people, including family members and friends who were diagnosed with cancer,” she says, remembering her intensifying awareness of the desperate need to find answers.

At Duke, Dr. Halabi works on clinical trials for prostate cancer, bladder cancer, and renal cancer. She has developed a nomogram, or multivariable model, for calculating probability of survival among patients with prostate cancer—a tool that may ease treatment decisions and help improve quality of life. A recent Research Project Grant (RO1) from the NCI is funding 4 more years of research as Dr. Halabi works to develop new prognostic models for use in treating men with advanced prostate cancer. Off-campus, Dr. Halabi is working with a team of researchers in another nonprofit organization, on a public health project addressing residential mercury—a potent carcinogen—in Peru and Bolivia. She is also active with ASCO and the Society for Clinical Trials—serving on the Society’s Board of Directors and on the program committees of both organizations, with plans to host their first joint workshop at the 2012 ASCO Annual Meeting. Dr. Halabi has served on the Grants Selection Committee for the Conquer Cancer Foundation of ASCO’s Young Investigator Awards and Career Development Awards for the past 4 years. “As we move deeper into the world of personalized medicine, biostatistics will play a huge role,” she says. “Both need and opportunity will be enormous in the very near future.” Growing the next generation of cancer researchers is very much on Dr. Halabi’s mind—and she believes that the Young Investigator Awards play a crucial role. “The pioneers who led the work that has contributed to our great progress in cancer research over the past 30 or 40 years—will be retiring in the next few years. It’s critical that we support the people who will lead us into the future.”

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The ASCO Post | NOVEMBER 1, 2011

PAGE 18

Direct from ASCO

GI Symposium Helps Oncologists Stay Abreast of Fast-moving Research

astrointestinal cancers are a key therapeutic area in research, and science is moving forward in that arena at a fast clip. But how are those who focus on gastrointestinal malignancies in the clinic supposed to stay on top of it all? One great way is to attend the annual Gastrointestinal Cancers Symposium, which will take place January 19-21 in San Francisco. The symposium—attended last year by 2,850 residents, post-docs, fellows, and all levels of faculty and private practitioners—offers a vast array of educational sessions and abstract presentations focused on GI cancers.

Cathy Eng, MD

“The whole point of this meeting is to take what is happening in current research, understand it, and if appropriate apply it to the clinical setting,” said Cathy Eng, MD, Scientific Program Chair of the symposium. “My goals are to provide a well-developed, well-

rounded program to provide fundamental knowledge in translational research, identify novel clinical findings, and/or discuss aspects of recent clinical trials in development.” Dr. Eng, who is Associate Professor and Associate Director of the Colorectal Center at the University of Texas MD Anderson Cancer Center Department of Gastrointestinal Medical Oncology.

Truly Multidisciplinary The 3-day meeting is the largest multidisciplinary GI-focused gathering in the United States. ASCO, the American Gastroenterological Association, the American Society for Radiation Oncology, and the Society of Surgical Oncology all cosponsor the meeting. “There is no other GI meeting like this one,” commented Richard M. Goldberg, MD, Chair of the symposium’s steering committee. “Sponsorship by so many academic societies whose specialists provide clinical management for patients with GI cancer and do research to advance the field means that the agenda reflects the latest advances and hot topics in the field.” Dr. Goldberg is Associate Director of Clinical Research for the University of North Carolina’s Lineberger Comprehensive Cancer Center and Physician-in-Chief of the N.C. Cancer Hospital.

Richard M. Goldberg, MD

Helping Initiate More Research While the meeting helps physicians keep updated on research and advance their own knowledge base, it also generates ideas for more research. In addition to the sessions themselves, much is gained from

The networking opportunities can be especially pivotal for young doctors. — Cathy Eng, MD

the symposium’s networking opportunities. Dr. Eng said that the ability to interact and network with colleagues to generate novel ideas for future research proposals has drawn her to the symposium year after year. “The networking opportunities can be especially pivotal for young doctors,” Dr. Eng pointed out. “We

hold a mentoring luncheon on the first day for the fellows and junior faculty so they can directly interact in small groups with leading experts in their field. This year, I have invited 12 of the world’s leading experts in GI malignancies, including ones from radiation oncology, medical oncology, and surgical oncology. Though it may seem short, this 1 hour can help individuals resolve questions about faculty development and potentially develop longlasting relationships with a mentor from another institution.”

Large, Yet Intimate The focused agenda and the opportunity for participants to interact with the world’s experts in GI cancer have led to growth in attendance every year. Though the numbers of attendees have been growing, the symposium is small enough to feel intimate, and this is key, Dr. Goldberg noted. “For clinicians and trainees, the program provides a concentrated immersion in GI cancer patient management and emerging findings in translational science that is much more user friendly than the large general oncology meetings that occur in the U.S. and elsewhere.” For more details on the GI Symposium or to register, visit gicasym.org .

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2012 Gastrointestinal Cancers Symposium Science and Multidisciplinary Management 2012 Gastrointestinal of GI Malignancies

Cancers Symposium

Science and Multidisciplinary Management of GI Malignancies

January 19–21, 2012 San Francisco, California TARG E T I NG

C A NC E R

C A RE

ASCOPost.com | NOVEMBER 1, 2011

PAGE 19

Direct from ASCO

ASCO Symposium Helps Practices Leverage Health IT, Understand EHR Policy Changes

o help community oncology practices and large institutions navigate recent health-care policy changes and leverage health information technology (HIT) to improve the quality of care, ASCO will hold the 2011 HIT/EHR Symposium at the Westin Peachtree Plaza in Atlanta on November 4–5.

This symposium has content for those preparing for EHR implementation as well as for more advanced early adopters of HIT who are seeking to leverage their investment. “This symposium has sessions for those beginning their electronic health record [EHR] transition or for those more familiar with the technology,” said Peter Paul Yu, MD, Chair of the 2011 ASCO HIT/EHR Symposium Program Committee. “The topics covered represent a natural progression from previous ASCO symposiums and center on the broad concept of information management. This symposium has content for those preparing for EHR implementation as well as for more advanced early adopters of HIT who are seeking to leverage their investment.” As payers and providers use new technology to improve efficiency and patient outcomes, ASCO supports the adoption of electronic health records and other technology to improve the quality of cancer care. To ensure that oncology practices are fully informed and equipped, the symposium will cover the full range of issues they face.

Fully understanding the EHR certification requirements to qualify for Meaningful Use Incentives, recent modifications by the Centers for Medicare and Medicaid Services to the eRx incentive program, and payment penalties for oncologists who fail to e-prescribe are just some of the most recent policy changes that challenge practices using or upgrading to EHR.

Symposium Topics The 2011 Symposium sessions include: ■■ Navigating cultural and financial challenges with EHR implementation ■■ Streamlining the integration of information technology into everyday practice ■■ Using EHRs to improve quality and safety of care ■■ Qualifying for stage 1 Meaningful Use and understanding the objectives of stages 2 and 3 ■■ Exploring new models of care such as Accountable Care Organizations (ACOs) and patientcentered medical homes Attendees will also have an opportunity for hands-on use of cuttingedge technology. The symposium will feature a challenge session for vendors, in which they are given a detailed patient case scenario and will be asked to demonstrate their effectiveness in performing several EHR tasks. In addition to the symposium, ASCO has assembled several resources to help oncologists with the many issues surrounding health IT. ASCO has also developed technical standards for EHRs and has actively commented on related government legislation. For more information on ASCO’s EHR efforts, please visit www.asco.org/ehr, and for questions about these activities, e-mail ehr@asco.org.

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Coming Soon—Survivorship Booklet for Patients and Their Families

new booklet from Cancer.Net explains survivorship and gives an overview of the challenges faced by cancer survivors. It provides the next steps cancer survivors can take after treatment, including the importance of follow-up care, rehabilitation, managing long-term side ef-

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official 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 Syndromes 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 Adenocarcinoma. 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

www.jco.org

fects, and maintaining lifelong health. Copies of the booklet can be ordered through the ASCO University Bookstore at www.cancer.net/estore or downloaded at Cancer.Net .

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What’s Hot in

JCO

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

JCO.org 1. Prostate Cancer: Evolution or Revolution? Eric J. Small, et al 29(27): 3595

7. Should the Presence of Germline BRCA1/2 Mutations Influence Treatment Selection in Breast Cancer? Mark E. Robson

2. FOLFIRINOX: A Small Step or a Great Leap Forward? Andrew H. Ko 29(28): 3727

29(28): 3724

8. Bendamustine Combined With Rituximab in Patients With

3. When Bad Things Happen to Good Studies Judith B. Manola, et al 29(26): 3497

Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study

4. Flaxseed and Breast Cancer: What Should We Tell Our Patients? Ruth E. Patterson 29(28): 3723 5. Can We Predict Who’s at Risk for Developing Bone Metastases in Breast Cancer? Larissa A. Korde, et al 29(27): 3600 6. Cardiovascular Toxicity of Androgen Deprivation Therapy: A New Door Opens Shabbir M.H. Alibhai 29(26): 3500

Group Kirsten Fischer, et al 29(26): 3559

9. Lost in Translation: A Fisherman’s Tale Michael J. Overman, et al 29(28): 3832

10. The Study of Collaborative Practice Arrangements: Where Do We Go From Here? Dean F. Bajorin, et al 29(27): 3599

The ASCO Post | NOVEMBER 1, 2011

PAGE 20

Issues in Oncology Cost of Care

New Technologies Are Driving Up Costs: Are They Worth the Price? By Ronald Piana

xpensive new cancer therapies and technologies are alluring for both physicians and their patients. Prostate cancer, because of the sheer volume of cases and the variability of

treatment options, serves as a dynamic disease model in the ongoing debate over how to curb spending and maintain high-quality care. Two recently published studies looked at the cost

implications of rapid adoption of new technologies and how costs of prostate cancer care vary with initial treatment choice. The ASCO Post spoke with the studies’ lead authors, Paul L Nguyen,

MD, Assistant Professor, Department of Radiation Oncology, Dana-Farber/ Brigham and Women’s Cancer Center, Harvard Medical School, and Claire F. Snyder, PhD, MHS, Associate Professor of Medicine, Johns Hopkins School of Medicine.

In with the New, Out with the Old Dr. Nguyen and fellow researchers examined usage patterns of radiation therapies and surgical procedures in prostate cancer.1 “Our study was looking to quantify increased utilization of more expensive therapies in prostate cancer, because it is sort of a litmus test for what’s going on in the broader health-care discussion,” said Dr. Nguyen. “In radiation therapy, we compared utilization of SEE PAGE 33 intensity-modulated radiation therapy (IMRT) vs the less costly three-dimensional conformal radiation therapy (3D-CRT). In surgery we compared robotic and laparoscopic minimally invasive radical prostatectomy with open surgery,” explained Dr. Nguyen. The researchers used SEER-Medicare linked data from 45,636 men aged 65 years or older who were diagnosed with localized prostate cancer from 2002 to 2005 and received definitive surgery or radiation therapy. They determined the costs attributable to prostate cancer by the difference in Medicare payments in the year after vs the year before diagnosis. “We wanted to discover what the cost implications over time were when using more expensive therapies over less costly options,” said Dr. Nguyen.

