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MARCH 15, 2011 ASCOPost.com

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

2011 Genitourinary Cancers Symposium

Intermittent Androgen Suppression Called New Standard of Care for Men with PSA Recurrence

A Paradigm Shift in Advanced Cancer Care

By Alice Goodman

n men with rising prostate-specific antigen Androgen Deprivation (PSA) levels after radical therapy for prostate can■■ In this study intermittent androgen suppression (IAS) was delivered for cer, intermittent androgen 8 months in each cycle and restarted only when PSA reached > 10 ng/mL suppression (IAS) was off treatment, compared to continuous androgen deprivation (CAD) treatment delivered without any breaks in androgen deprivation therapy. as effective as continuous androgen deprivation ■■ IAS is noninferior to CAD; it is associated with similar overall survival (CAD), with no overall difand quality of life. ference in survival between ■■ IAS is cost-saving, as patients are taking expensive hormonal therapies the two treatments, and only 27% of the time compared with CAD. the potential for huge cost ■■ IAS can be considered a new standard of care in this setting. savings with IAS. Intermittent androgen suppression treatment was delivered for 8 months in each cycle and These results of an intergroup phase III randomrestarted only when PSA levels reached > 10 ng/mL off ized, controlled trial promise to be practice-changing, treatment, vs continuous delivery of treatment adminaccording to experts interviewed by The ASCO Post.1 continued on page 8 istered without breaks in therapy. Medical Ethics

Ethics in Oncology: Lies, Big and Small, Matter Relatively few scientific papers retracted By Ronald Piana

By Thomas J. Smith, MD, FACP

ver the years, carefully conducted studies and collective introspection have brought the oncology community to a greater understanding of what it means to care for our patients who have incurable disease. When there are no curative therapies, the steady guidance needed to provide high-quality care should not vacillate in the face of impending death. As illustrated by the recent ASCO statement and the Journal of Clinical Oncology paper by Peppercorn et al,1 in this era of individualized therapies we must initiate a paradigm shift in the way we individualize cancer care in the advanced setting, beginning at the time of diagnosis. Patients want therapy, and physicians are trained to deliver it. It is not part of our medical culture to throw in the towel. But cancer care is not a zero-sum game; it is a delicate balance, a series of physical and emotional negotiations. The basic elements of individualized care dictate that patients with advanced cancer should continued on page 22

recent study in the Journal of Medical Ethics found that 788 research papers published in medical journals between 2000 and 2010 were retracted for serious errors or falsified data.1,2 Study author Grant Steen, PhD, told Grant Steen, PhD The ASCO Post that U.S. scientists were responsible for 169 of the papers retracted for inadvertent yet serious errors, as well as 84 papers retracted for blatant fraud.

If we cannot rely on the basic assumption of honest scientific reporting, then the whole system crumbles… —George W. Sledge, MD

Use your smartphone to view additional information about the studies discussed in this report. SEE PAGE 39

Dr. Smith is Professor of Medicine and Palliative Care Research, and Medical Director of the Thomas Palliative Care Unit at VCU Massey Cancer Center, Richmond, Virginia.

MORE IN THIS ISSUE

“In any case, during the sample period I used for the study, nearly 5 million papers were published, so the short version of what I found is that relatively few scientific papers are retracted,” said Dr. Steen. Yet, Dr. Steen noted an interesting, if not alarming pattern. “Among the papers retracted for error, only about 18% of authors had a previous retraction. However, among papers retracted for out-and-out fraud, more than half of those authors had previous retractions,” said Dr. Steen. According to Dr. Steen, this finding can be interpreted in two ways. Authors of a fraudulent paper are likely to have all their papers retracted, whether or not fraud or error was committed in each publication. “But the other explanation, which I tend to favor, is that people who engage in fraud have a pattern of abusing

Oncology Meetings Coverage 2011 Genitourinary Cancers Symposium �� 1, 2, 3 2011 Gastrointestinal Cancers Symposium ��12, 13, 23, 30 Direct from ASCO �� 16 Spotlight on Research �� 31 Letters to the Editor �� 37, 39

continued on page 11

A Harborside Press Publication

The ASCO Post | MARCH 15, 2011

PAGE 2

2011 Genitourinary Cancers Symposium Prostate Cancer

Important Briefs from the 2011 Genitourinary Cancers Symposium By Alice Goodman

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University William T. McGivney, PhD National Comprehensive Cancer Network James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria

ews was plentiful at the 2011 Genitourinary (GU) Cancers Symposium, held in Orlando, Florida, February 17–19. The ASCO Post will feature key reports from the meeting (see pages 1 and 3, and watch for coverage in future issues). In addition, other noteworthy studies presented in Orlando are summarized below.

Inappropriate Use of Imaging Despite the existence of national guidelines for imaging of men with newly diagnosed prostate cancer, physicians who treat Medicare patients are failing to adhere to the guidelines. A retrospective review of over 30,000 men in the SEER-Medicare database found that 36% of men with low-risk prostate cancer and 49% of men with intermediaterisk prostate cancer had imaging tests, all of which were inappropriate under the guidelines (abstract 120). On the other

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

Robotic-assisted laparoscopic radical prostatectomy should be done at high-volume centers…

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

— Prasanna Sooriakumaran, MD

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hand, 39% of men at high risk did not receive imaging according to the guidelines. Lead author Sandip Prasad, MD, University of Chicago Medical Center, estimated that the unnecessary imaging tests wasted $35 million of American taxpayers’ money, which is about 10% of the total research budget for prostate cancer at NCI. When asked about the reasons for inappropriate use of imaging, he said that some physicians may be practicing defensive medicine. However, Dr. Prasad was especially concerned about high-risk men not receiving appropriate imaging.

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Robotic Prostatectomy

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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times can take a large number of cases before reaching a plateau (abstract 102). The study tracked three different surgeons at three separate high-volume centers who performed a total of 3,794 such procedures between January 2003 and September 2009. It took a total of 1,600 procedures to achieve a positive surgical margin rate of < 10%, something widely considered as an expert level of proficiency by prostate cancer surgeons. Mean operating time was about 3 hours at the start of the study and plateaued at about 2 hours after about 750 cases. According to lead author Prasanna Sooriakumaran, MD, Weill Cornell Medical College, the take-home message of this study is that robotic-assisted laparoscopic radical prostatectomy should be done at high-volume centers. Surgeons who want to become proficient at the procedure should study at high-volume centers, he said.

Robotic-assisted laparoscopic radical prostatectomy is enjoying exponential growth across the United States. However, a retrospective cohort study shows that the learning curve for the procedure is much longer for certain outcomes than has been assumed, and operating

Open-label Degarelix after Leuprolide Therapy Open-label treatment with degarelix (Firmagon) slowed prostate-specific antigen (PSA) progression significantly in patients switched to the drug following 12 months of therapy with leuprolide (abstract 12). These results of an open-label extension study came on the heels of a pivotal phase III randomized trial comparing degarelix and leuprolide. In the original study, degarelix was superior to leuprolide in rate of suppression of androgen and PSA, risk of PSA failure or death, and reducing level of a biomarker associated with metastatic disease. The data reported at the GU Cancers Symposium were from a group of prostate cancer patients assessed by investigators as clinically appropriate for ADT and thus treated with either monthly degarelix or monthly leuprolide (apcontinued on page 6

ASCOPost.com | MARCH 15, 2011

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2011 Genitourinary Cancers Symposium Prostate Cancer

Abiraterone Improves Survival in Patients with Castration-resistant Metastatic Prostate Cancer By Alice Goodman

biraterone acetate significantly prolonged overall survival in patients with castration-resistant metastatic prostate cancer that progressed on docetaxel-based chemotherapy. The favorable effect of abiraterone was consistent across all prespecified subgroups, with a similar survival benefit as in the total population. These interim results of the international, multicenter, phase III COU-AA-301 trial led to stopping the study after improved survival was demonstrated, and placebo patients were then switched to abiraterone. The interim analysis was protocol-specified. “Abiraterone is a new treatment option that prolongs survival in men with castration-resistant prostate cancers that have been previously treated with chemotherapy. Considering castrationresistant prostate cancer as hormone refractory may deny these patients safe and effective treatment,” said lead author Howard Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center. Abiraterone is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical evidence

Table 1: Impact of Abiraterone Therapy in Men with Castration-resistant Prostate Cancer Baseline Variable

Subgroup

HR (95% CI)

1,195

0.66 (0.56–0.79)

0–1

1,068

0.64 (0.53–0.78)

127

0.81 (0.53–1.24)

659

0.64 (0.50–0.82)

≥4

536

0.68 (0.53–0.85)

833

0.63 (0.51–0.78)

362

0.74 (0.55–0.99)

PSA only

363

0.59 (0.42–0.82)

Radiographic with or without PSA

832

0.69 (0.56–0.84)

Yes

581

0.71 (0.58–0.88)

All subjects ECOG performance status

Howard Scher, MD

shows that abiraterone blocks androgen synthesis from adrenal and intratumoral sources, suppressing an important stimulus for growth of metastatic castration-resistant disease.

Brief pain inventoryworst pain (BPI-SF) Prior regimens Progression

Study Design and Results The study included 1,200 patients with castration-resistant metastatic prostate cancer for whom one or two previous lines of chemotherapy (at least one with docetaxel) had failed. Patients were randomly assigned to abiraterone plus prednisone vs placebo plus prednisone. The two arms were well balanced for demographic and disease characteristics. Abiraterone achieved significantly superior overall survival vs placebo: a me-

Abiraterone for Metastatic Castration-resistant Prostate Cancer ■■ Abiraterone is a selective androgen biosynthesis inhibitor that blocks the action of CYP17.

■■ Abiraterone therapy significantly prolongs overall survival in patients

with metastatic castration-resistant prostate cancer whose disease has progressed after docetaxel-based chemotherapy.

■■ Abiraterone’s effect on survival was consistent across subgroups. The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0905. Copyright ©2011 by Harborside Press, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $225; Individual International: $275; Institutional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

LDH > median

dian of 14.8 months vs 10.9 months, representing a 35% relative risk reduction of mortality (P < .0001). The survival benefit was consistent across subgroups in a preplanned analysis stratified for number of lines of prior chemotherapy, performance status, pain scores, and radiographic progression-free survival. Total and confirmed prostate-specific antigen response rates were also superior in the abiraterone-treated arm (see Table 1). Adverse events of all grades and of grades 3 and 4 were similar between the two treatment arms. The most frequent adverse events (of all grades) in the abiraterone-treated patients were fluid retention (31%), hypokalemia (17%), hypertension (10%), cardiac disease (13%), and liver function

test abnormalities (10%). “These side effects were manageable and SEE PAGE 39 consistent with the known hormonal effects of the drug,” Dr. Scher stated.

■

Financial Disclosure: Dr. Scher disclosed a relationship with Cougar Biotechnology, a subsidiary of Johnson & Johnson, but reported that he does not receive direct compensation. In addition, Cougar Biotechnology funded the study through an institutional clinical research agreement with MSKCC.

Reference 1. Scher HI, Logothetis C, Molina A, et al: Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, continued on page 11

Correspondence: Address general inquiries to Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; email: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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.

The ASCO Post | MARCH 15, 2011

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2011 Genitourinary Cancers Symposium Prostate Cancer

Important Briefs continued from page 2

proximately 200 patients per arm). Lead author Neal Shore, MD, Carolina Urologic Research Center in Myrtle Beach, South Carolina, said that the data support the durability of the significant PSA progression-free sur-

vival benefit achieved with degarelix vs leuprolide during the initial 12-month trial and was further confirmed during a 27.5-month follow-up.

Pomegranate for Rising PSA Two different doses of pomegranate extract prolonged the PSA doubling

time by 6 months in men with a rising PSA following local therapy for prostate cancer (abstract 11). Median PSA doubling time increased from 11.9 months before treatment with the pomegranate extract to 18.5 months afterward, noted lead author Michael Carducci, MD, of Johns Hopkins Kimmel Cancer Center.

Approximately 13% of patients had a decline in PSA level. But about 15% to 20% of the 104 patients enrolled in the trial had a reduction in PSA doubling time prompting treatment discontinuation. Patients who had undergone any previous definitive therapy (either surgery or radiation therapy) and had a rising PSA level of > 0.4 ng/mL or higher on three separate measurements were randomly assigned to 3 daily 1,000-mg capsules of pomegranate polyphenol (equal to one 8-oz serving of pomegranate juice) or 1 capsule of the extract and 2 capsules of placebo, and treatment was continued for 18 months. The study had several limitations, including lack of a control arm, and the fact that PSA doubling time is not a proven clinically meaningful endpoint.

Cabozantinib for Bone Metastases in Prostate Cancer Cabozantinib (XL184) achieved dramatic resolution of bone metastases after 12 weeks of treatment in the open-label lead-in period of a phase II randomized discontinuation trial, reported lead author David C. Smith, MD, of the University of Michigan Cancer Center (abstract 127). More phase II and III studies of the drug are planned. Cabozantinib is an inhibitor of tumor growth, metastasis, and angiogenesis. It simultaneously targets the key kinases MET and VEGFR2, which are involved in the development and progression of many cancers. Resolution of bone metastases occurred in 85% of 62 patients with available bone scans, and 8 additional patients had stable disease after 12 weeks of cabozantinib treatment. At baseline, about 50% of the 100 patients entered in the trial had experienced disease progression on docetaxel, 78% had bone metastases, 50% had significant pain, and 37% required narcotics for pain. A total of 26 patients dropped out before completing 12 weeks of treatment. Of 43 evaluable patients with bone metastases and bone pain, 60% reported improvement in pain at 6 and 12 weeks of treatment with cabozantinib. Of 33 evaluable patients who required narcotics for bone pain, 21 (64%) reported improvement in pain at 6 or 12 weeks, and 13 (46%) decreased or discontinued their use of narcotics.

■

SEE PAGE 39

Use your smartphone to view additional information about the studies discussed in this report

ASCOPost.com | MARCH 15, 2011

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Expert’s Corner Comparative Effectiveness Research

A Conversation with Peter B. Bach, MD, MAPP

Finding ways to get better clinical value for our health-care dollars By Ronald Piana

Peter B. Bach, MD, MAPP

he Affordable Care Act (ACA) of 2010 launched a national debate about how to curtail the unsustainable rise in health-care spending without impairing our delivery system. However, the national conversation about how to best allocate our precious health-care resources has been gathering steam for more than a decade. In 2005, Peter B. Bach, MD, MAPP, Director of the Center for Health Policy and Outcomes and Attending Physician at Memorial Sloan-Kettering Cancer Center, was appointed to the Centers for Medicare and Medicaid Services (CMS) as Senior Advisor on health-care quality and cancer policy. There, Dr. Bach helped shape the 2006 Oncology Demonstration Project, ostensibly a precursor to the current valueseeking initiatives authorized by the health-care reform bill. The ASCO Post recently spoke with Dr. Bach about using comparative effectiveness research to determine Medicare payment levels.

Clarifying the Terminology In 2006, you gave a presentation, Lessons from CMS, Coverage with Evidence Development (CED), which

looked and sounded a lot like comparative effectiveness research (CER). What is the relationship between these terms? Comparative effectiveness research covers a broader spectrum of health-care analysis than coverage with evidence development. Essentially, CER is comparing different interventions and strategies to prevent, diagnose, treat, and monitor health conditions, or even whole health systems in ways that determine which interventions are most effective for selected patient populations under specific conditions. Everyone agrees that we need to improve the way we deliver health care in this country. The big question

development is a specific Medicare payment approach in which a medical item, device, service, or procedure is covered only when its effectiveness in relation to explicit measures such as desired costs, outcomes, and toxicity has been prospectively analyzed within the context of that coverage. For instance, coverage with evidence development has been used as a coverage requirement threshold for particular medical devices or services, such as PET scans or entering a number of cancer clinical trials. CED is part of the evolution toward more prudent Medicare purchasing, an alternative to the traditional binary coverage determination that isn’t very effective in de-

Comparative effectiveness research… is about using comparative research techniques to choose the best medical approach for a population of patients. But applied correctly, CER will save money and/or spare patients unnecessary or toxic treatments. — Peter B. Bach, MD, MAPP

is: How do we get better clinical value for our health-care dollars across various clinical situations? Sometimes we can intuit the answers, but often we have to experiment our way to those answers. So the rubric of CER is simply using comparative analysis to figure out what works in health care and what doesn’t. The CER concept and methodology is painted across a very broad canvas, using a variety of data sources and methods to determine the best approach to delivering care. In contrast, coverage with evidence

Effectiveness vs Efficacy ■■ Effectiveness: To show effectiveness, specific treatment measures are

undertaken to increase the likelihood of positive results in a routine care condition. Effectiveness studies use real-world clinicians and clients, and patients may have multiple diagnoses or needs.

