TAP Vol 1 Issue 2 by Harborside Press LLC

Gene expression profiling 33

Trastuzumab cardiotoxicity 51

VOLUME 1, ISSUE 2

Physician-owned imaging services 53

JULY 2010 ASCOPost.com

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

Cover Feature

Investigational Agent Demonstrates First Survival Advantage in Advanced Melanoma

From the Editor-in-Chief

By Alice Goodman

or the first time, a drug has extended survival for patients with advanced melanoma. The novel agent ipilimumab, with or without a vaccine, extended survival by 34% compared to vaccine alone in patients with previously treated advanced melanoma according to results of a phase III, randomized, multicenter, double-blind trial. The study was published online in The New England Journal of Medicine1 to coincide with the presentation of results at the Plenary Session of the 2010 ASCO Annual Steven O'Day, MD Meeting.2 “Over the past 30 years, randomized clinical trials have repeatedly failed to demonstrate an improvement in overall survival in patients with advanced

Use your smartphone to view the original ipilimumab abstracts as presented at ASCO’s Annual Meeting and published in The New England Journal of Medicine. See page 55 for more information about using 2D barcodes

melanoma, which is extremely difficult to treat,” said lead researcher Steven O’Day, MD, who is Chief of Research and Director of the Melanoma Clinic at The Angeles Clinic and Research Institute in Los Angeles. “Finally we have good news. These results are an exciting advance, both for patients with advanced melanoma and for the field of cancer immunology.” Other experts said that this treatment, although a major advance, required further study. Metastatic melanoma is the fastest rising cancer in continued on page 6

Lung Cancer

Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC

By James O. Armitage, MD

he 2010 ASCO Annual Meeting may seem like history, but the studies and data presented in Chicago will remain in the forefront of oncology and hematology news in the weeks and months to come. In this second issue of The ASCO Post (TAP), I call your attention to the following important oncology-hematology news and compelling viewpoints outlined below and presented in this issue. Important news and perspectives: Look throughout this issue for authoritative and comprehensive reports on data from the Annual Meeting, including 10 key clinical studies, along with news from these other important 2010 oncology conferences: the Genitourinary Cancers Symposium, Digestive Disease Week, and the American Association of Clinical Research Annual Meeting. Plus don’t miss The ASCO Post’s in-depth interview with departing NCI Director John E. Niederhuber, MD (see page 4), and find out continued on page 5

By Caroline Helwick

n a phase I study in advanced non–small cell lung cancer (NSCLC) presented at the Plenary Session of the 2010 ASCO Annual Meeting, a multinational group of researchers reported impressive clinical activity with an investigational agent unfamiliar to many oncologists.1

Crizotinib in NSCLC ■■ The investigational oral agent crizotinib targets the EML4/ALK fusion oncogene, whichNum occurs in approximately 4% of fugitatest NSCLC patients

■■ A phase I international study evaluated the drug’s activity in heavily pretreated advanced disease.

■■ In preliminary results reported at ASCO,

crizotinib produced a 57% response rate, with 6-month progression-free survival predicted to be 72%.

The oral drug crizotinib (PF-02341066), an inhibitor of anaplastic lymphoma kinase, or ALK, produced tumor shrinkage in 57%, and prolonged remission in 72%, of heavily pretreated advanced NSCLC patients selected for ALK protein expression, reported Yung-Jue Bang, MD, PhD, Professor of Internal Medicine at Seoul National University in South Korea. “Our results were very impressive. The majority of patients responded, often within the first 2 weeks of treatment, and the responses were often durable,” Dr. Bang commented. Crizotinib targets a fusion protein called EML4/ ALK, which drives tumor growth in 3% to 5% of all NSCLC patients. In preclinical studies, crizotinib induces apoptosis in ALK-positive NSCLC cells. The data come from an ongoing phase I trial of patients with ALK-positive NSCLC treated with oral crizotinib, 250 mg twice daily. This is the first study of the drug in patients. Dr. Bang presented the results from the first 82 patients for whom data were avail-

MORE IN THIS ISSUE 2010 ASCO Annual Meeting Coverage Plenary presentations �� 1, 2, 7 Lung cancer �� 1, 2 Breast cancer ��14, 33, 51 Gastrointestinal cancer �� 36, 37 Prostate cancer �� 18, 38 Hematology �� 20, 31 A conversation with Dr. John Niederhuber �� 4 Direct from ASCO �� 23

continued on page 12

A Harborside Press Publication

The ASCO Post | JULY 2010

PAGE 2

News Lung Cancer

Doublet Significantly Improves Survival in Older Patients with NSCLC By Caroline Helwick lder persons with advanced non– small cell lung cancer (NSCLC) can gain 4 months in overall survival (OS) when treated with a paclitaxel/ carboplatin doublet, vs a single agent, according to French investigators who reported highly significant improvements at the Plenary Session of the 2010 ASCO Annual Meeting.1 The phase III study was devoted to determining safety and efficacy of relatively aggressive treatment in patients aged 70 to 89. Based on the findSee page 55 ings, weekly paclitaxel and monthly carboplatin represents a new treatment paradigm for the elderly, said principal investigator Elisabeth Quoix, MD, Professor of Medicine at University Hospital, Strasbourg, on behalf of The French Intergroup of Thoracic Oncology. “These results demonstrate that a more intensive regimen typically reserved for younger patients can be effective and tolerable in this group as well,” she said.

Impact in Europe vs United States ASCO guidelines state that first-line chemotherapy should not be selected based exclusively on the patient’s age,2

but those of the European Organisation for Research and Treatment of Cancer (EORTC) are more conservative, stating that third-generation single-agent treatment is the standard of care for elderly patients.3 Corey Langer, MD, who has led many NSCLC treatment trials in the elderly, called the study one of the most important to be presented at ASCO. “It was a well constructed trial showing a whopping survival benefit,” he told The ASCO Post. He said the findings will be particularly relevant in Europe, where doublets are not commonly used in the elderly, but informs U.S. practice as well, since aggressive treatment is often reserved for the fittest patients. Dr. Langer is Director of Thoracic Oncology at Abramson Cancer Center at the University of Pennsylvania, Philadelphia.

Trial Rationale The Intergroupe Francophone de Cancérologie Thoracique (IFCT)0501 study enrolled 451 patients aged 70 to 89 from 62 French centers. The investigators aimed to compare singleagent treatment to a platinum-based doublet specifically in elderly patients; no previous study dedicated to this group has been performed. The only indication in favor of a platin-based doublet was a subset analysis in a

Inside The ASCO Post – Don't miss these important perspectives: Page 3 Dr. Richard Boxer calls on President Obama to create a new public/private enterprise dedicated to the pursuit and protection of medical innovation in America. Page 23 Dr. Allen Lichter discusses the Medicare physician payment problem and explains why this must be fixed now. Page 41 Dr. Stanley Winokur calls on oncologists to learn how to listen to their patients in addition to treating their cancer. Plus: Page 42 Find out more about one of ASCO’s original founders, Dr. Jane Cooke Wright, and her personal recollections on ASCO’s beginnings plus her expert advice and guidance to ASCO members today. Page 53 Drs. Charles Bennett, E.W. Lingle, and Robert Langdon offer their viewpoints on whether oncologists should provide imaging services.

Elderly Patients with Advanced NSCLC ■■ Elderly patients (aged 70–89) with advanced NSCLC lived 4 additional

months (approximately 10 vs 6 months) when treated with a paclitaxel/ carboplatin doublet, rather than a single agent (gemcitabine or vinorelbine), in a French multicenter phase III study.

■■ Progression-free survival was doubled with combination therapy. ■■ Most elderly patients still do not receive aggressive chemotherapy, although studies show that it extends survival.

phase III trial conducted by Lilenbaum and colleagues, in which carboplatin/paclitaxel was more efficacious than the taxane alone.4 In the current study, patients’ median age was 77, most had stage IV adenocarcinoma but good performance status, and approximately 20% had never smoked. They were randomly assigned to single-agent therapy with either gemcitabine (Gemzar) at 1,150 mg/m2 or vinorelbine at 30 mg/m2 days 1 and 8 every 3 weeks for five cycles, or to combination therapy with carboplatin (area under the curve 1.0 –

Survival probability

[AUC] 6) every 4 weeks plus weekly paclitaxel at 90 mg/m2 (days 1, 8, and 15) for four cycles. Upon disease progression, all patients could receive erlotinib (Tarceva) at 150 mg/d. The median number of chemotherapy cycles was four for both arms.

Doublet Adds 4 Months to Survival The study was stopped early when an interim analysis found that OS and progression-free survival (PFS) were longer in the combination arm. Mecontinued on page 10

MST = 10.3 (95% CI = 8.3-13.3) 1-yr survival 45.1% (95% CI = 38.2-51.8)

0.8 –

MST = 6.2 (95% CI = 5.3-7.4) 1-yr survival 26.9% (95% CI = 21-33.1)

0.6 –

P = .00004

0.4 –

0.2 –

0.0 – 0

Doublet Single

Single

226

112

Doublet

225

150

Months

Fig. 1: Overall survival in IFCT-0501 trial, Intent-to-treat analysis. MST = median survival time. Courtesy of Elisabeth Quoix, MD.

Erratum In the June 2010 issue of The ASCO Post, an article on page 9 (“Cabazitaxel Improves Survival in Patients with Castration-resistant Prostate Cancer”) misstated the dosing interval for mitoxantrone and cabazitaxel used in the TROPIC study. The correct regimen is 10 mg/d of predniSee page 55 sone with either mitoxantrone at 12 mg/m2 or cabazitaxel 2 at 25 mg/m , both administered every 3 weeks. The corrected version of this article is available online at ASCOPost.com. See page 45 in this issue for more on cabazitaxel.

ASCOPost.com | JULY 2010

PAGE 3

Opinion

American Center for Cures Could Ensure Health-care Reform Leads to Reform in Health

Editorial Board James O. Armitage, MD Editor-in-Chief Professor, Internal Medicine Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Charles L. Bennett, MD, PhD, MPP Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis David Khayat, MD Salpetriere Hospital, Paris Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Douglas W. Blayney, MD Stanford University Medical Center

Michael P. Link, MD Stanford University Medical Center

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Eduardo Cazap, MD, PhD Buenos Aires, Argentina Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Elizabeth Reed, MD University of Nebraska Medical Center Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida

Harborside Press Publishing Staff

Conor Lynch Executive Editor Conor@harborsidepress.com

Wendy McGullam Director of Production Wendy@harborsidepress.com

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

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

Andrew Nash Associate Director of Editorial Andrew@harborsidepress.com

Anthony Cutrone President Anthony@harborsidepress.com

Sarah McGullam Assistant Editor Sarah@harborsidepress.com

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

Michael Buckley Graphic Designer Michael@harborsidepress.com

Contributing Writers Charlotte Bath, Barbara Boughton, Jo Cavallo, Alice Goodman, Caroline Helwick, Kathleen Louden, Larry Rosenberg, PhD, June Skinner, Matthew Stenger, Patrick Young

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

By Richard Boxer, MD, FACS

resident Obama and the congressional leadership should call for the creation of a new public/private enterprise dedicated to the pursuit and protection of medical innovation in America. This enterprise—referred to as the American Center for Cures (ACC)—would be designed to achieve breakthroughs in cancer and other devastating illnesses that affect Americans, thereby improving health, health care, and the health of the economy. The explosion of scientific knowledge in the past 50 years has been astounding, but cancer cases as a percentage of the population con-

The ACC would bring together the pieces of the puzzle produced by basic scientists. stitute the same proportion today as they did in 1950. It is appropriate and compelling to support not only improvements in health-care access, quality, and affordability, but also a new undertaking focused on achieving direct and dramatic improvements in the health of Americans.

Key Attributes The ACC should be an applications and translational center with special emphasis on the discovery of early biomarkers to prevent, diagnose, or cure disease. A well-funded, focused ACC will bring to bear the genius and resources of America to eliminate the scourge of so many chronic debilitating diseases such as Alzheimer’s, Parkinson’s, diabetes, depression, schizophrenia, arthritis, cancer, heart disease, and others. The ACC would bridge the basic science– to–industrial production gap to safely, efficiently, and expeditiously bring discoveries to the bedside. It would be responsible for bringing together

the pieces of the scientific puzzle produced by the world’s basic scientists. The ACC would be supported with public/private funding and directed by leadership from government, industry, academia, and nonprofit sectors. It would be mission-driven, accountable, and authorized to pursue high-risk/highreward translational and clinical research opportunities. In addition, it would be multidisciplinary, including biologic and physical sciences. The organization would be charged with establishing collaborative centers of excellence in regulatory science defined by transparency, collaboration, and data sharing. Such centers of excellence would be designed to bring best practices from industry into academia and to train a new cadre of investigators skilled in moving products through the development pipeline from proof of concept in humans to commercialization. The Center would be governed by a Board (Cures Council) appointed by the President, consisting of leaders in basic and clinical science, the physical sciences, patient advocacy, and entrepreneurs, with recommendations from the National Academy of Sciences. It would fall under the authority of the Secretary of Health and Human Services (HHS) with the power necessary to forge a new bridge across the HHS scientific infrastructure. Finally, it would be coordinated by a CEO charged with responsibility, accountability, and a sense of urgent mission to cure diseases targeted through cross-agency, multidisciplinary, global leadership.

Administrative Elements The Director of the National Institutes of Health (NIH) would henceforth also be called the Director (or Secretary) of Cures (DOC). This position ideally will be elevated to a cabinet post to demonstrate the commitment of the nation. The ACC will be located within the Office of the DOC. continued on page 17

The ASCO Post | JULY 2010

PAGE 4

Expert’s Corner

A Conversation with John E. Niederhuber, MD The departing director of NCI talks about his challenges and accomplishments. By Jo Cavallo with the ultimate goal of finding the genomic alterations that cause all cancers. The ASCO Post asked Dr. Niederhuber to reflect on his tenure as Director of NCI.

Greatest Challenges

John E. Niederhuber, MD

his month, John E. Niederhuber, MD, will step down as Director of the National Cancer Institute. For the past 5 years (1 year as NCI’s Chief Operating Officer and Deputy Director for Translational and Clinical Studies and 4 years as NCI’s Director), Dr. Niederhuber has spearheaded nine initiatives to propel the development of new cancer drugs, including the NCI Community Cancer Centers Program, whose major goal is to allow cancer patients to have access to the latest science and to be enrolled in early-phase NCI-sponsored clinical trials while remaining in their home communities. During that time, Dr. Niederhuber also oversaw the launch of The Cancer Genome Atlas—a joint project with the National Human Genome Research Institute—whose initial goal was to sequence the genomes of three cancers (brain, lung, and ovarian) and which has now been expanded to include sequencing the genomes of 20 more cancers,

What were some of the greatest challenges you faced when you became Director of NCI in 2006? Dr. Niederhuber: The greatest challenge was learning the magnitude of the Institute. All of us in the cancer field have interacted with the National Institutes of Health (NIH) and NCI in a variety of ways. We serve on committees and review boards. In my case, over the years, I’ve served on quite a few different committees and finally was the Chair of the National Cancer Advisory Board, so

increase in 2009 of over 2%, and another 2% in 2010. Both of those increases, which eventually took us over $5 billion in appropriated money each year, were less than inflationary increases, so the big challenge each year was in taking between $170 million and $175 million out of the budget just to keep even with the loss of our purchasing power due to inflation. That was certainly one of the bigger stressors.

Greatest Accomplishments Given all those challenges, what do you think were your greatest accomplishments during the past 5 years? Dr. Niederhuber: That will be for others to judge. But despite the flat budget we were able to start some new programs. We were able to increase

As a 25-year member of ASCO myself, I believe that all ASCO members need to recognize that we are moving into a new era, in terms of how science is going to drive new discoveries and eventual translation into the clinic. I thought that I really knew a great deal about NCI and NIH. I’ve always had grants from the NIH, and my laboratory of Tumor and Stem Cell Biology is here as well. But I think when you first come here, you think “wow, this is a big operation—a big responsibility.” Of course, the challenge when I took over in 2005 was coping with belowinflation budgets. We finally received an

the number of NCI-designated cancer centers from 61 to 65. One of the things that enticed me to come here was the opportunity to address the issue of accessibility to clinical trials and to evidence-based oncology care, which I have been concerned about for quite some time. That concern came about not just from taking care of patients, but also from taking care of my wife, Tracey,

as she was dealing with metastatic breast cancer. With her experience, I realized even more directly the struggles that our patients and their families have to deal with in terms of having access to our latest discoveries and to early-phase clinical trials. On one occasion, the only way Tracey could get a specific drug in a clinical trial was to leave our home in Wisconsin, travel across the country to the trial site, and be there for a week, away from her family. At one point after several of those trips Tracey said to me, “you know you really have to do something about this.” So I had an idea based on work my colleagues and I had done when I was Director of the University of Wisconsin Comprehensive Cancer Center. That project involved outreach into community settings to extend the clinical trial research we were doing to smaller hospitals. At NCI, I have tried to create a second rim of cancer care and access to clinical research outside of our well-established cancer centers program, taking the science of the cancer program supported by the NCI out to the communities where people live. We set up a pilot project called the NCI Community Cancer Centers Program (NCCCP) that involves a group of hospitals and community oncologists nationwide. The physicians have conferences once a week to discuss information on breast cancer, lung cancer, head and neck cancers, and gastrointestinal malignancies. They also talk about their new patients, review radiology and pathology reports, and make continued on page 21

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

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

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

ASCOPost.com | JULY 2010

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Editorial

From the Editor-in-Chief continued from page 1

more about the nine initiatives Dr. Niederhuber spearheaded to propel the development of new cancer drugs during his tenure at NCI. Insightful editorial from ASCO leadership: See page 23 for an important editorial from ASCO CEO Allen S. Lichter, MD, concerning the Medicare physician payment problem and why ASCO is fighting to find solutions to this $247 billion issue. Thoughtful commentary: See page 3 for a compelling opinion piece written by Richard Boxer, MD, on creating a new public/private enterprise dedicated to medical innovation in America; see page 41 for a personal viewpoint from Stanley Winokur, MD, on lessons he learned in caring for patients and simple steps you can take to better care for your patients. JCO Spotlight: See page 51 for a review of important clinical research on trastuzumab (Herceptin)-associated cardiac toxicity as published in a recent issue of the Journal of Clinical Oncology. TAP Caucus: Should oncologists own imaging centers? Robert Langdon, MD and Charles Bennett, MD, PhD, and Earle W. Lingle, PhD share their thoughts in a pro/con discussion on this contentious issue. See page 53. Note the Letter to the Editor on page 55 from Dr. Ann Murphy in response to the discussion on physician-assisted suicide. We would like you to contribute to our Letters to the Editor department and encourage you to share your thoughts on oncology issues in The ASCO Post. And don’t miss In the Spotlight, page 42, in which The ASCO Post presents a personal profile of one of ASCO’s original founders Jane Cooke Wright, MD. Dr. Wright was a pioneer in 20th century medicine, overcoming obstacles placed on her by society as a woman and as an African-American. But most of all she was a pioneer in chemotherapy taking those first small steps into the unknown and paving the way for the giant steps to follow. Dr. Wright shares her wisdom and guidance and some of the best advice she received, reminding us that to help others in a worthy mission is a noble goal for one’s life. Finally be sure to use the 2D barcode technology inside this and every issue. See page 55 for information on obtaining your free ScanLife application for your smartphone and access-

ing original resources relevant to the news reports in this issue. Clearly the data presented at ASCO’s Annual Meeting and reported in this issue of The ASCO Post will continue to challenge all of us in the oncology community. In the meantime, it is our intention that the clinical news and peer view-

points presented herein will be helpful in our efforts toward unraveling the complex processes inherent in a cancer diagnosis; finding answers to optimizing the prevention, diagnosis, and treatment of cancer, while minimizing the cost; improving the quality of care we deliver; and always, better serving our patients.

I hope you enjoy this issue and I invite you to contact The ASCO Post with your thoughts on how this publication can be an even more valuable and rewarding resource. I look forward to hearing from you. —James O. Armitage, MD Editor@ASCOPost.com

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

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Cover Feature

continued from page 1

the United States. Melanoma typically has a young age of onset, killing young adults in their prime within 6 to 12 months, Dr. O’Day told listeners. Ipilimumab, a fully human monoclonal antibody that is administered intravenously, represents a new class of drugs that activates immune system T cells to seek and destroy melanoma cells, Dr. O’Day explained. Ipilimumab inhibits the cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4) that downregulates the immune response. Blocking the activity of CTLA-4 stimulates the immune system to fight the melanoma. The gp100 vaccine, used as the control arm in the study, is an experimental melanoma peptide vaccine that also stimulates T cells to attack melanoma cells but has modest anticancer activity.

Three-Arm Trial The study enrolled 676 patients at 125 centers in 13 countries. Patients were randomized 3:1:1 to receive ipilimumab plus the gp100 vaccine (arm A), ipilimumab alone (arm B), or the gp100 vaccine alone (arm C). All patients had been pretreated for metastatic melanoma, and all were HLA0201–positive, which is a prerequisite for receiving the gp100 vaccine. About 12% of patients had been previously treated for central nervous system

metastases. Ipilimumab was given at 3 mg/kg every 3 weeks for four doses; gp100 was given at 1 mg every 3 weeks for four doses. Treatment arms were well balanced for demographic and disease characteristics. Patients enrolled in the trial were generally considered poor risk. Mean age was about 55 years, 70% had visceral metastases, 10% to 15% had been treated for central nervous system metastasis, 38% had elevated lactate dehydrogenase, and 23% received prior interleukin-2 (Proleukin) treatment for advanced melanoma. Overall median survival was improved from 6.4 months with the vaccine alone to 10 months in both ipilimumab arms; the difference in overall median survival was significant for arm A over arm C (vaccine alone, P = .0004), and for arm B over arm C (P = .0026). Both 1-year and 2-year survival rates were almost doubled in the ipilimumab arms compared to the vaccine alone (arm C); 1-year survival was 44% to 46% in the ipilimumab-treated patients vs 25% in the vaccine-alone arm; 2-year survival was 22% to 24% in the ipilimumab-treated patients vs 14% in the vaccine-alone arm. Dr. O’Day said that some of the patients were still alive at 4.5 years. The addition of the gp100 vaccine did not improve survival or add to toxicity, Dr. O’Day noted.

Ipilimumab for Melanoma ■■ For the first time, a drug has shown a survival advantage in advanced melanoma.

■■ Ipilimumab improved median survival by about 3.5 months compared with the gp100 vaccine (control arm).

■■ Ipilimumab has serious immune-related toxicity that requires prompt attention by an experienced multidisciplinary team.

■■ Further study is needed to establish the safety and role of this treatment.

Expert Point of View

ormal discussant of this trial, Vernon K. Sondak, MD, who is Chair of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center in Tampa, Florida, said “For the first time in 30 years we can say there was a documented improvement in survival in a phase III study.” In regard to potentially life-threatening ipilimumab-associated toxicity, a major concern, Dr. Sondak said, this could be managed by a Vernon K. Sondak, MD trained oncologist and an experienced multidisciplinary team “if they are careful, if they are thorough, and if they are aggressive with it.” In conclusion, Dr. Sondak alluded to there being a “light at the end of the long dark tunnel,” but he noted that improvements are needed and the best option for patients with advanced melanoma remains a clinical trial. Dr. Sondak’s full discussion may be viewed on ASCO’s Virtual Meeting (subscription required) by visiting http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting. Photo by © ASCO/Todd Buchanan 2010

Advanced Melanoma

■

Adverse Events Two-thirds of patients receiving ipilimumab had immune-related adverse events compared with one-third of the patients receiving the vaccine alone. The most common immune-related adverse events were skin and gastrointestinal toxicity, and much more rarely, liver or pituitary events (<10%). The majority of immune-related events were grade 1 or 2, reversible, and managed symptomatically. About 10% to 14% of these immune-related events were grade 3 or 4 and required highdose corticosteroid therapy. The vast majority of these resolved over 4 to 6 weeks with steroid taper. “Ipilimumab is a powerful drug and there were some treatment-related deaths on all arms of study, Dr. O’Day noted, adding that “a slightly higher percentage of treatment-related deaths was reported in the ipilimumab arms (2%-3% vs 1%-2%).” The majority of the immune-related deaths were attributable to gastrointestinal perfora-

tion and sepsis, Dr. O’Day said.

On the Horizon Ipilimumab is also being studied in other cancers, in combination with other treatments, and at different doses and schedules. The study was sponsored by Bristol-Myers Squibb, and the company expects to seek regulatory approval of ipilimumab in advanced melanoma this year.

■

References 1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. June 5, 2010 (epub ahead of print). 2. O'Day S, Hodi FS, McDermott DF, et al: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma. 2010 ASCO Annual Meeting. Abstract 4. Presented June 6, 2010.

Coming in the August 2010 Issue of ■■ Comprehensive coverage of the 2010 ASCO Annual Meeting, with important take-home messages and expert perspectives on breast cancer, lung cancer, gastrointestinal cancers, genitourinary cancers, hematologic malignancies, and more

■■ A Conversation with Owen O’Connor on the next advances in blood cancers ■■ Important Columns, Engaging Features, and Clinical Departments

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

ASCOPost.com | JULY 2010

PAGE 7

News Ovarian Cancer

Targeted Therapy Extends Progression-free Survival in Advanced Ovarian Cancer By Kathleen Louden

Proportion surviving progression free

omen with advanced ovarian cancer live longer without disease progression when they receive bevacizumab (Avastin) with first-line chemotherapy and then as single-agent maintenance therapy, a phase III clinical trial presented at the 2010 ASCO Annual Meeting finds. Results of the Gynecologic Oncology Group (GOG)0218 study were presented during the Plenary Session at the meeting.1 Progression-free survival (PFS) was nearly 4 months (or about 39%) longer in the experimental treatment arm receiving bevacizumab and standard chemotherapy, followed by bevacizumab-alone maintenance treatment. That group had a median

macroscopic residual (unresectable) tumor at the completion of initial surgery. None of the patients had received prior chemotherapy. Patients were randomly assigned to one of three double-blind treatment arms. The control arm (n = 625) received six cycles of standard IV chemotherapy—carboplatin at area under the curve (AUC) 6, and paclitaxel at 175 mg/m2—plus IV infusion of placebo (five cycles). This regimen was followed by placebo every 3 weeks during a maintenance phase lasting up to 10 months. Another 625 patients received standard chemotherapy plus IV bevacizumab (15 mg/kg) beginning with the second cycle, followed by placebo maintenance.