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Costs of Rapid Adoption Dr. Nguyen said that in the surgery cohort they found minimally invasive radical prostatectomy use increased from 1.5% of all diagnoses in 2002 to 28.7% in 2005; in radiotherapy, IMRT use increased from 28.7% in 2002 to 81.7% in 2005. For men receiving brachytherapy, supplemental IMRT also increased significantly, from 8.5% to 31.1%. During the 2002 to 2005 study period, the cost of IMRT was nearly $11,000 greater per case than that of traditional 3D conformal radiation therapy.

110715-130123

Visit www.emdserono.com to learn more about EMD Serono Oncology. 1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021. 2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

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PAGE 21

Issues in Oncology

“So we found a substantial increase in the use of these expensive new technologies, and the upward use trend for both therapies was happening before there were any data to show that either was cost-effective, or that the results of minimally invasive surgery were better than the results of open surgery,” said Dr. Nguyen. The study showed that the transition from traditional surgery and radiotherapy to the newer, more expensive approaches resulted in an additional $350 million in expenditures among prostate patients in 2005 alone. Dr. Nguyen pointed out that there have been no randomized clinical trials comparing IMRT and minimally invasive radical prostatectomy with the more traditional approaches of 3DCRT and open radical prostatectomy. With regard to benefits of newer technologies, Dr. Nguyen said, “Retrospective studies seem to consistently suggest that IMRT is associated with a significant reduction in long-term rectal toxicity, compared with 3D-CRT, whereas the surgical data comparing the side effects of minimally invasive vs open prostatec-

Paul L. Nguyen, MD

tomy have been mixed.” But he noted that most of the benefits of the more costly therapies were marginal, and the larger question remains: Are the benefits enough to justify the higher costs to our health-care system?

Widespread Use before Data Dr. Nguyen said, “Based on a 2006 study, IMRT now seems to be a cost-

effective approach in prostate cancer. The data show an incremental costeffectiveness of about $40,000 for a quality-adjusted life year, which falls into the generally accepted range of benefit over cost.” However, Dr. Nguyen stressed that by 2006, when the study was done, almost 90% of prostate cancer patients were already receiving IMRT. “So, as a field, we tend to embrace these new options before there are data to prove their cost-effectiveness. And to preserve our finite medical resources, it is important for us to be able to separate out effective treatments from those that are less effective,” said Dr. Nguyen.

prostate cancer.2 Investigators from the Johns Hopkins School of Medicine and Bloomberg School of Public Health reviewed SEER-Medicare data for 13,769 men, aged 66 years or older, diagnosed in 2000 with early-stage prostate cancer, and followed them for 5 years. Led by Dr. Snyder, the researchers divided the men into groups based on the treatment they received during the first 9 months after diagnosis: watchful waiting, radiation only, hormonal therapy only, hormonal therapy plus radiation, and surgery. Costs were divided into initial (from 1 month prior to diagnosis through the first 12 months postdiagnosis), long-

The most practical way to tackle this issue is probably through large national registries that capture the clinical data from cancer patients undergoing treatments. — Paul L. Nguyen, MD

According to Dr. Nguyen, it may not be practical to determine the efficacy and cost-effectiveness of all new technologies and therapies by conducting long and costly headto-head randomized clinical trials, which could result in delaying the deployment of valuable cancer fighting tools. “The most practical way to tackle this issue is probably through large national registries that capture the clinical data from cancer patients undergoing treatments. That way we can learn something from each patient who receives a more expensive therapy. And with that rich body of clinical evidence, we can then better determine which technologies and treatments are cost-effective,” said Dr. Nguyen.

Cost Varies with Initial Treatment Choice A recent study found that initial treatment choice has a strong influence on short- and long-term costs for

term (each consecutive 12 months), and total (full 61 months) expenses. “The incremental costs of prostate cancer care were calculated as the difference in medical costs for prostate cancer patients against similar men without cancer,” Dr. Snyder told The ASCO Post. Dr. Snyder explained that although costs tended to be highest in the initial year of treatment, they dropped substantially and remained fairly constant for ensuing years of treatment. Watchful waiting had the lowest initial costs of $4,270, with 5-year costs at $9,130. “Initial costs were the highest ($17,474) for men receiving hormonal therapy plus radiation. Hormonal therapy had the second lowest initial costs but the highest total costs ($26,896), telling us that certain treatments may be less expensive for the short term, but may have higher long-term costs,” said Dr. Snyder. Dr. Snyder cautioned that this study focused only on cost and that

Claire F. Snyder, PhD, MHS

quality of life and other outcomes need to be considered along with cost when evaluating treatment options. “However, these results give us a picture of the patterns of costs for the different treatment options for prostate cancer—information that may be useful to patients, providers, and policymakers,” concluded Dr. Snyder.

Conclusions The studies led by Drs. Nguyen and Snyder, although looking at different aspects of rising cancer costs, make a strong case that comparativeeffectiveness research is needed, not only to assess efficacy, but also to assess cost. Quality retrospective studies give us important data that help shape policy decisions. However, as Dr. Nguyen pointed out, large wellconstructed national data banks will ultimately provide the robust clinical outcomes data needed to determine the cost-effectiveness of new therapies as they are introduced into the market.

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Disclosures: Drs. Nguyen and Snyder reported no potential conflicts of interest.

References 1. Nguyen PL, Gu X, Lipsitz SR, et al: Cost implications of the rapid adoption of newer technologies for treating prostate cancer. J Clin Oncol 29:1517-1524, 2011. 2. Snyder CF, Frick KD, Blackford AL, et al: How does initial treatment choice affect short-term and long-term costs for clinically localized prostate cancer? Cancer 116:5391-5399, 2010.

Contact The ASCO Post EDITOR IAL CORR ESPONDENCE James O. Armitage, MD Editor-in-Chief

Cara H. Glynn Director of Editorial

Andrew Nash Assoc. Director of Editorial

e-mail: Editor@ASCOPost.com

e-mail: Cara@harborsidepress.com

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ASCOPost.com | NOVEMBER 1, 2011

PAGE 25

In the Clinic

Crizotinib: New Drug for ALK-positive Advanced Non–Small Cell Lung Cancer By Matthew Stenger

With In the Clinic, The ASCO Post provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication Crizotinib (Xalkori) is an oral inhibitor of receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-Met), and recepteur d’origine nantais (RON). In August 2011, the FDA granted the drug accelerated approval for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) that is positive for rearrangements of the ALK gene as detected by an FDA-approved test. Concurrent with crizotinib approval, the FDA approved the Vysis ALK Break-Apart FISH (fluorescence in situ hybridization) Probe Kit, a companion diagnostic test designed to detect these rearrangements. This indication for crizotinib is based on response rate observed in two singlearm trials in patients with locally advanced or metastatic ALK-positive NSCLC, most of whom had received prior systemic therapy (Fig. 1). No available data show improvement of survival. In one study

Of Note Concurrent with crizotinib approval, the FDA approved the Vysis ALK Break-Apart FISH Probe Kit, a companion diagnostic test designed to detect ALK rearrangements.

in 136 patients, which used the Vysis kit to identify ALK-positive NSCLC, there was 1 complete response and 67 partial responses, for an overall response rate of 50%. Median duration of treatment was 22 weeks, and median response duration was 42 weeks. In another study in 119 patients, which used several local clinical trial assays to identify ALK-positive NSCLC, there were 2 complete responses and 69 partial responses, for an overall response rate of 61%. Median duration of treatment was 32 weeks and median response duration was 48 weeks. Responses were observed within 8 weeks in 79% and 55% of responders in the two trials.

How It Works Translocations in the ALK gene can result in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the expression and signaling of the gene, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib inhibits ALK and c-Met phosphorylation, blocking activity of the gene; it has shown antitumor activity in xenografts expressing EML4or NPM-ALK fusion proteins or cMET. Approximately 5% of NSCLC patients harbor ALK translocations.

Of Note The most common adverse effects of crizotinib include vision disorder, nausea, diarrhea, vomiting, edema, and constipation.

How It Is Given Crizotinib is taken orally twice daily at a dose of 250 mg for as long as the patient is deriving clinical benefit. Capsules are swallowed whole and can be taken with or without food. If required, dose reductions are first to 200 mg twice daily and then to 250 mg once daily.

Crizotinib in Lung Cancer ■■ Crizotinib is a tyrosine kinase inhibitor indicated for the treatment of

patients with locally advanced or metastatic non–small cell lung cancer that tests positive for rearrangement of the ALK gene.

■■ The drug is administered orally twice daily at a dose of 250 mg.

Suggested Readings Cui JJ, Tran-Dube M, Shen H, et al: Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54:6342-6363, 2011. Hallberg B, Palmer RH: Crizotinib— latest champion in the cancer wars? N Engl J Med 363:1760-1762, 2010. Kwak EL, Bang Y-J, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010. U.S. Food and Drug Administration: Crizotinib. Available at http://www.fda. gov/AboutFDA/CentersOffices/CDER/ ucm270058.htm. Accessed October 13, 2011. XALKORI® (crizotinib) capsules, oral.

Prescribing information. Pfizer Labs, August 2011. Available at http://labeling. pfizer.com/showlabeling.aspx?id=676. Accessed October 13, 2011.

Report Adverse Events

ealth-care professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www. fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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Safety Profile The most common adverse reactions (≥ 25%) observed in both studies supporting crizotinib approval were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Vision disorders included visual impairment, photopsia, blurred vision, vitreous floaters, photophobia, and diplopia. Grade 3 or 4 adverse reactions in at least 4% of patients included increased ALT and neutropenia. Severe, life-threatening, or fatal treatment-related pneumonitis occurred in 1.6% of crizotinib patients in clinical trials. All cases occurred within 2 months after treatment initiation. Cost—The cost of crizotinib therapy is estimated at $9,600 per month, or $115,000 per year.

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Fig. 1: Response to ALK Inhibition—(A) Best response of patients with ALK-positive tumors who were treated with crizotinib, as compared with pretreatment baseline. Numbers along the x axis indicate arbitrarily assigned subject numbers from 1 to 79. The bars indicate the percent change in tumor burden from baseline. (B) The results of CT with coronal reconstruction in a representative patient at baseline (left) and after two cycles of therapy (right). This patient had undergone previous left lower lobectomy. ©Massachusetts Medical Society. Reprinted with permission from Kwak EL, et al: N Engl J Med 363:1693-1703, 2010.