■■ Efficacy: When a treatment is shown to be efficacious, it means that good outcomes were identified in advance and then produced in a highly controlled experimental trial.

■■ Translating efficacious techniques into methods that produce effective clinical results is one of the more challenging issues of evidence-based practice.

termining value. So although CER and CED are both based on learning more about what works and what doesn’t work in health care, they are substantively different in scope.

Assimilation Process Can a complex and politically sensitive term such as CER, which its opponents link to European-style rationing, gain traction in today’s contentious climate? No term or initiative gets you past self-interest because it’s just too easy to reframe and rebrand any concept. Comparative effectiveness research is definitively not about saving money; it is about using comparative research techniques to choose the best medical approach for a population of patients. But applied correctly, CER will save money and/or spare patients unnecessary or toxic treatments. Like any mechanism of change in our healthcare system, CER and other valuebased initiatives will go through a cultural and political assimilation process.

CER Administration and Objectives

he driver behind comparative effectiveness research (CER) is the newly created Patient-Centered Outcomes Research Institute. According to the Institute of Medicine, the purpose of CER is to “assist consumers, clinicians, purchasers, and policymakers to make informed decisions that will improve health care at both the individual and population levels.”

■

Practical Application In your recent Health Affairs article—using prostate cancer as a prototype—you and coauthor Steven Pearson proposed basing Medicare payments for new treatments on whether they are superior, comparable, or inferior to the alternatives.1 What was the reasoning behind your “suggestion” to CMS? We thought that an approach using comparative research that linked the extent of efficacy to the amount of payment made a lot more sense than trying to use research to make simple go/no-go coverage decisions. For instance, when the FDA approves a new cancer agent, Medicare should use an evidence development process to determine the reimbursement value for that indication; the agency shouldn’t be paying for a therapy unless there are proven clinical data to justify the expenditure, especially if there is a less costly alternative that provides similar or better clinical value. It’s an intuitive idea—getting what you pay for, if you will. Explained properly, I think the concept will certainly resonate in a bipartisan way across the political aisle. The other element of our proposal is that we don’t view this is as a day 1 issue. It is a comparative effectiveness approach that, under one time window, would be worked out over a 3-year period within the context of tiered Medicare coverage. We envision a process in which drug sponsors would actually meet with the regulators and decide on the appropriate trial design, including how the reimbursement levels would be continued on page 8

The ASCO Post | MARCH 15, 2011

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2011 Genitourinary Cancers Symposium Prostate Cancer

Androgen Suppression continued from page 1

“We showed that using IAS is not inferior to CAD, with a high level of confidence. We now have level 1A evidence from multiple trials that have

consistently shown no difference in overall survival between IAS and CAD,” said lead author Laurence Klotz, MD, Professor of Surgery at the University of Toronto. “Intermittent androgen suppression should be the new standard of

Expert Point of View

ommenting on the study reported by Laurence Klotz, MD, at the Genitourinary Cancers Symposium, Joel B. Nelson, MD, said, “If you believe that less therapy is better [and I do], I agree that IAS should be preferred over CAD. There was no difference in quality of life between IAS and CAD, although it is true that the men in both arms were assessed at the worst point in their treatment. Overall survival was equal between the two arms.” Dr. Joel B. Nelson, MD Nelson is the Frederic N. Schwentker Professor and Chairman of the Department of Urology, University of Pittsburgh School of Medicine, and Co-director of the Prostate and Urologic Cancer Center at the University of Pittsburgh Cancer Institute. Dr. Nelson said that the study presented by Dr. Klotz adds to a mounting body of evidence showing no survival difference between intermittent and continuous androgen deprivation. The problem, he continued, is that there is no well defined protocol for intermittent therapy. The length of time on treatment varies, and there is no consensus on when to restart IAS. A large ongoing Southwest Oncology Group (SWOG) study is designed to answer some questions. That study compares 7 months of IAS and then stopping vs CAD. If IAS turns out to be equivalent to CAD, then the protocol used in that trial will probably be adopted for IAS, Dr. Nelson said. Based on Dr. Klotz’s study and other studies, he said that physicians who always use CAD will change their practice to IAS. “In this era of health-care reform, we are pushed to reduce expenditures. Androgen deprivation therapy constitutes a significant portion of the Medicare budget, and if these drugs are not necessary continuously, that will be cost-saving,” he stated.

Study Limitations Taking a different point of view, Mack Roach, III, MD, Professor and Chair of Radiation Oncology at the University of California, San Francisco, noted that this study does not show superiority of intermittent vs continuous androgen therapy. He contended that because the follow-up is too short, the results have to be interpreted cautiously. In his view, the study suggested that both therapies were equal. “Relatively few of these men were 10 years out. As other studies have shown, it takes 10 to 15 years Mack Roach, III, MD to die of metastatic prostate cancer. You would need much longer follow-up to demonstrate a true difference between these two types of therapy,” Dr. Roach said. The study targeted men whose disease recurred, based on rising PSA levels, following radiation therapy. “Some of these men may have local recurrences only, so it is not surprising that more have not died of prostate cancer when offered androgen deprivation therapy,” he said. Dr. Roach’s concern was that men with only localized disease could have been cured by other local therapies instead of going on to hormonal ablation. “Some men with local recurrence only can be treated with local therapy. Those who recur after radical prostatectomy can get radiation. Those who recur after radiation should consider additional local therapy [such as brachytherapy, prostatectomy, or cryosurgery] before going on to hormone therapy,” he said.

■

Financial Disclosure: Dr. Nelson disclosed financial ties with AstraZeneca, OncoGenex, Pfizer, and Sanofi-aventis. Dr. Roach reported no potential conflicts of interest.

care for most patients with PSA recurrence after radical therapy,” he stated. The study also showed improved quality of life in patients treated with IAS when off therapy, and Dr. Klotz said there are putative benefits related to side effects associated with CAD, such as loss of bone mineral density and an increase in factors related to the metabolic syndrome. Moreover, the study has economic implications. Patients in the IAS arm were on therapy only 27% of the time, “reducing the cost of therapy on average by 73%,” Dr. Klotz said.

Interim Analysis The study presented at the Genitourinary Cancers Symposium was an interim analysis of 1,386 patients with rising PSA and nonmetastatic prostate cancer after radical therapy (either radical prostatectomy or radiation therapy) who were randomly assigned to IAS vs CAD. The two arms were well balanced for performance status, PSA level, prior radical prostatectomy, and time since radiation therapy. Median follow-up was 6.9 years. IAS patients completed a median of eight cycles of therapy. Median survival was 8.8 months in the IAS arm vs 9.1 months in the CAD arm. Time to development of castration resistance was close to 10 years and fa-

Peter B. Bach, MD, MAPP continued from page 7

adjusted depending on the results. That method is more transparent and interactive than simply using CER as a go/ no-go coverage mechanism. In short, efforts should be made to use CER to reward superior services and improve incentives for cost-effective innovation.

Long-range Feasibility One goal of the Obama Administration’s health-care reform package is to cut $500 billion of Medicare spending over 10 years. Is it possible to make such substantial cuts in spending without harming access and quality? It has to be possible for the Medicare system to sustain itself. We overpay for most units of health care and drugs in this country, at least compared with other developed nations. But even at the current rate, we could be smarter about what we provide to patients, using evidence-based methodologies. For one, we could be far less redundant, particularly in the cancer setting. We could do substantially less imaging and drastically reduce the delivery of expensive therapies, especially in clinical settings

vored IAS, but Dr. Klotz pointed out that the trial design was biased toward IAS. He noted that in order to achieve castration resistance status, patients had to be on treatment. Dr. Klotz added that some patients who had a rising PSA off treatment in fact may have had castrationresistant disease, but treatment had to be restarted and the PSA seen to continue to rise before this status could be defined. More non-prostate cancer–related deaths were reported in the CAD arm (134 vs 146 deaths, respectively), whereas more prostate cancer deaths occurred in the IAS arm (122 vs 97 deaths, respectively). These differences were not statistically significant. No difference in adverse events was reported between the two arms, including myocardial events and osteoporotic fractures, with the exception of more hot flashes in the CAD arm.

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

Reference 1. Klotz L, O’Callaghan CJ, Ding K, et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy. Genitourinary Cancers Symposium. Abstract 3. Presented February 17, 2011.

where the prospect of benefit is extremely low and patients might be better served by less aggressive approaches. Also, using comparative research, we could swap more expensive regimens for less expensive ones where there is no proven difference in efficacy. But to get to that point, we first need to reconfigure our system in a way that makes doctors comfortable in practicing medicine in a more cost-effective way. To do that, doctors need to be somewhat relieved of the cultural pressure to expend health-care resources at any cost. Moreover, we need to come to terms with a payment system that rewards all of the cognitive services provided by cancer care specialists, and get rid of the monetary incentives that inspire doctors to do more than they should.

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

Reference 1. Pearson SD, Bach PB: How medicare could use comparative effectiveness research in deciding on new coverage and reimbursement. Health Aff (Millwood) 29:2353, 2010.

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

To reach beyond convention…

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

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

9146401

(01/10)

Printed in USA.

www.avastin.com

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

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

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

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

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

ASCOPost.com | MARCH 15, 2011

PAGE 11

Perspective Medical Ethics

Ethics in Oncology continued from page 1

the literature,” said Dr. Steen. While it is impossible to look into the mind or motive of another, there are some things we can discern from patterns that emerge in studies such as Dr. Steen’s. Since falsified papers were more likely to appear in high-profile medical journals as opposed to less prestigious publications, we can intuit that the “publish or perish” ethos might be a factor behind this behavior. “We need to be cautious; some clinical researchers perceive a paper published in a journal with a high impact factor as an open door to an upward career move, and they are willing to falsify data to walk through that door,” said Dr. Steen.

Breaches of Trust Trust is the cornerstone of science and medicine, especially in the oncology setting where the specter of mortality is a constant companion. We have seen breaches in this fundamental compact; the infamous Tuskegee syphilis experiment is still cited as a reason for the reluctance of many African-Americans to enter clinical trials. The creation of the 1979 Belmont Report, which defines the basic ethical guidelines for the conduct of clinical trials, was created as a result of the Tuskegee episode. Guidelines are imperative, but they do not prevent data falsification in clinical research. Decades after Tuskegee, South African clinical investigator Werner Bezwoda fabricated data in two randomized breast cancer trials. Bezwoda’s scientific deception and its lamentable consequences have been widely discussed in the literature.

Did Bezwoda Make Us More Honest? The ASCO Post recently asked ASCO President George W. Sledge, MD, if the Bezwoda affair was a wakeup call, making data falsification less likely. “I don’t think so, but that’s not a negative judgment. The culture of scientific study is based on assumed honesty. We don’t have the inclination or time to critically analyze the

raw data underlying the published work. When I open an issue of JCO, my starting notion is that the content between the covers is honest reporting.”

George W. Sledge, MD

However, Dr. Sledge mentioned that most authors of scientific papers have an agenda, a bias, and to a certain extent they are going to generate data that will support their underlying hypothesis. “But if we cannot rely on the basic assumption of honest scientific reporting, then the whole system crumbles,” said Dr. Sledge. He stressed that distrust of scientific reporting stems from a small minority of investigators. “During my 30-year career, I can point to maybe a half dozen cases of data falsification in the oncology literature,” said Dr. Sledge.

Built-in Checks Dr. Sledge explained that concern over fraud in clinical research is justified; however, we have built-in checks protecting the system on multiple levels. “For instance, a positive result from a local institutional study will produce a host of investigators wanting to repeat those results. If identical trials using the same agent or combination are negative, people won’t necessarily assume fraud, but they will discount the data,” said Dr. Sledge. Dr. Sledge noted that Bezwoda claimed to have done a phase III trial in a single institution. “None of us knew anything about how things were done in Johannesburg, South Africa. But most of what we gain on a clinical level in oncology is from multicenter cooperative group phase III trials, and with their manifold levels of checks it is impossible to skew the data,” said Dr. Sledge.

A Brief History of Medical Ethics

he first medical ethics guideline was introduced between 460 and 377 BC. Hippocrates’ three-word phrase created the first ethical law in the field of medicine. The Hippocratic Oath began with the simple phrase, “Do no harm,” and evolved into the 181-word vow recited at medical school graduation ceremonies. In 1847, the AMA was formed to establish a definite code of medical ethics. The first code recognized the line between modern medical practitioners and faith-based healers, in addition to further defining proper medical conduct and relationships between doctors and patients.

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A Few Bad Apples In 2000, Dr. Sledge responded to the Bezwoda debacle in an editorial discussing the consequences that lies have on patients, disciplines, institutions, and science. Even though clinical research mischief is incredibly rare, Dr. Sledge acknowledged that breaches of ethical behavior such as Tuskegee and Bezwoda can “dog clinical research decades after their conclusion.” Asked if we need more emphasis on ethics in medical school, Dr. Sledge responded, “The ethics of caring for sick patients in the clinic are on a different level than those of writing a scientific paper, so I’m not sure teaching a general ethics course to freshmen medical students will make a whole lot of difference.” “However,” continued Dr. Sledge, “Discussions of scientific integrity should be a part of every researcher’s educational process, and certainly in the clinic as well as the lab. But this is more of a postgraduate than a medical school fundamental, since that is where people learn how to do research.”

As Dr. Sledge pointed out, we can interpret data in different ways, we can question trial design and methodology, but, in spite of a few bad apples, “we must trust the honesty of the data and the investigator at face value. If not, the whole system and everyone in it is in jeopardy.” Dr. Steen said that his study emphasized the need to back trust up with a healthy dose of scientific skepticism prior to publication. “If something seems too good to be true—as was the case with Bezwoda—then it is incumbent on the scientific community to replicate and verify,” concluded Dr. Steen.

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References 1. Steen RG: Retractions in the scientific literature: Do authors deliberately commit research fraud? J Med Ethics 37(2):113-117, 2011. 2. Steen RG: Retractions in the scientific literature: Is the incidence of research fraud increasing? J Med Ethics December 24, 2010 (epub ahead of print)

Prostate Cancer continued from page 3

a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC)

progressing after docetaxel-based chemotherapy. Genitourinary Cancers Symposium. Abstract 4. Presented February 17, 2011.

Expert Point of View

ommenting on Dr. Scher’s oral presentation, Oliver Sartor, MD, said: “This is a gamechanger. To me this will change practice. Abiraterone is a new alternative for castration-resistant metastatic prostate cancer.” Dr. Sartor is Director of the Prostate Cancer Program at Tulane University School of Medicine in New Orleans. Regulatory approval for castration-resistant prostate cancer drugs goes back almost 30 years, Oliver Sartor, MD Dr. Sartor commented. More recently, in 2004, docetaxel was approved. In 2010, sipuleucel-T (Provenge) and cabazitaxel ( Jevtana) plus prednisone were approved for treatment of castration-resistant prostate cancer. “According to science by press release, denosumab prevents the development of metastasis in nonmetastatic prostate cancer. We anticipate that abiraterone will be the next agent approved for castration-resistant prostate cancer,” Dr. Sartor said. In a separate interview, Nicholas Vogelzang, MD, Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology, Las Vegas, commented, “The striking activity of abiraterone was obvious after the first patients were treated in the phase I and II trials in 2005–2008. It is disappointing that our patients continue to lack access to the drug.”

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Financial Disclosure: Dr. Sartor is consultant to Amgen, Bristol-Myers Squibb, Celgene, Dendreon, GlaxoSmithKline, GPC Biotech, Medivation, Oncogenex, Pfizer, Sanofi-aventis, and Takeda. He has received research funding from Algeta, Astra Zeneca, Cougar Biotechnology, and Sanofi-aventis. Dr. Vogelzang serves as consultant for Amgen, Aveo, Bayer, Celgene, Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Medscape, Novartis, Pfizer, Sanofi-aventis, and Wilex. He has received honoraria from a number of pharmaceutical companies, and he has received research funding from Algeta, Pfizer, and Tokai Pharmaceuticals.