1.0 0.9

Patients with event, n (%)

0.8

Median PFS, months

0.7

Stratified analysis HR (95% CI)

0.6

Arm I CP (n=625)

Arm III CP + BEV BEV (n=623)

423 (67.7)

360 (57.8)

10.3

One-sided P value (log rank)

0.5

14.1 0.717 (0.625–0.824) <.0001

0.4 0.3 0.2

CP (Arm I)

0.1 0

+ BEV

BEV maintenance (Arm III)

Months since randomization

Fig. 1: Progression-free survival by treatment arm in GOG-0218. BEV = bevacizumab; CP = carboplatin/ paclitaxel; GOG = Gynecologic Oncology Group; PFS = progression-free survival. Courtesy of Robert Burger, MD.

PFS of 14.1 months vs 10.3 months in the control arm, which received only chemotherapy. “This regimen should be considered one treatment option for advanced ovarian cancer,” said lead researcher on this trial for the GOG, Robert Burger, MD, Professor in the Department of Surgical Gynecology and Director of the Women’s Cancer Center, Fox Chase Cancer Center, Philadelphia. “Bevacizumab is the first molecular targeted therapy and the first antiangiogenic agent to demonstrate benefit in this population,” he said. The NCI-supported trial conducted by the GOG enrolled 1,873 women with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer from four countries (United States, Canada, South Korea, and Japan). Two-thirds of the patients had stage III or IV disease with suboptimal tumor debulking, and the others had optimally debulked stage III disease but with

The remaining 623 patients received standard chemotherapy plus concurrent and maintenance bevacizumab.

Primary Endpoint Changed After the study began, the investigators changed the primary endpoint from overall survival (OS) to PFS. Maintaining blinding of the treatment at disease progression was unfeasible due in part to the commercial availability and common off-label use of bevacizumab in patients with recurrent ovarian cancer; in addition, a consensus by the Gynecologic Cancer Intergroup published in 2005 in the Annals of Oncology stated that PFS is perhaps a better primary endpoint in front-line phase III ovarian cancer trials. Unblinding at disease progression allowed crossover to bevacizumab treatment, Dr. Burger said. The use of bevacizumab during chemotherapy without maintenance doses (arm 2) did not provide a sta-

Bevacizumab in Advanced Ovarian Cancer ■■ Bevacizumab as primary maintenance treatment of stage III and IV ovarian cancer prolongs life without disease progression.

■■ This study did not show a gain in overall survival with the addition

of bevacizumab to chemotherapy and for single-agent maintenance treatment.

■■ Bevacizumab during and after standard chemotherapy is a front-line treatment option for women with advanced ovarian cancer.

tistically significant increase in PFS (median = 11.2 months). However, all analyses, including subgroup analyses, supported an improved PFS (Fig. 1) in the concurrent and maintenance bevacizumab group (arm 3), Dr. Burger reported. Therefore, he said, the study met its primary objective. To help determine PFS, the authors used serum cancer antigen 125 (CA-125) in addition to standard NCI response evaluation criteria in solid tumors (RECIST) criteria with radiographic imaging. At a median follow-up of 17.4 months, OS was similar in the treatment groups, but longer follow-up is needed, according to Dr. Burger. Besides OS, secondary endpoints included safety, quality of life, and translational laboratory studies

Adverse Events Tolerable The bevacizumab regimen was “generally well tolerated,” Dr. Burger said. Adverse events were similar to those occurring occuring in previous phase III trials of this agent in nongynecologic cancers. Among the adverse events that occurred more frequently in the two bevacizumab arms than in the control arm were grade 2 or greater hypertension or proteinuria; grade 3 or greater pain or gastrointestinal (GI) hemorrhage, perforation, or fistula; and grade 4 neutropenia. Less than 3% of patients in either bevacizumab arm had GI complications, he said. The proportion of patients who discontinued therapy because of adverse continued on page 12

Expert Point of View

lizabeth Eisenhauer, MD, of Queens University, Kingston, Ontario, Canada, the discussant for the abstract, said the study was well conducted and adequately powered. However, she questioned the change in primary endpoint to PFS, asking, “What does a gain in PFS mean for patients?” From the data presented, she said she could not determine whether quality of life improved in the patients who had a longer PFS. It also is unclear, she Elizabeth Eisenhauer, MD said, whether PFS is a surrogate for OS in maintenance therapy for this disease. “In some other bevacizumab randomized clinical trials in other types of cancer, OS improvement was at least 2 months less than PFS,” Dr. Eisenhauer said. “So we can’t say unequivocally that OS and PFS equate in ovarian cancer.” Dr. Eisenhauer roughly estimated that the median cost of bevacizumab for each year of PFS gained is $229,187 per patient (based on the median number of treatment cycles and median gain in PFS). She said “most would not consider this [amount] cost-effective.” Additionally, she asked if the use of bevacizumab for maintenance therapy only, without the expense of concurrent first-line therapy, would have provided sufficient benefit. “I hope this gain in PFS will translate to longer overall survival for these women, who desperately need it,” Dr. Eisenhauer said. “However, I don’t think any change in clinical practice is needed yet.”

■

For an effective option

Choose TREANDA® For 2nd-line treatment of indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed

TREANDA monotherapy produced robust responses in patients resistant to rituximab or rituximab-containing regimens1 • TREANDA was evaluated in a singlearm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles

Response rates

PR (n=57)

57 % Total ORR* 74%

CR/CRu (n=17)

(95% CI†: 64.3, 82.3)

17 % 0

50 60 Patients responding (%) Patients responding (%)

100

*Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). † CI=confidence interval.

TREANDA monotherapy provided durable responses that lasted a median of 9 months1 Median duration of response

CR/CRu

All responders

10.4 mo

(95% CI: 9.3, 13.6)

9.2 mo

(95% CI: 7.1, 10.8)

8.3 mo

(95% CI: 6.3, 10.8)

Important Safety Information TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.TREANDA is also indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. The following serious adverse reactions have been associated with TREANDA: myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/ TEN, other malignancies, and extravasation. Some of these reactions have been fatal, including myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN). Patients should be monitored closely for these reactions and treated promptly if any occur. Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA.

For front-line treatment of chronic lymphocytic leukemia (CLL)

TREANDA monotherapy tripled median PFS1‡§ • TREANDA was compared with chlorambucil in a randomized, open-label, Phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles

Survival distribution function

1.0 18 MONTHS MEDIAN PFS WITH TREANDA VS 6 MONTHS MEDIAN PFS WITH CHLORAMBUCIL

0.9 0.8

TREANDA (n=153) Chlorambucil (n=148)

0.7 0.6 0.5 0.4 0.3

P<.0001

0.2

PFS=progression-free survival. TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). || HR=hazard ratio. ‡

HR||=0.27 (95% CI: 0.17, 0.43)

0.1 0

Months Months

TREANDA monotherapy more than doubled ORR1¶ CR nPR

(n=13) (n=4)

TREANDA (n=153)

(n=73)

8% 3%

Total ORR

48%

59%

(95% CI: 51.03, 66.62)

(n=1)

<1% Chlorambucil (n=148)

25% nPR

26%

P<.0001

(95% CI: 18.64, 32.71)

(n=0)

Total ORR

Overall response rate (ORR) was defined as a best response of a complete response (CR), nodular partial response (nPR), or partial response (PR) during the study (ORR=CR+nPR+PR).

(n=37)

100

Patients responding (%)

TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA. The most common non-hematologic adverse reactions associated with TREANDA (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.The most common hematologic abnormalities associated with TREANDA (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. ™ Built for Action Please see accompanying brief summary of full Prescribing Information. www.TREANDA.com Reference: 1. Data on ﬁle. Cephalon, Inc.

The ASCO Post | JULY 2010

PAGE 10

News Elderly Patients with NSCLC continued from page 2

dian follow-up was 21.3 months as of the data cutoff in March 2010. Overall survival was significantly improved for patients receiving the paclitaxel/carboplatin doublet: 10.3 vs 6.2 months with the single agent (P = .00004). One-year PFS rates were 45.1% and 26.9%, respectively

(see Figure 1 on page 2). An OS benefit was observed for most subgroups, including patients older than 80 years, smokers, and those with poor performance status, lower activities of daily living scores, and greater weight loss. Similarly, median PFS was improved from 3.0 months with the single agent to 6.1 months with the

doublet (P < .000001). One-year progression-free survival was 2.3% vs 15.4%, respectively. Objective responses were observed in 10.9% of the single-agent arm vs 29% of the doublet arm (P < .00001). Progressive disease was observed in 21.8% of patients on single agents but only 7.1% of those on the doublet (P < .0001).

Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Hematologic toxicity was significantly greater with the doublet regimen, but neuropathy grade 3 or 4 was limited to < 3% of patients in this arm. There were more toxic deaths (6.6% vs 1.8%) with the doublet arm. However, early deaths (within 3 months) were more common with the single agents (25.6% vs 16.7%).

■

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53) 13 (7)

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

ASCOPost.com | JULY 2010

PAGE 11

News

References 1. Quoix EA, Oster J, Westeel V, et al: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced nonsmall cell lung cancer. 2010 ASCO Annual Meeting. Abstract 2. Presented June 6, 2010.

2. Azzoli CG, Baker S, Temin S, et al: American Society of Clinical Oncology Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 27:6251-6256, 2009. 3. Pallis AG, Gridelli C, van Meerbeeck JP, et al: EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology experts’ opin-

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

ion for the treatment of non-small-cell lung cancer in an elderly population. Ann Oncol 21:692-706, 2010. 4. Lilenbaum RC, Herndon JE, List MA, et al: Single-agent versus combination chemotherapy in advanced nonsmall-cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 23:190-196, 2005.

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

he study by the French Intergroup of Thoracic Oncology is an important contribution to the “maturity of cytotoxic chemotherapy” in establishing the benefit of platinum-based combinations in elderly patients with non–small cell lung cancer (NSCLC), said Martin J. Edelman, MD, who was the invited discussant of the paper (Abstract 2) at the 2010 ASCO Annual Meeting. Dr. Edelman is Professor of Medicine at the University of Maryland Greenebaum Cancer Center, Baltimore. While numerous studies have shown that platinum-based therapy extends life and improves quality of life, the average trial subject is just 62 years old—10 years younger than the typical patient with advanced NSCLC. Thus, the applicability of data to older patients has been questionable, Dr. Edelman said. He and his colleagues recently analyzed the Surveillance, Epidemiology, and End Results (SEER)/Medicare database of 21,285 patients with advanced NSCLC, aged 66 years and older.1 Although firstline platinum-based doublets increased 1-year survival (30.1% vs 19.4% with single agents), threequarters of patients received no chemotherapy at all, “let alone a combination regimen,” he reported. “If the elderly do get treated, it’s with a single agent.” Dr. Edelman suggested that the study design might have been improved with an established control arm (rather than physician’s choice) but acknowledged that gemcitabine (Gemzar) and vinorelbine are similar in efficacy and both appropriate. He concluded that the findings “should change day-to-day practice,” though clinicians should remain cognizant of the potential for toxicities in the elderly and “be selective” in their use of doublets.

■

DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

Expert Point of View

Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2010 Cephalon, Inc., or its affiliates. TRE-2064 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

Reference 1. Davidoff AJ, Tang M, Seal B, et al: Chemotherapy and survival benefit in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 28:2191-2197, 2010.

The ASCO Post | JULY 2010

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News

able as of April 7, 2010. The patients’ mean age was 51 years, 96% had adenocarcinoma histology, 76% were “never-smokers,” and 41% had undergone at least three prior regimens.

Striking Tumor Shrinkage Observed “Almost all patients had some degree of tumor shrinkage (Fig. 1), although more than half the patients (59%) had had at least two previous treatments,” Dr. Bang reported. Objective responses were observed in 57% of the cohort (63% when five unconfirmed partial responses are included), including more than half the patients with performance status 2 or 3. In terms of prior regimens, See page 55 80% of treatmentnaive patients responded, as did 52% receiving the drug as second-line therapy, 67% as third line, and 56% as fourth line or greater. Response duration ranged from 1 to 14 months, and the disease control rate (response or

Maximum change in tumor size (%)

stable disease at 8 weeks) was 87%. At a median follow-up of 6.4 months, median progression-free survival (PFS) was not yet reached. However, the probability of being progression-free at 6 months is 72%. Approximately 77% of patients remain on treatment, including seven patients for more than 1 year, he said. Treatment-related adverse events included nausea (52%), diarrhea (46%), vomiting (43%), and visual disturbance, ie, “shadows” (42%), but virtually all of these events were grade 1 and they tended to resolve over the course of treatment. Based on these preliminary findings, Dr. Bang maintained that “for patients with ALK-positive NSCLC, crizotinib may offer a potential new standard of care.”

Rapid Translational Research Mark Kris, MD, Chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York, who moderated a press briefing, commented that the findings are very important, not only for their clinical significance but as an example of rapid translational research. The fusion gene was first reported in 2007, Progressive disease

Stable disease Confirmed partial response

Confirmed complete response

20 0 –20

– 30%

–40 –60 –80

–100

Fig. 1: Tumor responses to crizotinib for patients with ALK-positive non–small cell lung cancer. *Partial response patients with 100% change have nontarget disease present. Courtesy of Yung-Jue Bang, MD, PhD.

Advanced Ovarian Cancer continued from page 7

events was slightly greater in the groups receiving bevacizumab. Adverse events leading to discontinuation of therapy occurred mainly in the chemotherapy phase. After a press conference about GOG-0218, moderator Jennifer Obel, MD, medical oncologist at NorthShore University HealthSystem and Assistant Clinical ProSee page 55 fessor of Medicine,

Physicians and patients must have an in-depth talk about whether the extra therapy is worth the longer progressionfree survival. – Jennifer Obel, MD

Expert Point of View

ccording to Martin Edelman, MD, Professor of Medicine at the University of Maryland Greenebaum Cancer Center, Baltimore, crizotinib should provide a targeted approach to “the other 50% of patients” ineligible for inhibitors of the epidermal growth factor receptor (EGFR). Use of the drug was applicable to 3% to 5% of all patients with lung cancer, he noted. Dr. Edelman was the invited discussant of Dr. Bang’s Plenary presentation. Martin Edelman, MD EML4/ALK has emerged as a new disease entity whose phenotype includes patients who are never or scant smokers, young, male, poor responders to standard chemotherapy (and EGFR inhibitors), and have adenocarcinoma histology (primarily signet ring morphology), he said. A search for EML4/ALK mutations will likely be added to the emerging testing strategy for NSCLC, possibly targeting nonsmokers (who should be carefully defined) and those with adenocarcinoma histology, he suggested. A clinically useful and possibly cost-effective algorithm is being proposed for NSCLC testing in which patients are initially screened for mutated KRAS. If negative, they go on to testing for the EGFR mutation, and if negative again, proceed to testing for the EML4/ALK translocation. Future targets would be added to this evolving algorithm. He said crizotinib may eventually change practice, but the drug is not yet commercially available. A phase III trial is in progress, though Dr. Edelman questioned the necessity of such a trial, given the urgent need for treatment options and the “superb response rate, durable PFS, and relatively little toxicity” seen with crizotinib in heavily pretreated patients. “Considering the results today, the [phase III] study is likely to be positive” and the drug should become “a major treatment advance” for this subset, he predicted. Photo by © ASCO/Todd Buchanan 2010

ALK-positive NSCLC continued from page 1

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he noted, and relevant clinical results are already being presented. “In just 3 short years we have gone from a description of an oncogene to a therapy” with which selected patients with the ALK mutation “can expect a dramatic benefit,” he said. “This speaks to the power of understanding the workings of the cancer cell, the mutations driving cancer growth, and how this can be parlayed into improvements in care,” he said, adding that the “apparatus” is already in place to begin testing a variety of emerging mutations.

References Bang Y, Kwak EL, Shaw AT, et al: Clinical activity of the oral ALK inhibitor PF02341066 in ALK-positive patients with non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract 3. Presented June 6, 2010.

University of Chicago, told The ASCO Post that a longer PFS is meaningful, because women with ovarian cancer tend to be asymptomatic when their cancer is not progressing. The downside, she said, is the need for months of maintenance chemotherapy. “We need to tell our patients clearly what progression-free survival means. This experimental therapy improves a patient’s chance of staying free of disease, but what we don’t know is whether a patient will live longer overall. Physicians and patients must

have an in-depth talk about whether the extra therapy is worth the longer progression-free survival,” Dr. Obel commented.

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Additional information on crizotinib (PF-02341066) clinical trials can be obtained by calling 1-877-369-9753 or visiting www.pfizercancertrials.com

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References 1. Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.

ASCOPost.com | JULY 2010

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News Personalized Medicine

Industry Leaders Pose Questions and Answers about Future Drug Development By Patrick Young

hould the pharmaceutical industry continue its current path of largely developing drugs that add only incremental increases in efficacy, or more aggressively develop and tap knowledge of disease processes to create medications that have a dramatic impact? “I’m in favor of a clinical development approach where hypotheses are derived directly from an understanding of the pathogenesis of the disease, and a strong hypothesis leading into clinical trials means a much lower risk of failure,” said William R. Sellers, MD, Global Head of the Novartis Institutes for Biomedical Research, at a Special Session of the American Association for Cancer Research (AACR) Annual Meeting, held in Washington, DC. Presentations at the Joint AACR/ ASCO Forum made clear that 21st century drug development will likely undergo major changes, including in clinical trials.

Five Challenges Dr. Sellers cited five major difficulties with targeting genetic alterations in cancer: 1. Most genetic alterations in cancer remain untreatable with drugs, including genetic alterations in the ras and myc oncogenes. “The pharmaceutical and academic communities will need to tackle the problem of drugging these hard targets,” Dr. Sellers said. 2. A large number of genetic alterations occur in tumor suppressor genes. There is a need to understand the interactions between suppresser pathways and druggable nodes. 3. Feedback loops can result in unanticipated signaling activation. 4. Cancers often have multiple pathways disrupted. Problems 3 and 4 need innovative approaches to identifying and developing novel drug combinations, Dr. Sellers noted. 5. Stratifying patients in clinical trials based on an understanding of the target cancer’s pathogenesis needs improvement. “The trial logistics of that have been incredibly hard, either from the perspective of getting biopsies or simply executing the clinical trials in which you have to screen huge numbers of patients to enroll a minor fraction,” Dr. Sellers said.

David P. Schenkein, MD, CEO of Agios Pharmaceuticals, addressed the problems of failing to stratify patients well. “One consequence—in addition to perhaps keeping us in a mode of incre-

mentalism as opposed to making transformative effects with our drugs—is whether we are actually throwing away important drugs,” Dr. Schenkein said. He cited a simulation study that suggested that without stratification

in Herceptin [trastuzumab] trials, the drug’s benefits would have been missed. “Drugs currently failing phase III studies and thrown away could potentially have been transformative continued on page 16

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

The ASCO Post | JULY 2010

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News Breast Cancer

Novel Agent Improves Survival in Women with Heavily Pretreated, Locally Recurrent, or Metastatic Breast Cancer By Caroline Helwick

n a phase III randomized study, patients with metastatic breast cancer who were treated with the novel agent eribulin mesylate lived on average 2.5 months longer than those treated with existing single agents, representing a statistically significant improvement in overall survival (OS) in an international study presented at the 2010 ASCO Annual Meeting.1 “Eribulin is unique in that it is the only single agent to show a survival benefit in women with heavily pretreated disease,” said principal investigator Christopher Twelves, MD, Professor of Clinical Cancer Pharmacology and Oncology at the University of Leeds in the United Kingdom. “The improvement seen is statistically significant and clinically meaningful for these women whose prognosis is poor.” Eribulin mesylate is a synthetic analog of halichondrin B that binds to a unique site on the microtubule via a novel mode of action. It has potent antiproliferative effects, is active against β-tubulin–mutated cell lines, and induces less neuropathy in preclinical models than paclitaxel, according to Dr. Twelves. The EMBRACE study (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus Eribulin) was a global, randomized, open-label phase III trial involving 762 patients with locally recurrent or metastatic breast cancer who had received a median of four prior chemotherapy regimens; all had received prior anthracycline and taxane treatment and over 70% had also received capecitabine (Xeloda). Most cancers were estrogen-receptor–positive and HER2-negative, and about half had more than two sites of metastases. Patients were randomized 2:1 to eribulin, 1.4 mg/m2 given intravenously on days 1 and 8 every 3 weeks (n = 508), or treatment according to physician’s choice (TPC, n = 254). TPC could consist of any single agent— cytotoxic, endocrine, See page 55 or biologic—approved for the treatment of cancer. Although best supportive care alone was acceptable, no patient received this, or a biologic agent, as sole treatment. The most commonly employed TPC was vinorelbine, followed by gemcitabine (Gemzar) and capecitabine.

“Our control arm was different from that of most trials. We allowed physician’s choice because there is no single established standard, and we felt it was inappropriate to restrict the options. This was a real-life comparison,” Dr. Twelves explained at a press briefing.

Overall Survival Improved by 2.5 Months Median OS, the primary endpoint, improved from 10.65 months with standard single-agent therapy to 13.12 months with eribulin, representing an overall 19% reduction in mortality risk (P = .04); the 1-year survival rate was 53.9% with eribulin and 43.7% in the TPC arm. Interestingly, progression-free survival (PFS) by independent review was also numerically superior, but this did not reach statistical significance: 3.7 vs 2.2 months with TPC (HR = 0.87; P = .14); by investigator review, however, the difference was highly significant (HR = 0.76; P = .002). Although the reasons for this discrepancy are not entirely clear, Dr. Twelves pointed out that many patients were censored in the independent review because their metastatic site was not radiologically evaluable. Objective response rates were modest, but overall responses were significantly more common with eribulin: 12.2% vs 4.7% (P = .002) by independent review and 13.2% vs 7.5% by investigator review (P = .028).

Manageable Toxicity “These benefits were achieved with a manageable toxicity profile,” Dr. Twelves announced. Serious adverse events were observed in about 25% of patients in each arm, and adverse events leading to treatment interruption, dose delays, and interruptions and discontinuations were very similar. Fatal adverse events occurred in 4.0% on eribulin and 7.3% on TPC, and were treatment-related in approximately 1% of each. Grade 3 or 4 neutropenia was observed in 45.2% of patients on eribulin and 21.1% of those receiving TPC, and peripheral neuropathy was seen in 8.2% and 2.0%, respectively. “The 8.2% rate of grade 3 or 4 neuropathy is very encouraging for a microtubule-targeted agent, especially since patients with neuropathy up to grade 2 at baseline were eligible,” he commented.

Expert Point of View

arold J. Burstein, MD, of the Dana-Farber Cancer Institute and an Associate Professor of Medicine at Harvard Medical School, Boston, commented on the findings and implications of the EMBRACE trial, first noting that the medical literature offers little guidance on the optimal treatment of metastatic patients. “We have a variety of single agents and regimens, yet there is remarkably little consensus on how best to use them in the first line and after Harold J. Burstein, MD multiple lines of treatment,” he observed. Responses may be seen in up to 45% of patients undergoing first-line therapy, with progression delayed for up to 8 months, but outcomes are progressively worse as more treatment is given. Virtually no data support more than four lines of therapy, yet patients frequently receive even more than this, he noted. A review from Dr. Burstein’s own practice of 35 patients who had passed away in recent years shows that treatment duration becomes shorter with additional lines of therapy, though different subsets respond differently. Patients with triple-negative breast cancer generally have short remissions, whereas patients with only HER2-negative cancer can continue to mount robust responses. The EMBRACE study helps answer the need for “high-level evidence for outcomes” in heavily pretreated metastatic disease, Dr. Burstein said. “Eribulin is associated with a survival advantage among such patients, which is a very notable result.” The study’s strengths were that it focused on heavily pretreated patients (with a median of four prior regimens)—“a setting of clear unmet need”— and that it included all comers and used a control arm reflecting “real-world options,” he said. Its limitations were its unblended design, and the likelihood that one-quarter to one-half of TPC patients received treatments to which they had previously been exposed. “Would survival differences be seen if these rechallenge patients were omitted from the analysis?” he questioned. Dr. Burstein found it interesting that progression-free survival was not improved, but reasoned that RECIST criteria for response (and hence time to progression) may not be relevant among heavily pretreated patients with multiple, and possibly unmeasurable, sites of disease. He also wondered whether treatment postprogression differed markedly between the groups and whether responders or certain tumor subsets derived a greater survival advantage. “More studies are warranted to understand how best to incorporate this novel agent into our standard treatment algorithm, but eribulin is a welcome addition to the armamentarium,” he concluded.

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“EMBRACE is the first phase III single-agent study in heavily pretreated metastatic breast cancer to meet its primary endpoint of prolonged overall survival, so these are striking findings,” Dr. Twelves concluded. “The 2.5-month improvement in median survival represented a 23% benefit. We see these findings as potentially establishing eribulin as a new treatment option for women with heavily pretreated metastatic breast cancer.” Eric P. Winer, MD, Director of the Breast Cancer Program at Dana-Farber

Cancer Institute, Boston, commented at a press briefing that a 2.5-month improvement is “a difference that is sufficient to make one look seriously at this agent.”