The ASCO Post | NOVEMBER 1, 2011

PAGE 26

Journal Spotlight Thoracic Oncology

Time to Reconsider Treatment Paradigm for Elderly Patients with Advanced Non–Small Cell Lung Cancer? By Charlotte Bath

ignificantly longer median overall survival among elderly patients with advanced non–small cell lung cancer (NSCLC) receiving doublet chemotherapy rather than monotherapy yielded a 36% reduction in mortality risk in a phase III randomized trial. “We saw a survival benefit with doublet chemotherapy of such magnitude that we believe the treatment paradigm for elderly patients with advanced NSCLC should be reconsidered,” stated investigators from the Intergroupe Francophone de Cancerologie Thoracique (IFCT).1 The current treatment paradigm, the investigators noted, recommends monotherapy in patients older than 70 years with advanced NSCLC. Building on subgroup analysis of trials suggesting survival benefits among carefully selected elderly patients receiving combined chemotherapy, investigators conducted a phase III trial (IFCT-0501) to compare monotherapy and platinum-based doublet therapy in this older population. Eligible patients were aged 70 to 89 with unresectable stage IV disease or stage III unsuitable for radical radiation therapy, and World Health Organization (WHO) performance status scores of 0 to 2. The median follow-up was 30.3 months. The results were published in The Lancet online. A total of 451 patients participated in the multicenter study, with 226 patients randomized to receive four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15), and 225 to receive five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine (Gemzar) monotherapy. The choice of the monotherapy was left to the discretion of the individual investigator. “We

Visit

chose carboplatin instead of cisplatin for the doublet chemotherapy regimen to keep toxic effects to a minimum, especially impaired renal function, nausea, vomiting, and peripheral neuropathy, although we recognised an increased risk of thrombocytopenia,” the authors reported. “Weekly paclitaxel was chosen because the regimen is less toxic than and at least as efficacious as a 3-weekly schedule.”

1-Year Survival Exceeds 44% Median overall survival was 10.3 months for patients receiving doublet chemotherapy and 6.2 months

tients with poor geriatric indices, for whom other therapeutic options remain to be studied.” Toxic effects occurred more frequently in the doublet chemotherapy group. The most frequent toxicities were a decreased neutrophil count (affecting 108 patients or 48.4% of the doublet group vs 28 patients or 12.4% of the monotherapy group) and asthenia (affecting 23 patients or 10.3% of the doublet group vs 13 patients or 5.8% of the monotherapy group. “Grade 3–4 neutropenia, febrile neutropenia, thrombopenia, and anaemia were significantly more frequent

Available data lend support to combination chemotherapy with carboplatin and weekly paclitaxel for selected elderly patients with advanced NSCLC, with aggressive supportive care to treat toxic effects. —Karen L. Reckamp, MD

for those receiving monotherapy. The 1-year survival rate was 44.5% in the group receiving doublet therapy and 25.4% in the monotherapy group. Median progression-free survival was 6.0 months for patients in the doublet group and 2.8 months for those in the monotherapy group. The 1-year progression-free survival was 13.4% in the group receiving doublet therapy and 1.8% in the monotherapy group. At 77, the median age of participants was higher than in other phase III trials specifically looking at NSCLC among elderly patients. “Nevertheless, most of our patients were fit, albeit with a performance status score of 2 in some,” the authors noted. “Our results, therefore, cannot be extrapolated to non-fit elderly pa-

among patients in the doublet chemotherapy group than among those in the monotherapy group, as was grade 3–4 sensory neuropathy,” the authors reported. Overall, 177 patients in the doublet chemotherapy group died, 10 attributable to treatment, and 199 patients in the monotherapy group died, 3 attributable to treatment.

Optimum Regimen Remains Unknown Citing results from this and other studies, Karen L. Reckamp, MD, of City of Hope Comprehensive Cancer Center, Duarte, California, wrote in an accompanying commentary,2 “Available data lend support to combination chemotherapy with carboplatin and weekly paclitaxel for selected elderly patients with advanced NSCLC, with

aggressive supportive care to treat toxic effects. With a median age of 77 years in IFCT-0501 and enrollment of 27% patients with [performance status] 2 in each group, these results can be generalised to a large proportion of patients, although patients had to have adequate renal and hepatic function. Both renal function and hepatic blood flow decrease with age, which could affect clearance, antitumour efficacy, and toxic effects of chemotherapeutic agents.” Questions remain about combination chemotherapy vs single-agent treatment in this population, Dr. Reckamp continued. “The appropriate assessment to predict efficacy and toxic effects of therapy has not yet been identified. The optimum chemotherapy regimen remains unknown because previous trials assessed multiple regimens that contained fractionated doses and non-platinum doublets. Older patients dominate the lung cancer population, but continue to be under-represented in clinical trials. Additional studies are needed that enroll adequate numbers of older adults, and include a comprehensive geriatric assessment to provide the knowledge required to properly assess the risk–benefit ratio in treatment decisions so that a personalized approach can be taken,” she concluded.

■

References 1. Quoix E, Zalcman G, Oster J-P, et al: Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT0501 randomised phase 3 trial. Lancet 378:1079-1088, 2011. 2. Reckamp KL: Combination chemotherapy for older adults with advanced non-small-cell lung cancer. Lancet 378:1055-1057, 2011.

website at ASCOPost.com

ASCOPost.com | NOVEMBER 1, 2011

PAGE 27

European Multidisciplinary Cancer Congress 2011 Gastrointestinal Onology

Panitumumab Is Not Beneficial in KRAS Mutations: No Exceptions

Study contradicts recent findings suggesting some mutated tumors may respond to cetuximab. By Caroline Helwick

he need to restrict treatment with panitumumab (Vectibix) to metastatic colorectal cancer patients with wild-type (normal) KRAS tumors was upheld in a study presented at the 2011 European Multidisciplinary Cancer Congress (EMCC). The investigation found a consistent lack of benefit for the drug across the most common KRAS mutant alleles.1 “We can say that patients with metastatic colorectal cancer harboring any of the most common codon 12 and 13 mutant KRAS alleles are unlikely to benefit from panitumumab treatment,” said Marc Peeters, MD, PhD, of Antwerp University Hospital, Edegem, Belgium. “Only patients with wildtype KRAS should be treated with EGFR inhibitors.”

prognosis in treatment-naive patients and with benefit from first-line cetuximab,3 essentially reversing the poor prognosis observed with chemotherapy alone, pointed out Pierre Laurent-Puig, MD, PhD, of the Université Paris Descartes in France, who discussed Dr. Peeters’ findings at the EMCC meeting.

Three Phase III Trials of Panitumumab

Dr. Peeters presented the retrospective analysis of patients treated in phase III studies of panitumumab plus first-line FOLFOX4 (leucovorin, fluorouracil [5-FU], oxaliplatin), second-line FOLFIRI (leucovorin, 5-FU, irinotecan), or best supportive care (monotherapy). Patients were screened for the seven most common KRAS mutations in codons 12 and 13 (KRAS G12A, G12C, G12D, G12R, G12S, G12V, G13D). “Collectively, mutant KRAS codon 12 and 13 alleles are established biomarkers for lack of response to anti-EGFR antibodies in metastatic Marc Peeters, MD, PhD Pierre Laurent-Puig, MD, PhD colorectal cancer. We evaluated the prognostic and predicInterestingly, the current analysis tive impact of individual codon 12 and of data by KRAS mutant allele status 13 KRAS mutations in three phase III contradicts recent findings regardstudies,” Dr. Peeters said. ing KRAS mutations in cetuximab Mutated KRAS codon 12 and 13 (Erbitux) trials. alleles were detected in 40% to 45% De Roock and colof tumors, and their distribution was leagues showed that conserved across studies and equally patients with KRAS balanced among treatment arms. G13D mutations SEE PAGE 33 KRAS Mutant Alleles did indeed have and Outcomes longer overall and progression-free In the control arm—in which a progsurvival with cetuximab treatment, nostic effect might be demonstrated— compared with patients harboring no individual mutant allele was consisother KRAS mutations.2 And at the 2011 ASCO Annual Meeting, Tejpar tently associated with progression-free and colleagues found the G13D muor overall survival outcomes. tation to be associated both with poor “What is more important is the pre-

Panitumumab and the G13D Mutation in Metastatic Colorectal Cancer ■■ A retrospective analysis of three phase III trials of panitumumab in

metastatic colorectal cancer found that no individual mutant KRAS allele was consistently associated with outcomes.

■■ The findings contradict recent evidence that patients with G13D

mutations in codon 12 and 13 might benefit from anti-EGFR inhibitors.

■■ Only patients with wild-type KRAS should receive panitumumab.

EXPERT POINT OF VIEW

xel Grothey, MD, of the Mayo Clinic, Rochester, Minnesota, found the findings presented by Marc Peeters, MD, PhD,1 at the 2011 European Multidisciplinary Cancer Congress to be of great interest, from both clinical and research perspectives. “We have two discrepant analyses now for G13D. When we heard the Tejpar data at ASCO,3 we thought, ‘Should these patients be treated? How can we withhold therapy from them?’ There has been a lot of interest in this question,” he told The ASCO Post. Axel Grothey, MD “At Mayo, we now record not just the existence of a KRAS mutation, but the specific codon. This is what we need to do now,” he said. “Clinically, the data by Dr. Peeters and colleagues now validates the standard of care, but going forward, I agree, we should be looking more at the differential effects of the different KRAS mutations on outcomes. We know from GIST tumors, for instance, that different exons have different therapeutics implications for drug resistance. All KRAS mutations may not be created equal.” Adding to the discussion, Pierre Laurent-Puig, MD, of the Université Paris Descartes in France, commented on G13D as a prognostic factor. He suggested that “in the first line, there is probably no specific impact of the G13D mutation on prognosis whatever the chemotherapy regimen used, but this should be documented by a meta-analysis. In the second and third lines, there is no argument for a role of G13D mutation in prognosis. In addition to the results presented by Dr. Peeters, the CO-17 [cetuximab] study by de Roock et al2 showed no prognostic impact after adjustment for other prognostic markers.” The G13D allele, however, is found in 8% of advanced colorectal cancer patients, therefore, Dr. Laurent-Puig finds it reasonable to conduct a randomized trial “to explore the possibility to treat G13D-mutated patients for whom we have nothing to propose after the second line of treatment.” Meanwhile, he agreed with Dr. Grothey: “There should be no change in clinical practice at this time.” Disclosure: Dr. Grothey reported no potential conflicts of interest.

dictive effect,” he said, “and there was no individual mutant KRAS allele consistently associated with progressionfree or overall survival outcome in all three studies,” Dr. Peeters said. Only in study 20050203 (panitumumab plus FOLFOX) were two individual mutant alleles significantly associated with outcomes: G12V was favorably associated with overall survival (P = .0369) and G13D was unfavorably associated with overall survival (P = .0018) in the panitumumab arm. In the pooled analysis, G12A was the only mutant allele significantly associated with a negative panitumumab treatment effect on overall survival.