The ASCO Post | MARCH 15, 2011

PAGE 12

2011 Gastrointestinal Cancers Symposium Colorectal Cancer

Dose-painted IMRT Matches Efficacy of Standard Radiotherapy in Anal Cancer, with Less Toxicity By Barbara Boughton

esults of a pivotal Radiation Oncology Therapy Group (RTOG) phase II trial indicate that dose-painted intensity-modulated radiation therapy (IMRT) has similar efficacy to two- or three-dimensional (3D) radiation therapy in treating anal cancer when combined with standard chemotherapy, but causes fewer acute side effects. In this trial of 52 patients with stage II or III anal cancer (RTOG 0529), researchers found that patients who received dose-painted IMRT with fluorouracil (5-FU) and mitomycin had similar 2-year outcomes but fewer significant acute toxicities, compared with patients on the RTOG 9811 phase III trial, who received standard radiotherapy and 5‑FU/mitomycin. Dose-painted IMRT allows dose distributions to be “painted” in such a way that their 3D shape agrees with the shape of the targets. Because it spares patients acute toxicity, dose-painted IMRT will be used as the platform and may allow for the investigation of novel agents and radiation dose escalation in future RTOG anal cancer trials, said lead researcher Lisa Kachnic MD, Chair of Radiation Oncology at Boston Univer-

sity. Dr. Kachnic presented the results of the dose-painted IMRT anal cancer phase II trial at this year’s Gastrointestinal Cancers Symposium.1

■■ Dose-painted IMRT allows dose distributions to be “painted” in such a

Toxicity Sparing

■■ A phase II trial of dose-painted IMRT for stage II/III anal cancer

In the trial, dose-painted IMRT with 5-FU and mitomycin for anal cancer was associated with significant sparing of grade 3 or higher dermatologic and gastrointestinal acute toxicity, Dr. Kachnic reported. About 20% of patients experienced grade 3+ gastrointestinal acute toxicities in the dose-painted IMRT trial compared to 35% on the 5‑FU/mitomycin arm of RTOG 9811 (P = .0082). The researchers also observed a striking difference between the two groups in occurrence of grade 3+ acute dermatologic toxicities: Slightly over 20% of patients in the dose-painted IMRT trial had grade 3+ acute skin toxicities, compared with just under 50% for those on the RTOG 9811 trial (P < .0001). Patients on the dose-painted IMRT trial also experienced fewer grade 2+ hematologic toxicities (P = .032). After a median follow-up of 26.7 months, the 2-year disease-free survival

Expert Point of View

Bruce Minsky, MD

he data from the newest phase II dose-painted IMRT trial in anal cancer are significant because they illustrate that grade 2 and/or grade 3 gastrointestinal, skin, and hematologic toxicities are reduced with IMRT, said discussant Bruce Minsky, MD, Professor of Radiation and Cellular Oncology at the University of Chicago Medical Center. Dr. Minsky noted that because total treatment time affects local control in anal cancer, IMRT may have an advantage over conventional radiation because it results in fewer treatment breaks and less treatment time.

Complex Treatment “The other aspect of the IMRT study that I want to underscore is how complex this treatment is. Overall, 81% of patients treated in this study required planning revisions, and of those 81%, half required multiple treatment revisions,” Dr. Minsky said. New treatment techniques often have a steep learning curve, and so there needs to be a robust educational effort to aid the understanding and planning of IMRT for anal cancer, Dr. Minsky said. “A quality assurance program is essential with these new techniques,” he said. Dr. Minsky also pointed out that there are often long-term toxicities in patients with anal cancer that affect their quality of life. Whether newer radiation techniques such as IMRT really impact these long-term toxicities has yet to be determined, he added.

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

Dose-painted IMRT for Anal Cancer way that their 3D shape agrees with the shape of the targets.

reveals that it produces patient outcomes at 2 years similar to those of standard radiotherapy, when both are combined with chemotherapy involving 5-FU and mitomycin.

■■ Patients in the dose-painted IMRT trial experienced fewer grade 3+

gastrointestinal and skin acute toxicities than those who received standard radiotherapy plus chemotherapy in the RTOG 9811 phase III trial.

■■ Rigorous quality assurance is necessary for dose-painted IMRT, and it will be used as the platform for future RTOG anal cancer trials.

rate in the dose-painted IMRT trial was 77% and the overall survival rate was 86%. Although significantly more patients in the dose-painted IMRT trial had node-positive disease, their survival outcomes as well as local-regional failure, colostomy failure, and distant failure rates were similar to those in the 5-FU/mitomycin treatment arm of the RTOG 9811 trial. After 2 years, patients in the 5-FU/mitomycin arm of the RTOG 9811 trial had a disease-free survival of 75% and an overall survival of 91%.

Patients and Objectives With the exception of the number of patients with node-positive disease, the investigators noted few differences between those treated in the dose-painted IMRT trial and those on the 5-FU/mitomycin arm of the RTOG 98-11 trial in terms of gender, performance status, histology, and tumor size. About 70% of patients in both the dose-painted IMRT trial and 5-FU/ mitomycin arm of the RTOG 9811 trial had tumors ≤ 5 cm, Dr. Kachnic said. The researchers’ primary objective was to reduce the combined acute grade 2+ gastrointestinal and genitourinary toxicities by 15%, a goal they did not meet. Secondary endpoints were patient outcomes after follow-up, acute adverse events, IMRT feasibility and compliance as well as duration and treatment breaks. Of the 52 patients in the trial, 51 completed dosepainted IMRT as planned, and 84% completed the planned two cycles of chemotherapy. The median dose-painted IMRT duration was significantly lower than in the 5-FU/mitomycin arm of the RTOG 9811 trial (43 vs 49 days), and there were fewer treatment breaks, according to Dr. Kachnic. “That’s important because we’ve

seen from other studies that the longer the duration, the more chance there is for having a local recurrence,” Dr. Kachnic said.

Planning Revisions All of the radiation plans received realtime quality assurance, prior to the patients being treated, Dr. Kachnic said. All radiation plans were reSEE PAGE 39 viewed by Dr. Kachnic or her co-investigators. Approximately 81% of patients required planning revisions since the investigators were more accustomed to performing prostate IMRT, and avoiding the rectum and mesorectum, rather than targeting these organs for anal cancer IMRT, Dr. Kachnic said. To aid the investigators, Dr. Kachnic and fellow researchers produced a radiation planning atlas to help with drawing the target volumes, she said. “On final radiation review, we found that most of the investigators were able to achieve the rigid tumor, nodal, and normal tissue radiation prescription constraints we had prescribed,” Dr. Kachnic said. “Dose-painted IMRT for anal cancer is feasible, but with rigorous quality assurance and continued education,” she said.

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Financial Disclosure: Dr. Kachnic has disclosed that she is an uncompensated consultant for Dor Biopharma.

Reference 1. Kachnic LA, Winter KA, Myuerson RJ, et al: Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Gastrointestinal Cancers Symposium. Abstract 368. Presented January 22, 2011.

ASCOPost.com | MARCH 15, 2011

PAGE 13

2011 Gastrointestinal Cancers Symposium Prognostic Testing

Utility of Circulating Tumor Cell Assays Expected to Broaden By Caroline Helwick

hile oncologists are becoming more familiar with the idea of using circulating tumor cells (CTCs) to obtain prognostic information on their patients, researchers at Massachusetts General Hospital (MGH) Cancer Center are moving to the next level. David T. Ting, MD, of the CTC Laboratory at MGH that designed the “CTC-Chip,” described what is possible with next-generation CTC capture devices in an invited lecture at the 2011 Gastrointestinal Cancers Symposium.

David T. Ting, MD

Next-generation Tools More Efficient The CellSearch test (Veridex) is the only FDA-approved CTC detection kit. It contains an antibody conjugated to ferromagnetic beads and directed against the Flat channel

and expression analysis, quantitative reverse transcription–polymerase chain reaction (qRT-PCR), and cell culture. Stains in addition to cytokeratin and CD45 will be used to improve CTC detection, such as prostate-specific antigen Herringbone channel

Why Look for CTCs? In metastatic cancers, the presence of CTCs has been associated with worse progression-free and overall survival and, in some studies, has also been predictive of treatment response. In the recent phase III CAIRO study in colorectal cancer patients,1 the 29% of patients with high CTC counts at baseline (≥ 3 per 7.5 mL) had a 1.5-fold increased risk for progression (P = .0003) and a 2.2-fold increased risk for death (P < .0001) vs those with low counts. Baseline and CTC counts at 2 weeks were also predictive of treatment response “and therefore clinically relevant,” Dr. Ting said. CTCs offer a noninvasive means of sampling for genetic markers, monitoring treatment responsiveness, indicating vascular invasion in localized disease, aiding in treatment decisionmaking, enhancing early detection, revealing metastatic precursors, and indicating novel drug targets.

epithelial cell adhesion molecular (EpCAM) epitope expressed differentially on CTCs. The system captures and enriches the cells, then stains them for cytokeratin. “But CellSearch is not perfect. We can do better,” Dr. Ting said. MGH scientists therefore developed the CTC-Chip, a high-throughput microfluidic device that comprises 80,000 “microposts” coated with the EpCAM antibody. With this device, CTCs are captured with “high yield and efficiency,” he said. “We envision that when the patient comes in we run fresh blood, and within 2 hours we process it on the Chip. We capture the cells fresh and therefore can perform many more diagnostic applications than is possible with CellSearch,” Dr. Ting said. Future applications will include immunostaining, fluorescence in situ hybridization (FISH), gene sequencing

The Promise of Circulating Tumor Cells ■■ CTCs are prognostic and predictive of clinical endpoints. ■■ Newer CTC platforms may improve sensitivity, yield more accurate

disease monitoring, and allow for adjuvant decision-making and early detection.

■■ CTCs are heterogeneous, disease-specific, and can travel in clusters. ■■ The future of CTC detection includes more advanced analyses, for example, with gene-expression profiling and culturing.

(PSA), HER2, mesothelin, S100, and glial fibrillary acidic protein (GFAP), “since not all CTCs will produce cytokeratin,” he pointed out. Some of these stains will be diseasespecific. In prostate cancer, for example, PSA-positive CTCs can discriminate between local and metastatic disease; in a recent MGH study, percent CTC-positive cells was 42% in localized disease and 64% in metastatic disease.2 “What was most interesting in this study was that the mean number of CTCs was about the same in localized prostate cancer (107/mL) as in metastatic (116/mL),” he said. The study also found more robust staining of Ki67 (proliferation) in CTCs in castrate-resistant patients than in castrate-sensitive patients. “This suggests that CTCs not only occur early and at a time when we can cure patients, but that they are heterogeneous,” he said. Similar findings are being made in other tumors. In non–small cell lung cancer, epidermal growth factor receptor (EGFR) mutations in CTCs were 90% concordant with the primary tumor, and novel secondary mutations were detected in 29%.3

Redesign: The Herringbone Chip But there are also limitations to the micropost technology: The opaque design poses challenges in imaging, posts are a

barrier for releasing and accessing cells for more detailed analysis, and the Chip is challenging to manufacture. The group, therefore, improved upon the design and created a more “scalable” next-generation device called the herringbone chip (HBChip). When blood is passed through a chamber lined with a herringbone pattern of grooves, a more chaotic flow is generated and this increases cell capture by several orders of magnitude (Fig. 1).4 The platform relies on immunoaffinity capture of CTCs of the EpCAM epitope like the CellSearch system, but has the additional benefit of microvortex mixing that greatly enhances yield. It also has optical and geometric properties that make more sophisticated analytical techniques possible. It is mounted on a glass slide for standard staining and opens to give access to CTCs for additional testing and growth in culture. Using the HB-Chip Dr. Ting and colleagues have also observed “clusters” of 4 to 12 CTCs, which previous technology had not identified. This and other next-generation devices will allow for gene expression profiling of CTCs (several profiles are in validation studies) and even culturing of the cells. The ability to move beyond simple CTC “counts” to fully understand their complexity will yield much more valuable information, according to Dr. Ting. “CTC counts are not what we should focus on,” he suggested. “CTC subsets are probably more clinically relevant.”

■

Financial Disclosure: Dr. Ting has received grant support from the Pancreatic Cancer Action Network, American Association for Cancer Research, and Andrew L. Warshaw, M.D. Institute for Pancreatic Cancer Research.

References 1. Tol J, Koopman M, Miller MC, et al: Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann Oncol 21:1006-1012, 2010. 2. Stott SL, Lee RJ, Nagrath S, et al: Isolation and characterization of circulating tumor cells from patient with localized and metastatic prostate cancer. Sci Transl Med 31:2(25):25ra23, 2010. 3. Maheswaran S, Sequist LV, Nagrath S, et al: Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366-377, 2008. 4. Stott SL, Hsu CH, Tsukrov DI, et al: Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107:18392-18397, 2010.

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

Oncogenic BRAF: A new potential therapeutic target1,2 The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2: ~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6 In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

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

The ASCO Post | MARCH 15, 2011

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Direct from ASCO

Michigan Practice Uses QOPI Data for Quality, Compensation Incentives QOPI®—The Quality Oncology Practice Initiative—gives practices data to compare their performance on quality measures to national performance.

he data reports generated by QOPI give the West Michigan Cancer Center (WMCC) in Kalamazoo valuable information to improve patient care, according to Terry McKay, President and CEO of the practice, which has seven medical oncologists. “If you give physicians data, they will change behavior,” she says. QOPI is the quality assessment and improvement program launched by ASCO in 2006 and available at no charge to all ASCO members. Practices registered in the QOPI program submit data from a sample of charts of patients seen in the office in the previous 6 months. Within 30 days after the data collection period, participating practices can access reports comparing their performance in more than 90 areas to the scores of other practices across the country. Michigan is one of two states in which practices also receive the average scores of practices within the state. “I enthusiastically endorse QOPI,” Ms. McKay declares. “It’s very hard to get comparable data, and the QOPI data is valuable because it has a significant number of participating phy-

sicians. Also, we are compared only with practices like ours.” QOPI has five categories for practices: academic center, employed physician practice, fellowship program, private independent practice, and private with academic affiliation practice.

Reports Provided by QOPI A mainstay of the data that practices receive is the QOPI Measures Summary Report, which gives the practice’s performance on each indicator along with the national averages and ranges for the same indicators. For instance, for the indicator “Staging documented within 1 month of first office visit,” a practice may have met that criterion in 74 of 85 cases, for an 87% performance rate. This may compare with a national aggregate rate, based on 4,500 charts, of 76%, with a range from 34% to 100%. (These rates are hypothetical and do not reflect an individual practice or aggregate QOPI data.) For each indicator, the practice can also access detailed reports that show all charts abstracted by QOPI chart ID number and whether each

chart met the indicator. This allows practices to review specific charts for educational or verification purposes. Practices can customize QOPI reports and download them in a number of formats, such as PowerPoint files. The bar graph shows an example of how the data can be manipulated for specific comparisons and for presentation. Ms. McKay presents data to all physicians in the practice as well as to the Board of Directors

Using the Data to Improve Quality of Care Ms. McKay reports that the board chose two QOPI indicators for improvement this year: “pain addressed appropriately” and “action taken to address problems with emotional well-being by the second office visit.” Improving the percentage of times these measures are done is tied to compensation levels. Noting that the board sets goals that “are a stretch” to achieve, Ms. McKay offered hypothetical numbers as an example. If the practice’s rate was 64%, and the national average was 73%, the practice must achieve a rate of 69% to “meet requirements,” a rate of 70% for “exceeds requirements,” and a rate of more than 70% for “far exceeds” requirements. Each level of performance is attached to a larger amount of at-risk income. Ms.

McKay adds, “Although these new goals are below the national average, they represent real improvement challenges, because it takes considerable effort for a practice to ‘move that needle’ in 1 year. The great thing about QOPI is that it identifies these areas to improve.” Ms. McKay is also held accountable and has an at-risk portion of her salary tied to performance on the quality measures. To help the physicians improve their performance in addressing pain, the medical assistants take the pain score every time the patient comes in and put the score in the electronic medical record. “If the pain level is 4 or more, the doctor had better do something about it,” she says. “In addition to having the score in the computer, we put it on a customized sticky and circle it in red so the doctor can’t miss it.” Ms. McKay says she is a big fan of QOPI because of its role in helping to improve quality. “It’s so enlightening and helpful to do your own self-examination, because you get affirmation that you’re doing things appropriately and also see where there is room for improvement. For more information, visit qopi. asco.org.