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Reference Twelves C, Loesch D, Blum JL, et al: A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. 2010 ASCO Annual Meeting. Abstract CRA1004. Presented June 8, 2010.

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

MEDIAN OS NOT REACHED FOR VcMP

% Patients Without Event

80 70 60 50 40 30 20 10

■ VELCADE+MP (n=344) ■ MP (n=338)

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

0 0

Kaplan-Meier estimate.

Months

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

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

Please see Brief Summary for VELCADE on next page. VELCADE is indicated for the treatment of patients with multiple myeloma. *VISTA, a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. †VcMP=VELCADE + melphalan/prednisone (MP).

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

The ASCO Post | JULY 2010

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6/4/10

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Drug Development continued from page 13

drugs if they had been subjected to the right patient populations,” he added.

Five Proposed Solutions Dr. Schenkein offered five possible solutions: 1. Gain a deeper understanding of

the pathway interactions that drive cancer tumors, because an effective drug needs to match a cancer’s genetic profile. 2. Provide the same incentives and investments to the discovery of diagnostics and biomarkers that are applied to discovering the drug itself. Discovering the biomarkers at

the time the drug is discovered is essential. 3. Change the clinical trial paradigm. Phase I trials need to become more adaptive in design to test a variety of biomarkers and perhaps imaging questions. That is happening more and more in industry and academia, Dr. Schenkein said.

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

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

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

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

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

4. Drug developers must work with the FDA to support adaptive designs that will enable testing of biomarkers in phase I, validation in phase II, and approval after a successful phase III study. “Early clinical trials are going to have to be longer and more expensive, and we all are going to have to agree to that,” Dr. Schenkein said. 5. Industry and academia need to demand more important treatment effects—which will dictate smaller treatment populations—and accept nothing less. Laurence H. Baker, DO, of the University of Michigan, President of the Southwest Oncology Group, said an internal review found SWOG needed to improve clinical trial designs and operation efficiencies, and develop new partnerships. This includes, for example, rethinking the definitions of clinical benefit and progression-free survival (PFS) as endpoints. “We clearly need to be more efficient,” he added. At the AACR meeting, Dr. Baker questioned the response evaluation criteria in solid tumors (RECIST) definition of stable disease (and, therefore, PFS). These criteria are “too permissive, allowing companies to compare a new agent to a placebo and demonstrating statistical difference but not clinical benefit,” Dr. Baker told The ASCO Post. For example, he noted, the many drugs recently approved for metastatic renal cancer were evaluated using such a design. “Now, some countries are not allowing use of some of these agents because the costs are great and the benefit very small. In other words, there is insufficient clinical benefit,” he said.

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Contact The ASCO Post Editorial Correspondence

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

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

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

Cara H. Glynn, Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Andrew Nash, Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

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

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

03/10

Editorial Office: Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

ASCOPost.com | JULY 2010

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Opinion

American Center for Cures continued from page 3

The new agency would be funded for success with new major appropriations and a bypass budget. The funding should be provided over 10 years for long-term commitment critical to scientific endeavors. The Cures Council will determine what projects the ACC takes on, based on the intersection of diseases that have the greatest impact on Americans and those with the greatest likelihood of cure. Each disease cure effort will have a CEO accountable for cure within 5 to 7 years. Each unit will invest in researchers and research institutions around the world to get specific answers to specific questions needed for cures and prevention. A Health Advanced Research Projects Agency (HARPA), modeled after the highly successful Defense Advanced Research Projects Agency (DARPA), will fund strategic highrisk/high-reward research and follow a “challenge model” to support innovative multidisciplinary research between NIH institutes, other federal agencies, grantees, and business partners, for projects with the potential for a significant impact on health. Funding for projects will be flexible and outcomes based. An Office of Translational and Applications Research will coordinate all clinical research within the NIH and work closely with the FDA, Centers for Disease Control and Prevention (CDC), Agency for Healthcare Research and Quality (AHRQ), Health Resources and Services Administration (HRSA), etc. The ACC will have a Center for Clinical Trials that will

centralize and organize protocols and streamline the institutional review board complexities throughout the NIH to supply the public with new treatments more quickly, safely, efficiently, and economically. Special emphasis through designated funding and coordination with other agencies (eg, the Small Business Administration) should focus on bridging the so-called “valley of death”—the often lengthy time between research/ development and commercial avail-

This new entity, the American Center for Cures, will have the authority and capacity to draw upon resources and scientific knowledge developed across DHHS, within health research (NIH, AHRQ), administrative (CMS), and regulatory (FDA) agencies, so that opportunities to leverage the collective strength and genius of the federal health enterprise are aligned and captured. For example, through new funding authorities the ACC may examine and support Cen-

This endeavor can achieve the key measurable and ancillary outcomes of creating and protecting millions of jobs and maintaining our nation’s global competitiveness in the life sciences. ability—that has killed innovation. Finally, an office would be established to coordinate efforts to reduce medical errors.

Justification for the ACC A new mechanism is required to accelerate innovation and applications of basic research that will lead to cures in the diseases affecting Americans. This mechanism must have the authority to work across the Department of Health and Human Services (DHHS), to bridge the widening gaps between laboratory discoveries, early proof-ofconcept applications in humans, and ultimate commercialization of lifesaving therapies. Such a mechanism should ultimately improve the health of individuals, health care, and the economy in the United States.

ters of Excellence in Regulatory Science within academia, develop broad resource networks with biotechnology firms, create opportunities for federal partnerships with industries in the “precompetitive” space, and forge new models for public/private partnerships across academia, industry, government, and the nonprofit sectors. The ACC will support America’s leadership with global partners in research and therapeutic product development, bringing creative, multidisciplinary focus (ie, physical and biologic sciences) to bear upon diseases and conditions that may be ripe for highrisk/high-reward investments with the potential of driving toward cures. Ideally, the venture will be funded through a new innovative funding source, allowing it to be sufficiently

endowed without requiring new taxes. Moreover, this endeavor can achieve the key measurable and ancillary outcomes of creating and protecting millions of jobs and maintaining our nation’s global competitiveness in the life sciences.

Answering Great Challenges America always answers great challenges, whether it is splitting the atom, preventing polio, or sending a man to the moon and returning him safely. It is time to meet the next great challenge and take on a cause greater than ourselves. Let it be said in 50 years that our children and grandchildren will not suffer from the same diseases that our generation and previous generations had because we took a stand in 2010 to do what we all know is needed—to bring the dream of the American Center for Cures to reality. Never has the time for such a project been better or the need been greater. Never has a more substantial wealth of knowledge been available in the quest to relieve patient suffering. Never has there been a clearer vision of what must be done.

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Dr. Boxer is Professor of Clinical Urology at the University of Miami. He is also Clinical Professor at the University of Wisconsin and the Medical College of Wisconsin. Dr. Boxer was a two-time finalist for U.S. Surgeon General (under both the William J. Clinton and George W. Bush administrations) and served on President Clinton’s Task Force on Health Reform. In addition, Dr. Boxer has served on the National Cancer Advisory Board, represented the United States at the World Health Organization, and was the Chair, National Health Policy Council.

The ASCO Post | JULY 2010

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News Prostate Cancer

Many Promising Strategies for Prostate Cancer in the Pipeline By Barbara Boughton

ithin the next few years, the number of therapies that can effectively target prostate cancer at a cellular and molecular level are likely to experience exponential growth—and provide new options to the oncologist treating this cancer, according to several speakers at an educational session at the 2010 Genitourinary (GU) Cancers Symposium in San Francisco, titled “Prostate Cancer—Future Pathways: What Is on the Way?” The symposium was cosponsored by ASCO, the American Society

for Therapeutic Radiology and Oncology (ASTRO), and the Society of Urologic Oncology.

Androgen Receptor Targeting The androgen receptor plays a critical role in maintaining the proliferation of prostate cancer cells, and is an important driving force for castration-resistant prostate cancer cells—both before and after androgen ablation, according to Donald J. Tindall, PhD, of the Mayo Clinic. But novel therapeutic strategies

Prostate Cancer Prospects ■■ Emerging agents that target the androgen receptor pathway in prostate cancer have shown that these drugs can be efficacious with durable effects, even in heavily pretreated prostate cancer patients.

■■ Outlaw pathways that promote cancer cell proliferation and survival and the tumor microenvironment play a critical role in the development and progression of prostate cancer. Promising therapies that target these pathways and the cancer cell microenvironment are likely to show clinical benefit in the near future.

■■ Exciting approaches to immunotherapy are under development in prostate cancer, but the most efficacious use of immunotherapies may be as combination agents with conventional treatments.

are focusing on inhibiting androgen receptor function—including MDV3100, abiraterone, and 17-AAG. These drugs block the nuclear localization of the androgen receptor, inhibit enzymes necessary for testosterone synthesis, and destabilize the androgen receptor, Dr. Tindall said. “The androgen receptor is playing a critical role in current prostate cancer research,” he said. Dr. Tindall noted that understanding the functions of the androgen receptor and identifying its interacting proteins are important areas of research in designing novel and targeted therapies, particularly for castration-resistant prostate cancer. The early success of androgen receptor–targeted therapies such as MDV-3100 and abiraterone serve as a validation of the androgen receptor– targeting approach, noted Charles J. Ryan, MD, of the University of California, San Francisco. Efficacy studies on abiraterone reveal that this drug is highly active in some patients, with response proportions ranging from 45% in heavily pretreated patients to 75% in patients without extensive secondary hormonal therapy or chemotherapy.1,2

Charles J. Ryan, MD

“Some responses are incredibly durable, and complete responses do occur,” Dr. Ryan said. New research reveals that some patients—depending on genetic variance—are more likely to respond to abiraterone, he noted. New research is attempting to answer questions about this therapy—whether it can be used with hormonal therapy to prolong survival in symptomatic metastatic disease, and whether it should be continued even after progression of disease to protect against tumor growth exacerbation. Investigators have also shown that MDV-3100 has clinical activity even in heavily pretreated patients, and is now being tested in phase III studies. Clinical trials that answer the questions of

Related Abstracts from the 2010 ASCO Annual Meeting Use your smartphone to view selected prostate cancer abstracts via the 2D barcode. For See page 55 more information about the 2D barcode, see page 55.

Abiraterone Trials Abstract 4545: A phase II study showed that discordant bone scans occurred in 12 of 23 patients with metastatic castrate-resistant prostate cancer receiving abiraterone. Over 80% of these scans were subsequently found to be “flare” phenomena, as demonstrated by improved follow-up bone scans. Thus, bone scan flare is common in this setting and should not be misconstrued as a treatment failure, the authors concluded. Abstract 4547: In a study of 56 patients being treated for castrateresistant prostate cancer, an “intracrine androgen signaling signature” (higher levels of bone marrow

aspirate testosterone, androgen receptor, and CYP17 expression), favored a treatment benefit with abiraterone plus prednisone (P = .048). The investigators concluded that abiraterone plus prednisone is a promising and well tolerated treatment, and that intracrine androgen signaling is implicated in prostate cancer progression in bone. Abstract 4635: A 54-patient study explored molecular profiling of circulating tumor cells (CTC) in patients with castrate metastatic prostate cancer receiving abiraterone after failure of docetaxel-based chemotherapy. Patients with < 5 CTC after 1 month of therapy had a median time to PSA progression of 28, weeks, vs 12 weeks in those with ≥ 5 CTC (P < .005). Abstract 4671: In a 33-patient study, 58% of patients with chemonaive castrate-resistant prostate cancer experienced prolonged responses to abiraterone (median time to PSA progression = 71 weeks). Moreover, the researchers noted durable complete responses in measurable lesions.

Abstract 4672: A British study of 102 patients with advanced castrateresistant prostate cancer revealed that delayed toxicity following abiraterone treatment was uncommon. The drug was safely administered for long periods (> 6 months, 6–51+ cycles) without concurrent corticosteroids.

Sipuleucel-T Trials Abstract 4550: Integrated analysis of three sipuleucel-T (Provenge) studies, involving 737 randomized patients with metastatic castrate-resistant prostate cancer, revealed consistent results across trials and within subgroups. The investigators noted a significant treatment effect (HR = 0.735, 95% CI = 0.613–0.882, P < .001), with independent baseline predictors of overall survival including ECOG status, number of bone metastases, nodal disease, age, weight, PSA, LDH, hemoglobin, and time from diagnosis to randomization. Abstract 4551: In another assessment based on the three-study integrated analysis described in abstract 4550, a sipuleucel-T treatment

effect was observed whether or not patients received subsequent docetaxel. Later use of the taxane improved overall survival compared with no later docetaxel use. However, when this factor was considered as a time-dependent covariate, it was not a significant predictor of survival (HR = 0.941, P = .54), and the sipuleucel-T effect remained significant (HR = 0.736, P < .001). Abstract 4552: In three trials of sipuleucel-T, researchers observed a positive correlation (P < .05) for each of three product parameters—CD54 upregulation, CD54positive cell count, and total nucleated cell count—which appeared to be independent of baseline prognostic factors. The authors found a significant correlation between overall survival and each of these parameters, supporting the conclusion that “broad engagement of the immune system” contributes to sipuleucel-T survival findings.

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ASCOPost.com | JULY 2010

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News

whether MDV-3100 could be used as initial androgen deprivation therapy and whether it could be utilized in a noncastrate setting may be warranted, although such trials may require significant expense and time, Dr. Ryan said.

Tumor Microenvironment In addition to the androgen receptor

pathways, numerous agents that disrupt the outlaw pathways that contribute to tumor proliferation and resistance are under investigation, according to William Kevin Kelly, DO, of the Yale Cancer Center. The tumor microenvironment also plays a critical role in the development and progression of advanced prostate cancer. For instance,

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

cancer cells, macrophages, and fibroblasts within the tumor can secrete multiple proangiogenic cytokines such as the soluble growth factors VEGF and tumor necrosis factor–alpha. “Most of the therapies that target the outlaw pathways and microenvironment in castration-resistant prostate cancer are in early-phase clinical trials, but we’re like-

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

1237674A6

DS-B0001A-06-09

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ly to see the landscape concerning these therapies change drastically over the next year as results from ongoing studies mature,” Dr. Kelly said. Therapies that target the outlaw pathways and tumor cell microenvironment include cediranib (a new agent that inhibits VEGF-1 and VEGF-2), bevacizumab (Avastin), thalidomide (Thalomid), and radioisotope therapies such as samarium Sm153 lexidronam (Quadramet), Dr. Kelly noted.

Immunotherapy Prostate cancer immunotherapies are also under development, and may play a role in prostate cancer treatment in the near future, according to Charles G. Drake, MD, PhD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer. The newly approved antigen-specific immunotherapy product sipuleucel-T (Provenge) has shown a survival benefit in phase III trials. In one phase III study of sipuleucel-T published in 2006, the investigators did not meet their primary endpoint of time to progression but did show a statistically significant survival benefit, which was a secondary endpoint in the study.3 Another phase III trial presented in 2009 showed a statistically significant survival benefit, with a hazard ratio of 0.78 in favor of sipuleucel-T. Other approaches to immunotherapy include those that involve blocking immune checkpoints—ie, cell surface molecules that restrict antitumor response. Among these agents, ipilimumab is farthest along in clinical development, Dr. Drake said. The viral-based vector PROSTVACVF has also shown a survival benefit in initial clinical studies, and a phase III clinical trial is in the planning stages and could be initiated within the next year. Such studies are proof of the concept that immunotherapy might provide real survival benefit for patients with castration-resistant prostate cancer, according to Dr. Drake. The most promising use of immunotherapy may be in combination with conventional treatments, because single-agent immunotherapy is usually not sufficient to induce an optimal antitumor response, particularly in patients with advanced disease. However, several factors need to be taken into account when combining immunotherapies with standard treatments, Dr. Drake noted. “Dose matters—the dose of chemotherapy used in combination has to be very different than that used in sincontinued on page 20

The ASCO Post | JULY 2010

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News

Strategies for Prostate Cancer in the Pipeline continued from page 19

gle-agent treatment, and the optimum schedule (for efficacy and safety) needs to be carefully assessed. But combination therapies may be the wave of the future,” he said. Research on drugs that target the androgen receptor pathway, outlaw pathways, and tumor cell microenvironment as well as immunotherapies represent Leukemia

important strides forward in cancer research, commented Maha Hussein, MD, of the University of Michigan, Chair of the GU Cancers Symposium. “We have had an incredible expansion of science and knowledge about the different pathways important in prostate cancer, as well as treatments that target these pathways,” she added. “It’s an exciting time for prostate cancer research, and will provide a better future for prostate cancer patients.”

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References 1. Ryan CJ, Rosenberg J, Lin A, et al: Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylaseC17, 20-lyase inhibitor in androgen-independent prostate cancer (AiPCa). ASCO Prostate Cancer Symposium Proceedings (abstract 278), 210, 2007. 2. Attard G, Yap TA, Dearnaley AH, et al: Activity, toxicity, and effect on steroid precursor levels of abiraterone (A), an oral irreversible inhibitor of CYP17 (17α

hydroxylase/17,20 lyase), in castrate men with castration refractory prostate cancer (CRPC). ASCO Prostate Cancer Symposium Proceedings (abstract 264), 203, 2007. 3. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006.

Dasatinib, Nilotinib Both Superior to Imatinib as Front-line Therapy for Chronic Myelogenous Leukemia By Alice Goodman

wo separate phase III randomized, controlled trials showed superiority of dasatinib (Sprycel) and nilotinib (Tasigna), respectively, compared with imatinib, the current standard of care for newly diagnosed, chronic-phase chronic myelogenous leukemia (CML). Even though these studies were positive, experts were hesitant to weigh in about which drug would be preferable as first-line therapy if both new drugs are approved by the FDA in this setting as expected. (See page 45 for news of nilotinib’s recent FDA approval.) Both second-generation tyrosine kinase inhibitors (TKI)—dasatinib and nilotinib—almost doubled the

12-month molecular response rates compared with imatinib, and presenters of both studies hailed dasatinib and nilotinib, respectively, as new standards of care for front-line therapy of CML. The studies were published online in The New England Journal of Medicine to coincide with the presentations at the 2010 ASCO Annual Meeting.

Dasatinib vs Imatinib The Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION) trial, funded by Bristol-Myers Squibb, randomized 519 newly diagnosed patients with chronic-phase CML to open-label treatment

Expert Point of View

asatinib was superior to imatinib, and nilotinib continues to show superiority to imatinib. Both drugs achieve faster and better complete cytogenetic response (CCyR) and better major molecular response (MMR) compared to imatinib, said formal discussant of these trials, Michael Mauro, MD, of Oregon Health and Science University in Portland. Michael Mauro, MD Dr. Mauro reviewed reasons for and against using the newer TKIs as first-line therapy. His bottom line was that with no good tool to sort out which patients need more therapy and which ones to select for optimal response to imatinib, his recommendation would be to use second-generation TKIs as first-line therapy for CML, if and when they are approved. He did not say to choose one of the newer drugs over the other; rather, further follow-up on efficacy and safety combined with individual assessments of patient risks and tolerances will shape the decision. One important distinction between the DASISION and ENESTnd trials is the reporting of MMR rate at 12 months vs by 12 months, Dr. Mauro told The ASCO Post. “The nilotinib report focused on data ‘at 12 months,’ which is a snapshot in time and more apt to be lower due to missing data, possible response gained then lost, etc. The dasatinib data is ‘by 12 months,’ which is more inclusive (all MMR responses achieved on or before the 12-month mark are thus counted).” He cautioned, “No one should compare results between the two trials.”

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DASISION and ENESTnd Trials ■■ The Dasatinib versus Imatininb Study in Treatment-Naive CML

(DASISION): The primary endpoint of confirmed complete cytogenetic response by 12 months was achieved in 77% of the dasatinib group vs 66% of the imatinib group (P = .0067).

■■ The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly

Diagnosed Patients (ENESTnd) trial: 18 month and continuous followup found that nilotinib was superior to imatinib in newly diagnosed chronic-phase CML.

with dasatinib at 100 mg/d or imatinib at 400 mg/d.1,2 Planned follow-up is 5 years. Patients were recruited from 108 centers in 26 countries. Treatment arms were well balanced for demographic and disease characteristics. Median age was about 47 years, median time from diagnosis was 1 year, and 19% of patients enrolled in the trial were deemed high risk. Median treatment duration in the trial was 14 months. The dose was escalated for suboptimal response in 5% of the dasatinib group compared with 14% of the imatinib group. The primary endpoint of confirmed complete cytogenetic response (CCyR) by 12 months was achieved in 77% of the dasatinib group vs 66% of the imatinib group (P = .0067). The CCyR rate by 12 months on at least one assessment was 83% vs 72%, respectively (P = .0011). Major molecular response (MMR) rate was 46% vs 28%, respectively (P < .0001). “Dasatinib was superior to imatinib at all time points over the first year, with about a 50% higher response,” said lead investigator Hagop Kantarjian, MD, Chairman of the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center in Houston. Progression to accelerated/blastic

phase occurred in 1.9% of the dasatinib group vs 3.5% of those treated with imatinib. Dr. Kantarjian pointed out that no patient who achieved MMR experienced disease progression, but progression was seen in two patients with a CCyR. Treatment was discontinued in 15.5% of the dasatinib group vs 18.6% of the imatinib group. Reasons for discontinuation included progression, toxicity, and other unrelated events. Hematologic toxicity was similar between the two arms, with the exception of more grade 3 or 4 thrombocytopenia with dasatinib: 19% vs 10%, respectively. Regarding nonhematologic adverse events that occurred in 10% or more of patients, more nausea, vomiting, and rash were seen with imatinib, whereas mild to moderate pleural effusions were more common with dasatinib (10% vs 0%). However, 24 of 26 patients with pleural effusions achieved CCyR by 12 months, and only 3 patients discontinued dasatinib because of pleural effusions.

Nilotinib vs Imatinib Eighteen-month and continuous follow-up of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients continued on page 31

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Expert’s Corner

A Conversation with John E. Niederhuber, MD continued from page 4

treatment decisions as a group. I’m certain that process raises the quality of care.

Other Initiatives Was there an increase in patient enrollment in clinical trials as a result of NCCCP? Dr. Niederhuber: There’s been a noticeable increase in patient enrollment at

all of the sites that are part of NCCCP. We’ve also been exploring how to use these sites for acquisition of tissue for our research programs, especially for The Cancer Genome Atlas (TCGA), a joint project with the National Human Genome Research Institute, to genomically characterize and sequence tumors. In addition, we’re moving forward with models of electronic health records to prepare our oncology care system to record the genetic profiles of patients, to quickly and precisely match them with new experimental therapies, devise molecularbased methods of preventing cancer, and develop techniques to detect cancer cells at their earliest stage. I’m very excited about the future of the NCCCP. I also had the idea that there were very talented people in science who weren’t working on the complexity of cancer, and I wondered if we could get them together to provide us with another set of eyes and another perspective on cancer biology. We started talking to astrophysicists, nuclear physicists, and people working in higher mathematics around the country and asked if they would be willing to come to NCI for a meeting. Nearly 90 scientists came, including several Nobel laureates. It was the most exciting meeting I’ve ever attended. We started talking about evolutionary theory, communication theory, and thermodynamics, and it underscored the fact that there is a whole area of science that we have not been applying to the complex questions we face as biologists studying cancer. We had two follow-up workshops, and out of these came an NCI request for research proposals. We wanted these projects to be set up in virtual centers so multiple investigators could work together.

We ended up funding 12 centers starting a year-and-a-half ago. This is a very exciting new program for NCI. What kinds of studies are you funding? Dr. Niederhuber: These are programs applying specialized knowledge and experimental backgrounds in the physical sciences as well as highly specialized technology to answering questions of cancer biology, such as what makes cells abnormal and how do

they brought into the world. It’s hard to get your mind around how powerful that new technology will be and how dramatically it will change medicine.

abnormal cells behave in the environment of the host? How do they talk to each other, and how do they move over chemical gradients? We hope that we will be able to use the knowledge that comes from these studies to find new technologies to diagnose cancer at its earliest stage of development and, of course, intervene in its progression.

medicine has always been a priority for us. I’ve been at good institutions throughout my career, and it’s always been part of our agenda to communicate with young people so they know about the available opportunities and to mentor them. At the universities where I’ve worked in the past, and certainly here at NCI and the NIH, we’ve spent a lot of time and resources trying to provide those kinds of opportunities to students. In my laboratory here at NCI, a high school student comes for the summer each year; I think all of those students who have participated in this program have gone into medicine. We also have college graduates who participate in what we call a “post-bac” program for 1 or 2 years. We work hard to give young people

Power of New Technologies Given the number of new cancer advancements that were announced at ASCO’s Annual Meeting in June, would you say that this is a critical time in cancer research? Dr. Niederhuber: It is an exciting time. I’ve said frequently that I wish I were 35 again because there is so much opportunity and so much new in terms

Recruiting Researchers How can NCI continue to attract the best and brightest scientists to advance cancer research? Dr. Niederhuber: Recruiting young people to work in science and to study

Soon we’ll be better able to match the right patient with the right therapeutic recipe, and that’s a very different model from how we’ve performed drug discovery and drug development in the past. of technology that is enabling us to do things in the laboratory we could never do before. These new technologies—for example, genomic characterization—are powerful. Eventually, we’ll be able to do complete genomic sequencing. And I think about how that is going to change medicine, not just in cancer care but in the practice of medicine generally—how we diagnose disease, how we follow individuals throughout their lives, in terms of how their environment interacts with what

opportunities to get their feet wet and see if this is something they feel comfortable with and have a desire to do. We need to continue to put adequate resources into these types of programs so we bring along the next generation.

