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Genitourinary cancer 8

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Non–small cell lung cancer 2, 9

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VOLUME 3, ISSUE 1

In memoriam: Michael C. Perry, MD 21

JANUARY 1, 2012

ASCOPost.com

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

2011 San Antonio Breast Cancer Symposium

BOLERO-2: Everolimus Thwarts Resistance to Hormonal Therapy in Advanced Breast Cancer

Integrative Oncology: Essential to Cancer Care

By Susan London

A

dding an inhibitor of the mammalian target of rapamycin (mTOR) to hormonal therapy for advanced breast cancer effectively circumvents resistance, suggest updated results of the randomized BOLERO-2 trial. With a median follow-up of 12.5 months, the likelihood of disease progression or death among the 724 women enrolled (all of whom had resistance to prior hormonal therapy) was reduced by 56% when the mTOR inhibitor everolimus (Afinitor) was added to exemestane, Gabriel N. Hortobagyi, MD, reported at the 2011 San Antonio Breast Cancer Symposium. The time to disease progression was prolonged by 4.2 months. (ReSEE PAGE 21 sults were simultaneously pub-

By Barrie R. Cassileth, PhD

Everolimus is the first therapeutic agent that significantly enhances the efficacy of endocrine therapy in patients with hormone receptor–positive, HER2-negative advanced breast cancer.

D

lished in The New England Journal of Medicine.1) Adding everolimus increased rates of certain toxicities, but not to the detriment of quality of life. Markers of bone turnover all increased with exemestane alone, but decreased with the combination.

uring the 1960s and 1970s, the concept of an expanded approach to oncologic treatment encompassing “body, mind, and spirit” grew in patient popularity and morphed into two basic categories: “alternative” and “complementary” therapies. Together, these later became known by the acronym CAM, for complementary and alternative medicine. However, because the term “alternative therapy” often refers to unproven or disproved treatments that have no place in legitimate care, the CAM terminology tends to be misleading and confusing. “Integrative medicine”—or, in our case, “integrative oncology”—increasingly has replaced CAM as a preferred term, one that hopefully removes CAM’s negative connotations.

continued on page 4

continued on page 35

—Gabriel N. Hortobagyi, MD

Hematology for the Oncologist

Ruxolitinib for Myelofibrosis Therapy: A Good Start but a Long Road Ahead

Dr. Cassileth is Chief, Integrative Medicine Service, and Laurance S. Rockefeller Chair in Integrative Medicine, Memorial Sloan-Kettering Cancer Center, New York. She is the author of The Complete Guide to Complementary Therapies in Cancer Care (World Scientific, 2011).

By Animesh Pardanani, MBBS, PhD

F

ollowing a priority review process for orphan diseases, ruxolitinb (Jakafi) recently became the first drug to receive FDA approval for the treatment of intermediate- and high-risk myelofibrosis. Discovery in 2004 of the JAK2V617F mutation in a significant proportion of patients with BCR-ABL1–negative chronic

myeloproliferative neoplasms spurred the development of several small-molecule JAK inhibitors. Ruxolitinib was first out of the gate, with time from phase I testing to drug approval of approximately 4 years. Myelofibrosis can develop de novo (primary myelofibrosis), or following fibrotic transformation of polycythemia vera or essential thrombocythemia. Current drug therapy for myelofibrosis is suboptimal. Hydroxyurea is widely used to control symphis article begins a series of papers tomatic splenomegaly and leukocytoin The ASCO Post, guest edited by sis/thrombocytosis, but is ineffective Ayalew Tefferi, MD, Professor of Mediin advanced disease stages; it does not cine at the Mayo Clinic, Rochester, Minimprove constitutional symptoms (fenesota. The series is intended to provide ver, night sweats, bone pain, cachexia, guidance in managing hematologic isweight loss) and may exacerbate sues that may present in your patients anemia or other cytopenias. Anemia with cancer. responses are relatively infrequent

Hematology for the Oncologist

T

Ayalew Tefferi, MD

MORE IN THIS ISSUE Oncology Meetings Coverage San Antonio Breast Cancer Symposium�������������������������������������������������� 3 Chemotherapy Foundation Symposium����������������������������������������� 8, 9 Pan-Pacific Lymphoma Conference����� 10 Direct from ASCO��������������������������������������� 22 Conversation with Ronald A. DePinho, MD����������������������������� 29

continued on page 15

A Harborside Press® Publication


The ASCO Post  |   JANUARY 1, 2012

PAGE 2

JCO Spotlight Thoracic Oncology

Presurgical Gemcitabine/Cisplatin Improves Survival in Lung Cancer By Charlotte Bath

Editorial Board  James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

ASSOCIATE EDITORS

William T. McGivney, PhD National Comprehensive Cancer Network

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

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

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD Stanford University Medical Center

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

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

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado 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 John A. Fracchia, MD New York Urological Associates 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

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

reoperative gemcitabine plus cisplatin had a statistically significant impact on outcomes among patients with stage IIB/IIIA non–small-cell lung cancer in a phase III randomized study comparing surgery alone or surgery plus preoperative chemotherapy. The 3-year progression-free survival rates were 55.4% for patients receiving chemotherapy plus surgery vs 36.1% in patients having surgery alone (P = .002). “The survival benefit at 3 years for patients with IIB/IIIA disease was 23.4%,” the researchers reported in the Journal of Clinical Oncology.1 Actual enrollment totaled 270 patients with stage I, II, or IIIA disease randomly assigned at 45 European centers in 15 countries. “Enrollment was stopped early following the documentation of positive results from randomized trials of adjuvant chemotherapy, because the investigators felt it would be unethical to continue the study with a surgery only treatment arm,” the authors said. The positive effect of preoperative chemotherapy was “almost exclusively evident” among patients with IIB/IIIA disease. “Differences in the IB/IIA group were nonsignificant likely because of lack of power,” the researchers

wrote. Two other trials that suggested a benefit from preoperative chemotherapy found no difference in treatment effect by stage (the Southwest Oncology Group 9900 trial) or showed that patients with earlier stages of disease had a greater benefit from chemotherapy (the Depierre et al trial). The primary analysis of the total study population revealed an absolute difference of 5.1% SEE PAGE 21 in 3-year progression-free survival in favor of the chemotherapy-plus-surgery arm (52.9% vs 47.9%; P = .03) and 7.8% in 3-year overall survival also favoring chemotherapy plus surgery (67.6% vs 59.8%; P = .02). Grade 3/4 hematologic toxicity in the chemotherapy-plus-surgery arm was 32%. No patients in the surgery-alone arm experienced hematologic events. Grade 3/4 nonhematologic events occurred in 16% of patients receiving chemotherapy plus surgery and 11% of patients receiving surgery alone.

Reference 1. Scagliotti GV, et al: J Clin Oncol, ­November 28, 2011 (early release online).

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) 692-0805. Copyright ©2012 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.

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

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.

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

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: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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

Wendy McGullam, Director of Production Wendy@harborsidepress.com

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

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Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan London, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations Disclosure information available at ASCOPost.com.

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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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2011 San Antonio Breast Cancer Symposium CLEOPATRA Trial Finds Dual HER2 Blockade Improves Progression-free Survival in Advanced Breast Cancer By Susan London

W

omen with HER2-positive advanced breast cancer are much less likely to have disease progression or die when two agents are used instead of one to target the HER2 signaling pathway, investigators for the international phase III CLEOPATRA trial found. The 808 women studied were randomly assigned to treatment with docetaxel plus trastuzumab (Herceptin), combined with either placebo or the investigational antibody pertuzumab. Like trastuzumab, pertuzumab inhibits HER2 signaling, but it binds to a different epitope on the HER2 receptor and has a complementary mechanism of action. Results reported at the 2011 San Antonio Breast Cancer Symposium showed that the new combination was safe and the trial met its primary efficacy endpoint, with a prolongation of progressionfree survival by 6.1 months with the dual vs the single HER2targeted therapy, corSEE PAGE 21 responding to a 38% reduction in risk. (The results were simultaneously published in The New England Journal of Medicine.1)

Practice-changing Regimen? “The magnitude of this effect is unprecedented; this is the most positive trial in the history of patients with HER2-positive advanced disease and, for that matter, in patients with advanced breast cancer,” said principal investigator José Baselga, MD, PhD, Chief of the Division of Hematology and Oncology at the Massachusetts General Hos-

pital Cancer Center in Boston. “This new regimen may be practice-changing in HER2-positive first-line metastatic breast cancer,” he noted. “I am looking forward to having [pertuzumab] approved as soon as possible. This drug is going to help patients, so I think the sooner, the better,” he said in a related press conference. One day, certain women with HER2-

proval for adjuvant use came shortly before the trial began. “This raises some question as to whether [the findings] could be applicable to more heavily pretreated patients,” he said. Additionally, only about half of patients with estrogen receptor (ER)-positive disease had ever received hormonal therapy, and none was given during the trial. Benefit was somewhat less in these

The magnitude of this effect is unprecedented; this is the most positive trial in the history of patients with HER2-positive advanced disease and, for that matter, in patients with advanced breast cancer. —José Baselga, MD, PhD

positive disease may be treated with targeted therapy alone, according to Dr. Baselga. “In some patient populations down the line, we might not even need chemotherapy. If we could identify those patients who are so sensitive [to HER2 targeting], one could envision a future in which you could possibly combine trastuzumab and pertuzumab, and just forget about docetaxel,” he commented.

Pretreatment Issues Discussant C. Kent Osborne, MD, of the Baylor College of Medicine in Houston, cautioned that many of the patients studied had not received any prior chemotherapy, nor any prior trastuzumab because that drug’s ap-

Dual vs Single HER2 Blockade ■■ In the phase III CLEOPATRA trial of first-line treatment for HER2-positive metastatic breast cancer, a regimen of pertuzumab, trastuzumab, and docetaxel significantly prolonged progression-free survival, compared with a combination of placebo, trastuzumab, and docetaxel (18.5 vs 12.4 months; HR = 0.62; P < .001).

■■ The benefit seen in the pertuzumab-containing arm was not accompanied by an increase in cardiotoxic effects.

■■ Interim analysis suggested pertuzumab improved overall survival as well, although these data are still immature.

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

patients, possibly because they are less sensitive to chemotherapy and/or because ER was not targeted, he said. “One has to imagine what the effect of simultaneously targeting ER might have been,” given that that pathway “is an obvious potential escape pathway.” The bottom line, Dr. Osborne said, is that “for patients meeting the eligibility criteria, this [treatment] is clearly a new standard and should be practice-changing.”

Generalizability of Findings While finding the data both exciting and practice-changing, Hope S. Rugo, MD, of the University of California, San Francisco, also queried the generalizability of the trial’s findings. “We are going to have to understand what the applicability is to the U.S. and European patient populations, who now will almost universally have received trastuzumab in the adjuvant setting,” she commented. Women were eligible for the trial, which is the registration trial for pertuzumab, if they had centrally confirmed HER2-positive metastatic or unresectable locally recurrent breast cancer and had not received chemotherapy or biologic therapy for metastases. They were randomly assigned to double-blind treat-

ment with docetaxel (at least six cycles were recommended) and trastuzumab, plus either pertuzumab or placebo. The patients had a median age of 54 years, and the majority were from Asia and Europe. Approximately 78% had visceral disease. Only about 45% had received neoadjuvant or adjuvant chemotherapy, and just 10% had received trastuzumab. With a median follow-up of 19.3 months, patients in the pertuzumab group had a markedly longer independently assessed median progression-free survival compared with their counterparts in the placebo group (18.5 vs 12.4 months; HR = 0.62; P < .0001).

Consistent Benefit The benefit was consistent across subgroups, except for patients having nonvisceral disease. “I think this relates more to the difficulty … of measuring bone disease alone, which is what these patients [have],” Dr. Baselga speculated. Benefit appeared similar in patients who had and had not received prior trastuzumab. Results for overall survival, although based on an interim analysis and still immature, suggested that adding pertuzumab also reduced the risk of death (HR = 0.64; P  = .0053). Patients in the pertuzumab group had a higher response rate as well (80.2% vs 69.3%, P = .0011), mainly due to a higher rate of partial response. The added pertuzumab increased the rate of grade 3 or higher febrile neutropenia (14% vs 8%) and diarrhea (8% vs 5%). “Of note, the majority of these events occurred during the first six cycles, when docetaxel was being given,” Dr. Baselga pointed out. “There was no signal of any increased cardiac dysfunction at all in the pertuzumab arm.”

Disclosure: : Dr. Rugo has received research funding from Genentech, Novartis, Merck, and Pfizer. Dr. Osborne is on advisory boards for Genentech, Novartis, AstraZeneca, and GlaxoSmithKline. Dr. Baselga has served in a consultant or advisory role for Novartis.

Reference 1. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. December 7, 2011 (early release online).

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  |   JANUARY 1, 2012

PAGE 4

2011 San Antonio Breast Cancer Symposium BOLERO-2 continued from page 1

Paradigm Shift

“Everolimus is the first therapeutic agent that significantly enhances the efficacy of endocrine therapy in patients with hormone receptor–positive, HER2-negative advanced breast cancer. This observation provides additional treatment options for these patients,” maintained Dr. Hortobagyi, who is Chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “The demonstration that the combination of an endocrine agent with an mTOR inhibitor results in superior outcomes compared to endocrine therapy alone represents a paradigm shift in the management of advanced hormone receptor–positive breast cancer,” he added. As study patients were fairly heavily pretreated, an attendee asked whether less heavily pretreated patients would derive benefit. Dr. Hortobagyi replied that ongoing correlative studies of biospecimens should help identify patients most likely to benefit. “This is clearly an option for patients who have hormone receptor–positive metastatic breast cancer. I cannot tell you that previously untreated patients will not benefit. I cannot tell you that this is a phenomenon of just very heavily pretreated patients,” he said.

Lisa Carey, MD, ScM

Hope S. Rugo, MD

positive cases, in which [this combination therapy] has been kicked around for a number of years with preclinical and early clinical studies. It’s nice to see a well-designed study that really does place it firmly clinically.” Given the treatment his-

ADRENALS

Low-hanging Fruit “I am excited” about these findings, Lisa Carey, MD, ScM, of the University of North Carolina at Chapel Hill, commented in an interview. “It’s nice to see [research on] the PI3 kinase–mTOR pathway coming to fruition. And the low-hanging fruit for this are the ER-

BOLERO-2 ■■ Adding the mTOR inhibitor

everolimus to hormonal therapy with exemestane reduced the likelihood of disease progression or death by 56% in women with advanced breast cancer who had developed resistance to prior hormonal therapy.

■■ Median progression-free

survival was 7.4 months with exemestane/everolimus vs 3.2 months with exemestane/ placebo (P < 1 × 10–16).

PROSTATE TUMOR TISSUE

TESTES

■■ Adding everolimus to therapy increased the incidence of grade 3/4 stomatitis and hyperglycemia.