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ASCO Advocates for Cancer Research Funding detriment of our nation’s health, our fragile economy, and our global competitiveness.”

hrough the strong voice of its members, ASCO is working to bolster policymaker support for federal funding for biomedical research and draw attention to progress made in cancer research over the past 4 decades. A major priority of ASCO over the next few years is to increase public funding for clinical cancer trials. “Federal investment in cancer research results in new, innovative, and personalized treatment, leading to longer, more productive lives for cancer patients,” said ASCO President George W. Sledge, Jr, MD. “Scien-

Allies and Activities tific opportunities for making continued progress are at their highest. Now is the time to push forward, not scale back.” ASCO members, through the ACT Network, began building and nurturing relationships with members of Congress when the 112th U.S. Congress took office in January. At the same time, ASCO and more than 270 medical research organizations, in a letter to Congress, warned that reductions in funding for the National Institutes of Health (NIH) will “squander invaluable scientific progress to the

One key booster of the nation’s fight against cancer is President Obama, who in his 2012 budget proposal asked for a $1 billion increase for cancer research. ASCO is calling for doubling NCI funding for Cooperative Clinical Research from $250 million to $500 million by 2015. To help emphasize the importance of cancer research, ASCO joined with One Voice Against Cancer to highlight the critical need for investments in clinical cancer research, including an NIH appropriation of $35 billion for FY 2012, which would provide the

NCI with $5.74 billion, and the FDA with $2.85 billion to ensure timely approval of safe and effective therapies. In another action to support clinical cancer research, ASCO, with the Institute of Medicine, convened research stakeholders for a daylong meeting to examine efforts to improve the publicly funded cancer clinical trials system. Federally funded cancer research has led to virtually every major advance in the field over the past 40 years. A new ASCO timeline that highlights progress against common cancers is now available at www.cancer.net/progresstimeline.

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ASCOPost.com | MARCH 15, 2011

PAGE 17

Direct from ASCO

Research Teams Use $1.35 Million Grants to Improve Patient Care

ast year, at ASCO’s 46th Annual Meeting in Chicago, two research teams each received a Conquer Cancer Foundation of ASCO Improving Cancer Care Grant (ICCG), funded by Susan G. Komen for the Cure®. The ICCG was established to provide research funding that would address important issues regarding health-care access, quality of care, and delivery of care, with general applicability in the breast cancer arena. The 3-year grant totaling $1.35 million is the largest grant disbursed to date by the Conquer Cancer Foundation of the American Society of Clinical Oncology (formerly known as The ASCO Cancer Foundation). It was developed as part of the Conquer Cancer Foundation/Komen for the Cure Research Initiative.

Young Women’s Intervention as well as for a control physical activity comparison. During the remainder of the grant, these interventions will be evaluated in comparison with another, through a randomized controlled trial in the community care setting.

Web-based Review Program The second grant was presented to Patricia Harrigan Hardenbergh, MD, of Shaw Regional Cancer Center, who is supported by coinvestigator Carol A. Hahn, MD, of Duke University. Drs. Hardenbergh and Hahn have developed a program that uses a Web-based radiation oncology treatmentplanning review program in an effort to connect small, rural radiation oncology practices to the rapidly advancing technology used

We know and are learning more about treating cancer, but we also have to make sure that our treatments get to the people that need it most. Intervention for Young Women with Breast Cancer The first grant was awarded to Ann Hart Partridge, MD, MPH, of the Dana-Farber Cancer Institute. Dr. Partridge and her team—Karen M. Emmons, PhD; Mary L. Greany, PhD; Kathryn J. Ruddy, MD, MPH; and Julie S. Najita, PhD—are addressing the issues facing young women undergoing breast cancer treatment, including fertility and preservation concerns, genetic issues, and psychosocial distress. Increased understanding of concerns that young women who undergo breast cancer treatment face “should lead to targeted clinical interventions aimed at reducing distress and improving outcomes,” Dr. Partridge said. During the first 6 months of grant support, the team has refined an exportable and sustainable educational and support intervention for young women with breast cancer. Both print and Web-based materials were developed for their

in many larger practices. This program, called Chartrounds, went live on December 1, 2010, and can be found at www.chartrounds.com. Through this project, radiation oncologists practicing in rural areas are virtually collaborating with some of the top breast radiation oncologists in the world, mimicking traditional patient chart reviews. Dr. Hardenbergh explained that the program’s goal is to “help community oncologists achieve access to disease-site experts and offer top-quality care to the 85% of patients with cancer who are treated in the community setting.” As of January 2011, there were already 17 breast specialists and 81 participants representing 30 states taking part in the program. Ten successful interactive Web-based sessions took place during the first 6 months of the grant support, and efforts are ongoing to assess the impact that these sessions can provide to improve the quality of patient care.

Third Grant to Be Awarded in 2011 Applications for a third Improving Cancer Care Grant, to be awarded in 2011, are currently under review. Dawn Hershman, MD, MPH, Chair of the review subcommittee, highlighted the importance of the Improving Cancer Care Grant program, saying, “This is a kind of grant that the Foundation has never really delved into in the past. We know and are learning more about treating cancer, but we also have to make sure that our treatments get to the people that need it most. And

Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

JCO.org

www.jco.org

this grant really focuses on asking investigators to come up with new ways to improve cancer quality. It’s critical and it’s an area that’s understudied, and the Conquer Cancer Foundation and Susan G. Komen for the Cure have taken a lead in recognizing this as an important area of research.”

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Selected portions reprinted from ASCO Daily News. © American Society of Clinical Oncology. (From “Research Teams Receive $1.35 Million to Improve Patient Care.” ASCO Daily News, Vol. 13, No. 1, 2010: 12A.) All rights reserved.

What’s Hot in

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

1. Addition of Bevacizumab to Chemotherapy for Treatment of Solid Tumors: Similar Results but Different Conclusions Alberto Ocaña, et al 29(3): 254

Phase II Study of the Antibody Drug Conjugate TrastuzumabDM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) – Positive Breast Cancer After Prior HER2-Directed Therapy Howard A. Burris III, et al 29(4): 398

Trastuzumab-DM1: Building a Chemotherapy-Free Road in the Treatment of Human Epidermal Growth Factor Receptor 2– Positive Breast Cancer Steven J. Isakoff, et al 29(4): 351 Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications Guido Marcucci, et al 29(5): 475

Sunscreen and Melanoma: What Is the Evidence? Phyllis A. Gimotty, et al 29(3): 249

Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight Nancy U. Lin, et al 29(3): 251

Serum Prostate-Specific Antigen for the Early Detection of Prostate Cancer: Always, Never, or Only Sometimes? Peter R. Carroll, et al 29(4): 345

Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial E. David Crawford, et al 29(4): 355

Hematologic Malignancies: Where Do We Stand in 2011? Hagop Kantarjian 29(5): 473

10. Phase III Trial of Prophylactic Cranial Irradiation Compared With Observation in Patients With Locally Advanced Non–Small-Cell Lung Cancer: Neurocognitive and Quality-ofLife Analysis Alexander Sun, et al 29(3): 279

The ASCO Post | MARCH 15, 2011

PAGE 18

Direct from ASCO

National Practice Benchmark Supplement to Appear Annually in Journal of Oncology Practice

ournal of Oncology Practice ( JOP) is facilitating innovation in oncology practices around the United States by initiating the annual publication of

each year’s National Practice Benchmark report, which will serve as the anchor for JOP’s “State of Oncology” issue printed each September. The

National Practice Benchmark, which is distributed as a survey to community oncology practices, is “the largest compilation of quantitative

operational and financial data gathered from oncology practices ever produced,” according to Thomas R. Barr, MBA, the General Manager of Oncology Metrics, a division of Altos Solutions in Los Altos, California. Mr. Barr worked with Elaine L. Towle, CMPE, Director of Consulting Services at Oncology Metrics, to aggregate and organize the data collected from the survey results; the results from 2009 and 2010 will be provided as supplements for JOP this year in March and in September, respectively. “From these data, Oncology

Journal of Oncology Practice

American Society of Clinical Oncology

THE AUTHORITATIVE RESOURCE

VOLUME 6

ISSUE 1

FOR

ONCOLOGY PRACTICES

JANUARY 2010

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

By Brenda Nevidjon, MSN, RN, FAAN, et al

Ensuring Quality Cancer Care Through the Oncology Workforce

“There is a crisis in the oncology workforce. Health professionals . . . are experiencing significant workforce shortages . . . because of the rapidly growing population of Americans requiring cancer care, an aging oncology workforce, and inadequate numbers of newly trained workers. This mismatch between supply and demand for cancer care could threaten patient care, safety, and quality.”

Role of Advanced Nurse Practitioners and Physician Assistants in Washington State By Jonathan C. Britell, MD

Practical Model for Psychosocial Care By Susan S. Hendrick, PhD, et al

Physician Assistant Perspective on the ASCO Workforce Study Regarding the Use of Physician Assistants and Nurse Practitioners By Maura Polansky, MS, PA-C, et al

Georgia Society of Clinical Oncology Forms a Patient Navigator Affiliate Basic Steps to Building a Research Program By Allison Baer, RN, BSN, et al

By Laura Levit, JD, et al

http://jop.ascopubs.org

Metrics produces a wide variety of benchmarks—over 50 graphs and figures. Using these to compare their own operations, oncology practices can understand where they are, relative to others in the industry. This offers them an opportunity to focus on areas where they may be able to enhance operations,” Mr. Barr says. In the supplement to the March issue of JOP, readers can analyze information from the 2010 report on 2009 data. In 2010, 189 practices from 44 states responded to the survey to provide demographic, operational, and financial data for the calendar year of 2009 or the most recently completed fiscal year.

Quality Improvement Process “The [National Practice Benchmark] provides a foundation of ‘real world’ measurements that lead to improvement in oncology operations. There is ample evidence that benchmarking is a proven way to improve operations in many settings,” Mr. Barr says. He adds, “When quantitative data exists in conjunction with definitions that allow these data to be used within many different practices, measurement and comparisons can then be made. These measurements form

ASCOPost.com | MARCH 15, 2011

PAGE 19

Direct from ASCO

the beginning of a reaare very diverse in terms of size, losoned quality improvecation, drug-buying channel, payer ment process, which environment, competitive pressures, invariably leads to imand technology. “This is the face of provement in efficiency the oncology care delivery system and standardization of in the United States today,” Mr. Barr processes.” says. Mr. Barr and Ms. Mr. Barr says the future for these Towle began conducting reports will be in clinical benchmarkbenchmarking research ing. “That is where the next stage of Thomas R. Barr, MBA Elaine L. Towle, CMPE in 2001, when they were operational efficiency will produce on the executive board dramatic gains in quality. Here we 2001 and close to 355 in 2009. Of of the Assembly of Oncology Hehave the opportunity to get at the real course, we see the increase in the cost matology Administrators, one of the drivers of predictable outcomes and of drug therapy for these patients and assemblies of the Medical Group costs—that is what we need to stay a reduction in the reimbursement for Management Association. Once this ahead of the cost curve in cancer care. these drugs. We also see an increase in information was The federal meanno longer availingful-use incentive able, the investo produce electroniThis [National Practice Benchmark report] is tigators began cally gathered stanthe face of the oncology care delivery system distributing nadardized data is the tional surveys. gateway to that cain the United States today. They have pubpability,” he says. As —Thomas R. Barr, MBA lished articles the National Practice on the basis of Benchmark report data from the encompasses more 2006 calendar year, as well as from data from more practices, it will conoperating efficiency resulting in lower 2007, 2008, and 2009. tinue to advance the improvement of overhead expense,” he says. Mr. Barr discusses his findings over standardization and efficiency of onUnique Report the course of time: “We have seen a cology practice in our nation. The National Practice Benchmark steady increase in the number of new © 2011. American Society of Clinical report is particularly remarkable in repatients being seen by each full-time Oncology. All rights reserved. gard to how unique it is. Participants oncologist, observing around 230 in

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Free Advanced Cancer Care Planning Booklet for Your Patients

o complement ASCO’s new policy statement, which recommends steps to ensure that physicians initiate candid discussions about the full range of treatment and palliative care options soon after patients’ diagnosis with advanced cancer, Cancer.Net has developed a comprehensive educational booklet for patients. It is designed to help guide patients through these difficult yet important doctor-patient discussions. Order free copies through ASCO’s bookstore (www. cancer.net/ordermaterials), or encourage your patients to view the content online (www.cancer.net/ advancedcancer). © 2011. American Society of Clinical Oncology. All rights reserved.

SAVE THE DATE

2011 ASCO Annual Meeting

Breast Cancer Symposium 2011

June 3-7, 2011

September 8-10, 2011

McCormick Place Chicago, Illinois

San Francisco Marriott Marquis San Francisco, California

EORTC-NCI-ASCO Annual Meeting on Molecular Markers in Cancer October 27-29, 2011 Square-Brussels Meeting Center Brussels, Belgium

Today biomarker testing may help deliver the right cancer treatment to the right patient. Thatâ&#x20AC;&#x2122;s the goal for the future of cancer care. The advent of bio-specific medicine is dramatically changing how oncologists treat cancer. In many instances, clinicians can now test a tumorâ&#x20AC;&#x2122;s distinct molecular characteristics with the goal of providing more targeted, more effective treatment with fewer side effects.

See how bio-specific medicine is changing cancer treatment at canceritspersonal.com

CRI00079

Advances in medical research have helped us to understand that cancer is not one disease. Rather, there are many kinds of cancer that require a more personalized treatment approach. This is a result of better identification and understanding of oncogenic pathways and, in particular, those genes that play a crucial role in contributing to tumor susceptibility, onset, and growth. Bio-specific medicine takes personalized medicine beyond routine patient disease assessment and into an understanding of the underlying differences in tumor biology that can help guide more targeted treatment strategies. This approach recognizes that tumors may have unique pathologic and molecular characteristics.

Biomarkers are the key to understanding and matching a tumor’s molecular characteristics to an appropriate treatment that may be more effective. Identifying those biomarkers is a pivotal first step. Biomarkers are already changing patient outcomes in many tumor types, such as: HER-2 in breast cancer KRAS in colon cancer EGFR in lung cancer c-KIT in GIST There are many other biomarkers being tested, some of which are showing great promise. It’s an exciting time for advances in cancer research. It’s an even better time for patients.

’

’ The righT TreaTmenT. The righT paTienT.

’

The ASCO Post | MARCH 15, 2011

PAGE 22

Opinion

Advanced Cancer Care continued from page 1

be well informed about their prognosis and treatment options. To that end, antineoplastic therapies should be offered only when there is reasonable proof of benefit in terms of survival or better quality of life. And any decision must be evaluated by reasonable cost. An ASCO committee set this care maxim back in 1996, and it still holds.2

Listen to the Data In the earlier period of cancer care, we tended to deliver a flurry of treatment activity at the time of primary diagnosis or recurrent disease, then another flurry of medical activity and hospitalization toward the end of life. From that type of sporadic system, we moved into an era in which we tend to deliver persistent and costly treatment right up until the end of life. In some clinical scenarios such as cancer that has progressed despite multiple regimens or patients with poor performance status, giving chemotherapy does more harm than good. Oncology is data-driven; we should listen to the data concerning end-of-life care. One striking example of datadriven change was a study conducted by Douglas Blayney, MD, who instituted the Quality Oncology Practice Initiative (QOPI) at the University of Michigan Comprehensive Cancer Center UMCCC).3 QOPI was pilottested predominantly in community practices, providing individual clinical feedback to oncologists. QOPI found that 50% of patients with incurable solid tumors were receiving chemo-

Palliative Care

his term originates from the Latin word pallium, referring to a covering garment or cloak. This specialty in effect is trying to “cloak” or mask the pain and suffering experienced due to illness. It applies to anyone with a serious or life-threatening illness, and not just to the dying.

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therapy within 2 weeks of their death. By pointing out this futile practice to oncologists, within a 3-month period that percentage of late chemotherapy delivery dropped from 50% to 20%. Naturally, oncologists do not try to harm their patients; many simply do not have the skills to transition away from delivering chemotherapy.

Do Not Postpone At the onset of diagnosis, we should be telling our patients that we are going to give them the best care to keep them living as long as possible, with good quality of life. And we need to take the time to explain what that means. Studies indicate that more than 90% of U.S. cancer patients want all the information available about their disease.