■

Disclosure: Dr. Peeters has disclosed a relationship with Amgen. Dr. Laurent-Puig has received honoraria from Merck Serono and Amgen.

References 1. Peeters M, Douillard JY, Van Cutsem E, et al: Evaluation of individual codon 12 and 13 mutant (MT) KRAS alleles as prognostic and predictive biomarkers of response to panitumumab (pmab) in patients with metastatic colorectal cancer (mCRC). 2011 European Multidisciplinary Cancer Congress. Abstract 33LBA. Presented September 25, 2011. 2. De Roock W, Jonker DJ, Di Nicolantonio F, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 27:1812-1820, 2010. 3. Tejpar S, Bokemeyer C, Celik I, et al: Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. 2011 ASCO Annual Meeting. Abstract 3511. Presented June 4, 2011.

The ASCO Post | NOVEMBER 1, 2011

PAGE 28

FDA Update

FDA Issues Safety Announcement on Dasatinib

he FDA is warning the public that the leukemia drug dasatinib (Sprycel) may increase the risk of pulmonary arterial hypertension (PAH). Information about this risk has been added to the Warnings and Precautions section

Gel for Blood Vessel Surgery Approved

he FDA has approved LeGoo (PluroMed Inc, Woburn, Mass), a gel that allows surgeons to temporarily stop blood flow during surgery so that they can join blood vessels without clamps or elastic loops. LeGoo has been shown to minimize blood flow into the surgical area without damaging blood vessels. This temperature-sensitive gel is liquid at room temperature and solid at higher temperatures. When injected into a blood vessel, LeGoo forms a gel plug that molds to the shape of the blood vessel and stops blood flow for up to 15 minutes. After the blood vessels are joined, the plug is expected to dissolve on its own in 15 minutes. In the event the plug needs to dissolve sooner, the surgeon can dissolve the gel plug by applying a cold pack or cold saline to the blood vessel. LeGoo is approved for temporarily stopping blood flow in blood vessels below the neck that are 4 mm or less in diameter. It is contraindicated for use on vessels supplying blood to the brain.

■

FDA Okays Breast Cancer Diagnostic

E Healthcare recently announced FDA 510(k) clearance of technology to aid the physician in breast cancer diagnosis. The new SenoBright Contrast Enhanced Spectral Mammography (CESM) technology is designed to produce contrast-enhanced images of the breast using an x-ray contrast agent and a dual energy acquisition technique. The resulting images specifically illuminate and highlight areas of iodinated contrast. Launched in 2010, SenoBright is already in use at 17 major mammography centers in France, Spain, Italy, Belgium, Germany, Austria, and Japan.

■

of the dasatinib drug label. In reported cases, patients developed PAH after starting dasatinib, including after more than 1 year of treatment. In symptomatic patients, if other

causes have been ruled out, a diagnosis of dasatinibassociated PAH should be considered. PAH may be reversible if dasatinib is discontinued. Health-care professionals should

evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to starting dasatinib and also during treatment. If PAH is confirmed, dasatinib should be permanently discontinued.

TREANDA® is his chemo.

This is his therapy.

■

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2011

PAGE 29

FDA Update

Bevacizumab Labeling Revised to Include New Risks

he FDA recently announced changes made to the bevacizumab (Avastin) package insert regarding new safety concerns. These changes include the following: â&#x2013; â&#x2013; A new Warning subsection de-

scribing the increased risk of ovarian failure in premenopausal patients receiving bevacizumab and chemotherapy and recommendation that females of reproductive potential be informed of the in-

creased risk of ovarian failure prior to starting treatment with bevacizumab â&#x2013; â&#x2013; Identification of osteonecrosis of the jaw as an adverse reaction of bevacizumab

Single-agent TREANDA produced a 74% ORR* TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkinâ&#x20AC;&#x2122;s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. ORR*: INDOLENT B-CELL NHL THAT HAS PROGRESSED

57%

PR (n=57)

17%

CR/CRu (n=17)

74%

Total ORR (95% CIâ&#x20AC; : 64.3, 82.3)

100

Patients responding (%) *Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be â&#x2030;Ľ20 mm. â&#x20AC; CI=confidence interval.

s 42%!.$! WAS EVALUATED IN A SINGLE ARM PIVOTAL STUDY OF PATIENTS WITH INDOLENT " CELL .(, THAT HAD progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen s 42%!.$! IS ADMINISTERED WITH A CONVENIENT DOSING SCHEDULE n 4HE RECOMMENDED DOSE IS MG M2 ADMINISTERED INTRAVENOUSLY OVER MINUTES ON $AYS AND OF A DAY TREATMENT CYCLE UP TO CYCLES TREANDA has an established safety profile s )N SINGLE ARM STUDIES OF PATIENTS WITH INDOLENT " CELL .(, THAT HAD PROGRESSED . THE MOST common non-hematologic adverse reactions (frequency â&#x2030;Ľ WERE NAUSEA FATIGUE

VOMITING DIARRHEA AND PYREXIA . 4HE MOST COMMON HEMATOLOGIC abnormalities (frequency â&#x2030;Ľ WERE LYMPHOPENIA LEUKOPENIA ANEMIA

NEUTROPENIA AND THROMBOCYTOPENIA Important Safety Information s 3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS

tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur s !DVERSE REACTIONS MAY REQUIRE INTERVENTIONS SUCH AS DECREASING THE DOSE OF 42%!.$! OR withholding or delaying treatment s 42%!.$! IS CONTRAINDICATED IN PATIENTS WITH A KNOWN HYPERSENSITIVITY TO BENDAMUSTINE OR MANNITOL Women should be advised to avoid becoming pregnant while using TREANDA

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

â&#x2013; â&#x2013; New information regarding the risks of venous thromboembolic event (VTE) and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.

â&#x2013;

The ASCO Post | NOVEMBER 1, 2011

PAGE 30

Perspective

Integrative Medicine Offers Added Value for Patients with Cancer By Carolyn M. Matthews, MD

ddressing a patient’s physical, emotional, and spiritual needs during the cancer journey, integrative medicine combines such time-honored therapies as nutrition, exercise, and medita-

tion alongside allopathic approaches to cancer care, with the ultimate goal of improving survival rates and reducing symptom burden. Not an alternative to allopathic care, integrative medicine is

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin’s Lymphoma That Has Progressed INDICATIONS AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176). System organ class, preferred term, and number (%) of patients* are shown. Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53). Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0. Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0. General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0. Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0. Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2). Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5). Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0. Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0. Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0. Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0. Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0. Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

intended to be an enhancement to each patient’s course of treatment.

Advantages The main advantages of integrative

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. L C5@D931<<I B53?>CD9DED5 5138 +) % F91< 1C 6?<<?GC L =7 +) % F91< 44 =# ?6 ?><I Sterile Water for Injection, USP L =7 +) % F91< 44 =# ?6 ?><I Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. L C5@D931<<I G9D84B1G D85 F?<E=5 >55454 6?B D85 B5AE9B54 4?C5 21C54 ?> =7 =# 3?>35>DB1D9?> and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear 1>4 3?<?B<5CC D? C<978D<I I5<<?G C?<ED9?> L ,C5 *D5B9<5 .1D5B 6?B !>:53D9?> ,*' 6?B B53?>CD9DED9?> 1>4 then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, ,*' 6?B 49<ED9?> 1C ?ED<9>54 12?F5 %? ?D85B 49<E5>DC 81F5 255> C8?G> D? 25 3?=@1D92<5 L '1B5>D5B1< drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

care include: ■■ It has a scientific rationale (pleioptropic effects of diet and exercise on gene expression) for potential improvement in survival rates and reduction of symptom burden. ■■ Healthy food is a fraction of the cost of a single injection of growth factor. Why not teach patients to eat in a way that avoids the inflammatory effects of the current American diet? ■■ It has a high therapeutic ratio, with an extremely low likelihood of morbidity for patients. For example, it is unlikely to cause such devastating events as bowel perforation or cardiomyopathy. ■■ It incorporates the patient as a partner in the cancer journey and allows individuals a sense of control over their future.

Manufactured by: Pharmachemie B.V. The Netherlands TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2262 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

Carolyn M. Matthews, MD

Environmental-Genome Interactions Research is showing that most chronic conditions, from heart disease and diabetes to cancer, share underlying common pathways of inflammation and/or oxidative stress and that the manifestations of those processes are a result of each person’s unique environmental-genome interactions. While we can’t change the genes we inherited from our parents, we can optimize gene expression as a result of our daily environmental experiences—from the bioactive components in the foods we eat to limiting as much as possible our exposures to known carcinogens and infectious agents. In 1934, Clive McKay of Cornell demonstrated that calorie reduction prolonged life; it has now been shown repeatedly to limit tumor formation. We know that eating high glycemic index meals rapidly upregulates genes related to inflammation. The modern American diet, in which approximately 70% of caloric intake comes from

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Perspective

refined and nutrient-poor foods, promotes hyperglycemia and hyperinsulinemia amid a background of inflammation.

Supporting Data

for 6 days a week.3 ■■ Kim Knoops’ Healthy Ageing: a Longitudinal study in Europe (HALE study) of aging and lifestyle revealed a 60% reduction in death from cancer among 70 to 90 year olds who adhered to a Mediterranean diet and a healthy lifestyle including nonsmoking, physical activity, and moderate alcohol use.4

A randomized, placebo-controlled study investigating the effects of diet on cancer survival would be impractical, as we are not inbred lab animals with the same genes and epigenes, and Effects of Exercise and Stress it is impossible to Numerous studies have now control for years exshown the benefits of exercise in actly what individuprolonging cancer survival rates and als and their predepromoting healthy aging. For excessors consume. SEE PAGE 33 ample, Meyerhardt showed reduced Nevertheless, there mortality in patients with colorectal are data to support the role of diet and cancer using recreational physical lifestyle in cancer patients, including activity.5 Similarly, Michelle Holmes the following findings: ■■ Rowan Cheblowski’s data from demonstrated a statistically signifithe Women’s cant reduction In te r v e n t i o n in risk of death Numerous studies have Nutrition in women with shown the benefit of stress breast cancer: Study (WINS) showed that in Compared with reduction techniques postmenopauswomen who ensuch as meditation, al women with gaged in less than early breast 3 MET-hours of mindfulness, guided cancers, a diactivity per week, imagery, and art therapy etary invention the relative risk of in reduction of group consumdeath from breast ing less fat had cancer was 0.50 symptom burden. a hazard ratio (95% CI = 0.34– for relapse of 0.74) for 9 to 14.9 0.76 vs the control group (95% CI MET-hours per week.6 Like diet, exercise modulates genetic expression = 0.60–0.98; P = .077 for stratified and has pleiotropic physiologic eflog rank and P = .034 for adjusted fects. Cox model). The effect was even We also know that chronic unregreater when considering only the lenting stress impacts not only our estrogen receptor–negative group sense of well-being but also our imof patients, with a hazard ratio for mune system. As psychoneuroimrecurrence of 0.58.1 ■■ Dean Ornish’s groundbreaking munology researchers Candace Pert work in men with prostate cancer and Esther Sternberg have so elohas shown that intensive diet and quently shown, our environmental lifestyle interventions can lead to interactions affect the function of 48 upregulated transcripts and our hypothalamic-pituitary-adrenal 453 downregulated transcripts in axis and the responsiveness of our serial prostate biopsies. He idenimmune system. Numerous studtified significant modulation of ies have shown the benefit of stress biologic processes that could afreduction techniques such as medifect tumorigenesis such as protein tation, mindfulness, guided imagmetabolism and modification, ery, and art therapy in reduction of ligases, and membrane traffic prosymptom burden. Likewise, healthy 2 teins. sleep patterns are also associated ■■ John Pierce’s data from the Womwith improvement in longevity and en’s Healthy Eating and Living well-being. (WHEL) trial showed a statistiIntegrative medicine is clearly valcally significant 44% risk reduction ue added for our patients, and it only in mortality for postmenopausal makes sense for oncologists to open our women with early breast cancer treatment armamentaria to these lowwho both ate five servings of vegcost, low-morbidity approaches. Disclosure: Dr. Matthews reported no etables and fruits daily and walked potential conflicts of interest. the equivalent of 30 minutes daily