Closing Thoughts What closing thoughts would you like to share with ASCO members? Dr. Niederhuber: As a 25-year member of ASCO myself, I believe that all ASCO members need to recognize

that we are moving into a new era, in terms of how science is going to drive new discoveries and eventual translation into the clinic. Many of the structures that we’ve used successfully over the years may need to be modified. Senior members should be aware of that and should help younger colleagues make the transitions needed to be sure that we can take our discoveries into the clinic more rapidly and less expensively. Soon we’ll be better able to match the right patient with the right therapeutic recipe, and that’s a very different model from how we’ve performed drug discovery and drug development in the past. We’ve had a good deal of participation from the private practice community of oncologists as well as academicbased oncologists in formulating the recommendations of the Clinical Trials Working Group. We’ve been working hard to implement those recommendations in a progressive way, and we’ve established a Clinical Trials Advisory Committee, which was the first new government-approved NCI committee in 10 years. That committee, which I’ve been chairing, has become an important advisory group. We worked hard to integrate the thinking of the Translational Research Working Group with that of the Clinical Trials Working Group. I think the message is that change is needed. I sit on the Institute of Medicine’s National Cancer Policy Forum, and as we were deliberating about the topics the Institute could get involved in to provide truly meaningful advice to the public and Congress, I noted that one of the big issues facing NCI— and facing the oncology community at large—concerns what we need to do next: What changes do we need to make in terms of how we do clinical research? A report from that group just came out, and it strongly supports the fact that we need to make changes if we’re going to work effectively in this new era of cancer medicine. But much more work needs to be done. We will certainly need more resources for clinical research, we need to have higher per-case reimbursement, we probably need to do fewer (and perhaps smaller) trials, and we need to be sure that trials are well grounded in science, especially in the early phase of drug development. What does the future hold for you? Dr. Niederhuber: I’ve put all my energy into this job. I have had a laboratory since I’ve been at NCI, and I’ve enjoyed my work in the lab. My immediate plan is to spend much more time there.

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Direct from ASCO

Now Is the Time to Fix the Medicare Physician Payment Problem By Allen S. Lichter, MD, ASCO CEO

edicare pays physicians according to a fee schedule established by Congress. This year, Medicare will pay the nation’s 850,000 physicians a total of $92 billion, or roughly $108,000 per physician. From this payment, physicians pay their nurses and office staff, office expenses, patient record and billing costs, and malpractice insurance. If any funds are left over, they can pay themselves a salary. Looked at another way, of the 45 million seniors cared for by Medicare, a little over $2,000 is allocated per beneficiary to the physician community. The government will spend about $520 billion on Medicare this year; 17% will go to physicians, and the remaining 83% goes to hospitals, nursing homes, laboratories, drugs costs, and the like. Are doctors paid too much by Medicare? The government thinks so. A formula was enacted in the late 1990s that set limits on the total amount of money Medicare can pay doctors, and the agency that runs the program has exceeded the payment cap. How much are we talking about? From 1996 to the present, Congress authorized aggregate payments of about $1 trillion dollars to physicians, and that number has been overspent by $19 billion. That’s a 1.9% cost over-

run on a $1 trillion program over a 14-year period. As federal programs go, one might think that being that close to budget over such an extended period of time would be cause for celebration. Instead, the law demands that the $19 billion be paid back by America’s physicians, and it must be paid back in a single year. This has created a serious crisis, and it needs to be fixed. Let me explain.

The ‘Doc Fix’ If $19 billion must be reclaimed in a 12-month period, physician fees have to be cut a staggering 21% in a single stroke. And the law requires that this be the new baseline for future years. Medicare today pays physicians, on average, about 20% to 30% less than private insurance for the same services. With a 21% cut, the gap would start to approach 50%. Everyone, including the leadership of the Medicare program and the vast majority of Congress, realizes that such a gap is unsustainable and will cause physicians to leave the Medicare program in great numbers. Seniors would find it difficult, if not impossible, to find care. No one wants that to happen, and Congress will not allow it to happen. So every year leading up to the present, Congress has refused to allow the cut to occur. Instead, they have put a series of “temporary” patches in place. Due to the failure to address this payment problem, today’s cost of fixing the physician payment scheme (the “doc fix,” as it is referred to inside the Beltway) is $247 billion. That number comes from the $19 bil-

lion cost overrun extrapolated out to 10 years with inflation costs built in. Some might wonder how a 1.9% cost overrun over 14 years can cost $247 billion to remedy—such is the math of the federal budget. But will it really “cost” that amount? Congress will no doubt continue to appropriate the funds to patch the system. The money will be spent. But if they don’t actually pass a doc fix, they don’t have to count the $247 billion against the nation’s deficit. They simply pay it out in dribs and drabs. It’s the same money and the same ultimate cost, but using this sleight of

In 2004, the doc fix would have cost $49 billion. Today, it’s $247 billion. hand, the cost does not have to appear in deficit forecasts and Congress looks more fiscally responsible. The fact is that fixing this problem permanently will require no more funding than will be expended anyway.

The Payment Roller Coaster So what’s the problem? Just let Congress apply a patch from time to time and move on. Unfortunately, it’s not so simple. Every time the doc fix comes up for debate, it is used as leverage in the discussion of deficits, health-care costs, and a host of other issues. Just this year alone, Congress has passed four short-term patches, two of them after the 21% cut actu-

ally went into effect. Starting Monday, June 14th, doctors were paid 21% less than on June 1st. On June 24th, the House approved a 6-month plan to reverse this 21% cut. But physicians, especially those who see lots of Medicare patients, cannot run their practices while riding this payment roller coaster. Cash-flow problems will start appearing in practices within a week or two as bills come due for payment and funds are not there. Long-term plans to hire staff or expand services cannot be made when revenue projections are so uncertain. The frustration that the nation’s physicians feel over this issue is entirely understandable. If the can is kicked down the road for another 3 or 4 years, the compound effect will make this “fix” cost in excess of $400 billion. At that point, this problem will never get solved and physician payments from Medicare will be a permanent political football, subject to the whims and uncertainties of any political process. Ultimately, physicians will figure out how to remove themselves from this unstable system and withdraw from Medicare. The damage to seniors from this eventuality will be immense. In 2004, the doc fix would have “cost” $49 billion. Today, it’s $247 billion. Tomorrow, who knows, but two things are certain: This problem has to be fixed or it will ruin Medicare, and it will never be cheaper to fix than today. That is why ASCO is fighting to get this done. —Allen S. Lichter, MD

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Journal of Oncology Practice Opens Search for Associate Editor

ournal of Oncology Practice ( JOP) has opened a search for an Associate Editor after the departure of Therese M. Mulvey, MD, who held the position since the journal’s inception in 2005. Dr. Mulvey will remain on JOP’s editorial board. John V. Cox, DO, Editor-in-Chief noted that JOP is seeking an oncologist grounded in practice and familiar with all aspects of running a practice, such as practice administration and improvement; billing and reimburse-

ment issues; and quality and efficiency of care. The Associate Editor will also conduct peer reviews and contribute to content development.

Associate Editors The current JOP Associate Editors include Gary H. Lyman, MD, Joseph O. Jacobson, MD, and Patricia Legant, MD. Dr. Jacobson is Chairman of the Department of Medicine at North Shore Medical Center, a regional

hospital system providing care for patients north of Boston. He is an Associate Clinical Professor of Medicine at Harvard Medical School. A practicing medical oncologist, he was among the founding members of the ASCO Quality Oncology Practice Initiative (QOPI). He is the Immediate Past Chair of the ASCO Quality Care Committee, and Chair of the QOPI Steering Committee. Dr. Lyman is Professor of Medicine and Director of Comparative Ef-

fectiveness and Outcomes Research at Duke University and the Duke Comprehensive Cancer Center where he is also Senior Fellow at the Duke Center for Clinical Health Policy Research. Dr. Lyman currently serves on both the Cancer Education and Clinical Practice Guideline Committees, and chairs several ASCO guideline panels. Patricia Legant received her BA degree from Stanford, PhD from Yale, and MD from Columbia College of continued on page 24

The ASCO Post | JULY 2010

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Direct from ASCO

New Leaders of ASCO A number of distinguished professionals took over new roles at ASCO during the 2010 Annual Business Meeting. and hematology/oncology at Children’s Hospital Medical Center, the Dana-Farber Cancer Institute, and Harvard University.

Board of Directors Community Oncologist: Robin T. Zon, MD, FACP George W. Sledge, Jr, MD

ASCO President, 2010-2011: George W. Sledge, Jr, MD Ballve-Lantero Professor of Oncology and Professor of Pathology and Laboratory Medicine at Indiana University Simon Cancer Center, George W. Sledge, Jr, MD, received his undergraduate degree from the University of Wisconsin and medical degree from Tulane University. He completed his residency at St. Louis University and fellowship at the University of Texas, San Antonio. Dr. Sledge has received the 2007 Jill Rose Award from the Breast Cancer Research Foundation and the 2006 Susan G. Komen Foundation Brinker Award for Scientific Distinction.

President-Elect: Michael P. Link, MD Michael P. Link, MD, is the Lydia J. Lee Professor of Pediatric Cancer and Chief of the Division of Pediatric Hematology/Oncology at Stanford University School of Medicine, and Director of the Bass Center for Cancer and Blood Diseases at the Lucile Salter Packard Children’s Hospital at Stanford. He received his medical degree from Stanford University. He completed an internship and residency in pediatrics at the Children’s Hospital Medical Center in Boston, and fellowships in immunology continued from page 23

Physicians and Surgeons. Having grown up in New Mexico, she then returned to the West for her internship, residency, and fellowship, all in Salt Lake City, where she has practiced hematology and oncology for 20 years. She has served on various ASCO committees, including the Clinical Practice and Health Servic-

Vice President and Partner at Michiana Hematology-Oncology, PC, Medical Director for Oncology Research at Memorial Hospital of South Bend and Principal Investigator of the local Community Clinical Oncology Program (CCOP)/research consortium, Robin T. Zon, MD, obtained her medical degree at Indiana University School of Medicine. She completed her residency at St. Vincent Hospital and Health Care Center and her oncology/hematology fellowship at Indiana University. Dr. Zon worked as a pharmaceutical research investigator and manager of medical diagnostic product research and development at Boehringer Mannheim Diagnostic Company and the Merrell Dow Research Institute.

Medical Oncologist: James L. Abbruzzese, MD, FACP James L. Abbruzzese, MD, is Professor of Medicine and Chair of the Department of Gastrointestinal Medical Oncology at The University of Texas M. D. Anderson Cancer Center, where he holds the M. G. and Lillie A. Johnson Chair for Cancer Treatment and Research. He completed his medical degree with honors from the University of Chicago. He completed his residency and a year of clinical fellowship in infectious diseases at the Johns Hopkins Hospital and a fellowship in medical oncology at DanaFarber Cancer Institute. es Research Committees, and was a member of the ASCO Board of Directors.

Consultant Editor Journal of Oncology Practice also recently named its first Consultant Editor: Elaine L. Towle, CMPE, formerly of the JOP editorial board. Ms. Towle is Director, Consulting Servic-

Non-U.S. Oncologist: Frances A. Shepherd, MD, FRCPC A Professor of Medicine at the University of Toronto, staff physician at the Princess Margaret Hospital of the University Health Network, and Scott Taylor Chair in Lung Cancer Research, France A. Shepherd, MD, received her medical degree from the University of Toronto and is a Fellow of the Royal College of Physicians and Surgeons of Canada in internal medicine and hematology. She was a rotating intern, junior assistant, and senior assistant at the Royal Victoria Hospital in Montreal. She also completed residencies at Mount Sinai Hospital and Toronto Western Hospital, and was a leukemia research fellow at Princess Margaret Hospital.

Radiation Oncologist: Lori J. Pierce, MD A Professor in the Department of Radiation Oncology at the University of Michigan School of Medicine and Vice Provost for Academic & Faculty Affairs, Lori J. Pierce, MD, completed her medical degree at Duke University. She was medical intern at Thomas Jefferson University Hospital, and completed her residency at the Hospital of the University of Pennsylvania.

Undesignated Specialty: Julie M. Vose, MD Julie M. Vose, MD, a Neumann M. and Mildred E. Harris Professor and Chief of the Section of Hematology/Oncology at the University of Nebraska Medical Center (UNMC), completed her internal medicine residency and hematology/oncology fellowship at the UNMC. She is currently enrolled in the Executive Program es for Oncology Metrics, a provider of data-driven education, tools, and knowledge for the oncology community. She has 25 years of experience in oncology practice management and was formerly practice administrator for a 15-provider medical oncology practice. Ms. Towle is a Past President of the Administrators in Oncology/ Hematology Assembly of the Medi-

for Masters of Business Administration in Health Care Administration at the University of Colorado, Denver.

Nominating Committee Howard A. Burris, III, MD, FACP Howard A. Burris, III, MD, is Chief Medical Officer and Director of Drug Development at the Sarah Cannon Research Institute. A partner of Tennessee Oncology, PLLC, he completed his undergraduate studies at the U. S. Military Academy and obtained his medical degree at the University of South Alabama College of Medicine. He performed his internship, residency, and fellowship at Brooke Army Medical Center, San Antonio, Texas.

Roy S. Herbst, MD, PhD A Professor in the Department of Thoracic/Head and Neck Medical Oncology, Chief of Thoracic Medical Oncology, Professor of Cancer Biology, and the Barnhart Family Distinguished Professor in Targeted Therapies at The University of Texas M. D. Anderson Cancer Center, Roy S. Herbst, MD, earned his doctorate in molecular cell biology at The Rockefeller University and medical degree from Cornell University Medical College. He completed his residency at Brigham and Women’s Hospital and was Chief Resident at West Roxbury VA Hospital. He completed his medical oncology fellowship at Dana-Farber Cancer Institute and a hematology fellowship at Brigham and Women’s Hospital.

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cal Group Management Association, and is on the Board of the Northern New England Clinical Oncology Society. She holds a graduate certificate in Community Health Care Management from Antioch New England Graduate School.

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Direct from ASCO

‘ASCO in Action’ Highlights ASCO’s Policy Efforts

very day, ASCO’s work involves advocating public policy that ensures patient access to high-quality cancer care and supports increased clinical cancer research. The ASCO in Action page on ASCO.org highlights ASCO’s efforts on research policy, practice management, clinical affairs, quality of care, and government and state relations.

Timely Information Although ASCO has previously communicated policy efforts on ASCO.org, this new page, which launched in March 2010, brings the timeliest updates to members, policymakers, advocates, and the general public. Important content from ASCO in Action is then funneled as appropriate to other member communication vehicles, such as Cancer Policy Today and ASCO Express. Topics covered include national health-care reform and private insurance issues; practice management issues such as Medicare, health plan policies, reimbursement, coding, and electronic health records; research policy and regulation surrounding clinical trials, research funding, and institutes such as NCI and FDA; and quality care issues such as clinical practice guidelines, disparities, prevention, end-of-life care, and ASCO’s Quality Oncology Practice Initiative (QOPI).

your local legislators’ contact information, see the daily House and Senate schedules, and find sample letters and talking points to send to your congressmen and congresswomen. The

the ASCO in Action page at publicpolicy@asco.org.

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Regular Updates

to help improve the lives of patients and their families.

ASCO is proud to demonstrate the actions it takes in advocating for members. For the Society’s positions on hot-button policy issues, multimedia directly from ASCO members on developments in cancer policy, and more information on how ASCO’s initiatives impact policymakers on Capitol Hill, be sure to check the regular updates on the ASCO in Action page. For more information on how you can contribute to ASCO’s advocacy efforts, visit the Grassroots Action Center on ASCO.org under the Public Policy section. Here, you can find Send us your feedback about the ASCO in Action page at publicpolicy@asco.org.

actions of our government have an enormous impact on quality cancer care, so please educate yourself and take action. Send us your feedback about

To find out more about our research, please visit www.sanofi-aventisoncology.com

The ASCO Post | JULY 2010

PAGE 26

Direct from ASCO

Breast Cancer Symposium to Focus on Clinically Relevant Translational Research National Harbor, Maryland, October 1–3

SCO invites all professionals interested in the prevention, evaluation, and management of breast cancer to attend this year’s Breast Cancer Symposium at National Harbor in the Washington, DC, metropolitan area. With presentations from experts in multiple disciplines, the educational sessions will present the latest scientific findings that affect current breast cancer management. Designed to facilitate interaction among attendees and faculty, the program includes discussion-based educational sessions, case presentations, audience response technology, and lunchtime discussion sessions on selected abstracts. The size of the meeting and the hotel setting foster collegial communication among participants. Fellows, residents, and junior faculty will have several opportunities to participate in exclusive networking events, including poster walks and a breakfast session focused on career development topics, with discussions led by the symposium faculty and committee members.

Sessions to Present Cutting-edge Research A new session format will integrate abstract findings and current trends into the topic presentations. Over the 2½-day program, experts from across the country will address

the following topics in nine general sessions: ■■ Prevention and Risk ■■ Imaging and Screening ■■ Biology of Metastases ■■ Integrating Radiation Therapy

■■ Health-care Policy and Reform ■■ Triple-negative Breast Cancer Each general session has two to four presenters on focused topics, such as genetics of race and ethnicity, bone marrow progenitors’

Gaylord National Hotel, National Harbor, Maryland.

and Breast Reconstruction ■■ Controversies in Radiation Therapy ■■ Survivorship ■■ Targeted Therapy Advances/New Approaches/New Designs

contribution to breast cancer metastasis, accelerated partial breast irradiation, sexuality and survivorship, and PARP inhibitors. Nancy E. Davidson, MD, recipient of the 2010 Gianni Bonadonna

Breast Cancer Award, will deliver the 2010 Gianni Bonadonna Breast Cancer Lecture. Dr. Davidson is Director of the University of Pittsburgh Cancer Institute. The Breast Cancer Symposium will take place in the Gaylord National Hotel, part of a 300-acre development known as National Harbor, across the Potomac River from Washington, DC. Built on the shore of the river, National Harbor contains a variety of shops and restaurants, from casual cafes that feature Maryland’s famous crabs and oysters, to award-winning restaurants offering fine dining. A cruise on the Potomac is among the evening entertainment options available, and Cirque du Soleil will be performing at National Harbor, October 1–3. Water taxis run from National Harbor to Old Town Alexandria and Georgetown, and a shuttle service takes passengers to Washington, DC, every 30 minutes. Shuttle service to Reagan National Airport is scheduled every 20 minutes from 6:00 AM to 8:00 PM. For more information and to register for the 2010 Breast Cancer Symposium, visit www.breastcasymposium.org. The deadline for early discounted registration is August 25.

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ASCO Relaunches Member Magazine with Companion Social Networking Website

he American Society of Clinical Oncology has relaunched its quarterly membership magazine— formerly ASCO News & Forum—under a new name and banner: ASCO Connection. The inaugural edition launches hand-in-hand with a new member social networking site of the same name—ASCOconnection.org. Both the new member magazine and accompanying website create opportunities for interaction between ASCO and its members, and between members and their colleagues.

The Membership Experience The print and online editions of the quarterly ASCO Connection highlight the membership experience— from the contributions and accomplishments of individual members to the collective work of ASCO and its membership as they tackle the concerns of today’s oncology community. In this pursuit, the July cover story focuses on the extraordinary contributions of ASCO members who traveled to the sites of recent natural disasters to tend to the sick and injured.

Other articles include an interview with ASCO President-Elect Michael P. Link, MD; a Q&A with International Affairs Committee Chair-Elect Clement Adebamowo, MD, ScD, on the growing epidemic of AIDS-associated malignancies in Africa; physician-authored debate on the hot topic of aspirin intake and breast cancer survival; interviews with participants in ASCO’s Leadership Development Program; and highlights from the Society’s past quarter. A regular column, Conversation

with the President, features blog entries posted by newly inducted ASCO President George W. Sledge, Jr, MD; and a new column, Staying Connected, captures the most interesting discussion points from the blogs, comments, and forum threads on ASCOconnection.org. New magazine departments include an expanded Member News section, as well as a column that gives readers a behind-the-scenes look at the “other lives” of ASCO members. First up in the July issue is an inter-

ASCOPost.com | JULY 2010

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Direct from ASCO view with Thomas Buchholz, MD, FACR, who made the news as a surprise caddie for three-time Masters winner Phil Mickelson at the Shell Houston Open this spring. The reader-friendly design of the publication makes ASCO Connection easy for busy members to skim for “just the facts,” while providing ample opportunity to connect online for expanded reading and real-time discussion and debate.

Online Meeting Place As the main social networking site for members, ASCOconnection. org features blogs by ASCO leaders and an open forum for member discussion. Although it is not a traditional social network like Facebook, ASCOconnection.org gives mem-

bers the opportunity to network with colleagues, share opinions, start conversations, and interact with ASCO leadership. The magazine section of the site features selected articles with opportunities for reader comment, as well as online exclusives and a “flipbook” of the current issue with embedded video clips and links to additional information. In addition to ASCO President George W. Sledge, Jr, MD, initial bloggers on the site include ASCO Connection Editor-in-Chief Jonathan S. Berek, MD; and “Blogger-in-Chief ” and Immediate Past Chair of ASCO’s Information Technology Committee L. Michael Glodé, MD. The site also offers RSS feeds to the blogs of ASCO’s Immediate Past President Douglas W.

Blayney, MD; Board of Directors Member Robert S. Miller, MD; and Journal of Oncology Practice Editor-in-Chief John V. Cox, DO. More bloggers and guest bloggers will be added as the site grows. ASCO members who log in to the site with their ASCO.org username and password have immediate access to read and comment on all posted articles and blogs, and to read, respond to, or initiate a discussion forum on any topic.

Nonmembers who register a guest account with ASCO.org can read and post on selected topics. For questions and comments about the new ASCO Connection and ASCOconnection.org, please send an e-mail to ascoconnection@asco.org.

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Molecular Markers in Cancer From Discovery to Clinical Practice Registration is now open for the October 18–20, 2010 meeting, Molecular Markers in Cancer, at the Westin Diplomat Hotel in Hollywood, Florida. The August issue of The ASCO Post will cover details of the educational program. For more information and to register, visit www.molecularcameeting.org.

What’s New at Cancer.Net?

ach week, new feature articles and multimedia content on a variety of topics are added to ASCO’s patient website, Cancer.Net (www.cancer.net).

Review Research News from the Annual Meeting The latest news from the 2010 ASCO Annual Meeting is available at www.cancer.net/ascoannualmeeting. Here you will find: ■■ written summaries, called Cancer Advances, that briefly describe studies, their findings, and what they mean for patients, as well as links to related topics ■■ audio podcasts with ASCO experts talking about the studies and placing them into context with other research ■■ videos of ASCO members summarizing key findings and describing what the news means for patients In addition, the site offers podcasts with Cancer.Net Editors discussing advances for specific cancers from the 2010 ASCO Annual Meeting.

View the Cancer.Net Video Library More than 20 patient education videos can be viewed at www.cancer. net/videos. The videos feature Cancer.Net Editors discussing general cancer topics for patients and their families, as well as updates on spe-

cific cancers. The videos are another way in which visitors to Cancer.Net can access information about cancer care and treatment. Titles include: ■■ What are Clinical Trials, with Richard Goldberg, MD ■■ What’s New in Lymphoma Care and Treatment, with John Sweetenham, MD ■■ Finishing Treatment: What Comes Next, with Lidia Schapira, MD

For Spanish Speakers: Expanded Content on Cancer.Net Español To improve access to ASCO’s comprehensive, oncologist-approved information for patients and families, Cancer.Net has expanded the translated content available on Cancer. Net en Español (www.cancer.net/ espanol), including new sections on caregiving, healthy living, and types of cancer treatment. This section also contains guides to 25 types of cancer, information on clinical trials, descriptions of tests and procedures, several of ASCO’s clinical practice guidelines for patients, and a glossary of cancer terms. Furthermore, the following printed materials are available in Spanish: ■■ ASCO’s Managing the Cost of Cancer Care booklet (Manejo del costo de la atención del cáncer) ■■ four fact sheets (Respuestas Sobre el Cáncer) on breast cancer, colorectal cancer, lung cancer, and

prostate cancer ■■ Guide to Breast Cancer (Guía de Cáncer de Mama)

Follow Cancer.Net through Social Media Social media is a great way to keep in touch with Cancer.Net and receive current content updates. Cancer.Net can be found on Facebook, YouTube, and Twitter. ■■ Cancer.Net on Facebook (www. facebook.com/cancerdotnet) is a way to stay up-to-date on the latest cancer information. ■■ Twitter is a real-time messaging service. CancerDotNet on Twitter (www.twitter.com) presents new articles and materials for patients. Twitter users can search the term #cancerinfo. ■■ Cancer.Net regularly posts videos on its YouTube channel, www. youtube.com/cancerdotnet.

ASCO Guidelines for Patients Recent clinical practice guidelines from ASCO provide guidance to oncologists, but what do the recommendations mean for patients? What to Know: ASCO’s Guidelines are easy-to-read summaries based on ASCO Clinical Practice Guidelines that offer a patient-oriented view of the guidelines. These guides provide background information, discuss the recommendations, explain what those recommendations mean for patients, and provide lists of ques-

tions that patients can ask their doctors. Each guide may be viewed and downloaded as a PDF file (www.cancer.net/whattoknow).

Order Materials Informational leaflets, cancer information prescription pads, referral cards, and posters are free. Just call 888-651-3038, send an e-mail to contactus@cancer.net, or visit the ASCO Bookstore at https://store.asco.org.

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Save the Date December 9–11, 2010 Chicago Chicago Multidisciplinary Symposium in Thoracic Oncology www.astro.org/Meetings January 20–22, 2011 San Francisco Gastrointestinal Cancers Symposium www.gicasymposium.org February 17–19, 2011 Orlando, Florida Genitourinary Cancers Symposium www.gucasymposium.org

LEAD WITH EFFICACY.

PFS=progression-free survival; ORR=objective response rate; OS=overall survival. References: 1. Data on ďŹ le. PďŹ zer Inc, New York, NY. 2. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-3590. Please see study description and brief summary on the following page.