Table 1: People Who Use Hospice Live at Least as Long, if Not Longer Disease

Added Survival

Congestive heart failure

+81 days, P = .0540

Lung cancer

+39 days, P < .0001

Pancreatic cancer

+21 days, P = .0102

Colon cancer

+33 days, P = .0792

Breast cancer

+12 days, P = .6136

Prostate cancer

+4 days, P = .8266

Reprinted from Connor SR, et al: Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symptom Manage 33(3):238-246, © 2007, with permission from Elsevier.

would do more harm than good. I tell her I would like her to speak to a special team of providers who will try their best to make every day of her life as fulfilling and symptom-free as possible. Having asked permission, I use the words “dying soon,

Patients who enroll in hospice for even 1 day, compared to those who do not, live weeks longer with better QOL. Here is a brief case study of a difficult doctor-patient conversation: I’ll call my patient Mrs. Persistence, a metaphorical name for a real patient, one whom oncologists see regularly. She is a 63-year-old doctor’s spouse whose breast cancer has progressed on the last three chemotherapy agents after good responses to two previous courses. In her weakened state, she now spends most of the day in bed or in a reclining chair. I explain the clinical situation to her and ask what she understands. She says heatedly: “Dr. Smith, I know there is something out there that can help me; I am absolutely not giving up! And don’t even mention hospice—that’s for dying people.” At this juncture, I pause and reflect on what my patient has just said. Her words and emotions are important, for her, for me, and for how we progress together. I take this opportunity to say that we are going to give her the very best care we can, but at this stage, there’s no treatment option left that has a reasonable chance of helping her, and to give her something

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likely weeks to months” and “hospice to keep you up and comfortable for as long as possible.” I tell her I will keep looking for better options, but that medicine does not have a way to fix her cancer. Every oncologist that is in the trenches of cancer care understands that when faced with an emotionally distraught patient like Mrs. Persistence, it is a lot easier to say, “OK, let’s try sixth-line gemcitabine.” We tend to remember the patients who respond, but not the ones who end up hospitalized with complications. The consequence of evasion in advanced cancer is poorer quality of life for our patients and their surviving caregivers.

Debunk the Myths Honest and reality-based conversations with our patients face roadblocks constructed of myths about palliative care and hospice services. Challenge those myths with facts. Several randomized studies show early initiation of concurrent palliative and usual care

ASCOPost.com

leads to equal or better survival, better symptom management, less depression, better communication, more time for necessary planning, better spiritual preparation, and less stress overall among patients and caregivers. Our own studies show that hope is mainained even when we give people bad news. Moreover, early integration of hospice services leads to longer and better quality of life. The data show that patients who enroll in hospice for even 1 day live weeks longer than those who do not use hospice (see Table 1). On a societal note, we should relieve ourselves from inaccurate preconceptions about end-of-life care and reset some of our expectations about cancer treatment. Oncology is a datadriven discipline. The data showing the clinical value of honest discussions and early initiation of concurrent palliative care and hospice services are out there. It is up to us to listen.

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References 1. Peppercorn JM, Smith TJ, Helft PR, et al: American Society of Clinical Oncology statement: Toward individualized care for patients with advanced cancer. J Clin Oncol 29:755-760, 2011. 2. American Society of Clinical Oncology: Outcomes of cancer treatment for technology assessment and cancer treatment guidelines. J Clin Oncol 14:671-679, 1996. 3. Blayney DW, McNiff K, Hanauer D, et al: Implementation of the Quality Oncology Practice Initiative at a university comprehensive cancer center. J Clin Oncol 27:3802-3807, 2009.

ASCOPost.com | MARCH 15, 2011

PAGE 23

2011 Gastrointestinal Cancers Symposium Colon Cancer

Adjuvant FOLFIRI/Cetuximab Improves Survival in Patients with Stage III Colon Cancer By Barbara Boughton

subanalysis of the phase III N0147 clinical trial suggests that adding cetuximab (Erbitux) to the chemotherapy regimen FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) may result in statistically significant improvements in outcomes for patients with stage III resected colon cancer, compared to treatment with FOLFIRI alone. Although researchers acknowledged that the number of patients in the FOLFIRI arms of the trial was small (n = 146), they noted that adding adjuvant cetuximab to FOLFIRI significantly improved disease-free and overall survival at 3 years.

Jocelin Huang, MD

In the analysis from researchers at the Mayo Clinic in Rochester, Minnesota, outcomes from 106 patients on FOLFIRI were compared to those of 40 patients on FOLFIRI/cetuximab at 3 years. Results of the analysis were reported at this year’s Gastrointestinal Cancers Symposium.

Promising Trends In the N0147 clinical trial, researchers found that disease-free survival was 86.6% with FOLFIRI plus cetuximab vs 66.7% for FOLFIRI alone, and overall survival was 91.8% for FOLFIRI-cetuximab vs 84.4% for FOLFIRI alone. “Adjuvant FOLFIRI alone resulted in a 3-year disease-free survival that was lower than that expected for FOLFOX [leucovorin, 5-FU, oxaliplatin],” said presenting researcher Jocelin Huang, MD, of the Mayo Clinic in Rochester. “Although there were trends toward improved disease-free survival and overall survival with the addition of cetuximab to adjuvant FOLFIRI, the study may be too underpowered to make any firm conclusions,” she added. Yet the trial showed promising trends both for patients with KRAS mutant stage III colon cancer and for those with KRAS wild-type disease treated with FOLFIRI plus cetuximab. In patients with KRAS wild-type colon cancer (n = 95), disease-free survival was 92.3% with the addition of cetuximab vs 69.8% for FOLFIRI alone (P = .04, HR = 0.31). Overall survival was also improved in these patients, from 85.2% with FOLFIRI alone to 92% with the addition of cetuximab, although the difference was not statistically significant, Dr. Huang said.

FOLFIRI plus Cetuximab to Treat Colon Cancer ■■ Patients with resected stage III colon cancer in the N0147 trial had

significantly improved disease-free survival and overall survival with an adjuvant regimen of cetuximab plus FOLFLIRI vs FOLFIRI alone.

■■ The addition of cetuximab to FOLFIRI showed a trend toward improved

outcomes in patients with KRAS wild-type or KRAS mutant colon cancer.

■■ Numbers of patients in the study were small, but the results suggest that

there may be a synergistic effect achieved by adding cetuximab to FOLFIRI.

Among patients with KRAS mutant disease (n = 46), a trend toward improved disease-free and overall survival was again seen with the addition of cetuximab, although the difference between the two arms was not statistically significant. In patients with KRAS mutant SEE PAGE 39 disease, 3-year diseasefree survival improved from 56.3% to 82.5%% with the addition of cetuximab, and overall survival was also significantly better with FOLFIRI/ cetuximab—90.9% vs 80.6% for patients who received FOLFIRI alone.

Adverse Events and Discontinuation Rates Despite the improved progressionfree and overall survival seen by combining cetuximab with FOLFIRI, pa-

tients who received cetuximab were more likely to experience nonhematologic grade III adverse events (46% with FOLFIRI alone vs 68% with FOLFIRI/cetuximab, P = .02). “Fewer patients in the cetuximabcontaining arm were able to complete the study per protocol (70% with FOLFIRI/ cetuximab vs 79% for FOLFIRI alone),” Dr. Huang said. The rate of discontinuation due to refusal or adverse events in the cetuximab arm was also double that in the FOLFIRI-alone arm, she added.

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Reference 1. Huang J, Sargent DJ, Mahoney MR, et al: Adjuvant FOLFIRI with or without cetuximab in patients with resected stage III colon cancer: NCCTG Intergroup phase III trial N0147. Gastrointestinal Cancers Symposium. Abstract 363. Presented January 22, 2011.

Expert Point of View

indings from the disease-free survival for FOLFIRI arms of irinotecan-based therapy the N0147 study are inas an adjuvant treatment teresting because they infor colorectal cancer was dicate that using irinoteabout 60%, she noted. can with cetuximab may The other two arms of the have a synergistic effect, N0147 study also demsaid discussant Johanna onstrated that cetuximab C. Bendell, MD, Direcused with FOLFOX does tor of Gastrointestinal Johanna C. Bendell, MD not improve survival. Oncology Research and “I think it is worth Associate Director for the Drug Depointing out that the average 3-year disvelopment Unit at the Sarah Cannon ease-free survival from MOSAIC with Research Institute in Nashville. FOLFOX was around 75%, and the “These are very surprising results, overall 3-year disease-free survival for because we’ve seen in three differFOLFIRI/cetuximab [in N0147] was ent large studies that irinotecan86.6%,” Dr. Bendell added. “Though based therapy in the adjuvant setsmall numbers, it begs the question of ting for colorectal cancer does not whether FOLFIRI/cetuximab could improve disease-free survival,” Dr. potentially improve disease-free surBendell said. In previous studies, the vival over standard FOLFOX therapy.”

Role of KRAS Status Although the number of patients in the FOLFIRI arms of the N0147 study was low, the two arms of the trial were well-balanced; about 65% of patients in both arms had KRAS wild-type disease, Dr. Bendell commented. Dr. Bendell pointed out that patients in the FOLFIRI arms of the N0147 trials derived disease-free survival benefit whether they were KRAS wild type or KRAS mutant. And the 3-year diseasefree survival and overall survival benefit with cetuximab plus FOLFIRI was superior to the FOLFOX arms of the N0147 trial, she noted.

Earlier Investigations Although the FOLFIRI arms of the N0147 trial produced results that seem to contradict previous studies with ei-

ther irinotecan- or cetuximab-based therapy, they also make sense when one considers preclinical data and trials in patients with refractory and metastatic colon cancer, Dr. Bendell said. Clinical data show that patients with irinotecan-refractory disease often show prolonged responses to the use of cetuximab with irinotecan, as well as improved progression-free survival, Dr. Bendell commented. In first-line trials of metastatic colorectal cancer, irinotecan-based therapies also seem to produce better results than oxaliplatin-based regimens, she noted. “A number of preclinical studies and clinical work have shown that there is synergy between EGFR inhibition and DNA damaging agents,” Dr. Bendell said.

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The ASCO Post | MARCH 15, 2011

PAGE 24

News Translational Research

New NIH Research Center to Launch in October By Jo Cavallo

Source: National Institutes of Health

ational Institutes of Health Director Francis S. Collins, MD, PhD, recently presented plans for the National Center for Advancing Translational Sciences (NCATS), NIH’s new agency launching October 1. The center, said Dr. Collins, will lead a “translational science effort to try to come up with a way to further facilitate the translational steps that result in advances in diagnostics, prevention, and therapeutics.”

Francis S. Collins, MD, PhD

Although the NIH is already doing translational research—Dr. Collins cited research showing that 20% of drugs approved from 1990 through 2007 originated at the NIH—new discoveries of potential targets for rare and neglected diseases, as well as for common diseases, prompted the development of NCATS and its formation of partnerships with myriad entities, including the FDA, pharmaceutical and biotech companies, academia, nonprofit organizations, and patient advocacy groups. Dr. Collins stressed, however, that the new center is not intended to be a drug development company, but rather an opportunity to develop safe and effective drugs and bring them to the clinic faster. “The idea is to work with the institutes and centers at the NIH to move projects just far enough along for them to be attractive for commercial investment,” Dr. Collins told reporters. He further characterized the undertaking as an effort to “take what is just a little too uncertain in terms of a possible drug development program, get it to the point where it seems a worthy investment, and then arrange for an appropriate handoff.”

Funding and Logistics Initial funding for the National Center for Advancing Translational Sciences is $700 million, culled from research projects already underway at various NIH institutes and centers, and that would move under one roof to NCATS.

Some programs slated to become part of NCATS include the Clinical and Translational Science Awards, a network of 55 research institutions located throughout the country; the Molecular

Libraries High-throughput Screening Centers; Therapeutics for Rare and Neglected Diseases; and the Rapid Access to Interventional Development program. Another $100 million is project-

ed to come from the Cures Acceleration Network, NIH’s new program under the Patient Protection and Affordable Care Act signed into law by President Obama last March.

■

An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients…

Start With SPRYCEL (dasatinib) SPRYCEL: Superior Response Rates vs Imatinib • Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259) vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519) at a minimum follow-up of 12 months1,2 — Primary endpoint was conﬁrmed complete cytogenetic response (CCyR)† by 12 months

Major Molecular Response (MMR)‡ at Any Time1 MMR at Any Time

52% SPRYCEL (95% CI, 46-58)

P<0.0001§

34%

SPRYCEL (n=259) Imatinib (n=260)

Imatinib (95% CI, 28-40)

50 60 MMR (%)

100

• Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1 • Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1 • Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with imatinib (n=177)1

Select Important Safety Information • SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related events; fluid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial infarction; and use in pregnancy • The most frequently reported serious adverse events in patients with newly diagnosed CP CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) • The most frequently reported adverse reactions reported in ≥10% of patients with newly diagnosed CP CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash • Please see detailed Important Safety Information on adjacent pages

Indication SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome.

ASCOPost.com | MARCH 15, 2011

PAGE 25

FDA Update

Oncology Drug and Device News

Fifth FDA Clearance Granted for MammaPrint Assay

gendia announced that the company has received its fifth U.S. FDA clearance for MammaPrint, its widely used breast cancer recurrence assay. The new clearance is comprised of two ad-

ditional Agilent Microarray scanners and two Agilent Bioanalyzers, expanding laboratory capacity to handle the increasing number of MammaPrint, TargetPrint, and BluePrint test requests.

The company said that the presence of FDA-cleared equipment in both of its locations (Amsterdam and Irvine, California) will further mitigate risk posed by a potential interruption to its business in

for Superior Response vs Imatinib in 1st Line

Start With Convenient Once-Daily Dosing

1 pill 100 mg 1 time per day

One tablet taken consistently, either in the morning or in the evening Tablets should not be crushed or cut; they should be swallowed whole Tablet not actual size.

• In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient1

SPRYCEL Can Be Taken Either With or Without Food1

FASTING

SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with: • No fasting requirements • No need to alter meal schedules • No need to take with food

Important Safety Information About Drug Interactions • Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should be avoided • Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided • Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided • Concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy is needed, the dose should be given 2 hours before or after SPRYCEL *Stratified by Hasford risk score.2 Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1 ‡ MMR (at any time) was defined as BCR-ABL ratios ≤0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples standardized on the International Scale.1 †

Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1

Please see detailed Important Safety Information, including Important Safety Information on Drug Interactions, on adjacent pages.

the event of an equipment breakdown at either location. MammaPrint previously received several FDA clearances for clinical use in the United States and remains continued on page 26

The ASCO Post | MARCH 15, 2011

PAGE 26

FDA Update

MammaPrint Assay continued from page 25

the first FDA-cleared in vitro diagnostic multivariate index assay on the market and the only FDA-cleared breast cancer recurrence test. MammaPrint was previously defined by the FDA as a qualitative in vitro

diagnostic test service, performed only in Agendia’s Irvine labs. The latest FDA clearance defines a new “intended use” that allows for the test to be performed in a central laboratory. This empowers Agendia to legally perform tests for the U.S. market in both the Irvine and Amsterdam CLIA- and CAP-accredited

facilities, and also additional future central labs under Agendia control.

Vosaroxin Gets Fast Track Designation for AML Sunesis Pharmaceuticals, Inc, announced that vosaroxin (formerly voreloxin), the company’s lead drug

candidate, has been granted Fast Track designation by the U.S. FDA for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine. Vosaroxin was granted orphan drug designation by the FDA for the treatment of AML in 2009.

Important Safety Information Myelosuppression: • Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities — Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated — Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation — Hematopoietic growth factor has been used in patients with resistant myelosuppression Bleeding-Related Events: • SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans — In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients • Most bleeding events were associated with severe thrombocytopenia — Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants Fluid Retention: • SPRYCEL is associated with fluid retention — In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported in these trials • Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray • Severe pleural effusion may require thoracentesis and oxygen therapy • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids QT Prolongation: • In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval) • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms • In clinical trials of patients treated with SPRYCEL (n=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled 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 when taking SPRYCEL. Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.

ASCOPost.com | MARCH 15, 2011

PAGE 27

FDA Update

Patients with first relapsed or refractory AML are currently enrolling in a phase III trial of vosaroxin, known as VALOR. The VALOR trial is a multinational, randomized, double-blind, placebo-controlled, pivotal trial of vosaroxin in combination with cytarabine, which is expected to enroll 450

evaluable patients at leading international sites.