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

tory of the BOLERO-2 population, the findings may be relevant only to patients having acquired hormonal resistance, according to Dr. Carey. “I don’t know if this [combination] will help with de novo resistance,” she noted. Hope S. Rugo, MD, of the University of California, San Francisco, comment-


ASCOPost.com  |   JANUARY 1, 2012

PAGE 5

2011 San Antonio Breast Cancer Symposium ed, “the nice thing is that this [exemestane/everolimus combination] is an alloral regimen.” Toxicity was increased but manageable with dose adjustments. The reasons for the favorable effect on bone turnover are unknown, she observed. “This may be due to an independent effect of everolimus, or it could just be because patients were responding

better.… We’ll need to look at this in the future to better understand this impact.”

Study Rationale Explaining the trial’s rationale, Dr. Hortobagyi noted that activation of the mTOR pathway by means other than estrogen receptor (ER) signaling is a known mechanism of resistance to hor-

monal therapy. “So … we hypothesized that inhibition of mTOR simultaneously with estrogen deprivation would overcome resistance to endocrine therapy.” Postmenopausal women with metastatic or unresectable locally advanced breast cancer were eligible for the international phase III trial if they had ERpositive, HER2-negative disease and

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

had experienced recurrence or progression on a nonsteroidal aromatase inhibitor (letrozole or anastrozole). They were randomly assigned 2:1 to receive exemestane plus either everolimus or placebo. The patients had a median age of 62 years. Some 70% had measurable continued on page 6


The ASCO Post  |   JANUARY 1, 2012

PAGE 6

2011 San Antonio Breast Cancer Symposium BOLERO-2

Key Data

continued from page 5

The median duration of progression-free survival as assessed locally by investigators was 7.4 months with exemestane/everolimus and 3.2 months with exemestane/placebo (HR = 0.44; P < 1 × 10–16). “This exceeded by far our initial projections,” he commented. The findings were the same when

disease, and 84% had had documented sensitivity to a previous hormonal therapy. Slightly more than half had received at least three prior therapies for metastases, indicating “this is clearly a population where resistance has set in,” Dr. Hortobagyi said.

progression-free survival was instead assessed by central review. And the benefit was of similar magnitude in all patient subgroups, including those with differing numbers of prior therapies. Patients in the everolimus group also had better rates of response (12.0% vs 1.3%, P < .0001) and clinical benefit (50.5% vs 25.5%, P  < .0001).

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

Overall survival data are not yet mature, but the mortality rate thus far is 17.2% with exemestane/everolimus and 22.7% with exemestane/placebo. Not unexpectedly, patients in the everolimus group had higher rates of grade 3/4 stomatitis (8% vs <1%) and hyperglycemia (5% vs <1%). Pneumonitis with the drug was uncommon.

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

6

7

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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2011 San Antonio Breast Cancer Symposium Any impact of everolimus dose adjustments will need to be further assessed, according to Dr. Hortobagyi. “As with several other drugs that we have developed in the past, this drug has its challenges too, and you need to acquire experience with managing it. With that experience and with clear guidelines, it is a drug that can be managed very ef-

fectively.” The relative dose intensity for everolimus was 8.7 out of a possible 10. “That tells you that the great majority of patients did complete treatment until progression of disease,” he said.

Disclosure: Dr. Rugo has received research funding from Genentech, Novartis, Merck, and Pfizer. Dr. Hortobagyi is a consultant to Novartis, and his institution receives research

support for a clinical trial on which he is the national principal investigator. Dr. Carey reported no potential conflicts of interest

Reference 1. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. December 7, 2011 (early release online).

ZYTIGA™ (abiraterone acetate)

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.

SABCS 2011 Watch for continuing coverage of the 2011 San Antonio Breast Cancer Symposium in future issues of The ASCO Post.

CONTACT

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NOVEMBER 15, 2011

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

08Z11008 2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer By Caroline Helwick

T

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 in Stockholm.1 months. “Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity. SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster By Hagop M. Kantarjian, MD

T

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States. Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

O

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era What prompted your introduction into HIV/AIDS research and treatment? In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I thought he had Hodgkin disease, so I arranged a lymph node biopsy. I remember looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematologic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that others could not. To my surprise, he said this pathology was something he’d never seen before.

A small piece of information or a major breakthrough in one scientific discipline can translate valuable information into another scientific area.

—Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ................15, 24, 41, 49 53rd ASTRO Annual Meeting ............................. 8–11, 14, 30 AACR Basic Cancer Research Meeting ..................................... 39 AACR Conference on Cancer Health Disparities ..................................... 52 Direct from ASCO ....................................... 27

continued on page 20

A Harborside Press® Publication


The ASCO Post  |   JANUARY 1, 2012

PAGE 8

Chemotherapy Foundation Symposium XXIX Genitourinary Oncology

Highlights of Bladder Cancer Research Include Novel Agents and New Approach to Identifying Biomarkers By Alice Goodman

I

t is an exciting time for researchers involved in developing new therapies for bladder cancer. More agents are in clinical development, drugs with novel mechanisms and novel trial designs are being implemented, and functional collaboration is occurring in the field, according to Noah Hahn, MD, Assistant Professor at Indiana University Simon Cancer Center, Indianapolis. Dr. Hahn spoke about new therapies in bladder cancer at the Chemotherapy Foundation Symposium.

VEGF and mTOR Inhibition One area of research is the role of vascular endothelial growth factor (VEGF) inhibitor therapy in bladder cancer. Promising improved overall survival results have been observed in metastatic

bladder cancer patients with the use of the VEGF inhibitor bevacizumab (Avastin) in combination with platinum-based chemotherapy. One clinical concern is a high rate of deep-vein thrombosis seen in the phase II experience with this combination, Dr. Hahn said. The ongoing Cancer and Leukemia Group B (CALGB) 90601 phase III trial is comparing cisplatin/gemcitabine plus bevacizumab vs cisplatin/gemcitabine in patients with metastatic urothelial cancer. The key inclusion criteria for the trial are no prior chemotherapy in the metastatic setting, good performance status, and adequate kidney function (defined as a creatinine clearance above 50 mL/min). Mammlian target of rapamycin (mTOR) inhibition is another interesting

EXPERT POINT OF VIEW

A

lthough bladder cancer is among the most chemosensitive of the solid tumors, and a large proportion of patients will achieve objective tumor regressions on first-line therapy with conventional chemotherapeutic regimens, response durations are relatively short and outcomes with existing second-line therapies are modest at best, explained Matthew D. Galsky, MD, Director, Genitourinary Medical Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York. Matthew D. Galsky, MD “Randomized clinical trials in both the first- and second-line metastatic settings have demonstrated that a ceiling in efficacy has likely been reached with conventional cytotoxic drugs [in bladder cancer], particularly in unselected populations, and novel approaches are urgently needed,” Dr. Galsky continued.

Patient Selection Commenting on Dr. Hahn’s presentation, Dr. Galsky said that each of the approaches he described is likely to be most successful if clinical and/or pathologic characteristics can be used to select patients who are most likely to derive benefit. “In this regard, a few of the strategies outlined by Dr. Hahn that have reached clinical testing are particularly intriguing,” Dr. Galsky said. “The COXEN approach, which utilizes the publicly available gene-expression profiling data and drug sensitivity data from the NCI-60 cell line panel as a ‘Rosetta Stone’ to predict chemosensitivity of gene-expression–profiled bladder cancer samples using a computational algorithm, may ultimately allow ‘smarter’ use of our existing armamentarium of cytotoxics. The DN24-02 active cellular immune therapy may one day provide a noncytotoxic option for adjuvant therapy for patients with HER2expressing locally advanced bladder cancers. Finally, drugs targeting FGFR3, in patients with tumors harboring FGFR3 mutations, may provide proof of concept for the elusive molecular ‘Achilles heel’ in advanced bladder cancer,” he elaborated. However, he added that none of these approaches will advance treatment of bladder cancer without a concerted commitment by the medical community and patients to complete ongoing clinical trials. “This is historically among the largest barriers to improving outcomes in this disease,” Dr. Galsky stated. Disclosure: Dr. Galsky reported no potential conflicts of interest.

State of the Art in Bladder Cancer Therapy ■■ New approaches to the treatment of bladder cancer include use of bevacizumab, mTOR inhibitors, and immunomodulatory therapy.

■■ The COXEN model is a novel approach for identifying optimal therapeutic agents in bladder and other cancers through comparison of predictive gene-expression signatures in cell lines and patient tumor samples.

■■ Commitment to enrolling and completing clinical trials is needed to ensure advances in the field.

strategy being pursued; mTOR inhibitors have demonstrated single-agent activity in preliminary studies in metastatic bladder cancer. Ongoing trials in patients in the second-line metastatic, front-line metastatic, and BCG-refractory carcinoma in situ settings should give some idea of the potential role of this approach within the next year, Dr. Hahn said.

“This is one of the first randomized adjuvant therapy trials in bladder cancer to open in the past 10 years and is therefore an important trial to complete successfully,” Dr. Hahn said.

FGFR Inhibitors and Immunologic Approaches Fibroblast growth factor receptor 3 (FGFR3) is a potential target in bladder cancer, Dr. Hahn continued. Mutation in this gene is present in about twothirds of low-grade bladder cancer, but its biologic significance and exact role in the pathogenesis of muscle-invasive and metastatic bladder cancer are not clear. “We need to identify the correct subsets of patients with bladder cancer who can benefit from FGFR3-targeted approaches,” he said. Several FGFR inhibitors are in clinical development in the United States, but none have been approved by FDA yet, and none are targeting bladder cancer as their lead indication. In addition to inhibiting FGFR-mediated signaling, many of them are multitargeted tyrosine kinase inhibitors, Dr. Hahn explained. Thus far, dovitinib is the only drug with this property being studied in bladder cancer. Immunologic approaches similar to sipuleucel-T (Provenge) vaccine in prostate cancer include DN24-02, a vaccine being developed for bladder cancer that is directed to HER2, which is overexpressed in 25% to 58% of bladder cancers. A randomized phase II trial has been undertaken to compare DN24-02 vs standard of care following cystectomy in patients with HER2-positive highrisk urothelial carcinoma. The trial will evaluate overall survival, safety, and magnitude of the immune response induced following administration of DN24-02.

Noah Hahn, MD

Biomarker Identification Investigators in the field of bladder cancer are also exploring novel trial designs to determine which biomarkers may be useful in selecting therapy. A standard approach used in many studies is to embed biomarkers in clinical trials and then study them retrospectively to see which ones have potential for clinical use. A new model for identifying biomarkers, called the coexpression extrapolation algorithm (ie, COXEN model), is currently under study. This model uses expression microarray data to identify drug sensitivity in cancer cell lines. Geneexpression signatures from the cell lines are compared to an individual patient’s tumor gene expression to determine optimal therapy for the individual patient. “This is a radically different way to identify biomarkers. The SWOG [Southwest Oncology Group] has initiated the design of a COXEN-directed neoadjuvant chemotherapy trial,” Dr. Hahn said.

Disclosure: Dr. Hahn reported that his institution receives research support from Novartis.

Reference 1. Hahn N: New therapies in bladder cancer. Chemotherapy Foundation Symposium XXIX. Presented November 11, 2011.


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Chemotherapy Foundation Symposium XXIX Thoracic Oncology

Advances in Lung Cancer Treatment Show Incremental Benefits, but Room for Improvement Remains By Alice Goodman

N

ewer therapies for the treatment of non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) were discussed at the Chemotherapy Foundation Symposium. More inroads have been made in improving outcomes for patients with NSCLC than for those with SCLC, but there is still room for improvement in both types of disease.

Chandra Belani, MD

Non–Small Cell Lung Cancer The discovery of driver mutations for NSCLC is moving the field along, explained Chandra Belani, MD, Miriam Becker Distinguished Professor and Deputy Director, State Hershey Cancer Institute in Hershey, Pennsylvania.1 Therapies targeting EGFR mutation and ALK rearrangement have achieved incremental benefits in treating the disease, but lung cancer remains the leading cause of cancer death in the United States, Dr. Belani told listeners. Based on studies by the Lung Cancer Mutation Consortium, EGFR and KRAS are the most common mutations in patients with stage IV adenocarcinoma, among 10 driver mutations and rearrangements evaluated. These abnormalities, at least for now, appear to be mutually exclusive, since 97% of patients studied had only one mutation, Dr. Belani said. EGFR mutations can be used to select patients for treatment with erlotinib (Tarceva). “The current treatment paradigm is to test patients with adenocarcinoma for EGFR mutation and initiate first-line treatment with erlotinib if it is present,” Dr. Belani said. A second targeted approach in lung cancer is the use of the ALK and MET inhibitor crizotinib (Xalkori), which is approved for ALK-positive NSCLC. Other targeted therapies being developed for NSCLC include the investigational agents afatinib, MetMab, and ARQ 197. The combination of afa-

tinib (a HER1/HER2 inhibitor) plus cetuximab (Erbitux) shows promise in NSCLC patients with EGFR mutation who develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors.

State of the Art in Lung Cancer Treatment ■■ Two targeted approaches are approved for non–small cell lung cancer: erlotinib for EGFR-positive lung cancer and crizotinib for ALK-positive disease.

■■ Several drugs that target the HGF/MET pathway in different places show promise in NSCLC; among these are MetMab, ARQ 197, and crizotinib.

MET Inhibitors Several drugs in various stages of development target different points of the hepatocyte growth factor (HGF)/ MET pathway, explained Paul Bunn, MD, Dudley Professor at the University of Colorado Cancer Center in Aurora, Colorado.2 He focused his remarks at the Chemotherapy Foundation Symposium on MetMab and ARQ 197, as these are entering phase III studies. Gene amplification studies using FISH analysis have shown that tumors with high copy numbers of the MET gene are associated with a worse prognosis and account for about 4% to 10% of NSCLC tumors, Dr. Bunn explained. Theoretically, these tumors will respond to MET targeting. A large fraction of patients have high MET expression by immunohistochemical staining, and this subgroup derives the benefit from MET inhibitors. MetMab, an anti-MET monoclonal antibody, showed promising results in a phase  II study evaluating MetMab combined with erlotinib vs erlotinib alone in patients with high MET expression. However, patients with low MET expression had a worse outcome with the combination. “The reasons for worse outcome with low MET expression are unknown,” Dr. Bunn said. ARQ 197 is a small-molecule oral

Paul Bunn, MD

MET tyrosine kinase inhibitor that attaches to the tyrosine kinase domain inside the cell and prevents signaling. A randomized phase II trial found that ARQ 197 (now called tivantinib) plus erlotinib showed improved progression-free survival and overall survival

■■ Small cell lung cancer remains challenging to treat; novel approaches and vaccines have not proved successful.

compared with erlotinib alone in patients with nonsquamous histology, but not in those with squamous histology. A subset analysis showed that high MET gene copy number, wild-type EGFR status, and KRAS mutations predicted benefit from this strategy. Several randomized phase III trials are now in progress to study ARQ 197 plus erlotinib in patients with nonsquamous histology as well as in those with KRAS mutations. Responses to another MET inhibitor, crizotinib, have been reported in patients with adenocarcinomas harboring MET amplification. Other multitargeted tyrosine kinase inhibitors are also being studied in NSCLC, Dr. Bunn said.