Important safety information Hepatic failure was observed in <1% of solid tumor patients treated with SUTENT, sometimes with a fatal outcome. Monitor liver function tests and if symptoms of hepatic failure are present, patients should have SUTENT discontinued. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Left ventricular ejection fraction declines to below the lower limit of normal have occurred. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies. SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered.

SUTENT is indicated for the treatment of advanced renal cell carcinoma (RCC).

LEAD WITH SUTENT. (SUNITINIB MALATE)

SUTENT: PROVEN EFFICACY IN 1ST-LINE mRCC VS IFNα*

MORE THAN DOUBLED MEDIAN PFS

100

SUTENT (n=37 (n=375)

PFS probability (%)

months m Median: (95% CI: 9.8, 11 11.7)

58% reduced risk of progression or death

50 IFN (n=375) Median:

5 months

(95% CI: 3.8, 5.5)

Hazard ratio (HR)=0.42 (95% CI: 0.32, 0.54) P<.000001

7 8 Time (months)

DEMONSTRATED 5-FOLD HIGHER ORR • 39% vs 8% with IFNα (95% Cl: 34.0, 44.3 and 5.7, 11.8, respectively; P<.000001) in the second analysis (June 2007)1 • 28% vs 5% with IFNα (95% CI: 23.0, 32.3 and 3.3, 8.1, respectively; P<.001) in the ﬁrst analysis (November 2005)

ALSO ACHIEVED MORE THAN 2 YEARS’ MEDIAN OS2 • 26.4 months vs 21.8 months with IFNα (HR=0.82; 95% CI: 0.673, 1.001; P=.051)

AN ESTABLISHED SAFETY PROFILE • The most common adverse reactions (ARs) occurring in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs IFNα) were fatigue (58% vs 55%), diarrhea (58% vs 20%), nausea (49% vs 38%), altered taste (44% vs 14%), mucositis/stomatitis (43% vs 4%), anorexia (38% vs 40%), bleeding, all sites (30% vs 8%), hypertension (30% vs 4%), vomiting (28% vs 14%), dyspepsia (28% vs 4%), rash (27% vs 11%), abdominal pain (22% vs 12%), asthenia (21% vs 24%), and hand-foot syndrome (21% vs 1%) *All data are from the large (N=750), phase 3, randomized, multicenter trial comparing SUTENT with IFNα in patients with treatment-naïve metastatic RCC.

Hypertension may occur. Monitor blood pressure and treat as needed. Hemorrhagic events including tumor-related hemorrhage, some of which were fatal, have occurred. Perform serial complete blood counts (CBCs) and physical examinations. Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice. Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection. CBCs and serum chemistries should be performed at the beginning of each treatment cycle. Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers. The most common grade 3/4 ARs (occurring in ≥5% of SUTENT patients) were hypertension (10% vs <1%), fatigue (9% vs 14%), asthenia (7% vs 6%), diarrhea (6% vs 0%), and hand-foot syndrome (5% vs 0%).

The most common grade 3/4 lab abnormalities occurring in ≥8% of patients receiving SUTENT (vs IFNα) included lipase (16% vs 6%), uric acid (12% vs 8%), neutrophils (12% vs 7%), lymphocytes (12% vs 22%), and platelets (8% vs 0%).

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PAGE 31

News Myeloma

Maintenance Therapy with Lenalidomide Halves Recurrence Rate in Multiple Myeloma By Alice Goodman

enalidomide (Revlimid) dramatically reduced the rate of recurrence in patients with multiple myeloma (MM) following first-line autologous stem cell transplant (ASCT), according to interim results of a phase III See page 55 study. The data were presented at the 2010 ASCO Annual Meeting by lead investigator Michel Attal, MD, of Purpan Hospital in Toulouse, France, speaking for the Intergroupe Francophone du Myélome.1 Despite the use of autologous transplant in patients with MM, residual disease is typically present and almost all patients will eventually relapse. Thus far, maintenance treatment has had limited effectiveness, with thalidomide (Thalomid) showing the most promise. However, its activity has been curtailed by cumulative toxicity, including peripheral neuropathy. “An interim analysis of our study suggests that lenalidomide may be the first effective maintenance therapy for MM,” said Dr. Attal. Lenalidomide is an oral analog of thalidomide, with less toxicity. The drug is FDA-approved as second-line treatment of MM and myelodysplastic syndromes. The present study sought to compare lenalidomide maintenance therapy vs placebo in patients who have undergone first-line ASCT. The study enrolled 614 patients under the age of

65 years with nonprogressive MM up to 6 months after first-line ASCT. All patients received consolidation therapy with oral lenalidomide at 25 mg/d on days 1 to 25 every 28 days for 2 months. One group was randomized to maintenance therapy with lenalidomide, 10 to 15 mg/d until relapse, or placebo.

Dasatinib, Nilotinib Superior to Imatinib

nilotinib were well tolerated. These data support nilotinib as a new standard of care in CML,” said lead author Richard A. Larson, MD, Professor of Medicine and Director of the Hematologic Malignancies Program at the University of Chicago Medical Center. ENESTnd’s primary endpoint was MMR at 12 months, analyzed by intention to treat. Both doses of nilotinib were significantly better than imatinib: 44% for the lower dose of nilotinib, 43% for the 400-mg dose, and 22% for imatinib (P < .001 for both comparisons with imatinib). For the 145 patients who have already had polymerase chain reaction (PCR) assessment at 24 months, MMR at 24 months was 86% and 88%,

continued from page 20

(ENESTnd) trial, funded by Novartis, found that nilotinib was superior to imatinib in newly diagnosed chronicphase CML. 3,4 The study enrolled 846 patients in a 1:1:1 ratio to nilotinib at 300 mg twice daily, nilotinib at 400 mg twice daily, and imatinib at 400 mg daily. Planned follow-up is 5 years. “With longer follow-up, the rates of MMR and CCyR are superior with nilotinib, and continue to deepen over time. Fewer progressions and deaths were seen with niloSee page 55 tinib. Both doses of

Study Data Patients in both groups had similar demographic and disease characteristics at baseline. Patients were stratified according to level of response to ASCT, ß2-microglobulin, and chromosome 13 deletions prior to consolidation therapy. At a median follow-up of 24 months from randomization, maintenance therapy was superior, so the study was unblinded, Dr. Attal said. Consolidation therapy with lenalidomide improved the rate of very good partial responses to about 70%—about 10% higher than after ASCT, he noted. At 3 years, progression of disease or death occurred in 77 of the 307 patients assigned to maintenance lenalidomide (25%) vs 143 of the 307 placebo-treated patients (47%). Median progression-free survival (PFS) has not yet been reached in the maintenance therapy arm but was 24 months in the placebo arm. The 3-year progression-free survival (PFS) rate was 68% in the group treated with maintenance lenalidomide vs 34% in the placebo group—a 54% difference that was highly statistically significant

Expert Point of View

ommenting on this study, ASCO Immediate Past President Douglas W. Blayney, MD, said that these results suggest that MM is moving into the chronic disease category. “Recurrence of myeloma is devastating and painful, and these results suggest that lenalidomide maintenance may be of value, although longerterm follow-up is needed,” he said. Dr. Blayney is Medical Director of the Stanford University Cancer Center. Douglas W. Blayney, MD “These results are especially encouraging given the favorable toxicity profile of lenalidomide,” added co-investigator Paul Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston. “They strongly support the positive outcomes seen from our large randomized Cancer and Leukemia Group B [CALGB] study, which also evaluated lenalidomide maintenance post-ASCT, although without consolidation.”

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(P < 10-7). PFS results were consistent across predefined subgroups for response to ASCT, ß2-microglobulin, and chromosome 13 deletion. At the first preplanned interim analysis, maintenance therapy was well tolerated, with a low discontinuation rate due to adverse events and no grade 3 or 4 neuropathy, Dr. Attal said. The fact that no significant differences in response were seen between the two groups after maintenance therapy indicated “a true maintenance effect,” according to Dr. Attal. Philip McCarthy, MD, of the Roswell Park Cancer Institute in Buf-

falo, NY, presented the CALGB data at the 2010 ASCO Annual Meeting.2

vs 48%, respectively. More nausea, muscle spasms, diarrhea, and vomiting were seen with imatinib, whereas rash, headache, pruritus, and alopecia were more common with nilotinib. Grade 3 and 4 adverse events were rare on all three arms. When asked which drug a clinician should choose for first-line therapy, Dr. Larson appeared to be on the fence. “Now we have three excellent choices for newly diagnosed CML,” he said.

2. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronicphase chronic myelogenous leukemia in chronic phase (CML-CP): Twelve-month efficacy and safety from the phase III DASISION study. 2010 ASCO Annual Meeting. Abstract LBA6500. Presented June 7, 2010. 3. Saglio G, Kim D-W, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. June 5, 2010 (epub ahead of print). 4. Larson RA, le Coutre PD, Reiffers J, et al: Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year. 2010 ASCO Annual Meeting. Abstract 6501. Presented June 7, 2010.

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References 1. Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. June 5, 2010 (epub ahead of print).

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References 1. Attal M, Cristini C, Marit G, et al: Lenalidomide maintenance after transplantation for myeloma (abstract 8018). Presented at the 2010 ASCO Annual Meeting, Chicago, June 6, 2010. 2. McCarthy PL, Owzar K, Anderson KC, et al: Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 10014 (abstract 8017). Presented at the 2010 ASCO Annual Meeting, Chicago, June 6, 2010.

The ASCO Post | JULY 2010

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News

Oncologists’ Compliance with Clinical Guidelines Reporting Varies Widely in Demonstration Project

demonstration project aimed at enhancing the quality of cancer treatment and care and promoting “evidence-based best practices that have been proven to lead to improved

patient outcomes” found that oncologists’ interpretations of the code for adherence to guidelines varied from “very loose” to “very strict.” This and other findings from the 2006 Medicare

Oncology Demonstration program were reported in the Journal of Oncology Practice.1 Oncologists and hematologists participating in the demonstration re-

AssociAte editor seArch

Complex Coding More than 40% of participating physicians considered the required coding, billing, data reporting, and documentation to be difficult or very difficult, although almost 66% said that they always submitted the codes for qualifying visits. Some physicians said they referred to clinical guidelines only if they were not familiar with the diagnoses, and others said that their fast-paced environment limited their ability to look up guidelines for every patient. Younger and less experienced physicians were more likely to refer to and adhere to the guidelines, while some older physicians criticized the guidelines for being too broad and lacking needed specificity. “Oncologists must remain actively engaged in adopting evidence-based medicine,” the authors concluded. “Inevitably, if they fail as a community to meet these challenges, complex and less helpful means of monitoring clinical guideline adherence will be imposed on them by payers and regulators.”

JOURnAl OF OnCOlOgy PRACTiCE

ASCO has opened its search for candidates to serve as an Associate Editor of the Journal of Oncology Practice. The Associate Editor is responsible for review of manuscripts and for development of editorial content. ASCO furnishes editorial and administrative support through its centralized editorial office in Alexandria, VA. A quarterly stipend will be provided. JOP provides authoritative information to allow oncologists to translate their science into action. Patient care demands healthy and efficient practice environments. JOP publishes original work addressing topics such as: • Daily practice operations • Efficiency of service provision • Health outcomes and health services research • Quality of care and access to care • Socioeconomics of cancer care • Cost-benefit and cost-effectiveness analyses • Use of technology and innovation • Public policy and regulatory issues that impact practice

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The successful candidate will be: • An oncologist grounded in practice (either private practice or institutional practice) • Familiar with all aspects of running a practice, including practice administration; billing and reimbursement issues; and quality improvement and efficiency of care • Able to devote time to providing constructive peer reviews as well as content development

Reference 1. Doherty J, Tanamor MY, Feigert J, et al: Oncologists’ experience in reporting cancer staging and guideline adherence: Lessons from the 2006 Medicare Oncology Demonstration. J Oncol Practice 6:56-59, 2010.

By October 10, 2010, interested candidates should submit a letter of interest and curriculum vitae to

Important Perspectives

John V. Cox, DO, MBA, FACP Editor-in-Chief Journal of Oncology Practice 2318 Mill Road, Suite 800 Alexandria, VA 22314

Page 3, Dr. Richard Boxer on health-care reform Page 23, Dr. Allen Lichter on Medicare

Candidates may also submit materials or request more information via e-mail to jopeditorsdesk@asco.org

ASC101127 JOP Assoc Editor Ad V4.indd 1

ported clinical information on cancer disease states through the Medicare billing system and 81 new codes developed in three categories: (1) current disease state as best understood clinically at the time of first visit; (2) the primary reasons for a patient’s evaluation and management visit; and (3) and physician self-reported assessment of whether the patient’s management adhered to clinical guidelines. Oncologists were encouraged to use clinical guidelines developed by ASCO and the National Comprehensive Cancer Network.

Page 41, Dr. Stanley Winokur on lessons learned from patients

6/2/10 1:47:48 PM

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TAP on Technology

Multiparameter Breast Cancer Gene Profiling Assays By Matthew Stenger

ene expression profiling is a technology for identifying genes potentially associated with disease prognosis and response to therapies. The technology identifies and quantifies cellular messenger RNA (mRNA), thus providing information on the global activity of genes producing the mRNA transcripts. Because mRNA is translated into proteins, differences in mRNA levels are ultimately related to differences in cellular protein composition as well as differences in properties and functions of cells and tissues.

with node-positive breast cancer. The MammaPrint test is available for newly diagnosed patients aged < 61 years with stage I or II node-negative disease ≤ 5 cm in diameter and is intended to predict the likelihood of

The Breast Cancer Profiling assay is a quantitative RT-PCR-based assay (also known as the H:I ratio test) that measures the ratio of the estrogen-regulated genes HOXB13 and IL17BR and four reference genes in formalin-fixed, par-

Although molecular profiling is well established in the treatment of breast cancer—for example, in decisions made on the basis of estrogen receptor (ER)/progesterone receptor and HER2 status—use of multiparameter gene profiling assays is relatively new. The first three such assays to become commercially available are the Oncotype DX breast cancer assay (Genomic Health), the MammaPrint test (Agendia), and the Breast Cancer Profiling test (developed by AviaraDx and licensed to Quest Diagnostics). The Oncotype DX assay is offered to newly diagnosed patients with node-negative, ER-positive disease who are to be treated with tamoxifen. It assigns a recurrence risk score: Low recurrence score (< 18) predicts optimal therapeutic benefit from tamoxifen and suggests that adjuvant chemotherapy may not be required, whereas a high recurrence score (≥ 31) suggests greater likelihood of benefit from adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) or MF adjuvant chemotherapy (reflecting the adjuvant regimens in the patient population in which the assay was investigated). The assay quantifies expression of 21 genes—16 cancerrelated genes and 5 reference genes— in RNA extracted from formalin-fixed, paraffin-embedded tumor tissue using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression of the cancer-related genes is normalized to the expression of the reference genes. The cancer-related genes include those associated with proliferation, HER2, estrogen, and invasion. The OncotypeDx assay was also shown to be predictive of the need for chemotherapy in a group of women

Available Assays

Fig. 1: Use of DNA microarray technology to detect concentrations of complementary RNA sequences (targets). Starting with fluorescent dye–marked RNA, the RNA is hybridized with the DNA microarray (probes). Using laser excitation, the two dye-marked RNA groups produce microarray analyses. These microarrays are scanned and the intensities of the signals are compared to detect relative levels of gene expression, or up- and downregulation of genes.

rapid recurrence of cancer. The assay measures 70 cancer-related genes and approximately 1,800 reference genes in fresh tissue samples containing a

affin-embedded samples. It is intended to predict recurrence risk in newly diagnosed patients with ER-positive, nodenegative disease.

These techniques offer considerable promise of producing gene profiles that can provide useful predictive and prognostic information about cancers. minimum of 30% malignant cells using a DNA microarray technique. Cancerrelated genes include those associated with cell signaling, growth factors, transcription, cell cycle, chromatin, nuclear proteins, adhesion, motility, cytoskeleton organization, cellular metabolism, intracellular transport, ubiquitination, apoptosis, and drug resistance.

RT-PCR and DNA Microarray Analysis The technologies underlying these assays are RT-PCR and DNA microarray analysis (see Figs. 1 and 2). In RTPCR, quantification of a specific RNA molecule is performed by reverse transcription of the RNA into its complementary DNA and amplification of the

DNA by PCR. The DNA is quantified after rounds of amplification through the use of fluorescent dyes that intercalate with double-stranded DNA or through use of modified DNA oligonucleotide probes that fluoresce when hybridized with complementary DNA. By attaching fluorescent dyes with different emission spectra to different probes, repeated implementations of PCR permit multiple DNA species to be quantitated in a single sample. RT-PCR is highly sensitive and is now widely used in quantifying absolute changes in gene expression and in validating results obtained with microarray and other techniques that measure global changes in gene expression. DNA microarray analysis is based on the natural pairing of complementary nucleic acids. A set of DNA sequences (probes) is arrayed on a miniaturized solid surface (microarray) and used to detect concentrations of corresponding complementary RNA sequences (targets) in a sample. Advances in this technique have made it possible to assess the expression of thousands of different genes in a single reaction. In a basic “two-color” microarray analysis, RNA labeled with a fluorescent dye is hybridized to the microarray and incubated with RNA from another sample labeled with a different dye. Samples can be compared directly or in relation to a reference RNA. The microarray is scanned to produce grayscale images corresponding to fluorescence intensities of each gene being analyzed. The intensities of the signals are compared to detect relative levels of expression, which are quantified through computational/statistical techniques.

Guidelines for Use These techniques offer considerable promise of producing gene profiles that can provide useful predictive and prognostic information about cancers. For the present, exactly how best to use information provided by existing assays to supplement clinicopathologic information in making treatment decisions remains somewhat uncertain. In part, this uncertainty arises because it is difficult to generalize about performance of the assays beyond the particular patient populations (in terms of both disease characteristics and treatments received) in which they were investigated and inicontinued on page 34

The ASCO Post | JULY 2010

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TAP on Technology

Gene Profiling Assays continued from page 33

score (≥ 31) can be treated with both (all recommendations for use of the assay are considered NCCN category 2B). The guidelines emphasize that the recurrence score should be used for decision-making only in the context of other elements of risk stratification for an individual patient.

Fig. 2: Reverse transcription polymerase chain reaction (RT-PCR). RNA is reverse transcribed into its DNA complement, and the complementary DNA is amplified by PCR, using primers specific for one or more genes. mRNA = messenger RNA; tRNA = transfer RNA.

For more information on multiparameter gene profiling in breast cancer, see:

See page 55

Randomized Trials

tially validated. The most recent ASCO breast cancer guidelines (2007), in which multiparameter gene expression analysis was a new topic, state that the Oncotype DX assay may be used to identify patients who are predicted to obtain the most benefit from adjuvant tamoxifen and who may not require adjuvant chemotherapy. On the other hand, the guidelines note that patients with high recurrence scores appear to achieve relatively more benefit from adjuvant chemotherapy (specifically CMF or MF) than tamoxifen. The guidelines further state that there are insufficient data to comment on whether these conclu-

sions generalize to hormonal therapies other than tamoxifen or to chemotherapy regimens other than (C)MF and that the precise clinical utility and appropriate application of other multiparameter assays remain under investigation. The 2010 National Comprehensive Cancer Network (NCCN) guidelines recommend considering the Oncotype DX assay as an option in patients with tumors of 0.6 to 1.0 cm with unfavorable features or > 1.0 cm and nodenegative, hormone receptor–positive, and HER2-negative disease. Those with a low score (< 18) can be treated with hormonal therapy, those with an intermediate score (18–30) can be treated with hormonal therapy with/without chemotherapy, and those with a high

Important information on the potential use of the Oncotype DX assay and the MammaPrint test is expected from two prospective randomized trials. The NCI-sponsored Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) is being conducted by the North American Breast Cancer Intergroup. In this study, women whose ER-positive, node-negative disease meets established clinical guidelines for adjuvant chemotherapy will receive hormonal therapy alone if they have an Oncotype DX recurrence score < 11 and hormonal therapy and chemotherapy if they have a score > 25. Patients with scores of 11 to 25 are being randomized to hormonal therapy alone or in combination with chemotherapy to determine whether hormonal therapy alone offers less benefit than the combination. The MINDACT trial (Microarray in Node-negative Disease may Avoid ChemoTherapy), conducted by the TRANSBIG network (a translational research arm of the Breast International Group), is comparing the MammaPrint test with a standard clinicopathologic prognostic tool (Adjuvant! Online) in selecting patients with 0 vs 1 to 3 positive nodes (hormone receptor–positive or –negative) for adjuvant chemotherapy. Patients with low risk on both measures do not receive chemotherapy, those with high risk on both measures do receive chemotherapy, and those with discordant risk assessment are randomized to chemotherapy or no chemotherapy. Both trials are also assessing outcomes according to different hormonal therapy and chemotherapy regimens.

■

Albain KS, Barlow WE, Shak S, et al: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with nodepositive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncology 11(1):55-65, 2010. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 33:5287-5312, 2007. Marchionni L, Wilson RF, Marinopoulos SS, et al: Impact of gene expression profiling tests on breast cancer outcomes. Evidence Report/ Technology Assessment no. 160. Prepared by The Johns Hopkins University Evidence-based Practice Center under contract no. 290-020018. AHRQ publication no. 08-E002. Rockville, MD; Agency for Healthcare Research and Quality; January 2008. http://www.ahrq.gov/clinic/tp/ brcgenetp.htm NCCN clinical practice guidelines in oncology: Breast cancer, V.2.2010. http://www.nccn.org/professionals/ physician_gls/PDF/breast.pdf. Sotiriou C, Pusztai L: Gene-expression signatures in breast cancer. N Engl J Med 360:790-800, 2009. Sparano JA, Solin LJ: Defining the clinical utility of gene expression assays in breast cancer: The intersection of science and art in clinical decision making. J Clin Oncol 28:1625-1627, 2010. See, also, references cited therein. For information on the TAILORx trial, see: http://www.cancer.gov/clinicaltrials/ ECOG-PACCT-1 For information on the MINDACT trial, see: http://www.cancer.gov/clinicaltrials/ EORTC-10041

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

■■ 2010 Digestive Disease Week Annual Meeting

■■ 2010 American Society of Clinical Oncology Annual Meeting

■■ 2010 Genitourinary (GU) Cancers Symposium

■■ Plus important columns, engaging features, and clinical

■■ 101st Annual Meeting of the American Association of Clinical Research (AACR)

departments.

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

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

All responders (CR+CRu+PR)

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

5 6 7 8 Time (Months)

10 11 12 13 14 15 16

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

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

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

9.3

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

Complete responders (CR+CRu)

VELCADE Warnings, Precautions, and Adverse Events

15.4

CI, 13.4-15.4) VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists.(95% Warnings and (n=12) Precautions for VELCADE include: advising0 women peripheral 1 2 to3 avoid 4 5pregnancy 6 7 8 and 9 breastfeeding; 10 11 12 13 14 15 16 neuropathy, sometimes severe may occur—manage with dose (Months)cations or discontinuation and carefully Timemodifi consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on next page. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. *PINNACLE, a single-arm, multicenter, phase 2 trial (N=155) evaluating the efﬁcacy and safety of VELCADE in mantle cell lymphoma (MCL) patients who have received at least 1 prior therapy.

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

The ASCO Post | JULY 2010

PAGE 36

News Pancreatic Cancer

Investigators Address Link between Intra-abdominal Fat and Survival in Patients with Pancreatic Cancer By Alice Goodman

study presented at the 2010 Digestive Disease Week Annual Meeting found that intra-abdominal fat was a predictor of survival in patients with pancre-

atic cancer, and the greater the amount of intra-abdominal fat, the worse the survival.1 The meeting was held May 1–5 in New Orleans.

“Obesity is linked to increased risk of several types of cancer, including colon, breast, prostate, and endometrial. In our study, the location of the fat was the key

to survival rates,” said David H. Berger, MD, coauthor of the paper. Dr. Berger is Professor of Surgery at Baylor College of Medicine, Houston. This study used intra-abdominal fat as a measure of obesity because body mass index (BMI) is not considered reliable. “Arnold Schwarzenegger has a large BMI but no fat,” stated the paper’s coauthor, Courtney Balentine, MD, a research fellow at Baylor.

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

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

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

Courtney Balentine, MD

No Extra Imaging Required Intra-abdominal fat was measured by CT scan in 61 patients who underwent a Whipple procedure for exocrine pancreatic adenocarcinoma during the years 2000 to 2009. The authors noted that CT scans are routinely performed prior to this type of surgery, so measuring intra-abdominal fat required no extra imaging. For comparison purposes, BMI was measured as part of the physical exam. After adjusting for age and perineural invasion status, the investigators found that preoperative BMI was not a significant predictor of overall survival, whereas the quartile of intra-abdominal fat did affect survival in a nonlinear fashion. People in the second quartile of intra-abdominal fat had a fourfold increased likelihood of death (HR = 4.018, 95% CI = 1.099–14.687, P < .035) compared with the lowest quartile. Those in the third and fourth quartile had a greater risk of death than those in the lower quartiles, but this difference did not reach statistical significance. According to Dr. Balentine, this novel approach to measuring intra-abdominal fat should be used to further explore the relationship between obesity and outcomes in pancreatic cancer.

■

Reference 1. Berger DH, et al: Intra-abdominal fat predicts survival in pancreatic cancer. 2010 Digestive Disease Week. Abstract W1681. Presented May 5, 2010.