Marketing Clearance for Treatment Planning and Delivery Software ViewRay, Inc, a privately held medical device company, has received

U.S. FDA marketing clearance for its radiotherapy treatment planning and delivery software. The software is a critical component of the company’s new radiation therapy system, which combines simultaneous magnetic resonance imaging and radiotherapy delivery. Now in the late stages of de-

Drug Interactions: SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4. • Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided • Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and 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 • Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. • In newly diagnosed chronic phase CML patients: — The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) — The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash — Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%) • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML — Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption — Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

Please see brief summary of full Prescribing Information on adjacent pages. References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb. 2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

For more information online, visit www.sprycel.com.

velopment, the integrated ViewRay system is currently available only as a non–human use research system. The system is being designed to provide continuous soft-tissue MRI during cancer treatment so that clinicians can see precisely where the radiation is being delivered.

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The ASCO Post | MARCH 15, 2011

PAGE 28

News Continuing Education

Nonprofit PLATO Foundation Advances Oncology Education By Caroline Helwick

ncologists seeking continuing medical education (CME) credits at scientific meetings and online will notice a nonprofit organization among the offerings typically

predominated by the pharmaceutical industry: the PLATO Foundation (Physicians Learning And Teaching in Oncology). The PLATO Foundation is a 501(c)(3), tax-exempt organiza-

Another Avenue for CME

tion established in July 2010 by prIME Oncology, a global medical education company accredited by the Accreditation Council for Continuing Medical Education.

SPRYCEL® (dasatinib) Tablet for Oral Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data will be required to determine long-term outcome. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens. Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse Reactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens. QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms. Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Use in Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings and Precautions]. • Bleeding related events [see Warnings and Precautions]. • Fluid retention [see Warnings and Precautions]. • QT prolongation [see Warnings and Precautions]. • Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively). The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 1). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML

The PLATO Foundation was formed to advance the medical education of emerging generations of oncology and hematology practitio-

included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and Table 2 for CML patients with resistance or intolerance to prior imatinib therapy. Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 cardiac dysfunctiona Pericardial effusion 2 <1 <1 0 Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 b 11 17 0 1 Rash Nausea 9 21 0 0 Fatigue 8 11 <1 0 Myalgia 6 12 0 0 6 5 1 1 Hemorrhagec Gastrointestinal bleeding 2 <1 1 0 d 5 5 0 1 Other bleeding CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

Table 2:

Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 100 mg Once Daily

Preferred Term

Fluid Retention Superficial localized edema Pleural effusion Generalized edema Pericardial effusion Congestive heart failure/ cardiac dysfunctiona Pulmonary edema Headache Diarrhea Fatigue Dyspnea Musculoskeletal pain Nausea Skin rashb Myalgia Arthralgia Infection (including bacterial, viral, fungal, and non-specified) Abdominal pain Hemorrhage Gastrointestinal bleeding CNS bleeding Vomiting Pyrexia Febrile neutropenia

Chronic (n=165) All Grade Grades 3/4

140 mg Once Daily Myeloid Blast Accelerated (n=74) (n=157) All Grade All Grade Grades 3/4 Grades 3/4 Percent (%) of Patients 35 8 34 7 18 1 14 0

34 18

4 0

18 3 2 0

2 0 1 0

21 1 3 0

7 0 1 0

20 3 0 4

0 33 27 24 20 19 18 17 13 12 12

0 1 2 2 2 2 1 2 0 1 1

1 27 31 19 20 11 19 15 7 10 10

0 1 3 2 3 0 1 0 1 0 6

12 11 2 0 7 5 1

1 1 1 0 1 1 1

6 26 8 1 11 11 4

0 8 6 1 1 2 4

Lymphoid Blast (n=33) All Grade Grades 3/4 21 3

6 0

7 0 0 0

21 0 0 0

6 0 0 0

4 18 20 20 15 8 23 16 7 5 14

3 1 5 1 3 1 1 1 1 1 7

0 15 18 9 3 0 21 21 3 0 9

0 3 0 3 3 0 3 0 0 0 0

8 19 9 0 12 18 12

3 9 7 0 0 3 12

3 24 9 3 15 6 12

0 9 3 3 0 0 12

a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].

ASCOPost.com | MARCH 15, 2011

PAGE 29

News

ners, as well as those in current practice. Through the award of fellowship educational grants (which will fund travel to medical conferences) and medical education programming, PLATO Foundation aims to meet the ongoing educational needs of these physicians. PLATO Foun-

dation collaborates with other nonprofit organizations during major national and international hematology and oncology congresses to provide completely independent CME activities with a broad international perspective. Jacqueline Melson, PLATO Foun-

Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL (n=258)

Imatinib (n=258)

Percent (%) of Patients Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0– 1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 4. Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML 100 mg Once Daily (n=165)

Advanced Phase CML 140 mg Once Daily Accelerated Myeloid Phase Blast Phase (n=157) (n=74) Percent (%) of Patients

Lymphoid Blast Phase (n=33)

Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 9 9 10 /L, Grade 4 <25 × 10 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0– 2.5 mmol/L, Grade 4 <2.5 mmol/L). Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL 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 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; <0.1% – protein losing gastroenteropathy. 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: 1%–<10% – cough, 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, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, 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; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <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,

dation’s fund-raising manager, said the organization was founded “to explore alternate educational opportunities” by partnering with medical institutions and other nonprofit groups. “We recognize the important contribution of the pharmaceutical industry to both clinical research and education. How-

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). Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib). 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. Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial lung disease. 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. 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. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL 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 well-controlled 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: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 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. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity. 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 given appropriate supportive treatment. 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). Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1284903

DS-B0001A-10-10

Rev October 2010

ever, many CME companies only work with industry. We are offering another avenue,” she said. Its first medical education activity was launched during the 33rd Annual San Antonio Breast Cancer Symposium. “Controversial Topics in Breast Cancer: Straight Talk with International Experts” was chaired by Larry Norton, MD, of Memorial Sloan-Kettering Cancer Center and Martine PiccartGebhart, MD, PhD, of Institute Jules Bordet, and was supported by The Breast Cancer Research Foundation and European School of Oncology. “The symposium was quite successful. It was attended by more than 600 health-care professionals,” she noted.

Using Resources ‘for the Greater Good’ James O. Armitage, MD, of the University of Nebraska Medical Center, Omaha, and Editor-in-Chief of The ASCO Post, serves on the Board of Directors for the foundation. He commented, “Anything you can do to help train future physicians will be important to the field of oncology and to the public. We hope the PLATO Foundation will stand apart by providing activities with an unquestionable lack of bias.” Dr. Armitage acknowledged prIME Oncology for “using its resources to do something for the greater good, to provide more education for young physicians.” The website launched March 1 (www.platofoundation.org), and explains the group’s mission and provides details about events.

■

Coming in future issues of

The ASCO Post Coverage of these important meetings: 2011 Genitourinary Cancers Symposium National Comprehensive Cancer Network 16th Annual Conference

The ASCO Post | MARCH 15, 2011

PAGE 30

2011 Gastrointestinal Cancers Symposium Sarcoma

Sorafenib Shows Promise in Imatinib- and Sunitinib-resistant GIST By Barbara Boughton

phase II University of Chicago consortium trial has demonstrated that sorafenib (Nexavar) can be a viable treatment option for patients with advanced gastrointestinal stromal tumors (GIST) resistant to the standard therapies, imatinib and sunitinib (Sutent). In the phase II trial, sorafenib halted disease progression in more than two-thirds of patients, some for as long as 3 years, according to research presented at the Gastrointestinal Cancers Symposium.1

Nicholas Campbell, MD

“After failure on imatinib and sunitinib, there are limited therapeutic options for patients with GIST. Our data demonstrate that sorafenib had definite clinical activity in imatiniband sunitinib-resistant GIST,” said Nicholas Campbell, MD, an oncology fellow who presented the data and works closely with the primary investigator of the trial, Hedy Kindler, MD, both from the University of Chicago. Sorafenib was reasonably well tolerated by patients in the trial, all of whom had an ECOG performance status of 0 to 2, although dose reductions were often required, Dr. Campbell said. “We believe that further investigation of sorafenib in GIST patients is warranted,” he added.

Study Data In the study of 38 patients with unresectable and treatment-refractory GIST from six medical centers, the use of sorafenib achieved a disease control rate of 68%. The 1- and 2-year overall survival rates were 50% and 26%, respectively. “Many patients were on sorafenib for a prolonged period; 42% were on therapy for at least 6 months and 26% received sorafenib for at least 1 year,” Dr. Campbell said. The median progression-free survival for all enrolled patients was 5.2 months, and the median overall survival was 11.6 months. About 13% of patients in the trial had a partial response to sorafenib, and 55% of patients achieved stable disease during treatment. Sorafenib was initially dosed at 400 mg orally twice daily for a 28-day cycle, and CT scans were performed every two cycles. Patients received a median of four cycles of therapy, but dose reductions were required in 61% of patients. Most commonly, dose reductions took place after patients developed hand-foot syndrome or hypertension. Forty-five percent of patients in the trial developed grade 3 hand-foot syndrome and 21%, grade 3 hypertension. Among the GIST patients, 32 had been resistant to both imatinib and sunitinib, and 6 were resistant to imatinib alone. Patients resistant to both of the standard medications for GIST were more likely to have a worse performance status and liver metastasis, Dr. Campbell said. The vast majority of patients in the phase II sorafenib trial had discontinued sunitinib and imatinib due to disease progression.

Sorafenib in Resistant GIST ■■ Sorafenib produced a disease control rate of 68% in patients with

imatinib- and sunitinib-refractory gastrointestinal stromal tumor (GIST).

■■ The data suggest that prolonged disease control is possible in refractory patients.

■■ Sorafenib was reasonably well tolerated, but dose reductions were often required.

Expert Point of View

edical oncologist Jennifer Obel, MD, of the Northshore University HealthSystem in Evanston, Illinois, said the phase II sorafenib study in patients with gastrointestinal stromal tumors (GIST) is a step forward in understanding what’s on the horizon for treatment of patients with GIST resistant to imatinib and sunitinib. “Our patients with metastatic GIST do very well and live on average at least 4 years after diagnosis,” she said. “But unfortunately, many have limited options at some Jennifer Obel, MD point during their illness.” Because of increased understanding of the molecular mechanisms behind GIST, researchers have made great strides forward in developing targeted treatments for patients with metastatic GIST, Dr. Obel noted. GIST treatment was revolutionized by the introduction of imatinib, which produces a disease control rate of 80% and a median progression-free survival of 24 months. Over the past 10 years, both imatinib and sunitinib have been approved for treatment of advanced and second-line GIST, she said. “This research presentation demonstrates that even more treatments may be available in the future because of our investment into clinical research,” she added.

■

Financial Disclosure: Dr. Obel has reported no potential conflicts of interest.

Further Findings In the trial, response was assessed by RECIST criteria. “Many patients with stable disease had tumor shrinkage, but they did not meet RECIST criteria for partial response,” Dr. Campbell said. A total of 26 samples from patients in the trial were analyzed for mutations. At baseline, 65% of these patients had exon 11 mutations, the majority of which were deletions. Another 15% of patients had exon 9 mutations. As expected, patients who were resistant to imatinib alone fared better after sorafenib treatment than those resistant to both imatinib and sunitinib. The median overall survival in patients resistant to just imatinib was 13.6 months, but in those resistant to both imatinib and sunitinib, the median overall survival was 10.5 months. More than half of the patients in the imatinib and sunitinib resistant cohort exhibited primary resistance (disease progression within 6 months of starting treatment) to sunitinib. However, a significant portion of these patients did not develop

primary sorafenib resistance. “It’s remarkable that 32% of these refractory patients had a partial response or stable disease on sorafenib that was maintained for at least 6 months,” Dr. Campbell said. “Our study shows that prolonged disease control is possible in these refractory patients, even in those with primary sunitinib resistance,” he added.

■

Financial Disclosure: Dr. Campbell has reported no potential conflicts of interest.

Reference 1. Campbell NP, Wroblewski K, Maki RG, et al. Final results of a University of Chicago phase II consortium trial of sorafenib in patients with imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Gastrointestinal Cancers Symposium. Abstract 4. Presented January 20, 2011.

SEE PAGE 39

Use your smartphone to view abstract 4 from the 2011 Gastrointestinal Cancers Symposium.

ASCOPost.com | MARCH 15, 2011

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Expert’s Corner Spotlight on Research

A Conversation with Steven J. Cohen, MD

The Fox Chase investigator discusses the past, present, and future of pancreatic cancer research. By Jo Cavallo

Steven J. Cohen, MD

teven J. Cohen, MD, was drawn to the field of gastrointestinal (GI) cancers because of their complexity and his desire to find more effective therapies for his patients. After completing his fellowship at Fox Chase Cancer Center in Philadelphia in 2002, Dr. Cohen joined the staff there and today is Chief of Gastrointestinal Medical Oncology and Associate Medical Director of Fox Chase Cancer Center Partners. Dr. Cohen has a particular research interest in pancreatic, colorectal, and esophagogastric cancers and, in his dual roles, spearheads the clinical research efforts in gastrointestinal malignancies at Fox Chase Cancer Center and its affiliated sites. Dr. Cohen is an active participant in the GI committee of the Eastern Cooperative Oncology Group and is leading a national study in refractory esophageal cancer. The Fox Chase GI program also collaborates extensively with other research consortia, including the Aptium GI Cancer Consortium (AGICC), the Translational Genomics Research Institute, the Pancreatic Cancer Research Team of the Translational Genomics Research Institute, and the Hoosier Oncology Group, to facilitate the completion of clinical trials to test new agents for patients with gastrointestinal cancers. In December, Dr. Cohen was named a recipient of the NCI’s Team Leadership Award in recognition of his clinical research. The ASCO Post talked with Dr. Cohen about the progress being made in pancreatic cancers, and how the NCI award will help advance his research.

Progress in Pancreatic Cancer Is this an optimistic time in the treatment of pancreatic cancers?

Dr. Cohen: Over the past year or two we’ve seen improvements in pancreatic cancer treatment. There’s a real opportunity for optimism that I don’t think existed a few years back. For the first time, people are feeling like we’re making some progress in terms of developing better treatments. We’re looking at pancreatic cancer from a number of different perspectives. One area has certainly been the development of new therapies. Chemotherapy combinations appear to be improving outcome for these patients, but the real advances will be made with a better understanding of the underlying biology and how to translate that information into clinical progress. We are studying circulating tumor cells and trying to figure out if we can develop that technology as a prognostic marker, and also as a means for identifying and selecting therapy. How close are you to discovering new therapies for pancreatic cancers? Dr. Cohen: We are working with AGICC to build on the gemcitabine and nab-paclitaxel (Abraxane) platform with the addition of erlotinib (Tarceva). We recently completed a phase I study of this combination, and we’re looking toward developing a larger study in this setting. Pancreatic cancer is the fourth leading cause of cancer death. When will these therapies and better diagnostic tools be in clinic use? Dr. Cohen: We are hoping it is over the short term. The study looking at FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) vs gemcitabine that was presented at the ASCO Annual Meeting in 2010 for the first time showed a significant survival benefit with a chemotherapy combination that didn’t include gemcitabine. And a phase I/II trial with gemcitabine and nab-paclitaxel has also shown encouraging results. I think the take-home message from a lot of these trials is that putting combinations together in a rational manner seems to be improving the outcome for our patients. Nab-paclitaxel isn’t approved yet for advanced pancreatic cancer but there’s hope that it may soon be an option for patients, maybe over the next year.

Incremental Progress Can you comment on the progress that has been made and next steps in research? Dr. Cohen: Historically, our progress has been incremental. Unfortunately, it’s been too incremental. We’ve seen some trials in which drugs like erlotinib were approved based on a survival benefit of only a few weeks, and while that might get a drug approved, it is not really helping many patients with pancreas cancer. There are many different strategies we’re working on. We conducted a phase I study looking at the radiolabeled PAM4 antibody; that has now moved into a combination phase I/II study with gemcitabine, and we’re seeing some real evidence of activity. Now the challenge is how best to integrate and test the new agents with some of the chemotherapy backbones that are already in use. What does the future hold in terms of pancreatic cancer treatment and prognosis? Dr. Cohen: For the first time we’re seeing not just stable disease or partial responses but actually complete responses with some of these chemotherapy combinations. Unfortunately, those responses are not permanent. Almost everybody then has some disease

progression at some point. But just the fact that we’re seeing more dramatic responses is incredible. Patients living a year and longer with pancreatic cancer is not that uncommon these days. The challenge proposed by some is how to convert these complete responses into more durable responses, and even cure, through the addition of different agents.