Corey Langer, MD

Small Cell Lung Cancer Despite therapeutic advances in lung cancer generally, treatment of small cell lung cancer remains challenging, according to Corey Langer, MD, Director of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia.3 On a positive note, the incidence of SCLC is declining, but it is a rapidly progressing type of cancer, and even patients with limited-stage disease have a 5-year survival rate of only 25% at best. Novel agents and vaccines have not improved survival in limited-stage disease. Strategies under study for limited disease include the ongoing Cancer and Leukemia Group B (CALGB) trial and the ongoing European CONVERT trial

(Concurrent ONce-daily VErsus twicedaily RadioTherapy). CONVERT is comparing two schedules of early concurrent chemoradiation, one with oncedaily and the other with twice-daily administration of radiotherapy. For extensive SCLC (about twothirds of new patients) chemotherapy alone is the standard approach, with radiation reserved for palliation. Four to six cycles of etoposide plus cisplatin or carboplatin is the standard approach in North America. Japanese studies have shown improved survival with irinotecan plus cisplatin vs etoposide plus cisplatin, but U.S. and European investigators have not been able to replicate these results. Diarrhea is the major toxicity with the Japanese regimen. Topotecan is FDA-approved for the treatment of SCLC relapses, and oral topotecan appears to be as effective as intravenous topotecan in relapsed SCLC. Amrubicin achieved superior progression-free survival over topotecan in a phase III trial, but failed to yield an increase in overall survival. It is not FDA-approved. This agent appears to be more effective in chemoresistant than in chemosensitive patients.

Disclosure: Dr. Bunn has received consulting fees from Daiichi-Sankyo, Genentech/Roche, Pfizer, and Amgen. Dr. Langer has served on advisory boards for Abbott and Lilly. Dr. Belani reported no potential conflicts of interest.

References 1. Belani C: NSCLC: Personalized therapy and recent changes in treatment paradigm. Chemotherapy Foundation Symposium XXIX. Presented November 11, 2011. 2. Bunn PA: Novel agents in lung cancer: MetMab and ARQ 197. Chemotherapy Foundation Symposium XXIX. Presented November 11, 2011. 3. Langer CJ: SCLC: Novel agents and future directions. XXIX Chemotherapy Foundation Symposium. Presented November 11, 2011.


The ASCO Post  |   JANUARY 1, 2012

PAGE 10

Pan-Pacific Lymphoma Conference Hematology

Update on Novel Treatments for Peripheral T-cell Lymphoma By Matthew Stenger

A

t the recent Pan-Pacific Lymphoma Conference in Kauai, Hawaii, Julie M. Vose, MD, from the University of Nebraska Medical Center, Omaha, discussed novel treatments for peripheral T-cell lymphoma (PTCL).

phoma, 32% for PTCL–not otherwise specified, 32% for angioimmunoblastic lymphoma, 32% for all NK/T-cell lymphoma, and 14% for adult T-cell leukemia lymphoma.1

Chemotherapeutic Approaches

Julie M. Vose, MD

PTCL is a heterogeneous group of aggressive T-cell/natural killer (NK) cell non-Hodgkin lymphomas involving more-mature, post-thymic cells rather than immature T cells. Conventional treatment paradigms for aggressive Bcell non-Hodgkin lymphomas, including initial treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone), do not work well in PTCL. A recent report from the International T-Cell Lymphoma Project detailed survival rates in patients with PTCL, more than 85% of whom had received an anthracycline-containing regimen. Five-year overall survival varied significantly according to subtype (P < .001), with rates of 70% for ALK-positive anaplastic large cell lymphoma, 49% for ALK-negative anaplastic large cell lym-

Change in tumor volume from baseline

The antifolate agent pralatrexate (Folotyn), which is designed to preferentially accumulate in cancer cells, produced good responses in the phase II PROPEL study in patients with relapsed or refractory PTCL and, in 2009, became the first agent approved for use

PTCL subtypes were permitted in the study; the majority of patients (53%) had PTCL–not otherwise specified. The overall response rate was 28%, with a disease control rate of 49%; 75% of patients with measurable disease had a decrease in tumor size (Fig. 1). Seventy percent of responders achieved response during cycle  1. The mean durations of treatment were 234 days in responders and 112 days in all patients. The median duration of response was 9.4 months, and median overall survival was 14.7 months.

100% 75% 50% 25% 0% -25% -50% -75% -100% Patients

Fig. 1: Maximum change in tumor size from baseline in patients with relapsed/refractory PTCL receiving pralatrexate in the PROPEL study. Adapted with permission from O’Connor O, et al.3 Copyright © 2011 by the American Society of Clinical Oncology. All rights reserved.

in this setting.2 In this trial, 111 patients received pralatrexate 30 mg/m2 via IV push once weekly for 6 weeks supplemented with vitamin B12 1 mg IM every 8 to 10 weeks and daily oral folic acid 1.0 to 1.25 mg/d.3 A wide variety of

State of the Art in Peripheral T-cell Lymphoma ■■ Survival rates in patients with PTCL vary significantly by subtype, from 70% in ALK-positive anaplastic large cell lymphoma (ALCL) to 14% in adult T-cell leukemia lymphoma.

■■ Pralatrexate decreased tumor size in 75% of 111 patients with relapsed or refractory PTCL in the phase II PROPEL study.

■■ Bendamustine produced an overall response rate of 47%, with complete response or unconfirmed complete response of 29%, in 38 patients with relapsed PTCL.

■■ Etoposide plus CHOP improved 3-year event-free survival to 75.4%, compared with 51.0% for CHOP alone in a German study of 343 PTCL patients.

■■ In a phase II single-arm study, romidepsin produced an overall response rate of 26%, complete response rate of 13%, and stable disease rate of 25% in 131 PTCL patients.

■■ Lenalidomide produced an overall response rate of 30%, with median

progression-free survival of 96 days and median overall survival of 241 days in a phase II study in 24 patients with relapsed/refractory PTCL.

■■ Brentuximab vedotin produced an overall response rate of 86%, with a

median duration of response of 12.6 months, in a single-arm study of 58 ALCL patients who had received a median of two prior therapies.

Adverse events were consistent with the antifolate class. Grade 3/4 adverse events consisted of mucositis (18%/4%), dyspnea (7%/0%), and fatigue (7%/0%) among nonhematologic adverse events, and thrombocytopenia (14%/19%), neutropenia (14%/8%), and anemia (16%/2%) among hematologic toxicities. A recent study of bendamustine (Treanda) in 38 patients with relapsed PTCL who had received a median of two prior therapies showed an overall response rate of 47%, with complete response or unconfirmed complete response in 29%.4 Median duration of response was 157 days. Grade 3 or 4 adverse events included neutropenia (28 episodes) and thrombocytopenia (18 episodes). The German High-Grade NonHodgkin Lymphoma Study Group recently analyzed outcomes in 343 patients from its clinical trials who had one of four major PTCL subtypes (ALKpositive or ALK-negative anaplastic large cell lymphoma, PTCL–not otherwise specified, and angioimmunoblastic Tcell lymphoma) and were treated with

six to eight cycles of CHOP or etoposide plus CHOP.5 The researchers found that in patients aged 60 years or less with lactate dehydrogenase less than or equal to the upper normal value, the addition of etoposide (n = 103) improved 3-year event-free survival to 75.4%, compared with 51.0% for CHOP alone (n = 41; P = .003).

Targeted Therapies Romidepsin (Istodax) is a novel, potent bicyclic histone deacetylase (HDAC) inhibitor that was approved for use in cutaneous T-cell lymphoma in 2009, and for PTCL in 2011. In a phase II single-arm study, 131 patients with a wide variety of PTCL histologies received romidepsin at 14 mg/m2 via 4-hour infusion on days 1, 8, and 15 every 28 days. At least one prior systemic therapy had failed in this population. As judged by an independent review committee, the overall response rate was 26% with complete response in 13% of patients; stable disease was observed in an additional 25% of patients. The most common grade 3 or worse adverse events (≥  10%) were thrombocytopenia, neutropenia, infection, and anemia. In a recent phase I study of the multikinase inhibitor dasatinib (Sprycel) in patients with a variety of relapsed/ refractory non-Hodgkin lymphomas, complete response was observed in two patients with PTCL (the only complete responses observed in the study), with partial response in one PTCL patient. The implication that dasatinib may have been particularly effective in PTCL due to its inhibition of platelet-derived growth factor receptor alpha is being evaluated in a phase II trial. Lenalidomide (Revlimid) has been investigated in PTCL on the basis of its antiangiogenic activity.6 In a phase  II study in 24 patients with relapsed/refractory PTCL, it produced an overall response rate of 30%, with median progression-free survival of 96 days and median overall survival of 241 days. Grade 4 toxicities included thrombocytopenia in 33% and grade 3 toxicities included neutropenia in 21%, febrile neutropenia in 17%, and pain in 17%. The CD30-directed antibody-drug conjugate brentuximab vedotin (Adcetris) was recently approved for treatment of patients with systemic anaplastic large cell lymphoma in whom at least one prior chemotherapy regimen continued on page 14


Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

1


Introducing the first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.


EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9) for ZELBORAF patients vs 4.5 months (95% CI <0.1-11.7) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms respectively at the time of analysis.3

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 vs 1.6-1.7) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.0001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%) There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. 2011; 3:1-4. doi:10.3410/M3-8. 3. Data on file. Genentech, Inc.

© 2011 Genentech USA, Inc. All rights reserved. BRF0000653200 Printed in USA.

www.zelboraf.com


The ASCO Post  |   JANUARY 1, 2012

PAGE 14

Pan-Pacific Lymphoma Conference Peripheral T-cell Lymphoma continued from page 10

has failed.7 In a single-arm study, 58 patients who had received a median of two prior therapies were treated with brentuximab vedotin at 1.8 mg/kg via IV infusion over 30 minutes once every 3 weeks; 72% of patients had ALK-neg-

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Considerable evidence suggests involvement of JAK-STAT pathways in PTCL. JAK-STAT inhibitors in development include ruxolitinib ( Jakafi, which was recently approved to treat myelofibrosis), SB1518, curcumin, flavopiridol, resveratrol, stiprimod, and OPD-31121.

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

-

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritis 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were  ≥ 65 years. Elderly disorders patients (≥  65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

8

-

-

7

-

-

12

-

-

10

-

-

-

-

-

14

-

-

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422000 Initial U.S. Approval: August 2011 © 2011 Genentech, Inc

Expert Perspective “Patients with most subtypes of PTCL have a very poor prognosis with standard therapies,” Dr. Vose told The ASCO Post. “Although several new therapies have been approved by the FDA in the past couple of years for some types of PTCL, we have a lot of research to do in trying to find curative therapies for PTCL patients,” she said. “PTCL presents several challenges for treatment, including the need for improved induction regimens with combinations of standard and novel agents, the need for conolidation of the induction, and the possible need for a maintanance regimen to keep the patients in remission,” Dr. Vose continued. “Only collaboration by physicians and PTCL patients to enter clinical trials will allow us to gain the knowledge necessary to help current and future patients with PTCL and other rare types of lymphomas.”

Disclosure: Dr. Vose is a consultant or advisor for Celgene, Onyx, Seattle Genetics, and Spectrum Pharmaceuticals. She has received research funding from Allos Therapeutics, AstraZeneca, Bristol-Myers Squibb, Celgene, and Exelixis.

References 1. Vose J, Armitage J, Weisenburger D, et al: International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol 26:4124-4130, 2008. 2. FOLOTYN (pralatrexate) prescribing information. Allos Therapeutics, January 2011. Available at http://folotyn.com/ sites/default/files/FOLOTYN%20PI_ PPI_08192011.pdf. Accessed Nov. 18, 2011. 3. O’Connor O, Pro B, Pinter-Brown L, et al: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: Results from the pivotal PROPEL study. J Clin Oncol 29:1182-1189, 2011. 4. Damaj G, Gressin R, Bouabdallah K, et al: Preliminary results from an open-label, multicenter, phase II study of bendamustine in relapsed or refractory Tcell lymphoma from the French Goelams group: The BENTLY trial. Ann Oncol 22(supp 4):Abstract 126, 2011. 5. Schmitz N, Trümper L, Ziepert M, et al: Treatment and prognosis of mature T-cell and NK-cell lymphoma: An analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 116:34183425, 2010. 6. Dueck GS, Chua N, Prasad A, et al: Activity of lenalidomide in a phase II trial for Tcell lymphoma: Report on the first 24 cases. J Clin Oncol 27(15s):Abstract 8524, 2009. 7. ADCETRIS (brentuximab vedotin) for injection prescribing information. Seattle Genetics, Inc, August 2011. Available at http:// www.seagen.com/pdf/ADCETRIS_US_ PI.pdf. Accessed Nov. 18, 2011. Safety:10"

ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced >  1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc  >  500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both  >  500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. 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 a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

ative disease. The overall response rate was 86%, with a median duration of response of 12.6 months; some responses were ongoing at the time of analysis. Complete response occurred in 57% of patients, with a median response duration of 13.2 months. Tumor reduction was observedSafety:7" in 97% of patients .


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PAGE 15

Hematology for the Oncologist

Myelofibrosis Therapy continued from page 1

(10%–20%) and not durable with use of erythropoiesis-stimulating agents, androgens, low-dose thalidomide (Thalomid), danazol, and corticosteroids. Given that the median age at diagnosis in myelofibrosis is 65 years, few patients are eligible for allogeneic stem cell transplant.

Animesh Pardanani, MBBS, PhD

Clinical Trial Data Supporting Drug Approval Two randomized controlled trials were conducted: (1) the Controlled Myelofibrosis Study with Oral Janus-associated Kinase (JAK) Inhibitor TreatmentI (COMFORT-I), a randomized (1:1), double-blind study comparing ruxolitinib to placebo; and (2) COMFORTII, a randomized (2:1) open-label study, comparing ruxolitinib to best available therapy (no therapy or best available therapy was selected by the investigator on a case-by-case basis). Key eligibility criteria included patients with intermediate-2 or high-risk primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis who were JAK inhibitor therapy–naive, with adequate organ function and hematologic reserve (minimum platelet count = 100 × 109/L). The primary endpoint was the

International Prognostic Scoring System for Primary Myelofibrosis Five independent predictors of inferior survival are used to stratify patients into low, intermediate-1, intermediate-2, and high-risk categories based on the presence of 0, 1, 2, or 3 risk factors, respectively. The five independent predictors of inferior survival are:

■■ Age >65 years ■■ Hemoglobin level <10 g/100  mL ■■ Leukocyte count >25 × 109/L ■■ Circulating blast cells 1% or greater

■■ Presence of constitutional symptoms

proportion of patients with ≥ 35% reduction in spleen volume at week 24 and 48 of therapy (COMFORT-I and COMFORT-II, respectively), assessed by blinded review of spleen MRI or CT. The key secondary endpoints for COMFORT-I were durability of spleen response and changes in symptom burden. The ruxolitinib dose was 15 or 20 mg twice daily, depending on a baseline platelet count of 100 to 200 × 109/L or > 200 × 109/L, respectively.

tions (overall/grade 3 or 4 for ruxolitinib vs best available therapy) were thrombocytopenia (44.5%/7.5% vs 9.6%/4.1%) and anemia (40.4%/11% vs 12.3/4.1%). Nonhematologic adverse reactions of any grade (ruxolitinib vs best available therapy) included diarrhea (24% vs 11%) and peripheral edema (21.9% vs 26%). There was no significant difference in the number of deaths between the two arms in this study.