■

References 1. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 98:1767-1776, 2006. 2. Ornish D, Magbanua MJ, Weidner G, et al: Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. PNAS 105:8369-8374, 2008. 3. Pierce JP, Stefanick M, Flatt SW, et al: Greater survival after breast cancer in physically active women with high vegetable–fruit intake regardless of obesity. J Clin Oncol 25:2345-2351, 2007. 4. Knoops KTB, deGroot LCPGM, Kromhout D, et al: Mediterranean diet,

lifestyle factors, and 10-year mortality in elderly European men and women: The HALE project. JAMA 292:1433-1499, 2004. 5. Meyerhardt JA, Giovanucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527-3534, 2006. 6. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:24792486, 2005. Dr. Matthews is a physician specializing in gynecologic oncology at Texas Oncology– Baylor Charles A. Sammons Cancer Center, Dallas. She is Director of Integrative Medicine at Baylor University Medical Center.

Now Available: The Complete Guide to Complementary Therapies in Cancer Care Essential Information for Patients, Survivors and Health Professionals

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

he Complete Guide to Complementary Therapies in Cancer Care is an invaluable resource in making educated health care decisions for managing life during and after cancer. This unique and comprehensive book guides the way through the often confusing maze of complementary and alternative therapies promoted to cancer patients and survivors. The functions, benefits, backgrounds and risks are clearly presented. Learning when, if and how to use them provides medical professionals, cancer patients and survivors with the information they need to better control the symptoms and side effects of cancer and its treatment. Unfortunately, using some of these therapies without this expert guidance can lead to medical complications, or worse. 354 pages; World Scientific

“Barrie Cassileth runs the most distinguished service and research team in the world, for complementary medicine … This book takes no prisoners and courageously investigates the good, the bad and the downright ugly of interventions practiced under the name of complementary therapy. Dr Cassileth comes across as a humane and passionate advocate for the needs of her patients.” Michael Baum, MD Professor Emeritus of Surgery and Visiting Professor of Medical Humanities University College London, UK “Dr. Cassileth pioneered the evidence-based approach to CAM. In this comprehensive and focused book, she eloquently describes clinical practice, credibility and effectiveness, directing the reader to professional sources. As we enter the new global culture of self-directed health care, this is an essential part of both the home and institutional library.” Stephen M. Sagar, BSc (Hons), MBBS, MRCP, FRCR, FRCPC, DABR, Professor of Radiation Therapy McMaster University, Canada

For more information, visit www.worldscientific.com

The ASCO Post | NOVEMBER 1, 2011

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News

Important Briefs from the 2011 Breast Cancer Symposium By Caroline Helwick

he 2011 Breast Cancer Symposium was recently held in San Francisco, bringing together a multidisciplinary group of specialists and sponsored by ASCO, the American Society for Radiation Oncology, the Society of Surgical Oncology, the American Society of Breast Disease, the American Society of Breast Surgeons, and the National Consortium of Breast Centers, Inc. The following reports are brief summaries of a few noteworthy presentations.

Irradiating Internal Mammary Nodes The value of irradiating the internal mammary nodes continues to be debated. This analysis from the British Columbia Cancer Agency in Vancouver found that intentional inclusion of the internal mammary node region did not result in a significant difference in survival, though a small and nonsignificant 3% survival benefit was observed in the subset with one to three positive nodes.1

Robert Olson, MD

The study included 2,413 women with early breast cancer who received locoregional radiotherapy and were evaluated according to whether this treatment included internal mammary nodes (n = 1,000) or not (n = 1,413). At a median follow-up of 6.2 years, 5-year recurrence-free survival was 81% and 82%, respectively; distant recurrence-free survival was 82% per arm, and overall survival was 85% and 83% (no statistically significant differences). In the subset with one to three positive nodes, overall survival was 91% for patients who received radiotherapy to the internal mammary nodes and 88% for those who did not—a 22% nonsignificant risk reduction. “Women with low-burden, nodepositive disease are most likely to ben-

efit from internal mammary node radiotherapy,” said Robert Olson, MD, who presented the findings. Barbara Fowble, MD, of the University of California School of Medicine, San Francisco, the formal discussant of the study, said she sees “problems with the data, but recognizing this, the study suggests there is no benefit.” The 3% overall survival benefit in node-positive patients is not necessarily a result of the internal mammary node radiotherapy, Dr. Fowble pointed out. After controlling for potentially confounding factors including age, stage, grade, histology, lymphovascular invasion, ER status, type of surgery, and systemic therapy, there was no significant benefit to intentional inclusion of the internal mammary nodal region (HR = 0.95; 95% CI = 0.78–1.15; P = .57). Within the subset of patients with one to three positive nodes, women who received internal mammary nodal radiotherapy had a nonsignificantly better overall survival than women who did not (HR = 0.78; 95% CI = 0.56–1.09; P = .18). She added that while toxicity data were not presented, there are “clues” from other analyses that internal mammary node radiotherapy will contribute to toxicity. In her own practice, Dr. Fowble utilizes internal mammary node radiotherapy only when patients are known to have positive internal mammary nodes.

Study Describes Clinical Presentation of Breast Cancer The importance of annual screening mammography, not only in women older than 50 years but also in women aged 40 to 49, was evaluated in an analysis of a statewide breast cancer registry of 5,903 Michigan women.3 Mammography detected 65% of the breast cancers. Women younger than 50 accounted for 26% of all breast cancers and were equally likely to have had their cancer found by mammography as by clinical exam or breast self-exam (46% and 54%, respectively). When compared with patients with mammographically detected tumors, patients who presented with palpable masses presented at later stages (50% stage II vs 18%) and were more likely to receive chemotherapy

Notable Findings at the 2011 Breast Cancer Symposium ■■ In an analysis of patients from the British Columbia Cancer Agency,

radiation to the internal mammary nodes did not improve outcomes; the subset of women with one to three positive lymph nodes had a modest, nonsignificant improvement in survival.

■■ Value was demonstrated for annual screening mammography, as well

as clinical and breast self-exam, among women aged 40 to 49 in a large Michigan registry.

■■ Nomograms based on risk factors can predict a woman’s chance of developing lymphedema after axillary lymph node dissection.

(22.7% vs 15.7%) and mastectomies (45.8% vs 27.1%). The United States Preventive Services Task Force (USPSTF) recommended in 2009 against routine screening before age 50 and against teaching breast self-exam at any age, and maintained that the evidence on clinical breast exam was insufficient. According to these recommendations, 42% of the Michigan cohort may have been affected by these proposed screening recommendations. At a press briefing, Jamie Caughran, MD, of the Lacks Cancer Center in Grand Rapids, Michigan, declined to say whether the study contradicts the USPSTF guidelines, but offered, “You are less likely to need chemotherapy [with mammographically detected tumors], so we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40,” because registry population was that of women who had a diagnosis of breast cancer, unlike USPSTF guidelines that examine a screening population. Andrew Seidman, MD, of Memorial Sloan-Kettering Cancer Center, who moderated the press briefing, said that while debate will continue, this study speaks to another important consequence of screening: reduced need for chemotherapy.

Jamie Caughran, MD

“This is a very important gain, independent of any potential survival benefit,” he said.

Andrew Seidman, MD

Nomogram Predicts for Lymphedema A new set of nomograms based on risk factors can predict a woman’s chance of developing lymphedema after axillary lymph node dissection, Brazilian investigators reported.4 The researchers followed 1,054 patients with breast cancer who had axillary lymph node dissection, evaluating the occurrence of lymphedema according to several risk factors. They developed three possible models that could be used at different time points (preoperatively, within 6 months of surgery, and 6 months or more postoperatively). The models incorporated age, body mass index, number of neoadjuvant and adjuvant chemotherapy infusions, extent of axillary lymph node dissection, location of radiation therapy field, and the development of postoperative seroma and early edema. Within 5 years of axillary lymph node dissection, 30.3% of the women developed lymphedema. All the risk factors in the model were significantly associated with SEE PAGE 33 the occurrence of

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News

lymphedema and were accurate 70% to 74% of the time. The investigators have converted the models into free, user-friendly calculators that will become public once their results are published.

■

Disclosure: Drs. Olson, Fowble, Caughran, and Seidman reported no potential conflicts of interest.

cer treated with locoregional radiation after six years of follow-up. 2011 Breast Cancer Symposium. Abstract 81. Presented September 8, 2011. 2. Revesz E, Zalles CM, Ivancic D, et al: Relationship of recent pregnancy and cytologic atypia in the contralateral breast of patients with breast can-

cer. 2011 Breast Cancer Symposium. Abstract 149. Presented September 9, 2011. 3. Smith DR, Caughran J, Kreinbrink JL, et al: Clinical presentation of breast cancer: Age, stage, and treatment modalities in a contemporary cohort of Michigan women. 2011 Breast Cancer Sympo-

sium. Abstract 1. Presented September 8, 2011. 4. Bevilacqua JB, Kattan MW, Yu C, et al: Nomograms for predicting the risk of arm lymphedema after axillary dissection in breast cancer. 2011 Breast Cancer Symposium. Abstract 8. Presented September 8, 2011.

References 1. Olson RA, Woods R, Lau J, et al: Impact of internal mammary node inclusion in the radiation treatment volume on the outcomes of patients with breast can-

Using QR Codes

What role may MUC1 play in NSCLC

The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further 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.

Position your device in front of the code so that it fills about half your screen.

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1

The code will scan automatically.

If the scan is successful, you will be rerouted to the targeted link.