Future Initiatives How will you use the NCI Team Leadership Award to further your research? Dr. Cohen: It is a great honor to receive this award, and I think it’s in recognition of not just my ability as a clinical investigator, but of the supportive environment at Fox Chase Cancer Center for the development of other clinical investigators as well. In our application, we outlined a number of initiatives we wanted to launch, including innovative clinical trials to bring some of the new agents into the clinic. We also want to continue to strengthen our clinical trials program with our community partner hospitals, which is where the majority of accruals to large clinical trials are usually accomplished.

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Financial Disclosure: Dr. Cohen reported he has received honoraria from Sirtex Medical and Nordion.

NCI’s Cancer Clinical Investigator Team Leadership Awards

ast November, NCI announced the recipients of its Cancer Clinical Investigator Team Leadership Award for 2010, recognizing exceptional contributions to the advancement of new therapies through collaborative team science. The awardees were: ■■ Dr. Rafat Abonour, Indiana University Melvin and Bren Simon Cancer Center ■■ Dr. Jeffrey Bradley, Siteman Cancer Center ■■ Dr. Steven Cohen, Fox Chase Cancer Center ■■ Dr. Linda Duska, University of Virginia Cancer Center ■■ Dr. Naomi Haas, Abramson Cancer Center ■■ Dr. Elisabeth Heath, The Barbara Ann Karmanos Cancer Institute ■■ Dr. Susan Kelly, The University of Texas MD Anderson Cancer Center ■■ Dr. Smitha Krishnamurthi, Case Comprehensive Cancer Center ■■ Dr. Suresh Ramalingam, Winship Cancer Institute ■■ Dr. David Rizzieri, Duke Comprehensive Cancer Center ■■ Dr. Cheryl Saenz, Moores Cancer Center ■■ Dr. Sheri Spunt, St. Jude Children’s Research Hospital Designed for midlevel clinical investigators, the 2-year awards provide recognition and $50,000 in funding for those who lead cancer research programs and clinical trials at NCI-designated cancer centers. The funding is provided to the recipient’s institution and can be applied toward the investigator’s salary, fringe benefits, and associated facilities and administrative costs. Recipients are expected to devote 10% to 15% of their time to the activities associated with the award.

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In the News Breast Cancer

Phase III Results for PARP Inhibitor Iniparib Quell Optimism about New Option for Triple-negative Metastatic Breast Cancer By Charlotte Bath

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

he cautious optimism generated by results of a phase II study that the PARP inhibitor iniparib (BSI-201) could offer increased survival for women with triple-negative metastatic breast cancer was punctured by a recent announcement from Sanofi-aventis and its subsidiary BiPar Sciences. According to that statement, the phase III trial failed to meet prespecified criteria for significance for the co-primary endpoints of overall survival and progression-free survival.

Lisa Carey, MD

No phase III data were released. “At this time, only top-line results are be-

ing communicated,” Paul Chew, MD, Senior Vice President, U.S. Chief Science Officer/Chief Medical Officer, Sanofi-aventis, told The ASCO Post. “We are fully analyzing the data to better understand the study outcomes of adding BSI-201 to gemcitabine and carboplatin. Full study results will be presented at an upcoming major oncology conference.” Iniparib was the first PARP inhibitor to enter phase III investigations and subject of “one of the largest trials in triple-negative breast cancer,” Lisa A. Carey, MD, told The ASCO Post. “Triple-negative breast cancer has relatively few options. Right now we are dependent on chemotherapy. Having other agents to use is very much an unmet need.” Dr. Carey is the Medical Director of the University of North Carolina Breast Center and Richardson & Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at UNC. The enthusiasm and excitement about iniparib were due to the new mechanism of action represented by PARP inhibitors and the data from the phase II study, which she added, represented the only data for triple-negative breast cancer not associated with BRCA1 or BRCA2 mutations, and the new mechanism of action used by PARP inhibitors. “A new drug using a new mechanism with a survival advantage in a small study is, just by defini-

Expect Questions from Your Patients and Colleagues

he promising results from the phase II iniparib study, followed soon afterwards by the much less promising phase III results, raise questions from physicians and patients alike. The answers await release of the full phase III data and findings from the many other clinical trials involving PARP inhibitors, some with other types of breast cancer and other cancers. A recent visit to the NIH website ClinicalTrials.gov revealed 54 clinical trials involving PARP inhibitors. PARP inhibitors represent “a new class of drugs, a completely novel approach. It is totally different from anything else we use to treat patients with breast cancer,” Dr. Carey said. “A huge number of questions remain about exactly how these drugs work, how similar they are to each other, or not, and whether they are going to have the same constellation of effects,” Dr. Carey said. These drugs “do have a shared provenance, which is that they all were designed to be PARP inhibitors, but we just don’t know enough about them,” she said. “We need to know how much of their activity is due to PARP inhibition and how much to other properties of the individual drugs.”

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Shared ‘BRCAness’

he use of PARP inhibitors against triple-negative breast cancer builds on the concept of shared “BRCAness,” a term coined by Turner, Tutt, and Ashworth in 20041 and expanded over the years, noted Lisa Carey, MD. BRCAness describes the “constellation of clinical and molecular characteristics that seems to go along with cancers that arise in BRCA1 mutation carriers,” she explained. “Many of the triple-negative breast cancers, particularly the basal-like subset within triple-negative disease, overlap in many of these shared characteristics of BRCAness. So in some respects, basal-like breast cancer has BRCAness, and that is why drugs that depend upon loss of BRCA1 or BRCA2 pathway function were tested in triple-negative breast cancer.”

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Reference 1. Turner N, Tutt A, Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814-819, 2004.

tion, exciting. But we also have to acknowledge we don’t really know how the drugs work yet,” Dr. Carey said.

Benefits in Second- and Third-line Settings In its announcement about the randomized phase III trial evaluating iniparib in patients with metastatic triple-negative breast cancer, Sanofiaventis pointed out “the results of a prespecified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the phase II study.” Debasish Roychowdhury, MD, Senior Vice President and Head of Sanofi-aventis Oncology, stated, “While this trial did not meet its primary goal, we believe that the improvement in overall survival and progression-free survival in patients in the second- and third-line setting are important findings. We are conducting in-depth analysis to gain further insight into these phase III results.” The phase II open-label study compared gemcitabine and carboplatin with or without iniparib among women with triple-negative breast cancer. The 61 women randomly assigned to receive iniparib had improved clinical benefit and survival, without significantly increased toxicity, compared to the 62 women randomly assigned to receive gemcitabine and carboplatin alone. Median overall survival was 12.3 months for women who received iniparib compared to 7.7 months for those who did

not, and median progression-free survival rates were 5.9 months compared to 3.6 months (P = .01). Overall response rates were 52% vs 32% (P = .02). The addition of iniparib had little effect on the rate of adverse events. “On the basis of these results, a phase III trial adequately powered to evaluate overall survival and progression-free survival is being conducted,” the investigators stated in their report published in The New England Journal of Medicine.1 The phase II and phase III trials “were very similar,” Dr. Carey said. “They had very similar eligibility, and the drugs and schedule were the same.” The differences in results may be explained as the phase III results are analyzed and released and may serve to validate the importance of doing phase III studies.

New Therapeutic Direction “PARP inhibitors represent an exciting new therapeutic direction in oncology: the rational targeting of tumor-cell vulnerability during DNA repair,” noted an editorial coauthored by Dr. Carey and Norman E. Sharpless, MD,2 which accompanied the New England Journal article about the phase II results. PARP inhibitors exploit a defect found in tumors in patients with BRCA1 or BRCA2 mutations. These tumor cells lack homologous recombination to repair DNA double-strand breaks, and “PARP inhibition leads to persistent double-strand breaks, inducing cell death,” the editorial continued on page 34

The ASCO Post | MARCH 15, 2011

PAGE 34

In the News

Iniparib and Breast Cancer continued from page 33

explained. Combining cytoxic chemotherapy with agents directly targeting the DNA damage response can improve therapy by “setting cancers up for the

Paul Chew, MD

next blow,” the editorialists asserted. “The data from the phase III trial is completely independent of other BSI201 trials and cannot be compared or applied to other studies in different types of cancer,” according to Dr. Chew. “The current clinical development program for BSI-201 will continue in breast, lung, and other cancers. BSI-201 is currently in phase III development for the first-line treatment of advanced squamous non–small cell lung cancer and in phase II development for a number of other cancers. In addition, BSI-201 is the subject of an extensive translational program designed to identify biomarkers predictive of response, both within and across tumor types.”

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Financial Disclosure: Dr. Carey reported no potential conflicts of interest. Dr. Chew is Senior Vice President, U.S. Chief Science Officer/Chief Medical Officer for Sanofiaventis. Dr. Roychowdhury is Senior Vice President and Head of Sanofi-aventis Oncology.

References 1. O’Shaughnessy J, Osborne C, Pippen JE, et al: Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364:205-214, 2011. 2. Carey LA, Sharpless NE: PARP and cancer—if it’s broke, don’t fix it. N Engl J Med 364:277-279, 2011.

March Is

Colorectal Cancer Awareness Month.

Emerging Clinical Data on Cancer Management BREAST CANCER Smoking before Menopause May Be Associated with Modest Increase in Risk of Breast Cancer Women who smoke before reaching menopause (and especially those who smoke prior to giving birth) may have a modestly increased risk of developing breast cancer, according to a report in the Archives of Internal Medicine. Using data collected from the Nurses’ Health Study, investigators at Brigham and Women’s Hospital and Harvard Medical School examined the records of 111,140 women from 1976 to 2006 for active smoking and 36,017 women from 1982 to 2006 for passive (secondhand) smoking. A total of 8,772 breast cancer cases developed during follow-up. Breast cancer incidence was associated with a higher quantity of current smoking (P for trend = .02) and past smoking (P for trend = .003), smoking for a longer period of time (P for trend = .01), younger age at smoking initiation (P for trend = .01), and more pack-years, defined as a product of the number of packs per day and the number of years that quantity was smoked (P for trend = .005). Conversely, never smoking and passive smoking in childhood or adulthood were not associated with an increase in breast cancer risk.

Major Conclusions “The results suggested that, although an elevated risk for light smokers and moderate smokers was not apparent, heavy smokers who started smoking early in life, smoked for a long duration, and smoked a high quantity were at the highest risk of breast cancer, supporting an independent and additive effect from various smoking measures on breast carcinogenesis,” the authors concluded. “Smoking before menopause was positively associated with breast cancer risks, and there were hints from our results that smoking after menopause might be associated with a slightly decreased breast cancer risk,” the authors also noted. “This difference suggests an antiestrogenic effect of smoking among postmenopausal women that may further re-

duce their already low endogenous estrogen levels.”

Xue F, et al: Arch Intern Med 171:125133, 2011.

Wide Variation in Surgeon’s Treatment Choice for DCIS Impacts Risk of Recurrence Wide variations among surgeons in treating ductal carcinoma in situ (DCIS) accounted for 15% to 35% of subsequent ipsilateral 5-year recurrence rates and 13% to 30% of 10-year recurrence rates, according to a retrospective study in the Journal of the National Cancer Institute. The study reviewed clinical, demographic, and long-term outcomes data from 994 women in two large tumor registries, one from upstate New York and the other from Detroit. The researchers found substantial differences by surgeons in “the three most important predictors of ipsilateral event-free survival in our outcomes models.” Those three predictors were the surgical treatment for DCIS, whether or not the women have received radiation therapy following breast-conserving surgery, and margin status.

Opportunities to Improve Care “BCS in the absence of radiation therapy resulted in substantially lower ipsilateral event-free survival than either [breast-conserving surgery] followed by radiation therapy or mastectomy, regardless of margins, confirming the role of radiation therapy in the treatment of DCIS demonstrated in randomized controlled trials,” the authors stated. “Regardless of treatments, positive or close margins following the last surgical treatment substantially compromised ipsilateral event-free survival,” they added. They estimated that with modest reductions in variation by surgeon, based only on changes among those surgeons with low rates of radiation therapy and high rates of positive or close margins, ipsilateral 5-year and 10-year event rates could be reduced by 15% to 30%. The variability in treatment choice that can be attributed to the physician also “points to important opportunities to improve or at least standardize DCIS care,” noted an editorial accompanying the article. “The challenge,” the editorialists stated, “is for the

professional community to identify factors that are associated with the currently unexplained physician variability and to use that information to promote identification of high-quality providers or quality improvement activities.”

Dick AW, et al: J Natl Cancer Inst 103:92-104, 2011. Virnig BA, Tuttle TM: J Natl Cancer Inst 103:81-82, 2011.

PROSTATE CANCER Behavioral Therapy Program Can Reduce Incontinence after Radical Prostatectomy Men who had experienced incontinence for at least 1 year after radical prostatectomy had a significant reduction in the number of incontinence episodes after participating in a behavioral training program that was part of a randomized controlled trial conducted at a university and two Veteran Affairs continence clinics in Alabama and Georgia. After stratification by type and frequency of incontinence, 208 men aged 51 through 84 years with incontinence persisting 1 to 17 years after radical prostatectomy were randomized to one of three groups: 8 weeks of behavioral therapy (pelvic floor muscle training and bladder control strategies); behavioral therapy plus in-office, dual-channel electromyograph biofeedback and daily home pelvic floor electrical stimulation (“behavior plus”); or delayed treatment, which served as the control group. Participants completed 7-day bladder diaries, and these were scored by a study staff blinded to group assignment.

Significant, Durable Improvement At the end of the 8-week treatment period, men in the behavioral therapy group reported an average reduction of incontinence episodes of 55% (from 28 to 13 episodes per week), while those in the behavior-plus group experienced an average reduction of 51% (from 26 to 12 episodes per week), indicating that adding biofeedback and electrical stimulation did not improve results. The reductions in incontinence episodes for both treatment groups were significantly greater than the 24% reduction

ASCOPost.com | MARCH 15, 2011

PAGE 35

In the Literature

(from 25 to 21) in the control group, the researches reported. “Improvements were durable to 12 months in the active treatment groups,” they added. The results were reported in The Journal of the American Medical Association. These findings “have important implications for urologists, primary care providers, and their patients,” the researchers stated. “Behavioral therapy should be offered to men with persistent postprostatectomy incontinence because it can yield significant, durable improvement in incontinence and quality of life, even years after radical prostatectomy.” Goode et al, JAMA 305:151-159, 2011.

ACUTE LYMPHOBLASTIC LEUKEMIA Risk-adjusted Intensive Chemotherapy Improves Prognosis for Older Adolescents with ALL Although the prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients, a review of outcomes for four consecutive treatment studies found that older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation. A total of 963 pediatric patients with newly diagnosed childhood ALL, including 89 older adolescents (aged 15 to 18 years), were enrolled in the four Total Therapy studies at St. Jude Children’s Research Hospital in Memphis. Compared to younger patients, the older adolescents were significantly more likely to have standard-risk or high-risk leukemia, T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction and were less likely to have the t(12;21) (ETV6-RUNX1).

Basis for Treatment Selection In three of the four studies, treatment selection was based on presenting clinical features and leukemic cell genetics, and the 44 older adolescents had significantly poorer eventfree survival and overall survival than the 403 younger patients. In the other study, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glu-

cocorticoid, vincristine, and asparaginase (Elspar), as well as early triple intrathecal therapy for higher-risk ALL. In this study, the “gap in prognosis was abolished” and event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7%

for the 453 younger patients. Overall survival rates were 87.9% ± 5.1% for the older patients and 94.1% ± 1.2% for the younger patients. The improved prognosis for older adolescents in the fourth study “was achieved without undue increases in toxicity,” the authors noted. “It should

PHA

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be stressed,” they added, that none of the adolescents in the fourth study “developed CNS relapse, despite complete exclusion of prophylactic cranial irradiation from the protocol.”

Pui C-H, et al: J Clin Oncol 29:386-391, 2011.

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continued on page 38

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The ASCO Post | MARCH 15, 2011

PAGE 36

JCO Spotlight Risk Reduction

Bisphosphonates and Reduced Risk of Colorectal Cancer in Postmenopausal Women By Matthew Stenger

isphosphonates are widely used to treat osteoporosis, as well as to treat bone metastases from breast cancer. Evidence has shown that use of these drugs in the treatment of osteoporosis is associated with reduced risk of breast cancer.1-3 In a recent article in the Journal of Clinical Oncology, Gad Rennert, MD, PhD, of the Carmel Medical Center, Haifa, Israel, Stephen B. Gruber, MD, of the University of Michigan, Ann Arbor, and colleagues reported the results of a populationbased, case-control study showing that use of oral bisphosphonates for more than 1 year was associated with Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY

933 postmenopausal women with colorectal cancer were matched with 933 control subjects for age, clinic location, and ethnic group. Patients were all cases diagnosed in the region since 1998 and controls were randomly recruited from a single health-care service source population between 2000 and 2006. Use of bisphosphonates was determined by pharmacy records. In addition to bisphosphonate use, the following variables known to be associated with colorectal cancer risk were included in risk analysis: family history of colorectal cancer, engagement in sports activities, Jewish ethnic group, vegetable consumption, body mass index, and use of statins, low-dose aspirin, calcium and vitamin D supplements, and postmenopausal hormone therapy.

Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

www.jco.org

a significant 59% reduction in risk for colorectal cancer in postmenopausal women.4 In this study (part of the Molecular Epidemiology of Colorectal Cancer study conducted in northern Israel),

Key Data The use of bisphosphonates for 1 year or longer (44 of 933 patients, 100 of 933 controls) was associated with a 50% reduction in risk for colorectal cancer (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.36–0.71). Significant preventive effects were also observed for greater than 2 years of bisphosphonate use (OR = 0.51, 95% CI = 0.34–0.79) and greater than 3 years of bisphosphonate use (OR = 0.39, 95% CI

Clinical Perspective

hen asked to comment on the potential clinical significance of these findings, Gad Rennert, MD, PhD, from the Carmel Medical Center in Haifa, Israel, and lead author of the study, told The ASCO Post, “What this study tells us is that the effect of bisphosphonates is broader than just the effect on breast cancer—that is, it’s not confounded by endogenous hormonal status. Further research might lead to the definition of this class of drugs as cancer-preventing agents. Given the relaGad Rennert, MD, PhD tively good safety profile of bisphosphonates based on use by millions of postmenopausal women, these drugs could become a ‘global remedy’ in a manner similar to low-dose aspirin and statins. Of course, this will only be possible after the effect we observed is replicated by other investigators and tested in a randomized intervention trial.” Dr. Rennert emphasized that the potential magnitude of the preventive effect of bisphosphonate use cannot be precisely estimated from the current case-control study. He noted, “the 59% reduction in risk should really be read as simply a ‘very significant effect,’ the true magnitude of which remains to be ascertained.”

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

Table 1: Conditional Logistic Regression Model of Association of Bisphosphonate Use with Colorectal Cancer Risk* Variable

Relative Risk (95% CI)

Bisphosphonate use > 1 yr

0.41 (0.25–0.67)

Family history of colorectal cancer in first-degree relative

1.89 (1.25–2.86)

Sports activity

0.57 (0.43–0.75)

Body mass index ≥ 30

0.57 (0.43–0.76)

Aspirin use, low-dose, once per day, ≥ 3 yr

0.64 (0.45–0.90)

Statin use ≥ 1 yr

0.59 (0.45–0.78)

Postmenopausal hormone use (any)

0.49 (0.33–0.74)

Vitamin D supplement use ≥ 1 yr

0.44 (0.25–0.78)

Vegetable consumption, ≥ 5 portions per day

0.82 (0.63–1.06)

Calcium supplement use ≥ 1 yr

0.66 (0.40–1.10)

* Study included 933 postmenopausal women with colorectal cancer and 933 matched controls. Reprinted with permission from Rennert G, et al.4 Copyright © 2011 by the American Society of Clinical Oncology. All rights reserved.

= 0.22–0.68), but not for less than 1 year of use (OR = 1.10, 95% CI = 0.71–1.72). In a conditional logistic regression model adjusting for other risk factors for colorectal cancer, bisphosphonate use for greater than 1 year was associated with a significant 59% reduction in risk (relative risk [RR] = 0.41, 95% CI = 0.25–0.67). On this model, sports activity, body mass index greater than or equal to 30, low-dose aspirin use for at least 3 years, statin use for at least 1 year, postmenopausal hormone use, and vitamin D supplement use for at least 1 year were also associated with significantly reduced risk of colorectal cancer, whereas family history of colorectal cancer in a firstdegree relative was associated with significantly increased risk (Table 1). The degree of risk reduction associated with bisphosphonate use for 1 year or more was similar for the right colon (OR = 0.49, 95% CI = 0.29–0.85), left colon (OR = 0.50, 95% CI = 0.29– 0.86), and rectum (OR = 0.50, 95% CI = 0.23–1.08). The oral bisphosphonate alendronate was used by 94.7% of bisphosphonate users, with 60% of alendronate users taking 10 mg/d and 40% taking 70 mg weekly. Estimated compliance rates were 89% with daily use and 96% with weekly use. Both bisphosphonates and statins act through blocking the mevalonate pathway, and use of each for a year or more was associated with a strong pre-

ventive effect for colorectal cancer. An analysis of concomitant use of bisphosphonates and statins in the study population showed no further risk reduction compared with use of either alone. In conclusion, the use of oral bisphosphonates for more than 1 year was associated with a marked reduction in risk for colorectal cancer in postmenopausal women, similar to the reduction in breast cancer risk recently observed with bisphosphonate use in this population.

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References 1. Chlebowski RT, Chen Z, Cauley JA, et al: Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 28:3582-3590, 2010. 2. Newcomb PA, Trentham-Dietz A, Hampton JM: Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 102:799-802, 2010. 3. Rennert G, Pinchev M, Rennert HS: Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 28:3577-3581, 2010. 4. Rennert G, Pinchev M, Rennert HS, et al: Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol February 14, 2011 (early release online).

SEE PAGE 39

Use your smartphone to view additional information about the studies discussed in this report

ASCOPost.com | MARCH 15, 2011

PAGE 37

Letters to the Editor Prostate Cancer

Sipuleucel-T Reconsidered

The Author Responds

By Mark Frohlich, Chief Medical Officer, Dendreon, and Medical Oncologist, Harborview Medical Center, Seattle

By Richard Boxer, Professor of Clinical Urology, University of Miami, and Clinical Professor, University of Wisconsin, Madison, and Medical College of Wisconsin

r. Richard Boxer’s January 15 column in The ASCO Post, “Prostate Cancer, Pediatrics, and Priorities,” raises some provocative questions. However, it contains important factual inaccuracies and gives a misleading perspective on the crucial debate about where we should be spending our health-care dollars.

Factual Errors There were two critical factual errors in the piece. First, sipuleucel-T (Provenge) is not priced at $10,000 a month, suggesting a treatment that is an ongoing cost to the system. The price of sipuleucel-T is $31,000 per infusion. A patient receives a total of three infusions, so, a complete course of therapy is $93,000, a price that is comparable to that of other novel oncologic agents that provide a clinically meaningful survival benefit. In contrast to sipuleucel-T, most oncology drugs require substantial additional supportive care costs, and none involve the highly personalized approach that sipuleucel-T does. Second, patient survival on sipuleucel-T is not an average of “maybe 4 months” with poor quality of life, as Dr. Boxer notes. The median—not mean—survival is 4.1 months; many patients may be benefiting more than that, all with a treatment that shows a markedly different side-effect and tolerability profile than that of traditional chemotherapy. To put sipuleucel-T into perspective, there are two other FDA-approved treatments demonstrated to prolong overall survival in advanced prostate cancer: the chemotherapies docetaxel and cabazitaxel ( Jevtana), each of which provides a 2.4-month median survival benefit.

Over the past 15 years, only three therapies in any metastatic cancer setting have shown a median survival benefit of 4 months or more, and sipuleucel-T achieves that with minimal toxicities and a short duration of therapy.

Health Spending Issue But Dr. Boxer’s larger point is that any investment in expensive end-oflife cancer care degrades our ability to put medical resources elsewhere. And while I cannot argue with his desire to improve preventive health care and slow the growth of health spending, oncology care is not the area to sacrifice in the name of cost savings. The curative therapies that Dr. Boxer says we should pay for will only become a reality if we invest in novel approaches like sipuleucel-T. The war on cancer, we have learned, is a slow and incremental one, with advances building on advances to the point where millions are now living longer and healthier lives than could have been imagined even a few decades ago. As an oncologist who has treated many patients with prostate cancer, I have seen far too many of my patients die over the years because we had nothing to offer them. We now have an entirely new treatment modality that prolongs survival by harnessing a patient’s own immune system to fight cancer. I fully support efforts for finding ways to keep medical costs reasonable, but denying patients effective therapies isn’t the way to do it. —Mark Frohlich, MD

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Financial Disclosure: Dr. Frohlich is Chief Medical Officer of Dendreon, manufacturer of sipuleucel-T.

thank Dr. Frohlich for his response to my op-ed commentary but take issue with the following points. First, I did not state that the patient will have “poor quality of life” as Dr. Frohlich contends. I stated that “the quality of extended life might not be very satisfying” (italics added). Is this one of the “important factual inaccuracies” Dr. Frohlich points to? Will the company offer a money-back guarantee if the patient does have a poor quality of his remaining life? As to the cost of the drug, I stand corrected: Sipuleucel-T (Provenge) does not cost $10,000 per month for patients with end-stage, metastatic prostate cancer. It costs $31,000 per month for 3 months for the median improvement of 4.1 months. Thus, instead of costing $10,000/month as I inaccurately stated in my op-ed piece, it costs $22,683/month or more for the half of the patients who survive 4.1 months or less. For the 50% who survive longer than the median, the cost would be decreasingly less per month ($93,000 amortized over their remaining life). But therein lies part of the problem: The patient has the potential benefit of a longer life, and society has the certain cost of the medicine. Dr. Frohlich is absolutely correct: Sipuleucel‑T is not the only medicine that costs an enormous amount of money. It is only an example of the cost of medical care that is consuming our economy.

Creative Economic Thought The great scientific minds that conceived of and proved the efficacy

SEE PAGE 39

Use your smartphone to view Dr. Boxer’s original column, “Prostate Cancer, Pediatrics, and Priorities.”

of sipuleucel-T should be matched by the creativity of public and economic policy experts. Patients deserve new medicines that improve their quality and quantity of life. Society deserves a creative and fair method of paying for it. Should medications that potentially improve life in its end stages be paid for by those receiving it? If a person is capable of paying $93,000 with a 50% chance of living another 4.1 months, why not have the person pay? If the person is unable to pay, then society may pay. Should a person pass to his family $93,000 in his will when he has had society pay for sipuleucel-T? Or should there be a risk-sharing with the company that takes all the money up front? If a person dies prior to the 4.1 months, should the company return a portion to the insurance company, Medicare/Medicaid, or the patient’s family? Society must deal with these provocative issues. The economic future of America demands it. —Richard Boxer, MD

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

See page 39 for more letters to the editor

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com. All correspondence will be acknowledged and considered for publication in “Letters to the Editor.” Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800; Fax: 631.692.0805 www.ASCOPost.com

The ASCO Post | MARCH 15, 2011

PAGE 38

In the Literature

Emerging Clinical Data continued from page 35

ORAL MEDICATIONS Oral Cancer Drugs Not as Persistently Taken in the Real World as in Clinical Trials

While it may seem that persistency in taking oral cancer medications for the prescribed duration and adherence to taking the drugs as prescribed would be greater than for other types of cancer therapies, “emerging real-world data indicates otherwise,” according to an article in the Journal of Oncology Practice.

“Persistency rates for oral cancer medications are generally lower in real-world settings compared with in clinical trials,” the authors reported, “especially for chronically administered medications.” For example, persistency in taking tamoxifen at 3.9 years was 71.7% in the Arimidex,

Tamoxifen Alone or in Combination (ATAC) trial, compared to 64.8% at 3.5 years among women identified in a pharmacy database. In the Breast International Group 1-98, persistence with letrozole was 84% at 4.25 years, compared to 77% at 1 year in an analysis of two large-claims databases. “Differences were not limited to patients with breast cancer,” they added, citing data for chronic myelogenous leukemia and imatinib.

Adherence vs Persistence “There is less information on adherence compared with persistence in clinical trials,” the authors stated. “The majority of adherence data is from the real-world setting, and these have shown variability,” ranging from 89% adherence to imatinib among patients with CML at 1 year when unlimited dosing gaps were allowed to 54% to 80% adherence among patients receiving hormonal therapy for breast cancer. Among the factors associated with nonadherence are disease complexity, poor communication, use of retail pharmacies, higher copayments, and patient perceptions and motivations, the authors stated. Strategies listed to increase adherence rates include “emphasizing the value of the prescribed regimen, simplifying the regimen, encouraging use of medication-taking systems, obtaining caregiver assistance, and reinforcing desirable behavior.”

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Hohnecker J, et al: J Oncol Pract 7:65-67, 2011.

Contact

The ASCO Post Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 email: Editor@ASCOPost.com ASCOPost.com HarborsidePress.com

ASCOPost.com | MARCH 15, 2011

PAGE 39

Letters to the Editor

Can Patient-focused Research Improve Accrual to Clinical Trials?

aroline Helwick’s report on Dr. George Sledge’s presentation at the San Antonio Breast Cancer Symposium (The ASCO Post, February 15) is one of many recent articles expressing concern regarding the status and future of oncology clinical trials. The Institute of Medicine report of April 2010 and the response to it by the National Cancer Institute (as summarized by Margot Fromer in the January 15 issue of The ASCO Post) appropriately highlight areas of the clinical trials process that need to be improved. The current process is certainly cumbersome, expensive, and lengthy. However, much less attention has been afforded to patients’ perspectives and concerns.

The advent of powerful biomarker analysis, becoming cheaper each year, is allowing the design of clinical trials fashioned to maximize patient clinical responses. The various and detailed recommendations for streamlining and improving the clinical trials process do not address one of the key impediments to an effective system—the lack of interest and low level of participation by the patient community (at least for adult oncology trials). The reasons for this are personal and varied but certainly include the desire to not be viewed as an experiment, the fear of being randomly assigned to the standard-of-care arm rather than a new therapy arm, and the suspicion that the same intervention given to a large group of people is probably not going to be equally efficacious for all.

Double-edged Sword of Advanced Technology In his presentation, Dr. Sledge paints a daunting picture of clinical trials in the future because of the enormous strides being made in biomarker technology and the likely continued dismal accrual rate of only 3% to 5% of patients. But perhaps the advances in technology present an opportunity

to stimulate interest and participation on the part of patients with cancer. The trial design math might look quite different if accrual rates were 25% or 50% or even higher, as they are in pediatric oncology trials. The advent of powerful biomarker analysis, becoming cheaper each year, is allowing the design of clinical trials fashioned to maximize patient clinical responses. Patients may no longer wonder whether specific interventions are right for them. Their genetic and biomarker profile will indicate their best options. It is possible that patients will want to search out the most appropriate trial for their particular type of malignancy. The TAILORx breast cancer trial begun in 2006 took this approach in allocating patients to treatment arms based on the results of a 21-gene assay. It would be interesting to see the rate of accrual to this trial compared with average accruals. In addition to matching patients to the best trial for them, it is now possible (using “adaptive design” clinical trials) to modify the course of treatment based on prospectively planned continuous or periodic analysis of response data. Such trials should foster confidence in patients that they are not part of a rigid experiment, and ongoing participation in a study will be adjusted to reflect their response to treatment.

Using 2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the Application There are three ways to download the ScanLife application:

Simply text the word “scan” to 43588.

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”.

Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

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.

Turning Around the Approach to Research Perhaps the approach to clinical trials needs to be turned around. Instead of starting with a scientific question and study, and then searching for patients to accrue, one could focus more on the patient, perform a standard screen, and then search for the trial that will afford access to new therapies, so as to optimize response and outcome. Rather than emphasizing the quest to answer a scientific question, patients should feel the goal is to cure them (and data gathered along the way will likely help to cure others). As Dr. Sledge comments, this will require a large national (and eventually multinational) health information system that can link patient profiles with open studies. Nevertheless, the technology is now available. —David Irwin, PhD American Institute of Biological Sciences Reston, Virginia

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Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates (ADCs) ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-4

Monoclonal antibody

Stable linker

Cytotoxic

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer activities1,3,5-7

conjugates cytotoxic to monoclonal antibody and is designed to allow ADC to remain inactive while in circulation1,2,7,8

incorporated into an ADC can be up to 1000-fold more potent than currently used chemotherapies2,5,7

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibodyâ&#x20AC;&#x201C;mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic.5-7 Preclinical studies show that these anticancer activities may include prevention of signaling, antibody-dependent cellular cytotoxicity, and induction of apoptosis.3,5,6

To learn more, visit the new ADC resource at www.ResearchADCs.com References: 1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 6. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.