COMFORT-I Results

Patients with intermediate-2 and high-risk myelofibrosis have a median survival of about 3.6 and 1.8 years, respectively. In this category, the ideal patient for ruxolitinib therapy has symptomatic splenomegaly and/or significant constitutional symptoms with well-preserved blood counts, and is not a candidate for early allogeneic stem cell transplant based on the presence of very high-risk disease features. The risk-benefit ratio is less optimal for the patient whose main disease feature is severe anemia, with or without other concurrent cytopenias. Anemia responses are relatively infrequent (10%–20% based on phase I data) and are counterbal-

In COMFORT-I, 309 patients were randomly assigned—155 to ruxolitinib and 154 to placebo. At week 24, 65 patients (41.9%) met the primary endpoint in the ruxolitinib arm vs 1 patient (0.7%) in the placebo arm (P < .0001). At this time point, 68 patients (45.9%) vs 8 patients (5.3%) achieved a minimum 50% reduction in the total symptom score in the ruxolitinib and placebo arms (P < .0001). The most frequent adverse reactions (overall/grade 3 or 4 for ruxolitinib vs placebo) were thrombocytopenia (69.7%/12.9% vs 30.5%/1.3%), anemia (96.1%/45.2% vs 86.8/19.2%),

Risk-benefit Considerations

The ideal patient for ruxolitinib therapy has symptomatic splenomegaly and/or significant constitutional symptoms with well-preserved blood counts, and is not a candidate for early allogeneic stem cell transplant based on the presence of very high-risk disease features. neutropenia (18.7%/7.1% vs 4%/2%), bruising (23.2%/0.6% vs 14.6%/0%), dizziness (18.1%/0.6% vs 7.3%/0%) and headache (14.8%/0% vs 5.3%/0%). In the initial report (median followup = 32.2 weeks), there was no significant survival difference in the two study arms; with longer follow (median ~1 year), significantly fewer deaths were noted in the ruxolitinib arm (n = 13) compared to the placebo arm (n = 24), with a hazard ratio of 0.5 (P = .04).

COMFORT-II Results In COMFORT-II, 219 patients were randomly assigned—146 to ruxolitinib and 73 to best available therapy (including hydroxyurea in 47% and glucocorticoids in 16%). At week 48, 41 patients (28.5%) vs 0 patients met the primary endpoint in the ruxolitinib and best available therapy arms (P < .0001). At week 24, the corresponding response rates were 31.9% vs 0% (P < .0001). The most frequent hematologic adverse reac-

anced by a relatively high incidence of treatment-emergent cytopenias.1 The current studies are not adequately powered to assess for survival benefit; further, the COMFORT-II study, which more closely reflects the “real-world” scenario wherein patients with advanced, symptomatic myelofibrosis receive “best available therapy” (rather than no therapy/placebo, as in the COMFORT-I control arm) showed no survival benefit for ruxolitinib. Consequently, any claims to the contrary, particularly if supported by comparison with a historical cohort, are potentially misleading, and should not be used as a basis for counseling patients regarding this issue. Patients with intermediate-1–risk disease have a median survival of about 7.8 years. In such patients with symptomatic splenomegaly or constitutional symptoms (eg. severe pruritus) that are not responsive to conventional measures, ruxolitinib treatment may be cautiously considered, but only after a full and trans-

Projected Cost of Ruxolitinib Current estimates of the cost of ruxolitinib are $7,000 for a 30-day supply, equating to about $84,000 per year.

parent discussion regarding potential risks and benefits. Patients should be informed about the lack of data regarding long-term treatment-related toxicities and the risk of rare serious adverse events. Low-risk myelofibrosis patients have a median survival of about 17.5 years and are generally not candidates for ruxolitinib treatment, with rare exception, given that they risk more harm (eg. anemia, thrombocytopenia) than good from such therapy.

Drug Discontinuation Patients and physicians should be informed regarding what to potentially expect when discontinuing JAK inhibitors. Relapse of disease symptoms occurs virtually universally in this setting. In the case of ruxolitinib, symptoms recur within days and in some patients may be associated with hyperacute features (“ruxolitinib withdrawal syndrome,” which may be characterized by rapid spleen regrowth with splenic infarction, or cardiopulmonary distress).2,3 Patients should be closely monitored during the drug discontinuation process and follow a tapering schedule rather than abrupt cessation.

Long-term Findings With respect to response durability and long-term toxicity, only limited longterm data are available, so just a preliminary analysis is possible. Phase I data have been previously reported;1 recently, longterm data were separately analyzed for the Mayo Clinic (n = 51) and MD Anderson Cancer Center (n = 107) cohorts. Treatment discontinuation rates at the Mayo Clinic at 1, 2, and 3 years were 51%, 72%, and 89%; discontinuations were largely secondary to loss of response and/or toxicity. At MD Anderson, 54% of patients continue on treatment after a median follow-up of 32 months. At the time of drug approval, 75% and 67% of patients who achieved a ≥ 35% reduction in spleen volume on COMFORT-I and COMFORTII, respectively, maintained that response. Cytopenias are generally managed with dose reductions; this can be problematic in that it may lead to loss of response and, consequently, treatment discontinuation. In some cases, drug is discontinued based on patient preference continued on page 21


The ASCO Post  |   JANUARY 1, 2012

PAGE 16

News Gastrointestinal Cancer

Gastric Cancer Is on the Rise: Screening and Education Are Vital By Libia F. Scheller, PhD

G

astric cancer is diagnosed in nearly 1 million people globally each year and is responsible for 740,000 deaths, making it the second leading cause of cancer death in the world. According to the American Cancer Society, more than 21,000 people in the United States were diagnosed with gastric cancer and more than 10,500 died from the disease in 2010. Currently, more than 64,000 Americans are living with gastric cancer, and studies have shown that incidence of the disease is rising in younger males due to a number of underlying factors that, if caught early enough, may help cure it.

Libia F. Scheller, PhD

Limited research is being conducted on gastric cancer for a variety of reasons, including a lack of funding and only a few physicians specializing in the disease. Per cancer death, gastric cancer receives the least amount of federal funding. In addition, there are currently limited places where patients with gastric cancer can turn for information and support services. When a person is diagnosed with incurable cancer, it is vital to receive the best advice and therapy, but this is difficult for patients without adequate accessible useful resources.

Education Gap Too many patients with gastric cancer are not diagnosed early enough. According to a recent survey conducted online,a among 2,398 U.S. This survey was sponsored by Can’t Stomach Cancer through an educational grant and conducted online within the United States by Harris Interactive via its QuickQuery omnibus product from May 12–16, 2011, among 2,398 adults ages 18 and older. This online survey is not based on a probability sample, and therefore no estimate of theoretical sampling error can be calculated. For complete survey methodology, including weighting variables, contact Can’t Stomach Cancer at 954-475-1200. a

adults aged 18 or older who were asked what disease they think of first when someone has all the following symptoms: indigestion, heartburn, bloating, mild nausea, loss of appetite, weight loss, and filling up quickly even though hungry—“stomach cancer” was selected by only 5%. In addition, 93% of U.S. adults who visit doctors regularly have not inquired about screening for stomach cancer. “These results tell us that fundamental knowledge of gastric cancer symptoms and its risk factors are not in the public consciousness, despite the fact that it is one of the deadliest cancers and the number two cancer killer in the world,” said Debbie Zelman, founder of Can’t Stomach Cancer (see sidebar). “My goal is to help educate doctors, patients, families, and caregivers about this disease.”

‘Can’t Stomach Cancer’ Seeks to Jump-start Research, Raise Awareness

Screening Is Key

A sense of urgency from living with incurable cancer as well as the huge toll it took on her family motivated Debbie to want to make a difference for other patients with gastric cancer. In 2009, she started Debbie’s Dream Foundation—now known as Can’t Stomach Cancer—to not only jumpstart the research critical to fight this disease, but also to raise the awareness necessary to identify it early and perhaps even prevent it. This nonprofit organization also provides education, resources, and support internationally for patients, families, caregivers, and health-care providers on its toll-free hotline. For more information on the organization, call 954-475-1200 (office number) or 855-475-1200 (toll-free hotline), or visit www.CantStomachCancer. org.

“If one is familiar with the risk factors for gastric cancer, the risk can be reduced. If one is familiar with the symptoms of gastric cancer, it can be diagnosed early. Both these factors can make a big difference in the outcome,” stated Jaffer Ajani, MD, Professor of Medicine at The University of Texas MD Anderson Cancer Center in Houston, and Chair of the Can’t Stomach Cancer Medical Advisory Board. “Unfortunately, these survey results show that people in the United States are not familiar with the symptoms or risk factors of stomach cancer,” he said. “However, in Asia, where the disease is much more common, gastric cancer screening is the norm (for example, in Japan), like our screenings for prostate, breast, cervical, and colon cancers. When you consider that the presence of two of the highest precursors to stomach and esophageal cancers—Helicobacter pylori and acid reflux—can lead to early diagnosis, physician and public awareness become critical to success,” he stressed. “If you are Asian or Hispanic, you may want to be tested for H pylori through a simple breath test. The high incidence of acid reflux or gastroesophogeal reflux disease, which

I

n April 2008, Debbie Zelman was 40 years old. The mother of three young children, married to a physician, and a practicing attorney with her own firm, she began to experience a strange sensation upon swallowing food. She was told that this was due to stress, but a few months later, she became very tired, felt nauseous, and had night sweats and heartburn. Debbie knew that something was not right, so she sought additional medical advice that led to a diagnosis of stage IV gastric cancer. In an instant, her life changed dramatically. She learned that her cancer was inoperable and incurable, and she would need chemotherapy for the rest of her life. At the time of her diagnosis, Debbie was told there were very few effective treatment options for advanced gastric cancer because it is relatively uncommon in the United States, and her chances of being alive in 5 years were less than 5%. Debbie began to educate herself about this disease and to seek the best available care. Experts agree that all patients with advanced gastric cancer should be tested for the overexpression of HER2, which is found in about 22% of patients. Debbie tested positive for HER2 overexpression and underwent treatment with trastuzumab (Herceptin) and chemotherapy.

Making a Difference for Others

has been associated with the rise of gastroesophageal cancer in younger white males, is also an indicator,” continued Dr. Ajani.

Bridging the Gap In order to bridge the gap and increase awareness among patients and general health-care providers, we need to unite the medical and patient communities through education. On April 21, 2012, Can’t Stomach Cancer will host its 2nd Annual Stomach Cancer Patient Education Symposium in Hollywood, Florida, which will also be accessible via live webcast. Lecturers will include Dr. Ajani; Michael A. Choti, MD, MBA, a surgical oncologist at Johns Hopkins Kimmel Cancer Center; and Kathleen Wesa, MD, an integrative medicine

specialist at Memorial Sloan-Kettering Cancer Center. “The goal of this symposium is simple: Provide a forum to make the nation aware that stomach cancer is on the rise, and inform the public about who is at risk for the disease. Stomach cancer can be prevented and is curable if we just understand the symptoms and know enough to be screened. Screening will save lives,” stated Ms. Zelman.

Disclosures: Dr. Ajani is an advisor to Amgen; has research grants from Taiho, Novartis, BMS, Sanofi, ACT, Genta, and Amgen; and honoraria from Sanofi, BristolMyers Squibb, Taiho, and Amgen. Ms. Zelman reported no potential conflicts of interest.

Dr. Scheller is on the Board of Directors of Can’t Stomach Cancer and Medical Director at the Institute for Medical Education and Research, Miami.


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PAGE 17

In the Clinic

New Indication for Cetuximab in Squamous Cell Carcinoma of the Head and Neck By Matthew Stenger

In the Clinic 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

C

etuximab (Erbitux) was recently approved by the FDA for use in combination with platinum-based therapy plus fluorouracil (5-FU) for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck.1-3 Cetuximab has prior indications in combination with radiation therapy in locally or regionally advanced squamous cell head and neck cancer and in recurrent or metastatic head and neck cancer that SEE PAGE 21 has progressed after platinum-based therapy. It also has indications in colorectal cancer. The most recent approval is based primarily on results of a study conducted outside the United States in 442 patients with metastatic or locally recurrent squamous cell carcinoma of the head and neck who were not suitable for curative treatment with surgery or radiation. The study used a European Union (EU)-approved cetuximab rather than the U.S.-approved cetuximab (Erbitux). Erbitux provides approximately 22% higher exposure than the EU-approved cetuximab; these pharmacokinetic data, together with the results of the study conducted in Europe and other data using Erbitux establish the safety

Of Note Cetuximab inhibits ligand-binding to EGFR, thereby blocking phosphorylation and activation of receptor-associated kinases, which inhibits cell growth, induces apoptosis, and decreases production of matrix metalloproteinase and VEGF. In cells with mutated KRAS, however, activated KRAS protein appears independent of EGFR regulation. Cetuximab also enhances the activity of cisplatin and other chemotherapies.

and efficacy of Erbitux at the recommended dose. In this trial, the addition of cetuximab (n = 222) to platinum-based therapy plus 5-FU (n  = 220) significantly increased median overall survival from 7.4 to 10.1 months, representing a 20% reduction in risk of death (HR  = 0.80, P  = .034), and significantly increased median progression-free survival from 3.3 to 5.5 months, representing a 43% reduction in risk of disease progression (HR  = 0.57, P  < .0001). Objective response rates were 35.6% in the cetuximab group and 19.5% in the chemotherapy-alone group (P = .0001).

How It Works Cetuximab is an IgG1 monoclonal antibody that inhibits ligand-binding to the epidermal growth factor receptor (EGFR) on both normal and tumor cells. Binding of cetuximab to EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. In cells with activating KRAS mutation, however, the KRAS proteins are continuously active and are independent of EGFR regulation. Cetuximab also stimulates antibody-dependent cell-mediated cytotoxicity and enhances the activity of a number of chemotherapeutic agents, including cisplatin.

First-line Cetuximab in Head and Neck Cancer ■■ In addition to previous indications in head and neck and colorectal cancer,

cetuximab is now approved for combined use with platinum-based chemotherapy plus 5-FU in first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck.

■■ For the new indication, the recommended dose is 400 mg/m2 as a

120-minute IV infusion on the day that platinum-based therapy plus 5-FU is started, followed by a weekly dose of 250 mg/m2 over 60 minutes until disease progression or unacceptable toxicity.

fusion reactions. The infusion rate should be reduced by 50% for grade 1 or 2 or nonserious grade 3 infusion reactions. Cetuximab should be immediately and permanently discontinued for severe infusion reactions. In cases of severe acneiform rash, administration should be delayed by 1 to 2 weeks, and cetuximab discontinued at the fourth occurrence. The weekly dose should be reduced to 200 mg/m2 after the second occurrence and 150 mg/m2 after the third. Cetuximab should be administered via infusion pump or syringe pump and through a low protein-binding 0.22-micrometer in-line filter.