110718-140032

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904. 3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35. 4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399. 6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

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In the News Genitourinary Oncology

Physicians Can Help Patients Set Realistic Expectations for Sexual Functioning after Treatment for Prostate Cancer By Charlotte Bath

odels that can be personalized to predict erectile function of individual patients following treatment for early-stage prostate cancer have been developed and validated in a study involving a total of 2,940 men, and are ready for use in clinical practice, according to Martin G. Sanda, MD, the study’s principal investigator. The study was published in The Journal of the American Medical Association1 and reported by major media, including the Associated Press, and The New York Times, and National Public Radio. While some of the media reports focused on aggregate rates for losing or regaining erectile function, Dr. Sanda said that one of the major contributions of the study was the impact it would have on individual patients. “We now have options beyond the one-size-fits-all counseling to help men anticipate possible treatment side effects,” he stated. Dr. Sanda is Director of the Prostate

We now have options beyond the one-size-fitsall counseling to help men anticipate possible treatment side effects. —Martin G. Sanda, MD

Care Center at Beth Israel Deaconess Medical Center and Associate Professor of Surgery/Urology at Harvard Medical School in Boston. “Because there are multiple treatments that can be quite confusing to sort through, helping people make informed decisions by giving them information and making sure their preferences are considered, has been a tradition in prostate cancer,” Michael J. Barry, MD, commented in an interview with The ASCO Post. “But we could do even better, particularly with better data of the kind we got from Dr. Sanda and his colleagues.” Dr. Barry, who wrote an editorial2 accompanying the JAMA report, is Medical Director of the John D. Stoeckle Center for Primary Care Innovation at Massachusetts General Hospital and President of the Foun-

dation for Informed Medical Decision Making in Boston.

Predictive Models To develop the predictive models, Dr. Sanda and his colleagues at Beth Israel Deaconess Medical Center analyzed patient demographic and clinical data from a cohort of 1,027 men with previously untreated clinical stage T1 to T2 prostate cancer who received prostatectomy (n = 524), external-beam radiotherapy (n = 241), or brachytherapy (n = 262) as primary treatment at nine universityaffiliated hospitals. “Details of treatment, such as plan for nerve sparing during prostatectomy or neoadjuvant hormone therapy with radiation, were collected prior to treatment to enable predictive models based on pretreatment information,” the investigators wrote. Patient-reported outcome measures were collected by third-party telephone interviews before treatment and at 2, 6, 12, and 24 months afterward. The survey instrument was used to “tease out” detailed information on sexual functioning that went “beyond yes or no,” to include whether erections were firm enough for intercourse, and how the men would describe the quality of their erections during the past 4 weeks, Dr. Sanda explained. Sexual outcomes among these men were used to develop models predicting erectile function, and the models were then validated among 1,913 patients in a community-based cohort. “One of the things that we developed in parallel with this JAMA article was an office-based version of the quality-of-life instrument,” Dr. Sanda told The ASCO Post. “It’s basically a 1-page version formatted to allow physicians to score the patient’s function at the point of contact.” The combination of having the data from the study and an assessment tool that can be used in routine practice can empower physicians to offer more individualized information for patients asking about expected sexual functioning following treatment for prostate cancer. “Sometimes with everything that needs to be tackled in the decisionmaking process, counseling about what is to be expected, the various quality-of-

Expect and Encourage Questions from Your Patients

atients and physicians need to be active coparticipants in discussions about prostate cancer treatment: “patients, by asking questions and making sure that doctors know their preferences—for example, how important sexual function or control of urination is to them—and clinicians, by inviting patients into the decision,” noted Michael J. Barry, MD, Medical Director of the John D. Stoeckle Center for Primary Care Innovation at Massachusetts Michael J. Barry, MD General Hospital, Boston. “Maybe the entrée into that conversation is, ‘Let’s talk about some of the things that are important to you in this decision,’” he continued. “Clinicians can raise the issue that these treatments can in some circumstances reduce the risk of dying of prostate cancer, but there are side effects, and two of the big ones are problems with sexual function and problems with control of urination. Certainly offering data from the paper by Sanda and colleagues to the many men for whom sexual function will be an issue is a great idea.” Dr. Barry advised that the information on sexual functioning gleaned from this study should be presented along with information from randomized trials about other outcomes. “As we get more data on all these outcomes, we can synthesize that for men and really give them a good evidence-based overview of the pros and cons of the different treatment choices,” he said. Dr. Barry, who is also President of the Foundation for Informed Medical Decision Making Information, suggested that patients and physicians visit the foundation’s website at www.informedmedicaldecisions.org.

■

Disclosure:. Dr. Barry receives salary support as president and a board member of the Foundation for Informed Medical Decision Making. The Foundation receives project funding and royalties from Health Dialog. His institution receives grant support from the NIH.

life domains, cancer control issues, and all the complexities of prostate cancer, it can be hard to accommodate the complexities of sexuality,” Dr. Sanda said. “The questionnaire facilitates that.”

Influential Factors Factors identified as influencing the increased probability of functional erections following treatment included better pretreatment sexual functioning, younger age, lower prostate-specific antigen level, nerve-sparing surgery for those undergoing prostatectomy, and no use of adjuvant hormone therapy for patients receiving radiation. Among the men in the initial cohort who were sexually potent before treatment, erectile functioning at 2 years posttreatment was reported by 63% of men receiving brachytherapy, 58% after external-beam radiation, and 40% of the men undergoing prostatectomy. The authors noted that the limitations of the study “are related to its

observational design, introducing the possibility of selection bias by treatment.” Therefore, they stated “our predictions of erectile function are best suited to guide outcome expectations within treatment groups based on individual patient characteristics and do not provide conclusive evidence of treatment superiority.”

Active Surveillance Absent Another limitation of the study “was that no outcomes were provided by men who chose a watchful waiting or active surveillance approach,” Dr. Barry pointed out in his editorial. Dr. Sanda explained that he had requested additional funding to include active surveillance in a revised study, but that the National Institutes of Health had turned down his request. “One of the comments from the review panel was that it was not clear that active surveillance was actually an important or sizable portion of pros-

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Patient’s Corner

tate cancer care, which from my perspective, completely misses the boat,” Dr. Sanda recounted. “Maybe in 2008 it was not that obvious, but those of us in the field knew this was going to be a growing part of the picture, and I think today it is very, very relevant.” He estimated that about one-third to one-half of the patients with prostate cancer seen at the multidisciplinary clinic at Beth Israel Deaconess Medical Center are eligible for active surveillance, and about one-half of those patients opt for it. “Its acceptance is growing and probably appropriately so. There are a lot of unanswered questions and a need for further study.” Dr. Barry noted that patients “often have different time horizons” when considering side effects of treatment. “Some people tend to think, What’s going to happen to me tomorrow, or over the next couple of years? Other people are more concerned about 10 or 15

years in the future. So part of the decision between clinicians and patients is getting a sense of the time frame for those concerns. For the patient, the decision about prostate cancer treatment often comes down to this: Do I accept a pretty substantial risk of side effects sooner, with treatment, to prevent me dying of prostate cancer, not 10, but maybe 15 or 20 years down the line. Some people will want to make that tradeoff, but others won’t.”

■

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

References 1. Alemozaffar M, Regan MM, Cooperberg MR, et al: Prediction of erectile function following treatment for prostate cancer. JAMA 306:1205-1214, 2011. 2. Barry MJ: Helping patients make better personal health decisions: The promise of patient-centered outcomes research. JAMA 306:1258-1259, 2011.

Expect More Answers in the Future

“W

e are still following patients from the initial cohort,” reported Martin G. Sanda, MD, principal investigator of the study published in JAMA, “Prediction of Erectile Function Following Treatment for Prostate Cancer.” At a median follow-up now of about 6 years, “there is evidence that there might be some additional recovery of erections from year 2 to 3 in patients who underwent prostatectomy,” he said. “Conversely, with brachytherapy there might be conMartin G. Sanda, MD tinued deterioration of erectile functioning.” An extension study is “looking with greater granularity at the extent of planned nerve-sparing prostatectomy,” Dr. Sanda added. While the recently reported study compared only nerve-sparing vs no nerve-sparing, the extension study will separate out complete bilateral nerve-sparing from less complete nerve-sparing. Another focus of the extension study will be “whether robotically assisted laparoscopic prostatectomy changes the observed vs predicted outcome,” Dr. Sanda said.

Practitioner-specific Differences A still unanswered question is, to what extent do practitioner-specific differences affect the outcome? “In the case of surgery, surgeons might not just have different skill sets— they may have different management strategies, for achieving that balance between optimal cancer resection and optimal function preservation,” Dr. Sanda said. “That same question holds for radiation treatment, be it external-beam radiotherapy or seed-implant treatment,” he continued. “Whether variations between practitioners actually translate into significant variations in outcome in terms of sexuality is not yet known, but we are planning to look into that.” Those studies will involve both the original and extension cohorts. The Radiation Therapy Oncology Group (RTOG) has studies nearing completion of accrual “that will provide some helpful information in a randomized setting on the radiation side,” Dr. Sanda noted. “Specifically RTOG 0232 is randomly assigning patients to brachytherapy alone or brachytherapy combined with external-beam irradiation. That study is evaluating cancer control as well as quality-of-life endpoints. I think it is going to be an important study, and hopefully its results will be available in the next couple of years.” Disclosure: Dr. Sanda reported no potential conflicts of interest.

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Fear of the Unknown: Cancer Treatment Can Be Scarier than the Disease Itself By Diane Tavegia, as told to Jo Cavallo

wo years ago, I was feeling fine except for a nagging problem with severe constipation. I believed this was caused by some loperamide I had taken to quell the episodes of diarrhea I experienced following dinner at a local barbecue restaurant. When the symptoms persisted for a couple of months, I decided to see my doctor. Although I was 58 at the time, I had never had a screening colonoscopy, and an examination of my colon showed a tumor about 1 inch in diameter. A subsequent biopsy of the mass and surrounding tissue found that I had stage IIIB colon cancer and that the cancer had spread to 5 out of 17 lymph nodes. My doctor assured me that once I had surgery to remove 18 inches of my colon and the malignant lymph nodes, followed by an adjuvant regimen of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy to kill any errant cancer cells, I had a 71% chance of remaining cancer-free.

Comfort in Understanding Getting a cancer diagnosis is pretty frightening, I admit, but the prospect of having chemotherapy was even scarier. I envisioned poison being put into my body and wondered whether it would burn or hurt. The fear of the unknown was just overwhelming to me. When I mentioned to my oncologist that I was afraid of having chemotherapy, he explained what side effects I could expect—fortunately hair loss wasn’t among them—and asked one of his nurses to give me a tour of the treatment room. It was comforting to see people attached to IV poles sitting in chairs watching TV, chatting with their neighbors or reading and no one screaming in pain. When it came time for me to start my chemotherapy, to my relief, my nurse explained what I might feel once the infusion started. When she had to adjust the dosage of saline I was getting to coincide with the end of my FOLFOX treatment, she again explained what she was doing. Once I understood what was happening, I felt fine.