ASCOPost.com | JULY 2010

PAGE 37

News Colon Cancer Colorectal Cancer

Adjuvant Cetuximab Does Not Improve Survival in Stage III Colon Cancer By Kathleen Louden

phase III clinical trial found that cetuximab (Erbitux) added to standard adjuvant chemotherapy for resected stage III colon cancer did not improve either overall survival or disease-free survival (DFS), even in patients with wild-type KRAS tumors. Results of the study, the North Central Cancer Treatment Group Intergroup trial N0147, were presented at the 2010 ASCO Annual Meeting. The trial, which enrolled nearly 3,000 adults, terminated early after a futility analysis showed adjuvant cetuximab had no benefit over a modified FOLFOX6 regimen (fluorouracil, leucovorin, and oxaliplatin) alone and had significantly more grade 3/4 adverse effects. The investigators had expected the monoclonal antibody to have benefits when added to FOLFOX based on prior research that found cetuximab extends life for patients with metastatic colon cancer expressing the KRAS wildtype gene. “What we learned is that [the cetuximab benefit in] metastatic disease does not necessarily apply to the adjuvant setting. This treatment should not be

used in patients with resected stage III colon cancer,” said lead researcher Steven Alberts, MD, Professor of Oncology at the Mayo Clinic College of Medicine in Rochester, Minnesota.

KRAS Status Important The trial opened before KRAS mutation status testing became available, and once it did in early 2008, the study was redesigned and researchers enrolled only patients with normal KRAS activity. Dr. Alberts reported the results in 1,864 patients with normal KRAS: 909 who received only FOLFOX therapy and 955 who received cetuximab as well.1 Richard Goldberg, MD, Professor at the University of North Carolina at Chapel Hill, presented the results of the 717 patients with KRAS mutations who were enrolled before testing was required.2 Of those, 343 patients received cetuximab in addition to FOLFOX, and 374 were in the FOLFOX-only arm. As in other studies, KRAS status was predictive of response to cetuximab, with patients who had mutations faring worse than those with the wild type, Dr. Goldberg said. Overall 3-year

Cetuximab, FOLFOX, and KRAS Status ■■ Cetuximab provides no survival benefit when added to standard che-

motherapy with a modified FOLFOX6 regimen for patients with resected stage III colon cancer, both with normal and mutated KRAS status.

■■ Cetuximab with FOLFOX had significantly more side effects than FOLFOX alone, regardless of KRAS status.

■■ Clinicians should not use cetuximab in patients with resected stage III colon cancer.

DFS for the cetuximab-plus-FOLFOX group was 62.3% for patients with mutated KRAS tumors vs 73.3% for those with wild-type tumors, according to the investigators. Patients who received FOLFOX alone had a 3-year DFS of 70.3% if they had KRAS mutations,

Steven Alberts, MD

results were negative,” Dr. Alberts said. “It may be that cetuximab acts differently in patients with micrometastatic disease than in established metastatic disease.” Dr. Weiner added, “It is possible that the colon cancer cells transiently lose EGFR dependency during the

Richard Goldberg, MD

compared with 74.1% for the wild type. “Clearly, cetuximab treatment of patients with KRAS mutations perturbs the tumor biology, in the opposite fashion of what we had hoped,” he said. Why Didn’t Cetuximab Work? “I find no flaws in study design or execution that would explain these results,” said the study’s discussant, Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center, and Chair of the Department of Oncology at Georgetown University Medical Center, Washington, DC. The lack of response to cetuximab is likely to hold true for other epidermal growth factor receptor (EGFR)-directed monoclonal antibodies, he said. “It is critical to understand why the

Louis Weiner, MD

process of metastasis. This would create new opportunities and challenges for drug development designed for the adjuvant therapy of colon cancer.”

■

References 1. Alberts SR, Sargent DJ, Smyrk TC, et al: Adjuvant mFOLFOX6 with or without cetuximab (Cmab) in KRAS wildtype (WT) patients (pts) with resected stage III colon cancer (CC): Results from NCCTG Intergroup Phase III Trial N0147. 2010 ASCO Annual Meeting. Abstract CRA3507. Presented June 5, 2010. 2. Goldberg RM, Sargent DJ, Thibodeau SN, et al: Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. 2010 ASCO Annual Meeting. Abstract 3508. Presented June 6, 2010. Colorectal Cancer

Addition of Cetuximab to Oxaliplatin Fails to Improve Overall Survival in First-line Treatment of Advanced Colorectal Cancer By Kathleen Louden

he largest clinical trial of epidermal growth factor receptor (EGFR)-targeted, first-line treatment of advanced colorectal cancer demonstrated negative results overall. Nevertheless, researchers identified possible subgroups of patients who may benefit from the addition of cetuximab (Erbitux) to oxaliplatin-based chemotherapy. Findings of the study, the UK-based Medical Research Council’s Cetuximab and Oxaliplatin (MRC COIN)

trial, were presented at the 2010 ASCO Annual Meeting during the Gastrointestinal Cancer Oral Abstract Session.

No Benefit in Total Population For the total population of 2,445 patients, the addition of cetuximab to the chemotherapy regimen did not change the overall survival (OS) or progression-free survival (PFS), according to principal investigator Timothy Maughan, MD, Professor continued on page 41

Cetuximab and KRAS in Colorectal Cancer ■■ Cetuximab, when added to first-line oxaliplatin/fluoropyrimidine

chemotherapy, does not improve survival in patients with advanced colorectal cancer, including KRAS wild-type disease.

■■ There may be a survival benefit for cetuximab in patients with limited

metastases and no KRAS mutations, especially for those receiving 5-FU rather than capecitabine. However, further analysis is needed.

■■ Mutation in either KRAS or BRAF has a poor prognostic effect in patients with advanced colorectal cancer.

The ASCO Post | JULY 2010

PAGE 38

News Prostate Cancer

ASCENT2 in Castration-resistant Prostate Cancer: Inferior Survival Outcomes with Docetaxel/Calcitriol vs Docetaxel/Prednisone By Larry J. Rosenberg, PhD

esults of the phase III ASCENT2 trial found that the combination of docetaxel and high-dose calcitriol provided no survival benefit compared with docetaxel and prednisone in men with progressive castrationresistant prostate cancer (CRPC). These findings, recently reported at

ity of at least a 50% reduction in PSA from baseline, longer follow-up suggested that survival was greater for patients on the ASCENT regimen compared with placebo (median = 24.5 vs 16.4 months). Interestingly, a possible reduction in the incidence of gastrointestinal (GI) and thromboembolic events was also noted on the ASCENT arm.

ASCENT2

Howard I. Scher, MD

the 2010 ASCO Annual Meeting by Howard I. Scher, MD, of Memorial Sloan-Kettering Cancer Center, fail to support data from a previous phase II trial that had suggested a survival benefit with the docetaxel/calcitriol regimen.1

ASCENT Calcitriol, a naturally occurring hormone and the principal active metabolite of vitamin D, has been shown to inhibit the growth of prostate cancer cells and to exert additive or synergistic effects when combined with chemotherapy, including docetaxel. A previous phase II study of highdose calcitriol plus weekly docetaxel showed promising activity in progressive CRPC. The randomized phase II trial, known as ASCENT (AIPC [Androgen-Independent Prostate Carcinoma] Study of Calcitriol Enhancing Taxotere), evaluated whether the addition of DN-101, an oral highconcentration formula of calcitriol, to weekly docetaxel could increase the prostate-specific antigen (PSA) response rate in men with metastatic CRPC.2 In this trial, 250 patients were randomized to treatment with docetaxel at 36 mg/m2 IV for 3 of 4 weeks plus either high-dose calcitriol (45 µg of DN-101) or placebo. PSA responses were noted in 63% of patients in the ASCENT arm and 52% in the control arm (P = .07). Although this trial failed to meet the primary endpoint of a predefined improvement in the probabil-

A subsequent phase III trial, ASCENT2, evaluated whether the addition of DN-101 to weekly docetaxel prolongs survival and reduces toxicity compared with docetaxel given every 3 weeks. Men were eligible for this trial if they had metastatic CRPC with disease progression, Eastern Cooperative Oncology Group performance status of 0 to 2, serum testosterone level less than 50 ng/mL, and normal renal and hepatic function. No prior chemotherapy was allowed. Patients (N = 953) were randomly assigned in a 1:1 ratio to the ASCENT regimen (36 mg/m2 of docetaxel, 45 µg of DN-101, and 24 mg of dexamethasone weekly for 3 of every 4 weeks) or the control arm (5 mg of prednisone twice daily, 75 mg/m2 of docetaxel, and 24 mg of dexamethasone every 3 weeks). The primary study endpoint was overall survival, with secondary endpoints of thromboembolic event rate, duration of skeletal-related event-free survival, and safety. The planned enrollment was 900 patients, which was amended to 1,200 patients in April 2007 to increase the power of the trial. However, 6 months later the trial was halted by the data safety monitoring board due to an increased number of deaths on the ASCENT arm compared with the control arm (17.0% vs 10.2%). With a median follow-up of 11.7 months, median overall survival

was 16.8 months (95% CI = 15.8–19.3) for men on the ASCENT arm and 19.9 months (95% CI = 18.6–22.7) for those on placebo (P = .002). Multivariate analysis confirmed that treatment with the ASCENT regimen was associated with a statistically shorter survival compared with control (HR = 1.33, P = .019). A competing risk analysis confirmed that treatment assignment (or treatment with ASCENT) was associated with prostate cancer–specific mortality but not with death from other causes after adjusting for important prognostic factors. Patient baseline demographics were well balanced between treatment arms. The toxicity profiles were also similar for both groups, noted Dr. Scher, including rates of severe adverse events. However, dose modification due to docetaxel toxicity was more common with ASCENT than with control treatment (229 vs 160 patients). The possible protective effect of this regimen on GI and thromboembolic events previously seen in the first ASCENT study was not confirmed in the present trial.

Docetaxel Schedules The similarity in survival times in trials of weekly docetaxel suggests that the addition of DN-101 did not adversely affect outcomes. In the TAX 327 trial, use of weekly docetaxel resulted in slightly shorter survival relative to docetaxel every 3 weeks used in the control arm, although the study was not designed to compare the two arms.3 The inferior survival observed in ASCENT2 may have been related to the weekly docetaxel used on the ASCENT arm compared with the every-3-week dosing on the control arm. Ian Tannock, MD, PhD, DSc, of the Princess Margaret Hospital and

University of Toronto, noted that although the trial may be criticized for using differSee page 55 ent schedules of docetaxel, “this was a pragmatic design, based on preclinical data and a prior phase II study that allowed maximum interaction of the two drugs.” The results underscore the importance of confirming apparently promising phase II results, concluded Dr. Scher.

■

References 1. Scher HI, Chi KN, De Wit R, et al: Docetaxel (D) plus high-dose calcitriol versus D plus prednisone (P) for patients (Pts) with progressive castration-resistant prostate cancer (CRPC): Results from the phase III ASCENT2 trial. Abstract 4509. Presented June 6, 2010. 2. Beer TM, Ryan CW, Venner PM, et al: ASCENT Investigators. Doubleblinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: A report from the ASCENT Investigators. J Clin Oncol 25:669-674, 2007. 3. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.

The ASCENT2 Trial ■■ The phase III ASCENT2 trial found that the combination of docetaxel and high-dose calcitriol was inferior to every-3-week docetaxel and prednisone in men with progressive castration-resistant prostate cancer.

■■ These data fail to support earlier results from the ASCENT trial that had

suggested a survival benefit and possible improved toxicity profile with docetaxel/high-dose calcitriol compared with placebo.

Inside this Issue Comprehensive coverage of 2010 ASCO Annual Meeting

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

and the molecular formula is C26H28CINO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growthstimulating effects of estrogen in the tumor. Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h. Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin. Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied. Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed. CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses CR1 + PR2 14+33 11+30 7+25 3+28 19+48 19+56 RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median

survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% 2% Vomiting 4% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug. WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis). Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/ kg/day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly. There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended. Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum. Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice. Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses. Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks. Pregnancy: Pregnancy Category D: (see WARNINGS). Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS). Pediatric use: There is no indication for use of FARESTON in pediatric patients. Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below. Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from heat and light.

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Lessons Learned Perspective

Optimizing the Doctor-Patient Relationship By Stanley Winokur, MD

Lessons Learned presents reflections from practitioners who have gained a greater understanding of clinical practice (and life) through sometimes surprising experiences. Send us your own Lessons Learned for consideration; write to Editor@ASCOPost.com.

very oncologist spends years learning how to treat cancer. Preparing ourselves to care for the full spectrum of our patients’ needs may not always be part of the curriculum. We begin our journey into the challenging world of oncology by studying tumor biology, biochemistry, radiology, and pathology. We progress to garnering an understanding of the natural history of tumors, and eventually to mastering proficiency in thera-

MRC COIN Trial continued from page 37

of Cancer Studies, Cardiff University School of Medicine, Cardiff, United Kingdom. “This result runs contrary to what we expected,” Dr. Maughan said. The investigators recruited patients from the United Kingdom and Ireland who had inoperable colorectal cancer and had never received chemotherapy. This study aimed to determine whether OS improves when the monoclonal antibody cetuximab is added to continuous chemotherapy with oxaliplatin and a fluoropyrimidine—either oral capecitabine (Xeloda) or infusional fluorouracil (5-FU) plus leucovorin. Among the tumor samples that underwent gene mutation analysis, approximately 55% of the tumors expressed the normal wild-type form of the KRAS gene, 43% had KRAS mutations, 8% had BRAF mutations, and 4% had NRAS mutations. Among patients with wild-type tumors, the 2-year survival rate was similar be-

peutic modalities including surgery, radiotherapy, and chemotherapy. As doctors who treat life-threatening disease, we add supportive care and hospice to our coursework. Then we take the boards and enter into the clinic to begin our life’s calling. Not enough time in our years of training, however, is dedicated to developing and understanding effective communication skills, or more simply, how to speak, and even more importantly, how to listen, to our patients.

He repeated, “No, take a break and sit down.” Again, I replied, “No, I’m fine.” Finally, he looked at me and said, “Doc, you don’t get it. I need you to sit down and listen to me…please.” Only then did I hear what he was

Our patients can teach us valuable things.

The Doctor–Listening Barrier My personal lesson in listening occurred one day in clinic when, like all practicing oncologists, I was immersed in caring for several complicated cases; these were seriously ill patients. During a particularly hectic period, I was rushed into the examining room and said a quick hello to my next patient, Harvey S., a 62-year-old man with stage IV colorectal cancer scheduled to begin his second round of chemotherapy. Mr. S. immediately said, “How are you, Doc? Go ahead and take a seat.” I thought he was simply being kind, offering me a break on a busy clinic day. “No, thanks,” I replied, “I’m okay, I’ll stand.”

saying. It struck me that we know about the blood–brain barrier in certain chemotherapies, but on this day a patient taught me about the doctor– listening barrier. Ironically, after years of medical school and rigorous clinical practice, a patient—not a professor, mentor, nurse, or colleague—taught me one of the most important lessons I learned as an oncologist. I couldn’t help but think about all the patients I had seen while moving from one exam room to the next, entering each room quickly, using my time efficiently, making a few key observations, taking notes, standing the whole time, and then leaving as quick-

tween treatment arms: 40% in the control arm and 38.8% in the cetuximab arm, Dr. Maughan reported. He said it is unclear why survival was poor in both arms. Patients with wild-type KRAS who received cetuximab had a better overall

survival with added cetuximab therapy for patients with one or fewer metastatic sites at baseline who had no KRAS, BRAF, or NRAS mutations, he said. Independent of the use of cetuximab, the median survival in patients with any mutation was only 12.7

What’s new and, I think, provocative is the analysis of KRAS mutations, that KRAS mutation may be prognostic and predicts nonresponse to EGFR antibodies. response rate than did the control arm (64% vs 57%, respectively), as assessed by the investigators. Furthermore, for the total population, fewer patients receiving cetuximab received secondline therapy than those in the control arm (56% vs 62%).

Predictive Covariates Subgroup analyses showed improved

months compared with 19.9 months for all wild-type patients. According to Dr. Maughan, this difference showed a strong prognostic factor for KRAS status.

KRAS Analysis of Interest Discussant Alan Venook, MD, called the results disappointing overall. He questioned the conclusions about

ly as I entered. I wondered how many of my patients felt as though I was not really taking the time to listen to their concerns.

Focus on the Individual To any doctor in practice or just beginning in training, I recommend that when you enter a room, be it in the office or hospital, find a chair, pull it up next to your patient, sit down, and look into the patient’s eyes. Nothing else, no other patient or issue you are confronting that day is as important as the seriously ill person before you. Patients may have waited a long time to see you. They may be anxious and frightened, or they may just have a story to tell. Our patients can teach us valuable things—some of the intricacies of personalized care we may never have learned in medical school or training—but in order to maximize our doctor-patient relationships and enhance our quality of care, we need to focus on the individual and make the time to listen.

■

Dr. Winokur is a retired oncologist who lives in Singer Island, Florida. He is the author of the book Grandfathered In, a memoir about finding balance between a career in medicine and a family.

the subgroup analyses and said the message from this trial is unclear. “What’s new See page 55 and, I think, provocative is the analysis of KRAS mutations, that KRAS mutation may be prognostic and predicts nonresponse to EGFR antibodies,” said Dr. Venook, Professor of Clinical Medicine at the University of California, San Francisco. Merck Serono helped fund this study, as did the MRC and Cancer Research UK. Reference 1. Maughan TS, Adams R, Smith CG, et al: Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): Mature results of the MRC COIN trial. 2010 ASCO Annual Meeting. Abstract 3502. Presented June 6, 2010.

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In the Spotlight

A Tribute to Jane C. Wright, MD

ASCO Cofounder and ‘The Mother of Chemotherapy’

Dr. Wright was a pioneer in 20th century medicine, overcoming obstacles placed on her by society as a woman and as an African-American, but most of all she was a pioneer in chemotherapy, taking those first small steps into the unknown, and paving the way for the giant steps to come.

n April 9, 1964, at the first meeting to discuss forming a society for “chemotherapists,” only one of the seven physicians in attendance was a woman, Jane Cooke Wright, MD. Dr. Wright recorded the minutes that day in Chicago when the seven physicians voted unanimously to form a society of clinical oncologists. Arnoldus Goudsmit, MD, PhD, who chaired the meeting, asked Dr. Wright to continue to serve as secretary at future meetings, and added, “Kindly consider the name of our organization and come up with a final suggestion.” By November 5, 1964, when the charter members of the organization met for the first time, the provisional title “The American Association of Clinical Oncologists” had been changed to “The American Society of Clinical On-

Dr. Ansfield

into the unknown, and paving the way for the giant steps to come.

Early Career Jane Cooke Wright was born in 1919 in New York City, not far from where she lives today in retirement. Her father, Louis Tompkins Wright, was a physician, as were his father and stepfather. Her mother, Corinne Cooke Wright, was an elementary school teacher. Dr. Louis Wright was one of the first African-Americans to graduate from Harvard Medical School and ranked third in his class. He was also the first African-American to join the staff at Harlem Hospital. Both of his children, Jane and her younger sister Barbara, would become physicians. Jane Wright grew up loving math and science but also painting and athlet-

Dr. Bisel

Dr. Freckman

Jane Cooke Wright, MD

Dr. Wright continued her training at Harlem Hospital where her father was Director of the Cancer Research Foundation of Harlem Hospital, which he founded. He invited his daughter to join him at the Foundation in 1949. Together they tested different chemical agents on leukemia in mice and began treating patients with anticancer drugs, with several patients achieving some degree of remission. In 1951, they tested methotrexate in breast cancer cells and did research on triethylene melamine. When

Dr. Goudsmit

ASCO Founders: In 1964 the founders formed a diverse group of physicians who shared an interest in the fledgling field of cancer chemotherapy with greater patient-related orientation. On April 9, 1964, the first organization meeting of ASCO's seven-member founding group assembled for lunch in a small meeting room in the

cology.” Dr. Wright, sometimes called “the mother of chemotherapy” for her early work in the field, was elected ASCO’s first secretary-treasurer, a position she held until 1967. Dr. Wright was a pioneer in 20th century medicine, overcoming obstacles placed on her by society as a woman and as an African-American, but most of all she was a pioneer in chemotherapy, taking those first small steps

Source: National Library of Medicine

By June Skinner

ics (she was on the swim team in both high school and college). She attended Smith College on scholarship, switching her major from art to pre-med her junior year. After receiving her MD degree with honors from New York Medical College in 1945, she interned at Bellevue Hospital in New York. She was married in 1947 to attorney David Dallas Jones, Jr, with whom she had two daughters.

Dr. Talley

Medical College. At that time, she was the highest ranked African-American woman at a nationally recognized medical institution. At New York Medical College, Dr. Wright created a program of study into cancer, heart disease, and stroke, and a program to teach physicians how to use chemotherapy and conduct medical research. She developed new techniques for delivering cancer agents and for using human tissue culture to test cancer drugs. She established a database to al-

Dr. Wilson

Dr. Wright

Edgewater Beach Hotel in Chicago. Founders included (L to R): Fred J. Ansfield, MD; Harry F. Bisel, MD; Herman H. Freckman, MD; Arnoldus Goudsmit, MD, PhD; Robert Talley, MD; William Wilson, MD; and Jane C. Wright, MD. Photos reprinted from www.ASCO.org © 2010. American Society of Clinical Oncology. All Rights Reserved.

her father died in 1952, Dr. Wright was appointed Director of the Foundation.

Later Work Dr. Wright left the Cancer Research Foundation in 1955 to continue her research at New York University Bellevue Medical Center. In 1967, she became Associate Dean, Head of the Cancer Chemotherapy Department, and Professor of Surgery at New York

low cross-referencing of patients and tissue culture responses to drugs. Her research also included the use of chemotherapy agents in sequence rather than combination. And she recognized the importance of monitoring chemotherapy patients for side effects and stopping the drugs when necessary. In 1964, President Lyndon B. Johnson invited Dr. Wright to join the cancer subcommittee of the President’s Com-

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In the Spotlight

Dr. Wright... is a trailblazer in clinical oncology... and instrumental in putting together our organization (ASCO). – Olufunmilayo Olopade, MD

mission on Heart Disease, Cancer, and Stroke. The subcommittee followed her suggestion to recommend the establishment of regional cancer treatment centers throughout the United

how progressive our organization was to embrace her and make her an ASCO officer.” She hopes that Dr. Wright is enjoying retirement and knows she will always be a role model for oncologists. The ASCO Post recently corresponded with Dr. Wright. See "A conversation with Jane Cooke Wright, MD" at right, in which Dr. Wright shares her wisdom and recollections over ASCO's 46-year history.

A Conversation with Jane Cooke Wright, MD

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Sources Changing the face of medicine: Dr. Jane Cooke Wright. www.nlm.nih.gov/ changingthefaceofmedicine/physicians/ biography_336.html. Accessed April 6, 2010. Creating the ASCO brand. www.asco. org. Accessed March 1, 2010.

The Historical Record Dr. Wright has donated her papers (collection number MS 177) to Smith College, where they are part of the Sophia Smith Collection. The 23 boxes include her correspondence, clippings, and articles by and about Dr. Wright, photographs, posters, audio recordings, awards, and memorabilia, and her published professional writings in medical journals and texts. For more information, visit www.smith.edu/libraries/libs/ssc.

AACR Award Not only was Dr. Wright a founding member of ASCO, she was a member of the American Association of Cancer Research (AACR) for more than 50 years. In 2006, the AACR established the AACR-Minorities in Cancer ResearchJane Cooke Wright Lectureship. Its first recipient was Nigerian scientist and researcher Olufunmilayo Olopade, MD. “Dr. Wright is an amazing woman, a trailblazer in clinical oncology,” Dr. Olopade said in an interview. “I was impressed that as far back as 40 years ago, she was a force to be reckoned with and instrumental in putting together our organization [ASCO].” When she received the AACR award, Dr. Olopade met Dr. Wright and her daughter. “She was gracious and engaging, and wanted to know about my research and everything going on at the meeting. I’ve seen her every year at meetings since then.” Dr. Olopade was particularly impressed with the work Dr. Wright did “as a woman of color in the 1960s, and

Exploring ASCO’s roots. www.asco.org. Accessed March 1, 2010. Krueger GM, Alexander LL, Whippen DA, et al: Arnoldus Goudsmit, MD, PhD: Chemotherapist, visionary, founder of the American Society of Clinical Oncology, 1909-2005. J Clin Oncol 24:4033-4036, 2006. Louis Tompkins Wright Biography (1891-1952). www.faqs.org/health/ bios/85/Louis-Tompkins-Wright.html. Accessed April 6, 2010. Wright, Jane Cooke. Encyclopedia of World Biography, 2008. www.encyclopedia.com/doc/1G2-2506300181.html. Accessed April 6, 2010.

States. She also served on the National Cancer Advisory Committee from 1966 to 1970 and, in 1971, was the first woman President of the New York Cancer Society.

In June 2010, more than 30,000 individuals from over 100 countries gathered for ASCO’s 46th Annual Meeting at McCormick Place in Chicago.