Of Note Cetuximab carries a boxed warning for infusion reactions and cardiopulmonary arrest. Serum electrolytes, including magnesium, potassium, and calcium, must be carefully monitored during and after cetuximab administration.

How It Is Given

Safety Profile

For the new indication, the recommended dose is 400 mg/m 2 as a 120-minute IV infusion, with a maximum rate of 10 mg/min, on the day that platinum-based therapy plus 5-FU is started. The infusion must be completed 1 hour prior to beginning platinum-based therapy plus 5-FU. The subsequent weekly dose is 250 mg/m2 over 60 minutes until disease progression or unacceptable toxicity. Patients should be premedicated with an H1 antagonist (eg, diphenhydramine, 50 mg) IV 30 to 60 minutes before the first dose of cetuximab; premedication for subsequent doses depends on clinical judgment and presence/severity of prior in-

Cetuximab carries a boxed warning for infusion reactions and cardiopulmonary arrest. Serious infusion reactions occurred in approximately 3% of patients in clinical trials, with fatal outcome in less than 1 in 1,000 cases. In patients with squamous cell carcinoma of the head and neck receiving cetuximab, cardiopulmonary arrest or sudden death occurred in 2% of those receiving radiotherapy and in 3% of those receving platinum-based therapy plus 5-FU. Serum electrolytes, including magnesium, potassium, and calcium, must be carefully monitored during and after cetuximab administration. In the trial supporting the current indication, the most common

adverse reactions (≥ 25%) in patients in the cetuximab group were nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia; conjunctivitis occurred in 10%. Other adverse reactions, sometimes severe, caused by cetuximab included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia. Death attributed to cardiovascular event or sudden death was reported in 3.2% of the patients in the cetuximab group and in 1.9% in the chemotherapy alone group.

References 1. U.S. Food and Drug Administration: What’s New from the Office of Hematology Oncology Products: Cetuximab. Available at http://www.fda.gov/AboutFDA/ CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm278957.htm. Accessed December 7, 2011. 2. ERBITUX® (cetuximab) injection, for intravenous infusion, prescribing information. ImClone LLC, a whollyowned subsidiary of Eli-Lilly and Company, and Bristol-Myers Squibb Company, November 2011. Available at http:// packageinserts.bms.com/pi/pi_erbitux. pdf. Accessed December 7, 2011. 3. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or 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).


ASCOPost.com  |   JANUARY 1, 2012

PAGE 21

In Memoriam

Michael C. Perry, MD, 1945–2011

M

ichael C. Perry, MD, a renowned cancer clinician, educator, researcher, and administrator at the University of Missouri, Columbia, for more than 35 years, passed away October 23, 2011, after a long and courageous battle with polycystic kidney disease and cancer. He was 66. Dr. Perry served as Director of Hematology and Medical Oncology, Chair of the Department of Internal Medicine, and a Senior Associate Dean at the University of Missouri School of Medicine. He also was the Nellie B. Smith Chair of Oncology, Medical Director of Ellis Fischel Cancer Center, and Medical Director of Clinical Trials for the University of Missouri’s Institute for Clinical and Translational Science. He became a Professor Emeritus in 2010. A past member of ASCO’s Board of Directors and a member of several professional societies, Dr. Perry was also a member of the FDA’s Oncology Drug Advisory Committee. He was dedicated to the Cancer and

Leukemia Group B (CALGB), an NCI-designated clinical research group, and served as Chair of its membership committee for more than 30 years. Dr. Perry also was an active member of the American Medical Association and Missouri State Medical Association. He served as President of the Southern Association for Oncology, Chair of the State of Missouri Organ Donor Advisory Committee, and President of the Boone County Medical Society. Editor of the books Toxicity of Chemotherapy and The Chemotherapy Source Book, Dr. Perry published more than 150 research papers and nearly 50 book chapters. He also held editorial positions at the Journal of Clinical Oncology, Seminars in Oncology, and Contemporary Oncology. Dr. Perry attended medical school at Wayne State. He then completed an internship and residency in internal medicine, as well as fellowships in hematology and oncology at the Mayo Clinic. He re-

Myelofibrosis Therapy

kines, but a modest and variable effect on circulating JAK2V617F allele burden.

continued from page 15

if treatment benefit is considered too modest to justify continued treatment, particularly when a new requirement for red cell transfusions develops.

Mechanisms of Action There are two potential mechanisms of ruxolitinib in myelofibrosis: (1) inhibition of constitutively active JAK-STAT signaling (that develops as a consequence of JAK2 mutations or other phenocopy mutations such as MPL, LNK and CBL), with direct inhibition of clonal myeloproliferation (accordingly, presence or absence of JAK2V617 does not influence the therapeutic response to ruxolitinib); and/ or (2) downregulation of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, via ruxolitinib’s JAK1 inhibitory properties. Suppression of the secondary, paraneoplastic, chronic inflammatory state in myelofibrosis may improve constitutional symptoms and indirectly control the underlying clonal myeloproliferation. Current data favor the latter as the dominant mechanism for ruxolitinib’s activity in myelofibrosis. Specifically, phase I data show potent suppression of cyto-

Michael C. Perry, MD

ceived a master’s of science degree in medicine from the University of Minnesota in 1975, when he joined the faculty at the University of Missouri. He is lovingly remembered by his family—wife Nancy; daughter Rebecca Perry Magniant, her husband Stanislas, and daughters Lucie and Charlotte, all of Paris, France; and daughter Katherine Perry Harris, her husband Jeff, and daughter Grace, all of Columbia. He also is survived by a brother, Paul Perry, of Taylor, Michigan, and numerous nieces and nephews.

USING QR CODES

Disclosure: Dr. Pardanani has served as Principal Investigator/Co-investigator for clinical trials that received institutional support (free drug and funding) from Incyte, sanofi-aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen and Cytopia have also provided support for laboratory studies relevant to clinical trials. Dr Tefferi has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen, Cytopia, and YM BioSciences have also provided support for laboratory studies relevant to clinical trials.

References 1. Verstovsek S, Kantarjian H, Mesa R, et al: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363:1117-1127, 2010. 2. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 365:1455-1457, 2011. 3. Tefferi A, Pardanani A: Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 86:1188-1191, 2011. Dr. Pardanani is Assistant Professor of Medicine, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.

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


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Direct from ASCO

Conquer Cancer Foundation Programs for Medical Students and Residents Support Diversity in Oncology Workforce

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he Conquer Cancer Foundation funds two programs, the Medical Student Rotation (MSR) and the Resident Travel Award (RTA), to facilitate the recruitment and retention of individuals from populations underrepresented in medicine to cancer careers, with a special focus on the development of clinical practitioners and investigators. The MSR and RTA were originally created as part of a collaboration between the Conquer Cancer Foundation, ASCO, and Susan G. Komen for the Cure®, with Komen funding these awards from 2009 to 2011. The Conquer Cancer Foundation recently had the chance to catch up with some of the 2009 MSR and RTA recipients to learn how the award cemented their interest in pursuing careers in oncology.

Past Recipients According to 2009 MSR recipient Kenisha Pemberton, a medical student at The Florida State University, Tallahassee, the greatest benefit of receiving the MSR was the “unique opportunity to work alongside leading pe-

RTA recipient, is currently working as an oncology fellow at Dana-Farber Cancer Institute/Massachusetts General Hospital, Boston. He said, “receiving the RTA was a wonderful experience for which I was and am very grateful to have had.” He added that the greatest benefit

diatric hematologists/oncologists.” Her advice to those considering applying for the MSR is “go for it … If you don’t apply, you will never receive this award … but if you do, you may have the unique opportunity to gain a wealth of information from leading oncologists.” Andy Aguirre, MD, PhD, 2009

of receiving the RTA “was a chance to go to the ASCO meeting and experience the larger oncology community. It was a really amazing opportunity.” Since receiving his RTA, Dr. Aguirre has received a fellowship to attend the Merrill Egorin Cancer Pharmacology course and he hopes to obtain additional re-

Weekly Online Polls Help Define Key Concerns of ASCO Members

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SCO members now have the opportunity to help the Society gather information and opinions about important cancer policy issues. ASCO in Action, ASCO’s revamped policy news website (http://ascoaction.asco.org), features weekly polls designed to gauge the views of ASCO members on a variety of topics related to their practice, patient care, or research. Each quick poll is designed to take less than a minute to fill out and submit, with just one or two questions. Polls have asked about topics including oncology drug shortages, the effect on practices of a reduction in the Medicare average sales price (ASP) of oncology drugs, and what guidance providers are seeking on the late effects of cancer care. The site’s recent poll on drug shortages helped ASCO learn more about the size and scope of the problem. “These snapshot polls will help ASCO get feedback about the top-

ics of most concern to our members,” said ASCO Government Relations Committee Chair Richard L. Schilsky, MD. “This feature is so new that many members don’t know about it yet. We hope more will participate by going to ASCO in Action frequently or subscribing to the website using an RSS reader to get e-mail updates.” ASCO in Action, updated almost daily by ASCO communications staff, provides members with important policy news covering the range of issues that the Society follows, from access to care to oncology workforce concerns. As a news site, ASCO in Action can be subscribed to by using an RSS reader to receive automatic updates. Also, readers on Twitter can receive updates from the site’s Twitter handle, @ascoaction.

© 2012. American Society of Clinical Oncology. All Rights Reserved.

search funding during his fellowship. Another recipient of the 2009 RTA, Zanetta Lamar, MD is currently in her second year as an oncology fellow at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina. She said, “receiving the travel award solidified my decision to pursue an oncology career. The greatest benefit was attending the ASCO meeting, speaking candidly with leaders in the field of oncology, and networking with future colleagues.” The Conquer Cancer Foundation of ASCO is currently accepting applications for the 2012 Medical Student Rotation and Resident Travel Award programs. Apply online by January 9, 2012. Questions? E-mail grants@ conquercancerfoundation.org

© 2012. American Society of Clinical Oncology. All Rights Reserved.

Young Investigator Award Renamed to Honor ASCO Founder Jane C. Wright, MD

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t the 2011 Annual Meeting, the Conquer Cancer Foundation renamed one of its annual awards to honor the legacy of one of ASCO’s groundbreaking founders. The Jane C. Wright, MD, Young Investigator Award (YIA) recognizes Dr. Wright’s leadership at ASCO, her contributions to the field of oncology, and her dedication and passion for finding a cure for cancer. The YIA is supported by the ASCO and Conquer Cancer Foundation Boards of Directors, and the first recipient was selected and honored during the Conquer Cancer Foundation Grants and Awards Luncheon at the Meeting. Though all of ASCO’s founders have immeasurably impacted the field of oncology, Dr. Wright’s story—as one of the few African-American female oncologists in the country at the time—is uniquely inspiring.

Breaking Barriers in Medicine Dr. Jane Wright graduated with honors from New York Medical College, interned at Bellevue Hospital, and completed her residency at Harlem

Jane C. Wright, MD

Hospital. She went to work with her father, Dr. Louis Tompkins Wright, who was Director of the Cancer Research Foundation at Harlem Hospital. At Harlem Hospital, Dr. Jane Wright performed patient trials in chemotherapy, which was still mostly experimental. In 1949, the two began testing a new chemical on human leukemias and cancers of the lymphatic system. Several patients who participated in the trials had some degree of remission. Following Dr. Louis Wright’s death in 1952, Dr. Jane Wright was appointed head of the Cancer Research Foundation at the age of 33. In 1955, Dr. Wright became an Associate Professor


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of Surgical Research at New York University and Director of Cancer Chemotherapy Research at New York University Medical Center and its affiliated Bellevue and University Hospitals. During her career, Dr. Wright analyzed a wide range of anticancer agents, explored the relationship between patient and tissue culture response, and developed new techniques for administering cancer chemotherapy. In 1967, she was named Professor of Surgery, Head of the Cancer Chemotherapy Department, and Associate Dean at New York Medical College. At a time when African-American women physicians numbered only a few hundred in the entire United States, Dr. Wright was the highest-ranking African-American woman at a nationally recognized medical institution. While pursuing private research at the New York Medical College, she implemented a new comprehensive program to study stroke, heart disease, and cancer, and created another program to instruct doctors in chemotherapy. In 1971, Dr. Jane Wright became the first woman President of the New York Cancer Society. She retired in 1987. During her 40-year career, Dr. Wright also published numerous papers on cancer chemotherapy and led delegations of cancer researchers to Africa, China, Eastern Europe, and the Soviet Union.

Dr. Wright’s Lasting Legacy: The Young Investigator Award Since its creation in 1984, the Young Investigator Award has helped launch the careers of a number of promising investigators, many of whom have become leaders in the oncology community and their fields. YIAs are intended specifically for investigators at the beginning of their careers, during the transition from a fellowship program to a faculty appointment. The first recipient of the Jane C. Wright, MD, YIA is Jung-min Lee, MD, a fellow at the NCI. Dr. Lee, with guidance from her mentor Elise C. Kohn, MD, plans to focus her research project on examining sequence-specific DNA damage with PARP inhibition and carboplatin in women’s cancers. She will investigate the best schedule for administering carboplatin with an experimental drug, olaparib, a PARP inhibitor. PARP—polyADP ribose polymerase—is a protein that is involved in DNA damage repair. DNA repair is beneficial in normal cells, promoting

healthy cell growth and proliferation. Studies have suggested that cancer cells may use the PARP enzyme-dependent DNA repair pathway to their growth and survival advantage. PARP inhibitors reduce DNA repair, leaving cancer cells susceptible to death. It is also suggested that cancer cells deficient

in normal DNA repair, such as those in patients with germline BRCA1 or BRCA2 mutations, will be selectively susceptible to PARP inhibition. For more information about Dr. Wright and the award, please view a short video “Paying Tribute to ASCO Founder Jane C. Wright, MD,” which

can be found online at: http://www. conquercancerfoundation.org/ foundation/Cancer+Professionals/ Grants+%26+Awards/ Researcher+Spotlights

© 2012. American Society of Clinical Oncology. All Rights Reserved.

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

37%

changed

63% confirmed

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)


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Direct from ASCO

Philanthropy Spotlight

ASCO President Michael P. Link, MD, Joins Colleagues in Honoring a Friend and Touching the Future through Philanthropy

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s an active member of ASCO, and as a leader of the Society in recent years, ASCO President Michael P. Link, MD, has a long history of giving to the Society-affiliated Conquer Cancer Foundation. “Our family has always felt that it’s a good thing to support,” he said. “The Foundation supports initiatives that we care about—from clinical and translational research, to ASCO’s educational programs, to the Young Investigator Awards that are so crucial to building our talent pipeline in cancer care and research.”

Michael P. Link, M

As a member of the ASCO Board of Directors, Dr. Link contributed generously to the Young Investigator Award, which is jointly funded by the Boards of Directors of ASCO and the Conquer Cancer Foundation. Then, last summer—just after he assumed the ASCO presidency—a personal and professional loss further intensified his relationship with philanthropy. James B. Nachman, MD, a Professor of Pediatrics at the University of Chicago and an internationally renowned pediatric cancer expert, died suddenly last June while on an annual rafting trip with former patients in the Grand Canyon. Dr. Link—who is the Lydia J. Lee Professor in Pediatric Oncology at Stanford University– is one of a group of pediatric oncologists who have established the James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology to celebrate the memory of one of their own.