During the course of my 12 treatments, another nurse would occasionally be assigned to me—one who wasn’t as forthcoming in letting me know what she was doing.

Diane Tavegia

So when she made an adjustment to the infusion machine, for example, my sense of panic immediately returned. Was something wrong, I wondered? No matter what the situation, whether it’s a meeting with my oncologist to review my status, having a new diagnostic test, or getting chemotherapy, I just need to understand what’s happening. Patients with cancer have enough to worry about without having to second-guess the meaning of an unfamiliar sensation following a test or chemotherapy or a slight tick up or down of a particular result on a laboratory report.

Looking Ahead I’m very lucky. I’ve been cancer-free since 2009, and my doctor now tells me that the chance my disease will recur is just 5%. During my illness I remained positive and tried to get on with my life. Married for nearly 41 years, I’m blessed to have raised four children. We’ve always had a tight family, and battling cancer has only brought us closer together. During my cancer treatment, the other patients with colon cancer and I referred to our group as the Chemosabies. Sadly, I’m the lone survivor of that group. I feel I was spared for a reason, and I think that reason is to help other people going through similar circumstances. I’m going to do the best I can to live up to that goal.

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Ms. Tavegia, age 61, lives in Villa Rica, Georgia.

The ASCO Post | NOVEMBER 1, 2011

PAGE 36

JCO Spotlight Breast Cancer

BRCA Mutation Has Little Effect on Outcome with Neoadjuvant Therapy

retrospective analysis to determine the efficacy of neoadjuvant systemic therapy for breast cancer patients with and without BRCA mutations found the overall prognosis was similar in both groups of patients. “No signifi-

cant differences were noted in survival outcomes with respect to BRCA status and type of [neoadjuvant systemic therapy] received,” reported investigators from the University of Texas MD Anderson Cancer Center in Houston.1

The researchers identified 317 women with breast cancer who underwent clinical genetic testing for BRCA 1 and BRCA2 mutations and received neoadjuvant therapy. Of these, 237 tested negative for mutations (the “noncarriers”); 57

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were found to be BRCA1 mutation carriers and 23 to be BRCA2 mutation carriers. Overall, 26% achieved a pathologic complete response after neoadjuvant systemic therapy. “The [pathologic complete response] rate was significantly higher in BRCA1 carriers (46%) compared with BRCA2 carriers (13%) and noncarriers (22%; P = .001),” the investigators stated in the Journal of Clinical Oncology. BRCA status did not significantly influence overall or relapse-free survival. Estimated 5-year overall survival rates were 90% in the noncarrier group vs 87% in the BRCA1 group and 100% in the BRCA2 group. Estimated overall 5-year relapse-free survival was 74%, with 73% in noncarriers vs 72% SEE PAGE 33 in the BRCA1 group and 93% in the BRCA2 group. Patients who achieved a [pathologic complete response] had a better relapse-free survival (93%) than those who did not (68%). On multivariate analysis independent predictors of pathologic complete response were BRCA1 status, estrogen receptor (ER) negativity, and concurrent trastuzumab use. “Our data indicate that BRCA1 status and ER negativity are independently associated with higher [pathologic complete response] rates after neoadjuvant systemic therapy. Importantly, overall prognosis of breast cancer in BRCA mutation carriers is similar to that of sporadic breast cancers, despite their identification with initial poor prognostic features,” the authors concluded.

Accompanying Commentary The report “underscores the fact that it is still not known whether a distinct treatment approach should be recommended to women with BRCA1/2 mutation–associated breast cancer outside the context of a clinical trial,” Mark E. Robson, MD, of Memorial Sloan-Kettering Cancer Center, noted in an editorial commenting on whether BRCA1/2 mutations should influence treatment selection.2 He stated that excellent results of anthracyclinetaxane therapy in the study “support the continued use of regimens containing these agents in the treatment of early-stage breast cancer in BRCA1 carriers.

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References 1. Arun B, et al: J Clin Oncol 29:37393746, 2011. 2. Robson ME: J Clin Oncol 29:37243726, 2011.

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ASCOPost.com | NOVEMBER 1, 2011

PAGE 37

Health-care Policy

Tobacco Remains the Dominant Global Risk Factor Underlying Cancer By Margot Fromer

espite clear evidence that tobacco causes at least 18 types of cancer, as well as many other diseases, many people all over the world smoke or chew tobacco, or are exposed to secondhand smoke. Although smoking among Americans has declined slowly but steadily over the past 40 years, it remains the leading cause of premature death in the United States and many other countries. Even worse, the burden of tobacco use disproportionately affects populations that can least afford it: the poor and those without access to health care. Disparities exist along the entire tobacco continuum: initiation of use, access to and efficacy of cessation programs, success in quitting, and the resultant health consequences, especially cancer. At the 4th Annual Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, Roy S. Herbst, MD, Professor of Medicine and Chief of Medical Oncology, Yale Comprehensive Cancer Center, listed a number of risk factors for developing and dying from tobacco-related cancers: geography, economic status, educational status, gender, race, and access to health care. Although tobacco use has been reduced in recent years, it has hit a ceiling at 20% in the United States. Disparities exist among different racial groups in use and consequences of tobacco. For example, “The incidence and mortality of lung cancer is much higher for blacks even though they smoke at about the same rate as whites,” he noted. The meeting was held by the Association for Cancer Research (AACR) on September 18–21 in Washington, DC.

Demographics According to the World Health Organization, tobacco is responsible for 12% of male and 6% of female deaths worldwide.1 Michele Bloch,

Michele Bloch, MD, PhD

MD, PhD, Acting Chief, NCI Tobacco Control Research Branch, said that overall around the globe, 41% of men and 9% of women smoke, and it is estimated that the total number of tobacco-related deaths will rise from 6 million today to 8 million in 2030. “Moreover, the burden of tobacco mortality is shifting from high-income countries to low- and middle-income ones. It is predicted to double in the latter and continue to decline in the former in the coming years. And in many countries, including the United States, tobacco use is stratified by socioeconomic status and other demographic variables and is an important contributor to health disparities,” she said. The challenges of smoking prevention and cessation are legion, she added, not the least of which is the role of the tobacco industry to promote smoking.

American Association for Cancer Research on Tobacco Use

oy S. Herbst, MD, Professor of Medicine and Chief of Medical Oncology, Yale Comprehensive Cancer Center, serves as the Chairperson of the AACR Task Force on Tobacco and Cancer. At the 4th Annual Conference on the Science of Cancer Health Disparities, he said that the evidence against tobacco use is clear, incontrovertible, and convincing, as is the urgent need for immediate action. The task force recommends: Roy S. Herbst, MD ■■ Investment in tobacco-related research, especially potential harms ■■ Prevention of initiation of tobacco use in youth ■■ Evidence-based treatments for tobacco cessation ■■ Effective public communication to prevent, reduce, and eliminate tobacco use ■■ Reduction of disparities in tobacco use across social groups and in developing countries ■■ Monitoring of tobacco products, use, and tobacco-related disease ■■ Science-based regulatory framework to evaluate tobacco products ■■ Domestic and international economic policies that support tobacco control ■■ U.S. ratification of the World Health Organization’s Framework Convention for Tobacco Control ■■ Deterrence of tobacco industry efforts to encourage tobacco use

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Regulation Efforts K. Vish Viswanath, PhD

K. Vish Viswanath, PhD, Associate Professor, Department of Society, Human Development, and Health, Harvard University School of Public Health, explained that the media both exacerbate as well as stem tobacco use around the world, depending on the right health and political contexts. “We know that tobacco advertising and promotion increases its use, that exposure to depiction of smoking in movies causes youth to begin smoking, and that the media pay a significant role in what we know, learn, think, feel, and believe about tobaccorelated issues.” He added that tobacco-related information is always unequally distributed among individuals and groups. That is, some people have better access to information, pay more attention to it, learn more from it, and have more capacity to act on it. Moreover, determinants such as socioeconomic position, income, occupation, and the like are mediated by demographics such as age, gender, and race/ethnicity.

The World Health Organization’s Framework Convention for Tobacco Control (FCTC) signed by 172 countries—but not the United States—is the first international treaty designed to protect people from the devastating effects of tobacco. It has become a critical force in spurring adoption of evidence-based tobacco control policies around the world.

has already taken significant steps, including banning cigarettes with fruit or candy flavoring, prohibiting misleading labeling, restricting children’s access to tobacco products, and instituting the large, graphic warning labels on cigarette packages and advertisements that are scheduled to begin next year, said Cathy L. Backinger, PhD, Deputy Director for Research, FDA Office of Science, Center for Tobacco Products. “We are also assessing the public health impact of menthol in cigarettes, which are smoked in disproportionate numbers by children and blacks,” Dr. Backinger said. “In fact, 75% of blacks who smoke, smoke menthol cigarettes, and are less likely to quit smoking compared with non-menthol smokers.”

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Cathy L. Backinger, PhD

In June 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act, which provides FDA with broad regulatory authority over the manufacture, distribution, and marketing of tobacco products to protect the public health. The agency

Disclosure: Drs. Bloch, Viswanath, and Backinger reported no potential conflicts of interest. Dr. Herbst has served as a consultant for Eli Lilly and has received research funding from Bristol-Myers Squibb.

Reference 1. World Health Organization: Global health risks: Mortality and burden of disease attributable to selected major risks. Geneva, World Health Organization, 2009.

ASCOPost.com | NOVEMBER 1, 2011

PAGE 39

Opinion

Do We Need the USPSTF? without consulting the various specialist bodies and societies, and without alerting the people who take care of cancer patients (ie, us) that they were about to create chaos in the patient and nonpatient populations. As it turned out, some of their interpretations of data probably had merit, but their recommendations were widely condemned, several government leaders disowned them, and the whole episode ended up in confusion and uncertainty—a questionable use of my tax dollars.

example George Bosl’s time-honored observation that delay in diagnosis correlates directly with stage and inversely with outcome.2 They might have spoken about the importance of primary tumor stage and size with regard to outcome of local treatment,3 and the fact that uneducated populations present usually later than those with good health education. They might have quoted the NCI statement4 noting that patients with a history of testicular cancer are at increased risk of developing a second testicular cancer, and that this requires lifelong follow-up.