As one of the original founders of ASCO, can you describe your vision and goals for formalizing a society for clinical oncologists in 1964? Jane Cooke Wright, MD: When Dr. Goudsmit invited the founding members of ASCO to meet for the very first time, he did so with the recognition that we needed to focus on the clinical side of oncology. He had a vision of developing a forum that would enable mutual education, to promote the goal of finding a cure for cancer and improving quality of life for individuals with this disease. He recognized that coming together as a group we could improve quality of care, because knowledge is power, and sharing information among ourselves and other interested doctors and scientists would give us the greatest chance of increasing awareness and saving lives. He also believed that providing physicians with proper educational material and opportunities to facilitate their own improved management of patients with neoplastic disease would enhance their interest in the field. Collaboration with other professionals was seen as a critical component of the organization, with a goal of enhancing professional education in both diagnosis and treatment of cancer patients. What were among ASCO’s greatest challenges and accomplishments over these past 46 years? Dr. Wright: Among ASCO’s greatest challenges has been the need to find cures for some of the deadliest forms of cancer. However, the difference in the death rate from some forms of cancer between 1964 and today has been small. Despite our greatest efforts, we need to continue making advances in this area. In terms of accomplishments, ASCO members have led the fight for effective cancer treatments, obtained increased funding for clinical and translational research, and sought cures for the many different types of cancer that strike millions of persons worldwide each year. ASCO has grown exponentially in membership over the years, demonstrating that together we can do more than any individual alone. The

growth of the organization over time has enabled a forum for information, formal communication, and mutual education among clinically oriented physicians with a commitment to the field of human neoplastic disease. The Society has been instrumental in sponsoring the publication of books and articles on the subject of clinical oncology, creating an important knowledge base for those working in the field. And the organization has facilitated the initiation of projects related to the investigation of cancer. What are some of the greatest advances you’ve witnessed in cancer research and treatment? Dr. Wright: We have seen major advances in the treatment of certain types of cancers, including leukemias, non-Hodgkin lymphomas, and estrogen receptor–positive breast cancer, sometimes producing complete, longterm cures. In some cases, a complete cure is not yet possible, but the course of the disease can be ameliorated considerably. With these improvements, patients can live longer with a better quality of life, sometimes remaining with us for years with productive lives. Still, some malignancies remain inaccessible to cure—pancreatic and ovarian cancers are in this group. What is the best advice you ever received? Dr. Wright: The best advice I ever received came from my father—a doctor himself—who encouraged me to be the best scientist possible and to work hard at everything that I do. I was told to never give up the good fight, persevere in working toward my goals, and know that with hard work and effort, positive outcomes occur. I was told to never fear failure, as failure is an inevitable part of success. I was told that to help others in a worthy mission is a noble goal for one’s life. What advice would you give to oncologists and ASCO members today? Dr. Wright: I would tell ASCO members to work hard, persevere, collaborate with one another, be pioneers in the field, and keep up the good fight. Someday we will all benefit from our collective efforts to find a cure for cancer, improve the quality of life for many, and ultimately save lives.

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Unable to Attend the

ASCO Annual Meeting?

One Remarkable Program - Two Great Locations The Best of ASCO® Meetings are an educational initiative that condenses highlights from ASCO’s Annual Meeting into a 1 1/2 day program that will be presented in two locations:

Best of ASCO® San Francisco July 16-17, 2010 The Palace Hotel

Best of ASCO® Boston July 23-24, 2010 Renaissance Boston Waterfront Hotel

Featuring premier abstracts from the ASCO Annual Meeting, Best of ASCO® offers a more personal and interactive setting to learn about the latest advances in oncology research and practice. Session topics include: • Breast Cancer • Developmental Therapeutics • Gastrointestinal Cancer (colorectal and non-colorectal) • Genitourinary Cancer • Gynecologic Cancer • Head and Neck Cancer

• Leukemia • Lung Cancer • Lymphoma • Myeloma • Patient Care • Sarcoma

ASCOPost.com | JULY 2010

PAGE 45

FDA Update

New Educational Module on Expanded Access: A Collaborative Effort by FDA and ASCO By Tamy Kim, PharmD, and Richard Pazdur, MD, FDA

o open the 2010 ASCO Annual Meeting on June 4th, the FDA and ASCO announced a collaborative effort with the launch of a new online educational program to explain expanded access programs. The initiative is intended to help patients and physicians understand the process of requesting an expanded access program, specifically for an individual-patient Investigational New Drug (IND) application. The FDA published the new rule on expanded access programs in August 2009, which clarified existing expanded access regulations, added the new intermediate-size expanded access program, and described the criteria, submission requirements, and safeguards for expanded access programs. Expanded access of an investigational drug is a mechanism that is used to provide a patient access to a drug that has not yet been approved by the FDA, if the patient has a serious or life-threatening disease and no satisfactory alternative therapy. The goal of providing investigational drugs to patients under expanded access is to treat a patient, which is different from the goal of learning about the efficacy and safety of a drug when investigational drugs are given to patients in clinical trials. Drug development should be continued with drug approval of a

ASCO Comment “The clinical trial system is a vital tool for testing promising new therapies, but many patients do not meet these often strict criteria. The FDA’s updated Expanded Access program provide a chance for access to investigational agents for patients in need, but many physicians and patients are still unclear about the requirements for doing so. We were pleased that FDA offered us [ASCO] the opportunity to help develop comprehensive educational materials to assist all doctors, and particularly oncologists, understand this process.” —ASCO President, George W. Sledge, Jr, MD

product. However, the FDA recognizes that there are situations where patients have serious or life-threatening diseases without appropriate treatment options. Expanded access is a mechanism to provide access of investigational drugs to those in need while preserving the drug development process.

Program Rationale Many physicians are unaware that an option to treat patients with serious or life-threatening diseases (and no satisfactory alternative treatment) could be to request access of an investigational drug for treatment under an individual-patient IND. The FDA acknowledged that many physicians were unfamiliar with the process of requesting an individualpatient IND. Hence, the FDA published the new rule on expanded access. To explain the new regulations to oncologists, the FDA and ASCO developed the expanded access learning modules with the objective of familiarizing physicians with this process. The program consists of three modules that provide an overview of the expanded access regulations, explain the process of requesting expanded access for an individual patient, and outline the responsibilities of physicians who request expanded access of an investigational drug for their patients. In an effort to simplify the development of paperwork related to an individualpatient IND submission, the module includes an expanded access checklist, helpful templates used in the expanded access process, and a glossary to explain regulatory terms. It is anticipated that after participating in the online module, physicians will become familiar with expanded access and its processes.

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The educational program is available online, free of charge for both ASCO members and nonmembers at the ASCO University website, http://university.asco.org/ExpandedAccess.

Dr. Kim is Acting Associate Director for Regulatory Affairs, Office of Oncology Drug Products (OODP), Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA). Dr. Pazdur is Director, OODP, OND, CDER, FDA.

Oncology Drug News FDA Approves Cabazitaxel for Advanced Prostate Cancer The FDA has approved cabazitaxel (Jevtana) in combination with prednisone to treat men with prostate cancer. Cabazitaxel is the first treatment for advanced, hormone-refractory, prostate cancer after failure of docetaxelbased therapy. “Patients have few therapeutic options in this disease setting,” said Dr. Richard Pazdur, Director of the Office of Oncology Drug Products. “FDA was able to review and approve the application for Jevtana in 11 weeks, expediting the availability of this drug to men with prostate cancer.” Cabazitaxel’s safety and effectiveness was established in a single, 755-patient phase III study, the results of which were presented at the 2010 ASCO Annual Meeting (abstract 4508). In men with metastatic castrate-resistant prostate cancer that had progressed on a docetaxel-based regimen, cabazitaxel plus prednisone (CBZP) significantly increased response rate and survival compared with mitoxantrone/prednisone (MP). Median overall survival in the CBZP arm was 15.1 months, compared with 12.7 months with MP (HR = 0.72; 95% CI = 0.61–0.84; P < .0001). The survival benefit was consistent across all subgroups, and secondary endpoints of progressionfree survival, response rate, and time to progression were also significantly improved with cabazitaxel therapy.

Nilotinib Approved for Newly Diagnosed CML The FDA has approved nilotinib (Tasigna) for the treatment of adult patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The approval was based on results of a phase III clinical trial known as ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients). Those results were recently published in The New England Journal of Medicine (362:2251-2259, 2010). The effectiveness of nilotinib is based on major molecular response and cytogenetic response rates. The

ENESTnd study is ongoing, and further data will be required to determine long-term outcome. With this approval, Tasigna becomes the first new therapeutic option for newly diagnosed patients since the introduction of imatinib mesylate (Gleevec). Nilotinib is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML. It is also active against a broad spectrum of Bcr-Abl mutations associated with resistance to imatinib. The first clinical trials of nilotinib began only 21 months after its discovery, with the drug receiving its first regulatory approval as a secondline treatment in 2007.

Pfizer Voluntarily Withdraws Gemtuzumab from Market On June 21, Pfizer Inc. announced the voluntary withdrawal from the U.S. market of the drug gemtuzumab ozogamicin (Mylotarg) for patients with acute myeloid leukemia (AML). The company took the action at the request of the FDA after results from a recent clinical trial raised concerns about the product’s safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials. Gemtuzumab was approved in May 2000 (under the FDA’s accelerated approval program) to treat patients aged 60 years and older with recurrent AML who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate. A confirmatory, postapproval clinical trial begun in 2004 was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred among patients who received gemtuzumab compared with those receiving chemotherapy alone. Patients who are currently receiving the drug may complete their therapy following consultation with their health-care professional. Health-care professionals should inform all patients receiving gemtuzumab of the product’s potential safety risks. Any future use of gemtuzumab in the United States will require submission of an investigational new drug application to the FDA.

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The ASCO Post | JULY 2010

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In the News Breast Cancer

‘Unclear Tests’ for HER2 Receptor Leave Patients with Breast Cancer Wondering if Their Cells Have the Right Targets for Targeted Drugs In the News focuses on recent reports in the mainstream press 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.

or women with HER2-positive breast cancer, trastuzumab (Herceptin) can reduce the risk of recurrence by 50% and of mortality by 40%, Gina Kolata reported in a lengthy New York Times article on targeted therapies, primarily those used for breast cancer.1 “But those so-called targeted therapies are only as good as tests to find their protein targets,” she noted. “And while most patients do not yet know it, those tests can be surprisingly unreliable.” The article, “Cancer Fight: Unclear Tests for New Drug,” follows the case of an MIT scientist whose own research involves the HER2 protein and who was diagnosed with breast cancer. Results from two tests for HER2 were mixed, partially negative and partially weakly positive. Ms. Kolata outlined the dilemma: Failing to use trastuzumab for a HER2-positive tumor could deny the patient the benefits See page 55 of reduced risk of recurrence and mortality. Using it for women without high levels of HER2 would be “a toxic and expensive placebo,” according to Antonio Wolff, MD, of Johns Hopkins Kimmel Cancer Center. Ms. Kolata estimates that trastuzumab costs “$42,000 a year wholesale,” and along with flu-like symptoms poses the risk of “a rare, serious side effect, severe heart damage that can even be fatal.” The patient ultimately decided to forgo trastuzumab and chose standard chemotherapy.

A Growing Concern Unclear tests for HER2 are “a growing concern for patients, but this article has really crystallized the information for the general public in a more open manner,” Edith Perez, MD, Director of the Breast Cancer Program at the

Mayo Clinic in Jacksonville, Florida, told The ASCO Post. In the Times article, Dr. Perez, one of the principal investigators of the national trastuzumab studies, pointed out that there is wide variation among labs in the types of tests and the methodologies used. The article also discussed one of Dr. Perez’s patients, a 64-year-old woman who had four different HER2 tests—two with positive and two with negative results. Dr. Perez recommended that the woman take trastuzumab. “We acknowledge that breast cancers are not homogeneous. There can be some variability within the tumors,” Dr. Perez said. “We worked hard to develop these targeted drugs, and our goal includes optimization of tests to determine whether the target is present in each patient’s tumor, so that we may offer the best potential treatments. There could be very serious consequences if we miss it. It could be a matter of life and death—being alive with breast cancer or even potentially being cured of it.”

sicians at Mayo Clinic adhere to the guidelines and participate in the development of guidelines, “while also utilizing newer data for decision-making related to how to interpret test results.” As the Times article mentioned, during the national trastuzumab studies in 2001, Dr. Perez was instrumental in getting the results of HER2 tests from multiple labs, hospitals, and centers retested in a central lab. The retesting revealed a false-positive rate of 20%. That led to the modification of studies to require retesting in a central lab and, ultimately, the ASCO/CAP guidelines. “We want the right therapy for the right patients, and in order to achieve

have recently completed chemotherapy. The trial is designed to examine whether one of the agents is more effective than the other, which is safer for patients, and what benefit will be derived by taking the drugs separately, in tandem, or together. The collection and testing of tumor samples has been standardized, and paraffin samples of tumors for all North American study participants are tested and stored at the Mayo Clinic in Rochester, Minnesota. Specimens for patients from other countries are being evaluated in central laboratories in Milan and Beijing. Dr. Perez expects data related to the reliability of central

Physicians should be able to tell patients that they are sending these tests to be done at experienced laboratories. Expertise and experience are important. – Edith Perez, MD

Experience Counts The HER2 testing guidelines developed by ASCO and the College of American Pathologists (CAP) acknowledge that there is no gold standard to ensure accuracy of HER2 testing. Moreover, they state that “no assay currently available is perfectly accurate to identify all patients expected to benefit or not benefit from antiHER2 therapy,” but they do include specific criteria for positive, negative, and equivocal results.2 More recently released joint ASCO/CAP guidelines are aimed at improving the accuracy of immunohistochemistry (IHC) testing for the expression of estrogen and progesterone receptor status in breast cancer.3 “Patients should be inquisitive with their physicians about where their tests are being done,” Dr. Perez said. In turn, “physicians should be able to tell patients that they are sending these tests to be done at experienced laboratories. Expertise and experience are important.” While assuring patients that the Mayo Clinic has “a tremendous amount of experience” in HER2 testing, Dr. Perez also stated that there are many other “excellent and experienced” centers throughout the world. Dr. Perez informs patients that phy-

that, we need to identify those targets appropriately,” Dr. Perez said.

More Results by Year’s End Dr. Perez confirmed that the falsepositive rate for HER2 testing is currently about 15% to 20%. “False-negatives have been a little more difficult to identify, but some estimates put the false-negative rate at about 3%. You might think 3% is not that much, but 3% of all patients with breast cancer in the United States could be an additional 5,000 women who could potentially be receiving lifesaving medications,” Dr. Perez noted. She also said that not all women who test positive for HER2 benefit from trastuzumab. “That is why we continue doing trials with other drugs that target HER2. We are also testing other markers that may help optimize prediction of benefit from trastuzumab.” Dr. Perez is the North American leader for the Adjuvant Lapatinib and/ or Trastuzumab Treatment Optimization (ALLTO) trial, a global study comparing trastuzumab and lapatinib (Tykerb) in women with early-stage HER2-positive breast cancer who

vs local laboratories, based on nearly 10,000 samples, to be released by the end of this year.

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References 1. Kolata G: Cancer fight: Unclear tests for new drug. The New York Times. April 20, 2010. Accessed at www.nytimes.com. 2. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007. 3. Hammond ME, Hayes DF, Dowsett M, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784-2795, 2010.

More breast cancer news in this issue See pages 14, 33, and 51

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

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The ASCO Post | JULY 2010

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In the Literature

Emerging Clinical Data on Cancer Diagnosis and Management HEMATOLOGIC MALIGNANCY OCT-1 Activity Predicts Long-term Outcome of Imatinib Therapy in CML White and colleagues reported that organic cation transporter-1 (OCT-1) activity prior to treatment is predictive of major molecular response (MMR), overall survival (OS), event-free survival (EFS), resistance, and leukemic transformation over 5 years in patients with chronic myeloid leukemia (CML) receiving imatinib (Gleevec). OCT-1 activity is a measure of OCT-1–mediated influx of imatinib into CML mononuclear cells and has previously been found to predict MMR at 1 and 2 years in patients with untreated CML. The study also indicated that early imatinib dose intensity might reduce risk for poor outcome indicated by initial low OCT-1 activity. In the study, 56 patients with untreated chronic-phase CML had OCT-1 activity (ie, the difference in intracellular concentration of 14C-labeled imatinib in the presence and absence of OCT-1 inhibition by prazosin) measured prior to initiating treatment with imatinib at 600 mg/d. The dose was increased to 800 mg/d in the absence of specific hematologic, cytogenic, or BRC-ABL response thresholds. High and low OCT-1 activity was defined as activity above and below the median value, respectively.

Key Findings Patients with high OCT-1 activity had significant improvements in MMR rate (89% vs 55%, P = .007), OS (96% vs 87%, P = .028), and EFS (74% vs 48%, P = .03) and a lower kinase domain mutation rate (4% vs 21%, P = .047). Differences between the highand low-activity groups in MMR and EFS were significant in patients who averaged < 600 mg/d of imatinib during the first year of treatment and not significant in those averaging dosages ≥ 600 mg/d. Only patients with OCT-1 activity in the lowest quartile developed leukemic transformation (21% vs 0% in all other quartiles, P = .002). The authors concluded that measurement of OCT-1 activity could be used to individualize imatinib dosing strategies to improve molecular response rates and long-term outcomes in CML. White DL, et al: J Clin Oncol April 26, 2010 (early release online).

GENITOURINARY CANCER Four-drug Combination Shows Promise in Castration-resistant Prostate Cancer Ning and colleagues reported promising outcomes in a phase II trial evaluating the combination of bevacizumab (Avastin), thalidomide (Thalomid), docetaxel, and prednisone in patients

with metastatic castration-resistant prostate cancer. The results suggested that definitive trials combining antiangiogenic agents with docetaxel should be performed. Previously, a median overall survival (OS) of approximately 19 months has been reported with the combination of docetaxel and prednisone in this setting. Recent findings have indicated potential benefits of adding antiangiogenic treatment. For example, phase II data demonstrated improved prostate-specific antigen (PSA) response and OS with the combination of thalidomide/docetaxel vs docetaxel alone and substantial antitumor activity with the combination of docetaxel and bevacizumab.

Treatment In the current study, a total of 60 patients with progressive disease received IV docetaxel at 75 mg/m2 and bevacizumab at 15 mg/kg on day 1 every 21 days plus oral thalidomide at 200 mg/d and prednisone at 10 mg/d. Patients also received enoxaparin (Lovenox), 1 mg/kg/d SC beginning on day 1 to prevent thrombosis, and pegfilgrastim (Neulasta), zoledronic acid, and ongoing androgen-deprivation therapy as indicated. The primary endpoint was PSA decline of at least 50%, and secondary endpoints were time to progression, OS, and safety.

PSA Response, Progression, and Survival Patients received a median of 20 cycles of therapy. Modification of thalidomide dose was required in 68% of patients (reduction in 55%, discontinuation in 13%), 27% had a 25% dose reduction in docetaxel, and 12% discontinued bevacizumab due to toxicity. Of 58 patients with PSA-active disease, 52 (89.6%) had PSA decreases ≥ 50%, 44 (75.9%) had overall declines ≥ 75%, and 51 (87.9%) had declines ≥ 30% within 3 months of starting treatment. Median time to progression was 18.3 months, and median OS was 28.2 months. Predicted OS in this group of patients (based on the Halabi survival nomogram) was 14 months. Toxicities were manageable. All patients developed grade 3 or 4 neutropenia, and a higher than expected rate of grade 2 osteonecrosis of the jaw was observed.

Ning Y-M, et al: J Clin Oncol 28:20702076, 2010.

CLINICAL TRIALS ASCO Survey Finds Researchers Plan to Limit Participation in NCI Clinical Trials A survey conducted by ASCO at research sites enrolling patients in cooperative group trials found that 33% of the 509 research sites responding plan to limit participation in clinical trials funded by NCI and an additional 9% were considering doing so. “The reduced participation would include limits on total number of patients accrued, number of trials open, and number of cooperative group affiliations,” according to findings reported in the Journal of Oncology Practice. The sites included academic medical centers, nonacademic hospitals, and private practices. Most survey respondents (75%) cited insufficient NCI per-case reimbursement as a reason for limiting participation in cooperative group trials. Some cited insufficient staffing as a contributing or sole determining influence. Among the reasons written in the “other” category were NCI grant mechanisms providing greater financial incentives for investigator-initiated trials, insufficient funding from reimbursement to support staff salaries, and cancer center leaders placing less emphasis on the importance of cooperative group trials compared with other studies.

Reimbursement Unchanged for 10 Years “We believe the NCI is underestimating the importance of adequate funding as a means of sustaining enrollment and participation in NCI-supported cooperative group trials,” the authors stated. They note that the per-case reimbursement of $2,000 has not increased in 10 years and that studies indicate this is significantly below the cost of conducting clinical trials. “Although funding is not the only factor affecting whether sites participate in NCI-funded trials,” the authors concluded, “the significant and growing disparity between actual research costs and the amount provided by the NCI to cover those costs serves as a significant deterrent. Without increased funds, the NCI will not be able to increase the number of trials, increase the number of participants enrolled onto trials, or maintain the current infrastructure

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In the Literature

to support the safe conduct of clinical trials.” Baer AR, et al: J Oncol Pract 6:114-117, 2010.

DRUG SIDE EFFECTS Assessing and Managing Hypertension in Patients Taking Angiogenesis Inhibitors To avoid complications from acute hypertension in patients taking drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP), clinicians should carefully assess, monitor, and aggressively manage blood pressure throughout the course of treatment. Principles for safer, more expansive use of VSP inhibitors and recommendations for the individual treating physician were detailed in a Journal of the National Cancer Institute commentary by the Cardiovascular Toxicities Panel convened by NCI’s Angiogenesis Task Force. The panel noted that four agents within the VSP subclass of angiogenesis inhibitors have been “approved for marketing by multiple regulatory bodies worldwide.” These agents are bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient). The panel also listed several VSP inhibitors in the later stages of development: aflibercept (VEGF Trap), axitinib (AG-013736), cediranib (AZD2171, Recentin), motesanib (AMG 706), and vandetanib (ZD6474, Zactima). “Blood pressure elevation is an effect common to all VSP inhibitors, with hypertension reported as an adverse event in every trial of these drugs,” the panel reported.

Frequent Assessments Recommended The panel recommended that treating physicians conduct and document a formal risk assessment of potential cardiovascular complications prior to VSP inhibitor treatment and actively monitor blood pressure throughout treatment. More frequent assessments should occur during the first treatment cycle, “typically when the bulk of the blood pressure elevation is expected to occur and when most patients unexpectedly present with elevations warranting treatment even in the absence of preexisting cardiovascular risk factors,” the panel noted. The goal should be a blood pressure of less than 140/99 mm Hg for most patients, lower in patients with preexisting risk factors such

as diabetes and chronic kidney disease. While many classes of antihypertensive agents have been successfully used to control hypertension induced by VSP inhibitors, prescribing these agents requires awareness of pharmacology, cautions, and contraindications. In addition, the panel reminded physicians of other agents that could magnify the blood pressure–elevating effects of the VSP inhibitors. These include excessive alcohol consumption, nonsteroidal anti-inflammatory drugs, adrenal steroid hormones, erythropoietic agents, and oral contraceptives. Maitland ML, et al: J Natl Cancer Inst 102:596-604, 2010.

LUNG CANCER MicroRNA Signatures Predict Survival of Patients with Non–Small Cell Lung Cancer Hu and colleagues reported identification of a four-microRNA signature from serum of patients that may serve as a noninvasive biomarker for overall survival (OS) in non–small cell lung cancer (NSCLC). MicroRNAs are small non–protein-coding RNAs that act as negative gene regulators. Earlier investigations have found that microRNA expression profiles and presence of specific microRNAs in lung tissue are correlated with prognosis and clinical outcome in lung cancer. The authors and other groups found that large quantities of stable microRNAs are present in serum/plasma, raising the possibility of identifying noninvasive biomarkers for lung and other cancers.

Identification of MicroRNAs Associated with Risk The current study involved samples from 303 patients with stage I to IIIA lung adenocarcinoma or squamous cell carcinoma who had undergone both surgery and adjuvant chemotherapy. Sequencing for serum microRNA was performed in 60 patients (discovery data set): 30 with longer survival (alive, with a mean survival of 49.5 months) and 30 with shorter survival (dead, with mean survival of 9.5 months) matched for age, sex, and disease stage. A total of 109 microRNAs in the longer-survival group and 101 in the shorter-survival group were identified. Of these, 11 met the criteria of having at least 50 copies in samples from either group or exhibiting fivefold altered expression between

groups. Quantitative reverse transcription polymerase chain reaction showed that levels of four (miR-486, miR-30d, miR-1, and miR-499) differed significantly between groups, and levels of these four were significantly associated with risk of cancer death in a dose-dependent manner.

Predictive Effects of MicroRNAs Testing for predictive effects of these four microRNAs was then performed in samples from 243 additional patients, randomly divided into a training data set (n = 120) and a testing data set (n = 123). In the training set, high levels of miR-486 and miR-30d (above median) and low levels of miR-1 and miR-499 (below median) were individually associated with unfavorable survival. Application of the threshold values showed similar hazard ratios and significant P values in the testing set. For all 303 patients, those with high serum expression levels of the “risk microRNAs” and low levels of “protective microRNAs” had a significantly lower median survival time (MST) than patients with low levels of risk microRNAs and high levels of protective microRNAs. MST ranged from 22.9 to 31.3 months for higherrisk levels of each microRNA and was not reached for lower-risk levels of each. Overall, the presence of 0 or 1 microRNAs at higher-risk levels was associated with MST of not reached, vs MST of 50.7 months with 2 present, 17.8 months with 3 present, and 12.8 months with all 4 present.

Predictive Effect of Signature A four-microRNA signature was then constructed using a risk-score method, and patients in the training set were ranked according to risk score and divided into high-risk and low-risk groups using the median risk score as the cutoff. Patients with a high risk score had significantly shorter MST (20.3 months vs not reached, P < .001) and HR for cancer death of 10.74. When the scoring system was used in all 303 patients, patients with high risk scores had MST of 18.4 months vs MST of not yet reached in those with low risk scores (P < .001, HR for cancer death 9.31). Hazard ratios for cancer death among patients with high risk scores were comparable for disease stages I, II, and IIIA, as well as for adenocarcinoma and squamous cell carcinoma. Hu Z, et al: J Clin Oncol 28:1721-1726, 2010.