Establishing an Enduring Legacy “Jim was well-known, well-liked, and a really good guy in addition to being a great physician and scien-

tist,” Dr. Link recalled. He initiated a number of important studies and made significant contributions to the field of pediatric oncology. “He was a friend as well as a colleague and highly regarded in the international pediatric oncology community. His science and his wonderful sense of humor are already missed. A few of us got together to figure out how to establish something enduring in his memory. We agreed that ASCO was the place to do it, and that it should be something that reflected Jim’s interest in building the next generation of pediatric oncologists who are just getting started.” They contacted the Conquer Cancer Foundation of ASCO, and the Nachman Award was born. “Within a heartbeat of getting the professionals at the Conquer Cancer Foundation involved, we had a spreadsheet reflecting how much money we would need, a sense of what it would take to get there, and a plan to make it happen,” said Dr. Link. “We’re already well on our way to endowing the award.”

Physician as Collaborator and Advocate Medicine was always in Dr. Link’s sights—and, during medical school, it became clear that pediatric oncology was his passion. “This field gives you the best of both worlds,” he said. “You make an intervention over a long period of time, take a child and his family through a serious illness, and hopefully watch them emerge on the other side. You have the privilege of really becoming part of their lives.” Over the years, ASCO has also become a passion—one that he hopes to share with more and more pediatric oncologists. “With our history of high-impact clinical research and collaboration on clinical trials, pediatric oncologists should intuitively understand the value of being part of a multidisciplinary society like ASCO—now, more than ever,” he said. “Molecular pathways don’t know what tissue they’re in. And the scientific breakthroughs ad-

About the Nachman Award

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lans call for the first James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology to be awarded at the 2012 ASCO Annual Meeting. The award will be given each year to a junior faculty member who submits the highest-scoring abstract in pediatric oncology for the ASCO Annual Meeting, as determined by the ASCO Scientific Program Committee. The total award is $3,000, which includes honorarium and costs associated with attending the ASCO Annual Meeting.

James B. Nachman, MD

The Conquer Cancer Foundation celebrates the lead donors who established the Award, as well as those whose philanthropic support has enabled the Foundation to grow it to scale. To learn more about the Nachman Award or other initiatives of the Conquer Cancer Foundation, or to find out how you can support the Foundation’s work, please visit www. conquercancerfoundation.org or contact info@conquercancerfoundation.org. Award Founders: William L. Carroll, MD, NYU-Langone Medical Center Susan L. Cohn, MD, University of Chicago Stephen P. Hunger, MD, University of Colorado Denver School of Medicine and Children’s Hospital Colorado Kara M. Kelly, MD, Columbia University Medical Center/Children’s Hospital of New York-Presbyterian Michael P. Link, MD, Stanford University School of Medicine and Lucile Packard Children’s Hospital at Stanford Cindy Schwartz, MD, MPH, Warren Alpert School of Medicine of  Brown University and Hasbro Children’s Hospital Tanya Trippett, MD, Memorial Sloan-Kettering Cancer Center The Conquer Cancer Foundation gratefully acknowledges the donors for their extraordinary support to establish this award. For a complete listing, visit the Our Donors page at www.conquercancerfoundation.org.

vanced by and disseminated by ASCO have enormous relevance for those of us who treat children with cancer. Pediatric oncologists actually have much more in common with other oncologists than they do with the other pediatric specialties represented in their departments.” Over the years, Dr. Link said, he has gained a steadily increasing appreciation for ASCO’s public policy focus—a mission that is especially critical today. “Virtually all of our curative therapies are based on drugs that are now in short supply, and ASCO

is working hard to publicize and resolve this crisis—for all of us and for our patients,” he said. “The Conquer Cancer Foundation helps to fund that work—as well as the ASCO Annual Meeting, patient education programs, and scores of awards in support of clinical research—including our Young Investigator Awards, which are absolutely essential in today’s research environment, where it’s next to impossible to secure seed funds for early-career work.” “No one provides those bridge funds—which allow young faculty to pursue their research, collect


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data, and establish the track records they need to secure support from the NIH, NCI, and other sources—in the same way and at the same scale as ASCO and the Conquer Cancer Foundation do through the Young Investigator Awards,” he continued. “It’s really a wonderful organization to support.”

To Touch the Future

when a friend dies suddenly, it really makes you stop and think. Am I ready? What am I leaving behind? The reality is that within two generations, the average person is unknown. Even the second generation of your family won’t remem-

ber you or know about the small, specific things that make you a unique individual. We wanted to say something about our friend’s life—to say this person made imB:7.875” portant contributions and shouldn’t T:7.75” be forgotten. Philanthropy has S:7”

healing properties when you’ve experienced a loss, and also offers a unique opportunity to make an impact far into the future.”

© 2012. American Society of Clinical Oncology. All Rights Reserved.

Visit Booth #1 at ASCO GI for more information

In his clinical life, Michael Link touches the future. One of the most rewarding aspects of treating children with cancer, he said, is watching them grow up. A former patient, now a surgeon himself, recently called to consult on a difficult case. Dr. Link regularly has coffee with another former patient who works at Stanford, and, he said, “we talk about kids, work, ordinary life topics, and cancer doesn’t come up. These are the stories that drive us to continue to do what we do each day.” Philanthropy, he said, offers the same opportunity. “Jim Nachman was exactly my age,” said Dr. Link. “When a friend and colleague dies, and especially

Help Your Patients Start Off Healthy in 2012

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he beginning of a new year is an opportunity for a fresh start for many, including people with cancer. To help your patients set and achieve their health and wellness goals, direct them to Cancer.Net (www.cancer.net), ASCO’s patient website, where they can learn about seven steps for a healthier new year. They will also find a section on cancer risk factors and prevention (www.cancer. net/prevention) that includes topics such as cancer screening, diet and nutrition, physical activity, and more.

© 2012. American Society of Clinical Oncology. All Rights Reserved.

There is more to

angiogenesis than VEGF-A VEGF-A DOES NOT ACT ALONE As tumors grow, other angiogenic factors such as VEGF-B and placental growth factor (PlGF) can also contribute to angiogenesis.1-3 Inhibiting additional angiogenic factors beyond VEGF-A has become an important area of oncology research. For additional information about the role of VEGF-A, VEGF-B, and PlGF in angiogenesis, go to www.VEGFandBeyond.com. Sano and Regeneron are investigating the potential impact of broad blockade of angiogenic growth factors, including VEGF-A, VEGF-B, and PlGF.

References: 1. Zhang F, Tang Z, Hou X, et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. PNAS. 2009;106:6152-6157. 2. Taylor AP, Rodriguez M, Adams K, et al. Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int J Cancer. 2003;105:158-164. 3. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463-475. US.AFL.11.11.002 12/11 Printed in U.S.A. © 2011 sano-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.


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In the Literature

Emerging Clinical Data on Cancer Management LYMPHOMA Intensified Chemotherapy with R-ACVBP Improves Survival in Younger Patients with Diffuse B-cell Lymphoma Compared with standard R-CHOP (rituximab [Rituxan], doxorubicin, cyclophosphamide, vincristine, and prednisone), intensified immunochemotherapy with R-ACVBP (doseintensive rituximab, doxorubicin, cyclophosphamide, vindesine [not available in U.S.], bleomycin, and prednisone) significantly improves survival of patients aged 18 to 59 years with diffuse large B-cell lymphoma with low-intermediate risk, according to the International Prognostic Index, researchers from the Groupe d’Etudes des Lymphomes de l’Adulte (GELA) reported in The Lancet. The results are from an open-label phase III randomized trial comparing R‑ACVBP with subsequent consolidation vs standard R‑CHOP. Eligible patients were aged 18 to 59 years with untreated diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index equal to 1. The authors noted that “rituximab in association with CHOP chemotherapy has substantially improved the outcome of patients with diffuse large B-cell lymphoma. However, the results of the R-CHOP regimen, which has been widely thought the standard of care, remains suboptimum in the treatment of younger patients.”

Trial Details The multicenter study enrolled 380 patients at 73 hematology or oncology departments of GELA (Group d’Etude des Lymphomes de l’Adulte) in France, Belgium, and Switzerland. All but one received at least one dose of SEE PAGE 21 the planned protocol treatment. A total of 54 patients did not complete treatment. The most commonly cited reasons for discontinuance were treatment-related toxic effects in the R-ACVBP group and treatment failure in the R-CHOP group. At a median follow-up of 44 months, the 3-year estimated eventfree survival was 81% in the R-

ACVBP group and 67% in the RCHOP group. The 3-year estimates for progression-free survival were 87% vs 73%, respectively. Overall survival was 92% among patients receiving R-ACVBP vs 84% for patients receiving R-CHOP. More patients (42%) in the RACVBP group experienced a serious adverse event vs 15% in the R-CHOP group. Hematologic toxicities of the intensive regimen were increased but manageable, the authors noted. Grade 3/4 hematologic toxic effects were more common in the R-ACVBP group, with 38% experiencing a febrile neutropenic episode compared to 9% in the R-CHOP group. “The lower rate of disease progression during the treatment phase and fewer relapses in patients who reached a complete response accounted for the prolonged progression-free survival and overall survival in our R-ACVBP group. However, we do not know which phase of the R-ACVBP regimen improves the outcome,” the researchers commented. A trial is underway aimed at assessing the quality of remission after RACVBP and R-CHOP. Récher C, et al: Lancet 378:1858-1867, 2011.

GASTRIC CANCER Adjuvant Chemotherapy with S-1 Improves Survival in Stage II/III Gastric Cancer Postoperative adjuvant therapy with the oral fluoropyrimidine derivative S-1 improved overall survival and relapse-free survival in patients with stage  II or III gastric cancer who had D2 gastrectomy. Five-year survival rates in the phase III study were 71.7% for patients in the S-1 group vs 61.1% in the surgery-only group, and the relapse-free survival rates were 65.4% vs 53.1%, respectively. Results were reported in the Journal of Clinical Oncology. Patients eligible for the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) had histopathologically confirmed diagnoses of stage II (except for T1 disease), IIIA, or IIIB gastric cancer; R0 resection (with no tumor cells at the margin) with D2 or more extensive lymph node dissection; and no evidence of hepatic, peritoneal, or dis-

tant metastasis and no tumor cells in peritoneal fluid on cytologic analysis. A total of 1,059 patients were enrolled at 109 centers throughout Japan, and 529 were assigned to the S-1 group and 530 to the surgery-only group. In both groups combined, 44.8% had stage II disease, 38.6% had stage IIIA disease, and 16.5% had stage IIIB disease. Patients in the S-1 group received an 80- to 120-mg daily dose of the drug, assigned on the basis of body surface area, in two divided doses for 4 weeks, followed by 2 weeks of rest. Treatment continued for 1 year after surgery. Patients assigned to the surgery-only group received no anticancer treatment postoperatively until the confirmation of recurrence.

Study Conclusions “Our present results confirmed that postoperative adjuvant chemotherapy with S-1 alone reduced the risk of death by 33.1%,” the researchers stated. “This reduction in the risk of mortality is comparable with that obtained with combined regimens for adjuvant chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial and the Intergroup 0116 (INT0116) trial.” The authors said that it remains uncertain whether the results of the ACTS-GC trial can be extrapolated to countries outside East Asia “because of possible differences in pharmacokinetics of S-1 between whites and East Asians” and because more limited surgery is performed for these cancers in Europe and the United States.

Sasako M, et al: J Clin Oncol 29:43874393, 2011.

MELANOMA Physician-based Screening Leads to the Detection of Thinner Melanomas with More Favorable Prognosis Physician-based screening leads to detection of thinner melanomas that were less likely to have negative prognostic attributes such as ulceration and dermal mitosis, according to a retrospective review of patient records and biopsy logs from 394 patients diagnosed with cutaneous melanoma. The

results were reported in the Archives of Dermatology. The study participants were 269 men and 125 women who were either established or new patients of a pigmented lesion clinic at Memorial Sloan-Kettering Cancer Center in New York. The mean age was 61.8 years, with a range of 17 to 91 years. Established patients were defined as those who have received professional services at the clinic for at least 3 months.

Findings at 10 Years Over a period of 10 years, 527 melanomas were identified in the 394 patients, 323 (61.3%) in situ, 171 (32.4%) invasive, and 33 (6.3%) metastatic. “Importantly, the detection of early melanoma was not the result of the increase in the biopsy of benign lesions,” the authors noted. “Established patients had more in situ disease (70% vs 57%; P < .001) and thinner invasive melanomas (0.45 mm vs 0.82 mm; P = .002) and were less likely to present with negative prognostic attributes such as ulceration and dermal mitoses compared with new patients,” the researchers wrote. “In new patients, 63% of melanomas were physician detected vs 82% in established patients; 18% of all melanomas were patient detected. Dermatologist-detected melanomas were thinner compared with self-detected melanomas. The majority of self-detected melanomas were noted by patients because of change (64%).” “Our results suggest that physician screening leads to detection of thinner melanoma,” the authors commented and “have implications for promoting physician and self-screening and for emphasizing the important role that a specialized [pigmented lesion clinic] setting may play in the early diagnosis of melanoma.” They also noted the importance of educating patients to recognize melanoma signs and symptoms and perform skin selfexamination. “It is crucial,” the authors concluded, “to emphasize that a combined strategy of physician detection and patient participation must continue to be implemented to ensure early melanoma diagnosis.”

Kovalyshyn J, et al: Arch Dermatol 147:1269-1275, 2011.


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Special Report

The Newly Diagnosed Patient with Cancer and Access to Care Three of four new patients face roadblocks in securing their first appointment. By Caroline Helwick

A

study presented at the 2011 ASCO Annual Meeting raised concerns that newly diagnosed cancer patients are having trouble seeing an oncologist. Interviews with several cancer centers and community practices, however, suggest that the process runs smoothly, for the most part.

four callers never reached a scheduler. Other times we got through, but for various reasons were refused an appointment.”

The most common reason for not scheduling a new-patient appointment in the first phone call was demand for medical records (39%), followed by

failure to reach a scheduler (24%) and referral requirement (18%). Lack of insurance was not an issue. continued on page 28

Majority of Patients Could Not Be Scheduled on First Contact In a simulation exercise to evaluate patient’s access to care, more than three-quarters of newly diagnosed advanced cancer patients were unable to book an appointment with an oncologist, investigators from the University of Pennsylvania in Philadelphia and the Leonard Davis Institute of Health Economics reported at ASCO.1

y Jour nal of Clinical Oncolog

JCO C e l e b r at e s t h i rt y y e a r s Journal of Clinical Oncology (JCO), the pre-eminent, international medical journal devoted to clinical cancer research, celebrates its 30th anniversary in 2012. From its start as a monthly publication in 1983 with a circulation under 5,000, JCO now publishes three issues per month and has a print circulation of over 25,000, plus a monthly online readership of more than 300,000 unique visitors.