USPSTF Strikes Again….Twice

Responsibility for Context

Now the USPSTF has done it again…twice! First, its members decided to assess the utility of screening for testicular cancer. In a new guideline published by Annals of Internal Medicine,1 the Task Force announced that they still do not recommend screening for testicular cancer, as there are no new data, and gave this recommendation a D grading (defined as: “The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits”). They went on to note that the disease has a low incidence and that it is associated with favorable treatment outcomes, thus vitiating the need for any screening approach or further attention to the issue. Had there been real experts involved, after noting the lack of level 1 data on screening, they might have commented on the many papers that have given useful information on the topic—for

I’m not attempting to endorse screening for testicular cancer, because I think that the Task Force is probably correct that there are no level 1 or level 2 data to support its routine use. However, I do think that if you grab the bully pulpit (and expend taxpayer dollars), you have a responsibility to tell the complete story, applying the pulpit in a useful fashion that helps educate patients and their medical attendants. Young men should be made aware that testicular cancer exists and is curable, and that achieving cure of testicular cancer by chemotherapy for an advanced presentation (while an excellent advance in the past 25 years) is harder and associated with more morbidity than achieving cure by an uncomplicated inguinal orchiectomy for stage I disease. Whether screening and testicular self-examination are effective or not, it is clear that educated men who know about testicular cancer will have a better chance of cure, and with less morbid

continued from page 1

treatment. When a learned body makes a statement on the topic, if there are no level 1 data, one could at least expect a modicum of common sense in providing the big picture.

USPSTF Takes on PSA Not content with the above nonevent, they now have reconsidered the data that have been published on randomized screening trials for prostate cancer. This has been—and will be—covered ad nauseam in the medical and lay press, and I won’t delve into the details. It was appropriate for an independent body to review this issue for the government, although disappointing that none of the Task Force committee members apparently has specific expertise in this domain. They concluded that there is no role for the use of prostate-specific antigen (PSA) tests in routine screening for prostate cancer in the community.5 Based on the published trials, they are probably correct, as it is hard to endorse a screening test that does not produce an overall survival benefit. The reduction of deaths from prostate cancer per se in some of the trials is potentially very important, but is negated by the fact that the overall death rates are apparently the same in screened and unscreened patients. Some members of the urology community have dealt with this observation by questioning the constitution and execution of the trials—but it actually doesn’t work that way! You can’t just dismiss major randomized trials because you don’t like the results. If screening is to be used routinely in a community struggling to pay its medical bills, there needs to be published level 1 data that show an overall survival benefit at some time point. In fact, that may eventually be demonstrated, just by following the published trials for a longer period, as the natural history of prostate cancer from early detection is long. So why am I concerned? Once again, it is the pathway that is the problem. A group of non-experts have done a reanalysis of well published data, and have chosen to release draft guidelines, apparently with no consultation with any serious expert body—American College of Physicians, American Urological Association, perhaps even the ASCO Prostate Cancer Panel. The Task Force has repeatedly argued that such expert groups have conflicts of interest, and they don’t wish their pristine thoughts to be compromised by venal self-interest. Fair enough—so why could they

not send their draft review and recommendations for a response from professional societies, consider those responses, identify any possible flaws in their own arguments, and take advice on framing the information for public distribution? Instead they have, again, acted unilaterally, causing chaos among the medical profession, and more importantly, in the patient community. Of particular importance, potentially the most at-risk groups—African-Americans and men with family histories—are now even more confused about their appropriate management, and whether screening should have an ongoing role. These populations were not analyzed by our friends in the U.S. Preventive Services Task Force, but the blanket statements in the draft report seem to cover these patients nonetheless.

Dubious Benefit The U.S. Preventive Services Task Force seems, again, to have shown a capacity for ineptitude that has led to another waste of the money that we pay the government each year, without obvious benefit to the community at large. We are moving into a time of budgetary restraint by government. I wonder if congressional budgetary planners might consider an investigation of the function and composition of the USPSTF, and whether this panel really needs to exist. Moreover, the editors of Annals of Internal Medicine might consider whether government committees should have a free ride to publication.

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

References 1. U.S. Preventive Services Task Force: Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 154:483-485, 2011. 2. Bosl GJ, Vogelzang NJ, Goldman A, et al: Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet 2(8253):970-973, 1981. 3. Raghavan D, Vogelzang NJ, Bosl GJ, et al: Tumor classification and size in germ-cell testicular cancer: Influence on the occurrence of metastases. Cancer 50:1591-1595, 1982. 4. National Cancer Institute: Testicular cancer screening (PDQ®). Available at www.cancer.gov/cancertopics/pdq/ screening/testicular/patient/page3. 5. Chou R, Croswell JM, Dana T, et al: Screening for prostate cancer: A review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. October 7, 2011 (early release online).

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.8 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.9 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)]. 5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information]. 5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.10) in the full prescribing information]. When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. 5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. 5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. 5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy. 5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. 5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients. 5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally

suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Nonneoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. 5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. [see Use in Specific Populations (8.1)] 5.12 Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended. [see Postmarketing Experience (6.13)] 5.13 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. 6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively. These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment. 6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients. 6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation. 6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9. Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 (continued)

Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia 13.2 4.9 12.9 3.4 (ANC <1.0 x 109/L) Sweating 12.7 4.6 8.5 2.8 Other hemorrhage 12.3 6.7 13.3 6.1 Weight gain 12.0 1.0 10.6 0.6 Alopecia 11.9 4.3 14.8 3.2 Dyspepsia/heartburn 11.5 0.6 10.9 0.5 Neutropenia/granulocytopenia 11.5 3.1 16.1 4.1 Rigors/chills 11.0 4.6 10.2 3.0 Dizziness/lightheadedness 11.0 4.8 10.0 2.8 Creatinine increase 10.8 0.4 10.1 0.6 Flatulence 10.0 0.2 10.1 0.1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3 Lymphopenia 6.0 0.7 10.1 1.9

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Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10. Table 10 Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg 600 mg (n=73) (n=74) % % CTC Grades1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters – Anemia 3 0 8 1 – Thrombocytopenia 0 0 1 0 – Neutropenia 7 3 8 3 Biochemistry Parameters – Elevated Creatinine 0 0 3 0 – Reduced Albumin 3 0 4 0 – Elevated Bilirubin 1 0 1 3 – Elevated Alkaline Phosphatase 0 0 3 0 – Elevated SGOT (AST) 4 0 3 3 – Elevated SGPT (ALT) 6 0 7 1 1CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L) Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11. Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital Edema 47.2 14.5 1.2 0 Hemoglobin Decreased 46.9 27.0 0.6 0 Peripheral Edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal Pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight Increased 16.9 11.6 0.3 0 Liver enzymes (ALT) Increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil Count Decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White Blood Cell Count Decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 (continued)

Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Liver Enzymes (AST) Increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood Creatinine Increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight Decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation Increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal Distension 7.4 6.4 0.3 0.3 Back Pain 7.4 8.1 0.6 0 Pain in Extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial Edema 6.8 1.2 0.3 0 Blood Alkaline Phosphatase Increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal Pain Upper 6.2 6.4 0.3 0 Neuropathy Peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet Count Decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper Respiratory Tract Infection 5.0 3.5 0 0 Vision Blurred 5.0 2.3 0 0 (1)All adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. 6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec. Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema, Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased, Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis, Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease, General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis

Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including some fatalities 6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec. 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. Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/ myopathy, growth retardation in children Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including some fatalities 777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers. [see Dosage and Administration (2.9) in the full prescribing information]. 7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations. 7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin. 7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window. 7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 μM). Co-administration of Gleevec (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Gleevec pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Gleevec at doses >400 mg/day or the chronic use of concomitant acetaminophen and Gleevec. 888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)]. Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg). There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. 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.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information]. Table 12 Liver Function Classification Liver Function Test Normal Mild Moderate Severe (n=14) (n=30) (n=20) (n=20) Total Bilirubin ≤ULN >1.0-1.5x ULN >1.5-3x ULN >3-10x ULN SGOT ≤ULN >ULN (can be Any Any normal if Total Bilirubin is >ULN) ULN=upper limit of normal for the institution 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.9) in the full prescribing information]. Table 13 Renal Function Classification Renal Dysfunction Renal Function Tests Mild CrCL = 40-59 mL/min Moderate CrCL = 20-39 mL/min Severe CrCL = <20 mL/min CrCL = Creatinine Clearance 108OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. T2011-40 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

GLEEVEC® (imatinib mesylate) tablets are indicated for adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival.

Important Safety Information

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• GLEEVEC is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening, and be advised to report any rapid, unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. If severe fluid retention occurs, manage with diuretic therapy and withhold GLEEVEC until the event has resolved and then resume depending on the initial severity of the event • Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). Dose reduction or treatment interruption may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations) • Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated • Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed depending on the initial severity of the event • In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds • In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC • Bullous dermatologic reactions (eg, erythema multiforme and StevensJohnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction • Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients • Consider potential toxicities—specifically liver, kidney, and cardiac toxicity— and immunosuppression from long-term use • Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus • Growth retardation has been reported in children and pre-adolescents receiving GLEEVEC. The long-term effects of prolonged treatment with GLEEVEC on growth in children are unknown; therefore, monitoring of growth in children taking GLEEVEC is recommended • Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken • In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among patients receiving GLEEVEC. In Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), severe adverse reactions (NCI Grades 3/4/5), including abdominal pain (14%; 12%), edema (9%; 13%), fatigue

(12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%), were reported among patients receiving GLEEVEC • In the adjuvant treatment of GIST trials (GLEEVEC; placebo), severe (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), white blood cell count decreased (1%; 0%), and periorbital edema (1%; 0%), were reported among patients receiving adjuvant treatment with GLEEVEC • There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation • GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John’s wort, and enzyme-inducing anti-epileptic drugs, eg, phenytoin. The use of concomitant strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50% and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) • Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment

Common Side Effects of GLEEVEC Tablets • Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied* • In the adjuvant treatment of GIST trials, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), arthralgia (15%; 15%), and myalgia (12%; 12%)* • In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation* • Supportive care may help reduce the severity of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary • For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron • GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation • Patients should be informed to take GLEEVEC exactly as prescribed, and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose *For more detailed study information, please see full Prescribing Information. Please see brief summary of Prescribing Information on the following pages.

Reference: 1. GLEEVEC® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2011.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Printed in USA

9/11

GLI-1030000

Her struggle is fresh, but she can

move on with new confidence.

GLEEVEC for adjuvant therapy in KIT+ GIST ■

With a median follow-up of 14 months, more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (HR=0.398 [95% CI: 0.259, 0.610], P<0.0001): GLEEVEC 30/359=8.4%, placebo 70/354=19.8%1

■

Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism1

■

The most frequently reported adverse reactions at the time of discontinuation were edema, GI disturbances, fatigue, decreased hemoglobin, and rash1

GLEEVEC Significantly Improves RFS vs Placebo1 100

Patients with RFS (%)

ACTIVE TREATMENT PERIOD

NONTREATMENT FOLLOW-UP GLEEVEC (n=359)

Placebo (n=354)

0 0

Time to recurrence (months) Patients at risk: GLEEVEC

359

258

207

166

105

Placebo

354

243

186

138

A Phase 3, randomized, double-blind study of adjuvant GLEEVEC vs placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence or death from any cause.

Please see Important Safety Information and brief summary of Prescribing Information on the following pages.