CANCER SCREENING It Takes a Team to Address Overdiagnosis in Cancer Diagnosing cancers that would not go on to cause symptoms or death may not only lead to unneeded treatment, but may also affect patients’ physical health, sense of well-being, and ability to get health insurance, according to a review in the Journal of the National Cancer Institute. Based on randomized trials, the authors estimated the magnitude of overdiagnosis at about 25% of mammographically detected breast cancers, 50% of lung cancers detected by x-ray and/or sputum tests, and 60% of prostate cancers detected by prostate-specific antigen test. The authors also cited 30-year incidence and mortality data reported by the Surveillance, Epidemiology and End Results (SEER) program, showing increased rates of new diagnoses but not deaths for cancers of the thyroid, kidney, prostate, and breast, as well as for melanoma. For each of these cancers, increased screening or imaging tests have been associated with an increased rate of diagnoses. To address the phenomenon of cancer overdiagnosis, the authors propose educating patients to make sure they understand the trade-off “between the potential to avert a cancer death and the risk of overdiagnosis.” They suggested using “simple one-page balance sheets that frame the trade-off” and offer a sample for screening mammography. Raising the threshold at which to label test results abnormal, or the threshold to intervene, is offered as a potential clinical strategy. “But most important,” the authors said, “may be to add an additional threshold that must be observed before labeling a screening test abnormal—that of growth.” “What we need now in the field of cancer is the coming together of physicians and scientists of all disciplines to reduce the burden of cancer death and cancer diagnosis,” noted two cancer surgeons in an editorial accompanying the review. “Our radiology colleagues must participate, redefining what they call ‘suspicious’ or ‘abnormal’ on imaging. It will be challenging and take courage, but we need to make it an explicit goal to raise the threshold for what we biopsy and diagnose.” Welch HG, Black WC: J Natl Cancer Inst 102:605-613, 2010. Esserman L, Thompson I: J Natl Cancer Inst 102:582-583, 2010.

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JCO Spotlight

Trastuzumab-associated Cardiac Toxicity Closely Scrutinized By Caroline Helwick

rastuzumab (Herceptin) has markedly improved the clinical course of HER2-positive breast cancer, but concerns about cardiotoxicity have arisen, especially in the adjuvant setting and in conjunction with anthracyclines. Two important analyses recently published in the Journal of Clinical Oncology ( JCO) found that symptomatic heart failure was rare—2.0% or less—and largely reversible in the majority of patients treated in three adjuvant trials. “Patients cured of early breast cancer remain at long-term risk of cardiac toxicity and must be watched carefully, but these studies are fundamentally reassuring,” commented Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York.

Longer-term Assessment of HERA Population Procter et al reported a cardiac assessment of 3,401 patients in the Herceptin Adjuvant (HERA) trial at a median follow-up of 3.6 years.1 HERA is a three-arm randomized trial comparing observation vs 1 year of trastuzumab vs 2 years of trastuzumab after adjuvant chemotherapy (mostly with anthracyclines). In this report on just the patients assigned to observaSee page 55 tion or 1 year of trastuzumab, the authors sought to determine the likelihood and timeline for trastuzumab-associated cardiac dysfunction and recovery. Coauthor Thomas M. Suter, MD, Professor of Medicine and Chief of Inpatient Services at the Swiss Cardiovascular Center, University Hospital Bern, Switzerland, told The ASCO Post, “We were concerned that patients who experience trastuzumab-associated cardiac dysfunction may have the same fate as those with anthracyclineassociated toxicity—that is, late development of chronic, progressive disease that is largely not reversible. “But we found out that cardiac toxicity associated with trastuzumab is different,” he said. “When it does occur, by and large it happens during treatment. In 80% of cases it is reversible, and patients have a good intermediate-term prognosis.” After a median follow-up of 3.6

years, the incidence of cardiac endpoints (cardiac death or severe congestive heart failure [CHF]) remained low, though higher in the trastuzumab group compared to observation. Severe CHF was diagnosed in 0.8% vs 0.0% of patients, respectively, and confirmed significant left-ventricular ejection fraction (LVEF) declines were observed in 3.6% and 0.6%, respectively. The one cardiac death occurred in the observation group. Among the 73 patients with a cardiac endpoint, 59 (80.8%) recovered, and 52 of these 59 patients were considered by the cardiac advisory board to have a favorable cardiac outcome. The median time to acute recovery was 6.4 months (range: 9–33.1 months). “With anthracyclines, the real toxicity occurs 5 to 10 years after treatment,” Dr. Suter cautioned, “so we have not observed trastuzumab-treated patients long enough to be absolutely sure about their prognosis. So far, however, the data are fairly promising that most recover and look stable thereafter.”

NSABP B-31 and N9831 Combined Analysis Russell et al reported a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials.2 An independent Adjuvant Cardiac Review and Evaluation Committee systematically reviewed cases of symptomatic CHF events to uniformly define the cardiac event rate among patients receiving doxorubicin and cyclophosphamide followed by paclitaxel, with and without trastuzumab. Committee members were blinded to trastuzumab treatment and the investigators’ original cardiac diagnoses. CHF was rigorously defined by symptoms, physical signs, and objective findings, including an LVEF drop > 10% or absolute LVEF < 50%. At a median follow-up of 1.9 years, the investigators identified and reviewed a total of 173 cases: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumabtreated patients had a 2.0% incidence of symptomatic CHF events, vs 0.45% with chemotherapy alone. Complete or partial recovery was observed in 86.1% of the trastuzumab recipients who had symptomatic heart failure events. continued on page 52

Trastuzumab Benefit Far Outweighs Risk, but Longer Follow-up Still Needed

n a coauthored editorial accompanying the studies, Patrick G. Morris, MD, Special Fellow on the Breast Cancer Medicine Service at Memorial Sloan-Kettering, and Dr. Hudis, commented on the findings.1 With the widespread adoption of adjuvant trastuzumab, it is appropriate to ask about the associated frequency and severity of the cardiac toxicity, and what modulates the risk, Dr. Morris comPatrick G. Morris, MD mented. He said the main question has involved the long-term clinical significance for asymptomatic declines in LVEF. For both reports, the increased rates of clinical CHF should be seen in the context of the absolute improvements in disease-free survival at 3 years—6.3% in HERA and 11.7% in B-31/ N9831—attributable to the addition of adjuvant trastuzumab to anthracycline-based chemotherapy, Drs. Morris and Hudis emphasized. “Each of these two independent reviews of large prospective clinical trials offer evidence that Clifford Hudis, MD long-term cardiotoxicity with trastuzumab following anthracycline-based chemotherapy for HER2-positive early breast cancer is relatively infrequent and generally associated with a favorable outcome,” they wrote (See Table 1 on page 52).1 However, “if this is reassuring, there remain several cautions and considerations,” they added. Cases were selected based on previously documented cardiotoxicity, and original data were not reviewed. Therefore, some cases may have been missed, they noted. In addition, the reversibility of cardiotoxicity was not prospectively assessed, and, based on previous experience with anthracyclines, the follow-up is still inadequate to be sure of the long-term outcomes, they pointed out. “But there is good evidence that cardiac toxicity is not an overwhelming problem,” Dr. Hudis said in an interview. “And, to expand a bit,” he added, “our best doxorubicin-containing regimen, ie, dose-dense delivery, can be given safely,” additional studies would suggest. Other questions will be important to answer, Dr. Morris acknowledged. “We still don’t know how to treat patients with clinical heart failure or low LVEF at baseline because they were not included in the studies. It is a risk:benefit analysis. If a patient with a borderline ejection fraction has highrisk early breast cancer, it is tempting to treat with an anthracycline and, if HER2-positive, trastuzumab. But the current data are not informative about this group,” he noted. One option is to use a non–anthracycline-containing regimen. However, Dr. Morris and Dr. Hudis pointed out that the TCH regimen (docetaxel, carboplatin, trastuzumab), popularized in the Breast Cancer International Research Group (BCIRG) 006 study and adopted by some oncologists, has only been tested in a single trial. Long-term cardiac safety data for this regimen are lacking. Dr. Hudis stressed that the strategy of using an anthracycline followed by trastuzumab, “which offers a more consistently demonstrated overall survival advantage,” should not be abandoned. In addition, topoisomerase II expression cannot be recommended as a means of selecting patients for anthracyclines, he added, because there have continued on page 52

The ASCO Post | JULY 2010

PAGE 52

JCO Spotlight Table 1: Long-term Cardiac Risk-Benefit Analysis of Trastuzumab-based Adjuvant Chemotherapy

Study and Treatment

No. of Evaluated Patients

Absolute DFS Benefit of Tras at 3 Years (%)

1,775 1,799

HR (95% CI)

Cardiac Event Rate per Study Protocol (%)

Cardiac Event Rate-independent Review (%)

Recovery Rate from CardiacindependentReview (%)

Absolute OS Benefit of Tras at 3 Years (%)

HR (95% CI)

Cardiac Deathindependent Review (%)

0.48 (0.39 to 0.59)

0.3-0.9 3.3-3.8

0.5 2.0

43 86

0.67 (0.48 to 0.93)

0.11 0.17†

0.6

0.7

3.6

4.3

DFS

B-31 + N9831 AC AC

Pac Pac + Tras

HERA Anthracycline-based chemo* Anthracycline-based chemo + Tras*

1,698 1,703

0.64 (0.54 to 0.76)

0.1 81

0.66 (0.47 to 0.91)

FinHer Anthracycline-based chemo Anthracycline-based chemo + Tras

116

1.7

116

0.65 (0.38 to 1.12)

0.9

0.55 (0.27 to 1.11)

1,073 1,074 1,075

6 5

0.64 (0.53 to 0.78) 0.75 (0.63 to 0.90)

0.7 2.0 0.4

4 2

0.63 (0.48 to 0.81) 0.77 (0.60 to 0.99)

0 0 0

BCIRG 006 AC Doc AC Doc + Tras TCH (Doc, Carb, Tras)

NOTE: Data are based on the most recently available publications. AC = doxorubicin cyclophosphamide; B-31 = National Surgical Adjuvant Breast and Bowel Project B-31 trial; BCIRG 006 = Breast Cancer International Research Group 006 trial; Carb = carboplatin; chemo = chemotherapy; DFS= disease-free survival; Doc = docetaxel; FinHer = Finland Herceptin trial; HERA = Herceptin Adjuvant trial; N9831 = North Central Cancer Treatment Group N9831 trial; OS = overall survival; Pac = paclitaxel; Tras = trastuzumab. *Ninety-four percent received anthracycline-based chemotherapy. †Two of these three events occurred prior to trastuzumab administration. Adapted with permission from Morris and Hudis.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

Trastuzumab Cardiac Toxicity continued from page 51

Among five patients who died, only one had received trastuzumab. In a multivariate model, independent predictors for cardiac events were age > 50 years (3.0-fold increase) and treatment with trastuzumab (4.4-fold increase). The relative risk of a cardiac event increased in both treatment arms as LVEF declined. “My impression is that the cardiotoxicity related to trastuzumab is quite low and usually reversible,” said Stuart D. Russell, MD, Chief of Heart Failure and Transplantation at Johns Hopkins Hospital, Baltimore. “Our paper had some methodology limitations, but based on the results, physicians should be reassured that it is a safe drug to use.”

Clinical Implications The authors of the JCO article— both cardiologists—discussed the implications of their findings. “Based on these findings, I think we can be a little more aggressive with treatment,” Dr. Suter suggested. “If patients drop the LV ejection fraction during trastuzumab treatment but remain asymptomatic, we frequently continue trastuzumab and add cardiac supportive medications such as an ACE- inhibitor. However, we would stop trastuzumab if the LVEF drops below 40%.” “The vast majority of patients who

developed LV dysfunction had an improvement once the drug was stopped, so it is probably acceptable to try these patients on trastuzumab,” Dr. Russell said. “Also, the risk of death from breast cancer is greater than the risk of death from heart failure, so I think an aggressive approach is justified.” Dr. Suter also pointed out that the manner in which trastuzumab is given may affect toxicity risk. The HERA treatment schedule may have less potential for cardiotoxicity than some other protocols, he suggested. “Anthracycline pretreatment is an important risk factor for trastuzumab-associated cardiotoxicity. It appears that concomitant treatment is detrimental, and it is better to delay trastuzumab rather than give it soon after the anthracycline,” he said in an interview. In HERA, trastuzumab was begun a median of 86 days after standard chemotherapy. Dr. Russell added that any underlying risk factors for cardiac toxicity should be stringently addressed. “If a patient is older and has a borderline ejection fraction, I start her on medications that have proven beneficial in heart failure—ACE inhibitors and beta blockers—prior to letting the oncologist start trastuzumab,” he said.

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References 1. Procter M, Suter TM, de Azambuja, E, et al: Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin

Trastuzumab Benefit Outweighs Risk continued from page 51

been “extensive inconsistencies” in studies examining it as a biomarker. “We need long-term follow-up of existing studies to inform us on these controversial areas of how to treat patients with cardiac symptoms or borderline ejection fraction at baseline, how long we need to give trastuzumab, and whether trastuzumab is indicated for ‘low risk’ HER2-positive patients, ie, subcentimeter node-negative tumors,” Dr. Morris said.

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Reference 1. Morris PG, Hudis CA: Trastuzumab-related cardiotoxicity following anthracycline-based adjuvant chemotherapy: How worried should we be? J Clin Oncol. June 7, 2010 (early release online).

Oncol. June 7, 2010 (early release online). 2. Russell SD, Blackwell KL, Lawrence J, et al: Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy:

A combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. June 7, 2010 (early release online).

Change of Address ASCO Members (US-based): To cancel your subscription to The ASCO Post or 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 to The ASCO Post or to update your mailing address, please email Subscriptions@harborsidepress.com; fax (631) 692-0905.

ASCOPost.com | JULY 2010

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TAP Caucus

Should Oncologists Own Imaging Services? Physician-owned Imaging Centers Offer High-quality, Integrated Services

Physicians Should Not Own Imaging Centers By Charles L. Bennett, MD, PhD, MPP, and E.W. Lingle, PhD

By Robert M. Langdon, MD

he ability of an oncology practice to own and operate its own imaging center provides patients with higher quality, better efficiency, lower costs, and consistent care. Physician-owned imaging centers provide improved quality through collaborative work with oncologic radiologists who are dedicated to reading scans from a cancer view. These centers can ensure quality through accreditation with organizations such as the American College of Radiology. Robert M. Langdon, MD The practicing oncologist can immediately consult with on-site radiologists to review the patient’s studies and make special requests in regard to issues under question. During clinical trials, these radiologists are attuned to providing accurate tumor measurements and characteristics to meet Response Evaluation Criteria in Solid Tumors (RECIST) and other criteria set forth in the trial. The affiliated facility provides for reduction in patient migration from imaging center to imaging center for procedures. This

The efficiency of an oncology imaging center within a multidisciplinary freestanding cancer center is extraordinary. allows easy access for the imaging procedure to consistently assess accurate staging and tumor response on therapy. It also provides a rapid comparison when there are questions of relapse, progression, or a new malignancy.

Full-spectrum Care Under One Roof The efficiency of an oncology imaging center within a multidisciplinary freestanding cancer center is extraordinary. The patient has the convenience of receiving the full spectrum of outpatient oncology care under a single roof. Patients commonly come into the imaging center for all of their imaging studies as well as a medical oncology visit and treatment on the same day, whether on active treatment or during follow-up in support groups and survivorship programs, all in a single facility. Because the multidisciplinary physicians— specifically the radiologist and medical and radiation oncologists—meet under the same roof, the patient benefits from open collaboration and assessment in a timely manner. This is in contradistinction to outpatient situations in many facilities, where the assessment, radiology, and scanning needs to be done in a minimum of one day in advance of the patient’s visit.

Convenience and Cost The convenience of working in a dedicated oncology imaging center is that the staff becomes intimately acquainted with each patient and understands his or her individual needs, anxieties, and clinical situation. Adjustments in timing of procedures and approach can be individualized. The freestanding facility can provide urgent procedures without the patient ever having to leave the outpatient cancer center. These procedures include the primary diagnosis of deep-vein thrombosis, pulmonary emboli, pericardial effusions, and superior vena cava syndrome. The diagnosis can be confirmed within the outpatient facility without undue and sometimes unnecessary movement to a hospital-based facility. In the era of frequent precertification, this process can be streamlined and performed in an efficient fashion. A dedicated staff that is knowledgeable about an individual continued on page 54

hysicians should not own their own imaging centers. Period. End of story. The United States spends more of its GDP on health care than any other country, and that share is rising. Supporters of our health-care Charles L. Bennett, MD, PhD, MPP E.W. Lingle, PhD system point to the large and increasing maze of regulatory requirements as an important component of health-care costs—and unnecessary costs at that—accounting for between $58 billion and $340 billion annually. Another estimate is that $8 billion annually is derived from physicians’ additional income that results from ownership of outpatient facilities, including diagnostic imaging centers, testing laboratories, day-surgery facilities, and procedure laboratories.

Conflict of Interest and Overuse of Facilities Conflict-of-interest concerns affect the entire economy, not just health care. Empirical studies in medicine concerning conflict of interest are particularly powerful. They consistently show that when physicians own their own laboratories, imaging equipment, pharmacies, and surgical centers, there is marked excess in the use of these facilities.1 Using the quality-of-care paradigm outlined

Physician-owned imaging centers are as far away from transparency as one can get. by Mark Chassin, MD, the current President of the Joint Commission, this excess almost always represents overuse of these facilities (as opposed to underuse or misuse).2 Although regulatory approaches including Independent Diagnostic Testing Facility Performance Standards are designed to prevent meaningful responses to overutilization, it is not clear in practice that these standards are workable or even meaningful.3

Safety and Legal Issues A second concern reflects patient safety. Recent studies have reported on the long-term safety risks of CT scans.4 Excessive use of CT scanning appears to be a significant cause of preventable cancers. These safety concerns will only increase as the rates of utilization of outpatient imaging centers increase. A third concern is legal—physician-owned imaging centers are increasingly targets in the coming health-care reform setting, and have been targets historically. Multiple concerns related to self-referral, including conflict of interest and increased costs to the Medicare program, resulted in a ban on self-referral arrangements under the Medicare program. Under health-care reform, oversight of physician-owned imaging centers will expand in ways yet to be determined. Violations of Stark provisions are increasingly difficult to prevent among physicians who own imaging centers.5,6

Competition and Transparency A fourth concern involves competition. For markets to run efficiently, there must be fair competitive practices and transparent pricing options. Health-care economists recognize that the U.S. health-care system does not meet the criteria to catcontinued on page 54

The ASCO Post | JULY 2010

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TAP Caucus

High-quality, Integrated Services continued from page 53

insurance company’s requirements can also anticipate those needs. In the area of cost, particularly outof-pocket costs to the patient, outpatient imaging centers generally charge about one-third of the costs generated by the

hospital-affiliated imaging center. This difference most readily benefits patients in terms of lower out-of-pocket costs. From a societal point of view, this lower charge, which does translate into lower reimbursement, is a more cost-effective way to deliver a comprehensive cancer treatment, Based on our diagnostic needs and response criteria, this invariably in-

volves heavy use of radiologic services. In the anticipated paradigm of service bundling, oncology outpatient radiology units should provide a more streamlined means of making accurate and cost-effective proposals.

Conclusion In summary, outpatient radiology

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services combined with freestanding cancer centers owned and operated by physician practices can provide highquality, integrated, efficient, and cost-effective imaging. For the patient, this can relieve a significant part of the burden of dealing with a malignant disease.

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Dr. Langdon is Managing Partner of the 14-physician group Oncology Hematology West, PC, in Omaha.

Physicians Should Not Own Imaging Centers continued from page 53

egorize it as a free market. However, physician-owned imaging centers are as far away from transparency as one can get. As with all economic inefficiencies, a marked disequilibrium clearly exists between supply and demand in these instances. Hence, in this tumultuous period of large-scale health-care reform, it may be an opportune moment for legal and regulatory mandates to target physicianowned imaging centers. Caveat emptor to physicians who own these centers.

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References 1. Impact of physician self-referral on use of imaging services within an episode. In: Report to the Congress-Improving incentives in the Medicare program. Washington DC: Medicare Payment Advisory Commission, June 2009; pages 81- 96. Accessed June 25, 2010 at http://www.medpac.gov/ documents/Jum09_EntireReport.pdf). 2. Chassin MR, Galvin RW: The urgent need to improve health care quality. Institute of Medicine National Roundtable on Health Care Quality. JAMA 280:1000-1005, 1998. 3. Smith-Bindman R: Is computed tomography safe? N Engl J Med 363:1-4, 2010. 4. Smith-Bindman R, Lipson J, Marcus R, et al: Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2078-2086, 2009. 5. Anscher MS, Anscher BM, Bradley CJ: The negative impact of stark law exemptions on graduate medical education and health care costs: The example of radiatoin oncology. Int J Radiat Oncol Biol Phys 1289-1294, 2010. 6. Manchikanti L, McMahon EB: Physician refer thyself: Is Stark II, phase III the final voyage? Pain Physician 725-741, 2007. Dr. Charles L. Bennett is Center of Economic Excellence Endowed Chair in Medication Safety and Efficacy and the Frank P and Josie M Fletcher Professor of Pharmacy at the South Carolina College of Pharmacy/University of South Carolina, Columbia. Dr. E.W. Lingle is Associate Professor, Pharmacy Administration, South Carolina College of Pharmacy, University of South Carolina, Columbia.

ASCOPost.com | JULY 2010

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TAP Caucus Letter to the Editor

In Support of Physician-assisted Suicide I read with interest the differing opinions expressed by Drs. Nancy Crumpacker and Kevin Olson as published last month in TAP Caucus (The ASCO Post, June 2010, page 73). I have written lethal prescriptions for a few of my patients under Washington’s Death With Dignity Act and have attended at two deaths from these prescriptions. I can attest to the enormous gratitude of the patients involved to the voters of Washington State for having passed the legislation that empowered them to be in control of their own deaths. While physician-aided dying or physician-assisted suicide is not the answer for most patients, just having the op-

tion to choose this course of action is a source of solace for some patients with terminal illness. Dr. Olson argued that if a treatment is not used very often, it is not needed. Applying that same logic, one could argue that treatment with 2-chlorodeoxyadenosine (2-CdA) is not necessary since we so rarely see patients with hairy cell leukemia. Dr. Olson’s experience with the patient who requested a lethal prescription, only to find he had been misdiagnosed, highlights the necessity of the built-in safeguards of waiting times and second opinions.

The ASCO Post invites you to comment on whether oncologists should own imaging services. Send your thoughts to Dr. James Armitage, c/o TAPCaucus@ASCOPost.com. Selected responses will be published online and in future issues of The ASCO Post.

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Ann E. Murphy, MD Poulsbo, Washington

What Are Two-Dimensional Barcodes? two-dimensional (2D) barcode, also known as a matrix code, is a graphic image that contains information stored both horizontally (like the one-dimensional UPC used in supermarkets) and vertically. The added dimension in a 2D barcode enables the image to represent thousands of characters—essentially a portable database—compared with only 10 to 20 characters stored in the conventional unidimensional barcode. Given that added capacity, 2D barcodes are increasingly being used for fast data access in a variety of settings, and in documents from drivers’ licenses to tax returns. Perhaps not surprisingly, the real boom in 2D barcode use has been in mobile marketing. Companies have developed technology that enables camera phones to scan matrix codes from a website, print publication, or poster. The consumer can then access content embedded in the code or be redirected to targeted content via the phone’s Web browser. The 2D barcodes used in this issue of The ASCO Post will connect readers to further information about the articles they are reading. For instance, a report from the ASCO Annual Meeting may include a barcode that will connect readers online to the original abstract of the study discussed. In this way, the editors of The ASCO Post hope to provide readers with further resources and validated information about the news in these pages. Find examples of 2D barcodes on the pages of this issue. Using the ScanLife application (see right), scan these codes with your camera phone, and see where they bring you. Watch for more barcodes in future issues of The ASCO Post.

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

Scanning 2D codes When you see a code that you would like to scan, start the ScanLife application. The screen will look similar to camera mode. Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically. A short audio chime will indicate a successful scan and the phone will contact the server for further instructions. This may take up to a minute depending on data speeds and phone type.

What’s this?

www.BioOncology.com

After multiple lines of HER2+ MBC treatment

What’s next?

Options can run out for patients with HER2+ metastatic breast cancer When faced with how to treat advanced HER2+ metastatic breast cancer, the answer is never simple. While there is a wide variety of agents used in this patient population, there is no accepted standard of care in the management of HER2+ metastatic breast cancer once the disease has progressed after multiple lines of treatment.1-3 Without clear consensus guidelines, and with no data to support the superiority of one regimen over another, treating these patients can be particularly challenging.2-5

Difficult choices Therapies that target HER2-overexpressing tumor cells have revolutionized treatment for women with HER2+ disease. However, once these patients progress after several lines of therapy, existing treatment options offer limited efficacy and may not be tolerated well by patients.2,4,6 Some patients may stop responding to treatment altogether, or may refuse active treatment, valuing quality of life over the limited results they are likely to achieve.4,7

New answers are required Patients with heavily pretreated HER2+ metastatic breast cancer need treatment options that can give you clearer answers the next time you ask yourself, “What’s next?” A pioneer in HER-signaling research, Genentech remains committed to the discovery and development of medicines that help improve the lives of women with HER2+ breast cancer throughout all stages of disease. References: 1. Cardoso F, Castiglione M. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(suppl 4):iv15-iv18. 2. Wardley A. The need for advanced breast cancer treatment guidelines: results of an internet-based survey. Breast. 2008;17:275-281. 3. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. V.1.2009. http://www.nccn.org. Accessed October 20, 2009. 4. Cardoso F, Di Leo A, Lohrisch C, Bernard C, Ferreira F, Piccart MJ. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Ann Oncol. 2002;13:197-207. 5. Kalaja VV, for the ESMO Guidelines Working Group. Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2007;18(suppl 2):ii9-ii11. 6. Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamidemethotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243-1252. 7. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. In: Yu D, Hung M-C, eds. Breast Cancer Chemosensitivity. New York, NY: Springer-Verlag. 2007:1-22. Advances in Experimental Medicine and Biology; vol 608.