Keerthi Gogineni, MD

“We found that no appointment was made 77% of the time. Out of 432 simulated newly diagnosed cancer patients, only 99 (23%) actually got an appointment with an oncologist,” said Keerthi Gogineni, MD. The study aimed to determine the ability of a test cancer patient to get an appointment in a representative sample of U.S. hospitals. Researchers simulated patients newly diagnosed with inoperable hepatocelluar carcinoma and varying insurance statuses. The callers (who followed scripts) contacted 160 sites, including NCI centers, academic medical centers, and hospitals caring for low-income patients in the top 25 metropolitan areas (details on responses from individual sites were not available.) “The goal was to get through to a live person to try to obtain an appointment,” Dr. Gogenini explained. “We tried calling three times, without leaving a callback number. One out of

JCO would like to thank the authors, editors, reviewers, board members, subscribers, and advertisers who have contributed to and supported the Journal since its inception.

JOIN US IN CELEBRATING THIS ACHIEVEMENT.


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Special Report

Access to Care continued from page 27

“I wouldn’t say that 77% of the time a patient would never get an appointment,” she clarified, explaining that there were often obstacles to scheduling an appointment at first contact. One-quarter of the time, schedulers made an appointment contingent on the patient having medical records by the first visit, which Dr. Gogineni views as a reasonable approach. “There are always concerns about clogging the system and inappropriately triaging patients, but we should at least be able to get patients started in the process,” she said. “While the study patients were fictitious, they represent individuals who in real life are dealing with a frightening diagnosis. They are being asked to gather a lot of information, which is reasonable, but there is a time and place for these expectations,” she commented. “We need to address barriers that delay access to care for patients with

MBA, Senior Director of Patient Access and Therapeutic Services at Roswell Park, said it is rare that patients reach voicemail rather than a scheduler, even with 2,000 new-patient calls per month. “The results surprised me too,” she agreed. “We make sure every person reaches an individual. We have a system set up to ensure that. Our goal is to have the patient talk to someone who can get the process started.” Through careful monitoring of the new-patient scheduling process, the call center has reduced the “call abandonment rate” during business hours (patient calls and hangs up without leaving a message) to less than 4%. In the odd instance that the “patient access representative” is not immediately available, calls go through several other “live” channels before hitting voicemail. If callers do reach voicemail, they are asked to have their physician fax their records, and their call is usually returned on the same day. “Virtually no calls go to voicemail,” she said.

Even though we think we do a terrific job—and in fact we do—we all have opportunities for improving the patient’s experience, and one of these is optimizing patient access. —Stephen Edge, MD

advanced cancer,” Dr. Gogineni concluded. She suggested that patient access might be improved through “more socially nuanced and medically informed intakes” and, for vulnerable patients, the use of patient navigators at the earliest point of contact.

Numbers Hard to Believe Stephen Edge, MD, Director of the Breast Center and Chair of Health Services and Outcomes Research at Roswell Park Cancer Institute, Buffalo, New York, was surprised by the findings. “The results don’t make sense to me. I can’t believe that 75% of the patients calling my center would not get an appointment,” he commented. Indeed, Kimberly Sweeney, RN,

Ms. Sweeney acknowledged that depending on the type of cancer, medical records may be requested before an appointment is made, primarily in order to schedule the appropriate service, though her office does the legwork on all of this. But for certain diagnoses, Roswell Park offers “instant access” to newly diagnosed patients, including same-day appointments. “We just ask patients to make the first call, and we do the rest,” she said. “And we are always looking to improve the patient experience.”

Scheduling Goal Achieved 75% of the Time At Vanderbilt-Ingram Cancer Center in Nashville, the goal is to

Kimberly Sweeney, RN, MBA

Carol Eck, RN, MBA

have all new patients see a provider within 5 business days, and within 48 hours for acute leukemia patients, said Carol Eck, RN, MBA, Administrative Director. “We accomplish this goal about 75% of the time,” she estimated, “though it can take a little longer when our surgical oncologists request more diagnostic studies, or when we have to work with a provider’s secretary to find a slot. But in general I would say that more often than not, an appointment is made upon the first phone call.” To be scheduled for a new appointment with a medical oncologist, patients need only to have a definitive cancer diagnosis. The cancer site– specific “pre-appointment” team will handle the gathering of records, which they make available electronically to the appropriate providers. “We do ask about insurance status, and if a patient is uninsured we have them meet with a financial counselor. They are usually not denied an appointment, though if uninsured they may be offered an appointment with our staff at the city hospital,” she added. Patients seeking care in the community—as over three-quarters do— also should not have these problems, according to Patrick Cobb, MD, of Frontier Cancer Center and Blood Institute in Billings, Montana. “We usually get new people in within a few days, and usually by the time they see us they at least have a pathology report. It’s rare that a patient has to wait,” he said, suggesting that in smaller areas this process may be easier to accomplish. Dr. Cobb said the concern grows as more oncologists become “employees.” He commented, “When you are in practice for yourself, you have more incentives to stay longer and see more patients.” He predict-

Patrick Cobb, MD

ed that patient access could become more problematic due to the shortage of medical oncologists in training and their uneven distribution across the country.

Need for Vigilance Dr. Edge also pointed out that many of the problems or irregularities faced by the simulated patients in Dr. Gogineni’s study might have a rational basis, if SEE PAGE 21 they were investigated in more detail. Nevertheless, he offered, “The study highlights the need for ongoing quality improvements in our cancer centers.” The dilemma that Dr. Edge sees for patient access offices is how to balance between “making the appointment on the first call and being sure the patient gets the appointment with the right person and in the most efficient manner”—both in terms of having the right materials (eg, records) for the appointment and getting the appointment quickly. “It can be a very hard job for the patient access staff,” he said, “Yet what the patient may perceive that they want is an appointment at that first call—and I don’t blame them!” “We are sometimes surprised to see our deficiencies,” he commented. “Even though we think we do a terrific job—and in fact we do—we all have opportunities for improving the patient’s experience, and one of these is optimizing patient access.”

Disclosure: Drs. Gogineni, Edge, and Cobb, and Ms. Eck reported no potential conflicts of interest.

Reference 1. Gogineni K, Armstrong K: Appointment access for new cancer patients. 2011 ASCO Annual Meeting. Abstract 6128. Presented June 4, 2011.


ASCOPost.com  |   JANUARY 1, 2012

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Expert’s Corner

MD Anderson Cancer Center’s New President Has a Bold Vision A Conversation with Ronald A. DePinho, MD By Ronald Piana source for the cancer community and, as such, I serve as the face of this institution with respect to interactions with the external world, here in the United States as well as on the international scene.

Embracing Oncology

Ronald A. DePinho, MD

O

n September 1, 2011, Ronald A. DePinho, MD, became only the fourth President in the 70year history of The University of Texas MD Anderson Cancer Center in Houston. Dr. DePinho spent the previous 14 years as head of DanaFarber’s Belfer Institute for Applied Cancer Science. In a recent interview with The ASCO Post, Dr. DePinho spoke about being the new face of MD Anderson and shared the bold vision that will define his presidency and further shape the path of cancer care.

Professional Changes Moving from Dana-Farber, what do you see as the major adjustments you’ll need to make in your new position? I feel comfortable in my new role given my diverse experiences. As Director of Dana-Farber’s Belfer Institute, I headed a novel academic construct wherein industry-like teams worked in a concerted way to bring basic discoveries to clinical endpoints. I also ran a research lab focused on cancer and aging, organized program projects, developed many strategic alliances within the pharmaceutical industry, and worked with a number of public and private organizations such as the American Association for Cancer Research and NCI. I also cofounded several biotechnology companies, which provided excellent business experience. The greatest challenge for me in my new position at MD Anderson lies in the fact that I’m responsible for all components of the institution—academics, research, as well as the very extensive clinical services we provide to over 100,000 patients per year. Given its size, MD Anderson is a vital re-

ASCO identified an impending workforce shortage of oncologists. What would you say to encourage bright young medical students to pursue a career in this very difficult discipline? First, I would challenge that descriptor about it being a very difficult discipline. Oncology is the most exciting field in medicine, and we are entering a period in which the most sophisticated science and technology applied to the human condition will be in the arena of cancer research and treatment. The stars are aligned in our field: We have the human cancer genome project that will give us a complete atlas of genetic alterations, technologies that enable functional validation

Yes, I do. A major priority for me is to implement science-driven clinical care in the coming decade. We are extremely proud of the ongoing work at MD Anderson in adaptive trial design. We believe that this design is paradigm-shifting in the way that clinical trials will be conducted in the years ahead; studies will be sleeker, more precise, and deliver better data and outcomes. We are going to be exploiting our newfound ability to analyze human biospecimens in ways that clarify which patients should be enlisted onto which clinical trials, and determine more quickly whether those individuals are responding to treatment—not so much with survival endpoints, but by more accurately gauging response to give a targeted assessment of outcome. I see the next era of clinical trials as being far more interventive, helping us understand which drug to match with which genotype and cancer type. And MD

The financial stress on cancer services is a challenge, but at the end of the day, we will be judged by how we treat the disadvantaged. of such alterations in cells and model organisms, and the ability to genotype patients (so-called personalized cancer therapy) so that we can match the right drug to a patient’s tumor genetic profile. There are also faithful genetically engineered models of human cancer that will enable testing of safer and more effective therapies for our patients. So, to those aspiring medical students, I say that oncology brings an enormously exciting opportunity to be part of the primary edge of science-driven clinical care. I believe that cancer is going to be leading a world-changing effort in medicine, and that’s why it should appeal to the brightest of our country’s medical students.

Clinical Trial Design Do you feel that your background in translational research will add to the ongoing trial design work at MD Anderson that endeavors to streamline trials and bring drugs to market quicker?

Anderson will play a large role in that revolution.

Managing Financial Stress Does the difficult economic/political environment in today’s health-care system present challenges to your mission at MD Anderson? All academic medical centers are facing enormous levels of financial stress driven by a confluence of forces such as pressure from managed care, decreasing NCI paylines, the health-care reform act, and everincreasing operational overhead associated with today’s economic challenges. We at MD Anderson and other cancer centers need to recognize that in the coming years we’ll face contracting revenue streams. It’s up to us to find ways to do things more efficiently and diversify our revenue streams, while increasing our income base so we can maintain the highest level of research and care. It’s important to note that aca-

MD Anderson’s ‘Critical Mass’ ■■ Employs over 18,000 people ■■ Serves 100,000 patients ■■ 10,000 patients enrolled in clinical trials

■■ 125 INDs under investigation demic institutions serve a multitude of care needs for challenged communities whose needs are the greatest. For instance, we provide a lot of indigent care at this institution and we do community outreach work to educate underserved populations about the importance of regular cancer screening and prevention methods. These vital services are not reimbursed, so that increases our fiscal challenge; however, we are very proud of the role we play in caring for the underserved. Our commitment to such activities remains strong and must remain intact.

Special Position What makes this position at MD Anderson special for you? One of the primary reasons I took this job relates to the fact that MD Anderson has a tremendous “critical mass,” with over 18,000 employees comprising highly talented faculty spanning basic, translational, and clinical research, as well as a dedicated staff and management. We serve approximately 105,000 patients and enroll over 10,000 in clinical trials each year. We are conducting research on about 125 investigational new drugs (INDs). Our survival rates are outstanding, and we are consistently ranked as the top cancer hospital by US News & World Report. Given its size, MD Anderson has the resources, the talent, and the academic and clinical infrastructure to move the entire field of oncology forward. On this foundation, we are organizing a bold and ambitious “moonshot plan” for cancer—not just focusing on the next experiment, but rather, organizing our efforts to understand cancer to a level that enables ultimate cure. We certainly do not have all of the knowledge needed continued on page 33


2011

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ASCOPost.com  |   JANUARY 1, 2012

PAGE 31

In the News Breast Cancer

Benefits of Radiation after Breast-conserving Surgery Cut Risk of Recurrence in Half By Charlotte Bath

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

in a Lancet commentary,3 “a 50% proportional reduction in 10-year recurrence exceeds that from chemotherapy alone or hormonal therapy alone, and is roughly equivalent to the benefits of trastuzumab (Herceptin) for patients with HER2/neu–positive disease.”

Historical Perspective

Dr. Buchholz provided historical perspective on the data. “Back in the fter breast-conserving surgery, 1980s and 1990s, a lot of people beradiotherapy to the conserved lieved that radiation was effective at breast halves the rate at which the reducing breast recurrences but that disease recurs and reduces the breast it didn’t really matter because it might cancer death rate by about a sixth,” not improve overall survival. These the Early Breast Cancer Trialists’ Coldata really conclusively demonstrate laborative Group (EBCTCG) conthat that’s not true—that radiation cluded in a meta-analysis published in given upfront at the time of the initial The Lancet.1 “This is some of the most treatment has the capability of improvimportant data we have with respect ing the patient’s rate of cure,” he said. to radiation benefits in breast cancer,” “The benefits of radiation are persisThomas A. Buchholz, MD, Head of tent over time,” Dr. Buchholz continued. the Division of Radiation Oncology at “The proportional benefit that radiation The University of Texas MD Anderson provides over time is maintained and Cancer Center in Houston, remarked consistent. So it’s not just a temporizing 2 in an article in The New York Times. measure. There’s evidence that it really “Most importantly,” Dr. Buchholz said is eradicating and curing.” After 10 or in an interview with The ASCO Post, 15 years, “the benefits of radiation have the study “confirms with very long peaked—they don’t further decrease, follow-up that radiation improves the they don’t further increase. And that overall survival of patients with breast makes sense because over that period of cancer.” time, if a patient was going to have a reThe meta-analcurrence, it would ysis looked at indihave happened,” The absolute benefits vidual patient data Dr. Buchholz said.” from radiotherapy vary for 10,801 women The finding of in 17 randomized improved overall substantially according trials of breastsurvival underto the characteristics of conserving surgery scores how radiawith or without tion has been imthe patient and they can radiation therapy. proved and refined be predicted at the time “Median followover the past few when treatment decisions decades. “Some up was 9.5 years at risk per woman of the very first need to be made. and 25% of women phase III trials in were followed up medicine were infor more than a decade,” the EBCTCG vestigating radiation in this setting afreported. ter mastectomy. But back in the 1950s “The Early Breast Cancer Trialand 1960s, the techniques of delivering ists’ Collaborative Group was able to radiation were crude, really obsolete by today’s standards,” Dr. Buchholz said. compile the raw data from almost ev“Radiation had some downsides, ery phase  III trial done in the United particularly with respect to the heart,” States and Europe. And they reanalyze he continued. “If you irradiated the data every 5 years,” Dr. Buchholz exheart as an ‘innocent bystander’ beplained. Those findings showed that cause it lives next door to the left radiation reduced the probability of breast, you could promote cardiovasrecurrence of any type (locoregional cular disease and increase the risk of or distant) by 50%. “To put this bendying of heart disease. There was a efit into context,” Dr. Buchholz wrote

“A

Expect Questions from Your Patients

“T

he message” of a meta-analysis of 17 randomized trials of breast-conserving surgery with or without radiation, “should be that the benefits of radiation are not temporary, that it provides an increased chance of cure,” Thomas A. Buchholz, MD, told The ASCO Post. The meta-analysis was conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) and published in The Lancet. Thomas A. Buchholz, MD “Most people recognize the importance of radiation after breast conservation, and radiation is already established in the National Comprehensive Cancer Network guidelines and other important guidelines,” according to Dr. Buchholz, Head of the Division of Radiation Oncology at The University of Texas MD Anderson Cancer Center in Houston. The EBCTCG meta-analysis could, however, provide more answers for people at high risk of recurrence but who still question the value of receiving radiation upfront, thinking they could “save it” in case they have a recurrence later. “That is the wrong way to think about it,” Dr. Buchholz said, “because if you take that approach, you may compromise your overall survival.”

Omitting Radiation for One Subgroup Following the initial trials establishing radiation’s benefits among women who had breast-conservation surgery, later trials tried to tease out whether there is a favorable group for whom we can omit radiation, Dr. Buchholz said. “Omission of radiation was tried in a variety of settings. They tried it by substituting chemotherapy for radiation, and that didn’t work. They tried doing bigger surgeries with bigger margins, and that didn’t work. But eventually there was one study that defined a subgroup of patients—women over the age of 70 with stage I estrogen receptor–positive tumors and negative margins that are also going to be also treated with hormonal therapy. In this setting, radiation still reduces breast recurrence, but the baseline recurrence rate for those without radiation is low enough that it is reasonable to discuss the possibility of not using radiation,” Dr. Buchholz said. “Of course, some 71-year-olds are in great shape and have a 15-year life expectancy. For them, you might be more apt to use radiation because they are going to have a longer period of their life that is at risk, in contrast to someone who is 85 and has heart disease and diabetes. In such a patient with a life expectancy from these other illnesses of a couple of years, you wouldn’t want to be overly aggressive in using radiation,” Dr. Buchholz added. “So it becomes a judgment call based on competing risks of dying of another disease as well.”

concern that any benefit in terms of reducing breast cancer death would be offset by an increase in cardiovascular death. Now we have been technically able to overcome that challenge,” he stated, “and if you have a decrease in breast cancer recurrence, you are going to see an overall survival advantage.”

Proportional vs Absolute Benefits The proportional benefits of radiotherapy following breast-conserving surgery “vary little between different

groups of women,” the EBCTCG noted in its interpretation of the results from the meta-analysis. “By contrast,” the authors continued, “the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.” These patient characteristics include age, tumor grade and size, estrogen receptor (ER) status, and use of tamoxifen. “Halving a big risk produces a bigcontinued on page 32


The ASCO Post  |   JANUARY 1, 2012

PAGE 32

In the News

Radiation Benefits continued from page 31

ger absolute benefit than halving a small risk,” the authors explained. Most of the women (7,287) had nodenegative (pN0) disease, and in these women, “the annual recurrence rate without radiotherapy was strongly cor-

related with age (inversely), tumour grade, tumour size, ER status (especially when tamoxifen was used in ERpositive disease), and extent of surgery (inversely),” the EBCTCG reported. “The absolute recurrence reduction produced by radiotherapy also depended strongly on these factors.”

Strategies for ER-negative and Triple-negative Disease In this and other studies, Dr. Buchholz pointed out, reductions in risk of recurrence were greater for patients with ER-positive disease than for those with ER-negative or triple-negative disease. “These in-

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sights suggest that intensification of locoregional treatment should be studied for ER-negative disease,” he wrote in his commentary for The Lancet. Elaborating on this during the interview with The ASCO Post, Dr. Buchholz said, “I think we are starting to appreciate—and this is another important insight from the study— that not all breast cancers are identical. ER-negative or triple-negative disease is almost a different cancer from ER-positive disease. When you hear the term triple-negative, you can assume that three targets—the estrogen receptor, progesterone receptor, and HER2—are missing. What need to find some positive targets, and then we can develop strategies.” He compared this process to what happened with HER2—first the discovery that HER2 status is an important determinant of outcome for patients with breast cancer, but “most importantly being able to design a therapy specifically against HER2 and completely change that prognosis.” He stressed that we can already do things to help address the higher risk of recurrence in women with ERnegative disease. “For instance,” he said, “we could ensure that we achieve good surgeries, or negative margins. If there is a close margin in ER-positive breast cancer, I might approach it differently than in ER-negative disease, where we would be likely to reexcise. We could use tumor bed boost in addition to whole-breast irradiation to escalate the dose in that region.” He explained that “age and biology both come into play as to how much additional absolute risk reduction a boost will provide, but clearly for a younger patient with ER-negative breast cancer, it would be the standard of care.”

Oncology

9/6/2011 5:08:17 PM

References 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 2. Grady D: Benefit in radiation after breast cancer surgery. The New York Times, October 19, 2011. 3. Buchholz TA: Radiotherapy and survival in breast cancer. Lancet 378:16801682, 2011.


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Patient’s Corner

Ronald A. DePinho continued from page 29

nor the technology, but now is the time for concerted action. I cannot predict when that moment will come, but it is clear to me that now is the time to articulate a plan to make that mission possible. MD Anderson will develop an integrated multidisciplinary, multitechnology plan to help make that goal a reality.

Interinstitutional Collaboration In a recent speech to MD Anderson faculty and staff, you outlined a 12-point priority list for your administration, one of which is fostering better interinstitutional collaboration. How does that figure into your bold assault on the cancer problem? Even with the power, the will, and the vast collaborative talent pool within the walls of MD Anderson, it is clear that we can’t do it alone. I’ve spent my career establishing such multi-institutional interactions and learned of the great potential realized by working together. I will continue such activities at MD Anderson. MD Anderson will continue to reach out to other institutions around the world to bring forward the best ideas and technologies to best attack all dimensions of the cancer problem. One of the first things I did even before my official presidency began was to establish a an exciting program involving collaboration among

MD Anderson, Baylor University, and Massachusetts Institute of Technology. Our mission will be to study neurodegeneration, which is one of the other great medical problems facing humanity and involves mechanisms of action intimately related to the development of cancer as well as toxic effects of therapy on the brain.

Addressing Disparity Disparities in cancer care pose a lingering problem in our nation. Given the impact of today’s financial stressors on our precious cancer care resources, what message would you leave members of the cancer care community? The financial stress on cancer services is a challenge, but at the end of the day, we will be judged by how we treat the disadvantaged. It is vital for our society to ensure that we bring superlative cancer care to individuals from all walks of life. To that end, we have to work more intensively to deliver education and care to those who are struggling in our society. Often, the underserved don’t have the background to understand that real opportunities exist to help them improve their health. As members of an institution in the field of cancer care, we have the responsibility to let those who are challenged know that we are at the ready to help them in their time of greatest need.

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

Humor Is Helping Me Survive Cancer At just 38, I was a marked man but didn’t know it. By Myles Beskind, as told to Jo Cavallo

D

espite a strong family history of colon cancer—all five of my mother’s siblings had colon cancer, and my mother died of the disease 10 years ago—when some flecks of blood started showing up on my toilet tissue in early 2005, I figured it was from hemorrhoids. At 38, I was a marathon runner and in great shape, and although I didn’t feel quite as invincible as I did when I was 20, Myles Beskind it never occurred to me that I could have have been successful in shrinking the a deadly disease. But when the bleeding tumors, and my oncologist says I’ll have continued over a couple of months, my to be on maintenance therapy for a year. wife Marcie urged me to see a gastroenHe also says that certain types of colon terologist. Due to my family history, the cancer are being turned into chronic disdoctor ordered a colonoscopy. A polyp eases, and if that’s the case for me, I can that was removed turned out to be stage live with that. But 0 (carcinoma in I’m still wondering, situ) colon cancer. I found that making how did this hapBecause the canjokes about having cancer pen? Were all the cer was contained doctors wrong in within the polyp made me feel better and not recommending and there didn’t more in control—I was adjuvant therapy afappear to be any ter my initial cancer spread of malignant able to be more me. diagnosis, and could cells to surrounding it have prevented tissue in my colon, these renegade malignant cells from inmy surgeon said further treatment was vading other parts of my body? unnecessary. He recommended that I have annual colonoscopy screenings Cancer as a Laughing Matter and to immediately report any changes I’ve had to come to grips with the fact in my health. So I sought out the advice that I’ll never know the answers to those of my gastroenterologist and an oncoloquestions, and it really doesn’t matter. I gist for a second and third opinion, and just have to focus on doing everything I they both agreed that I didn’t need to do can to get well, and having a sense of huanything else. mor about cancer really helps. Were All the Doctors Wrong? When I launched my blog (http:// Five years later, when I began having kickincancersbutt.blogspot.com) after severe, nagging lower-back pain, both my cancer recurred, it was intended my orthopedist and I were convinced as a vehicle to keep friends and family it was due to either an injury to my scimembers up-to-date on my progress. atic nerve or a herniated disc. But as the But I found that making jokes about months passed with no relief despite having cancer and the treatment side pain medication and physical therapy, effects made me feel better and more my doctor prescribed a CT scan, which in control—I was able to be more me. showed a spot on my pelvis. Still, I wasn’t I’m not unrealistic about my situaconcerned because all my follow-up tion. I know that having metastatic colon colonoscopies and blood tests since cancer is serious, but writing about my my cancer diagnosis were negative, and experience is helping me stay centered my doctor assured me that colon canon the things that matter most to me: to cer doesn’t usually spread to the pelvis. continue to be a good husband, father, However, a biopsy of the pelvic tumor employee, and friend. It’s also providing confirmed that my colon cancer had mea record of how well I’m succeeding. tastasized. A full-body CT scan picked Myles Beskind, 45, is the Chief Financial Officer up another malignant spot on my lung. of a technology company in Atlanta, and the auRadiation therapy and a regimen of thor of the e-book, Welcome to the Club! Sur5 months of XELOX (capecitabine and viving Cancer, One Laugh at a Time. oxaliplatin), plus bevacizumab (Avastin)

© Eric Lewis/The New Yorker Collection/www.cartoonbank.com


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Perspective

Integrative Oncology continued from page 1

Integrative oncology is a synthesis of mainstream treatment and complementary therapies in cancer care. These are noninvasive, nonpharmacologic adjuncts to mainstream treatment that improve patients’ strength and control the physical and emotional symptoms associated with cancer and cancer treatment. They also provide patients with a sense of control and self-empowerment at a time when many feel vulnerable and life seems out of control.1

The Integrative Approach Although today’s successful oncology treatments cure increasing numbers of patients, they also result in adverse effects, some of which are lasting. Side effects from cancer surgery, hormonal blockade, chemotherapy, and radiation treatments are common, and they impact the quality of patients’ lives during treatment and after. Therefore, optimal care must include attention to more than the tumor. It requires a broadened attention to patients’ physical and emotional needs, both during the course of treatment and into the years of survivorship that, for many, lie ahead. Mainstream medical treatments already include successful approaches to alleviating side effects, but many of these are marginally successful, costly, and have their own side effects. As a result, patients increasingly seek complementary therapies to assist them in coping with the rigors of care. They also look for ways to improve strength and mood, to decrease stress, pain, and anxiety and often to enhance their clinical status.2 Unfortunately, some patients gravitate to the use of widely promoted disproved or unproven “alternative” modalities to achieve these goals. No less than mainstream cancer therapies in common use, complementary therapies must be evidence-based or, lacking firm evidence, must at least have a rational basis.

Integrative Oncology in the United States Most U.S. cancer centers and cancer programs have at least some component of integrative medicine. This may include music therapy for inpatients, occasional lectures, or perhaps massage therapy for outpatients. Some are engaged exclusively in research. Others focus on specific subsets, such as pediatric inpatients. Although the availability of integrative therapies varies widely, it would be difficult to find a major cancer program in the United

States that does not include at least some attention to complementary modalities. Integrative cancer care in other countries is not far behind. The Integrative Medicine Department at Memorial Sloan-Kettering Cancer Center provides inpatient and outpatient clinical care as well as education, training, and research, all in collaboration with clinicians, researchers, and others throughout the institution. A primary focus of our program is to study and provide appropriate complementary therapies to patients, survivors, their families, staff, and the community. These approaches may be perceived as extensions of the supportive care associated with oncology for decades past. We also have developed a website to provide physicians and the public with evidence-based information about herbal remedies, vitamins and other dietary supplements, and bogus cancer treatments, all at no cost (www.MSKCC.org/AboutHerbs). This information is continuously updated and accessed internationally, receiving more than 2 million hits in the past 10 months alone. At the same time, we work diligently to stop the use of unproven ″alternative” therapies that are promoted in lieu of mainstream cancer treatment. These fake cancer cures constitute a multibillion dollar business in the United States and other developed countries. Such quackery has no place in proper cancer care.

therapies are widely used by patients with successful results. ■■ Fitness and Nutrition: Exercise and physical fitness improve clinical outcome and decrease negative side effects. Physical activity is an important recommendation of virtually every oncology organization internationally. Data increasingly show that physical activity directly increases survival. In recently diagnosed patients, adherence to a Mediterranean diet as part of comprehensive lifestyle intervention alters gene expression3 and improves clinical outcome.4,5 ■■ Acupuncture: Among the most studied of complementary therapies, acupuncture research demonstrates safety, physiologic benefits, and symptom relief, as well as insight into its mechanisms of action. Ongoing research on acupuncture for conditions such as neuropathy, xerostomia, and lymphedema is especially important, as available mainstream treatments often fail to control or reduce these and other difficult problems. Integrative oncology continues to grow in popularity. It is increasingly available clinically and appropriately subjected to study in a growing number of academic centers. These therapies are

safe, inexpensive, and effective. Many are self-applied, thus providing patients some control over what they perceive as an uncontrollable circumstance. These therapies are a needed component of contemporary cancer care.

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

References 1. Deng, G, Frenkel M, Cohen L, et al: Evidence-based clinical practice guidelines for integrative oncology: Complementary therapies and botanicals. J Soc Integr Oncol 7:85-120, 2009. 2. Barnes PM, Bloom B, Nahin R: Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Report No. 12, 2008. Available at nccam.nih.gov/news/ camstats/. Accessed December 8, 2011. 3. Ornish D, Magbanua MJ, Weidner G, et al: Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proc Natl Acad Sci USA 105:8369-8374, 2008. 4. Meyerhardt JA: Beyond standard adjuvant therapy for colon cancer: Role of nonstandard interventions. Semin Oncol 38:533-541, 2011. 5. Zeng H, Irwin ML, Lu L, et al: Physical activity and breast cancer survival: An epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Breast Cancer Res Treat. August 12, 2011 (early release online).

Major Components of Integrative Oncology This field is too new for perfect agreement about what constitutes complementary therapies, and variations in language exist. However, the following categories are commonly applied and are available in the Memorial Sloan-Kettering program: massage therapy; mindbody techniques including meditation, self-hypnosis, yoga, and tai chi; music therapy; acupuncture; exercise/physical fitness; and advice about nutrition, herbs, and other dietary supplements. Each of these evidence-based approaches has an important role in enhancing well-being and contributing to overall patient and survivor care. A few are highlighted below. ■■ Mind-Body Therapies: Research demonstrates the clinical benefit as well as cost-effectiveness of mindbody treatments such as meditation and self-hypnosis. Patients can learn to use these techniques as needed, to decrease symptoms and improve quality of life. These

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