tap vol 1 issue 5

A Harborside Press Publication

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

VOLUME 1, ISSUE 5

OCTOBER 2010

continued on page 12


MORE IN THIS ISSUE

2010 Best of ASCO Meeting CoveragePancreatic cancer ...................................4Lung cancer ............................................5Esophageal cancer ..................................9

Direct from ASCO ....................................16JCO Spotlight: Colon cancer ...................22

Nagahiro Saijo, MD, PhD

Many multinational clinical trials have recently been conducted to enable

the rapid accrual of patients and the use of registration data in multiple countries. Such trials often include multiple ethnicities, and regional differences sometimes affect the treatment results. Many factors can cause regional differences, including medical care, medical insurance, and clinicopathologic fea-tures, as well as pharmacogenomics. When discrepant data are observed between Asian and Caucasian populations, new clinical tri-als should be scheduled in specific popula-tions. This commentary discusses three ex-amples of such trials.

EGFR Tyrosine Kinase InhibitorsDuring phase II trials of the epidermal

growth factor receptor (EGFR) tyrosine ki-nase inhibitor gefitinib (Iressa), such as the Ir-essa Dose Evaluation in Advanced Lung Can-cer (IDEAL) 1 and 2 studies,1,2 the response rate appeared to be higher among Japanese patients than among Caucasians.


Breast Cancer

Global Perspective

Multinational Trials Reveal Striking

Regional Differences

Perspective: Tort reform 3 | Antidepressants and tamoxifen 28 | Oncology drug news 33

Although chemotherapy is the standard neoadju-vant treatment in postmenopausal women with

large breast tumors, an endocrine approach may be more suitable and may, in fact, help further optimize systemic treatment as well.

“Estrogen receptor (ER)-positive disease is highly heterogeneous, and this heterogeneity can be stud-ied and treatment person-alized by taking advantage of the neoadjuvant setting,” said Matthew J. Ellis, PhD, MB, BChir, of Washington University, St. Louis.

Dr. Ellis, who has been studying the characteris-tics of ER-rich tumors for

years, is leading the multicenter phase II American College of Surgeons Oncology Group (ACOSOG)

Z1031 study, which is evaluating the benefit of an endocrine neoadjuvant approach in postmenopausal patients with ER-rich tumors. Preliminary analyses, reported at the 2010 ASCO Annual Meeting by Dr. Ellis, showed clinical response rates to exceed 60%, and the breast-conservation rate to be 51% for pa-tients slated for mastectomy at presentation.1

‘Dramatic Effect’“For the 150 or so women in this study who were

clearly headed for mastectomy this is really a dramatic effect, achieved with very low toxicity, and arguably

Neoadjuvant Endocrine Treatment Makes Sense for Estrogen Receptor–rich Breast Tumors But early failure to suppress proliferation may signal need for chemotherapy By Caroline Helwick

Matthew J. Ellis, PhD, MB, BChir

A panel of experts in global health made news re-cently by emphasizing the disparity in cancer

care between countries of low and middle income and those with more resources, such as the United States. The report, which was published online August 16th in The Lancet,1 called for more recognition of the global burden of cancer and outlined strategies that might an-swer the specific needs of poorer countries.

The report was authored by Paul Farmer, MD, of Harvard School of Public Health, and an international consortium of 22 participants ranging from ASCO President Douglas Blayney to cancer survivor and cy-clist Lance Armstrong.

Julie Gralow, MD, Professor of Oncology at the University of Washington, Seattle, noted the “unique-ness” of the collaboration. “Very few cancer-specific spe-cialties are actually represented among the authors. We have infectious disease experts, health economists, and

public health specialists,” she pointed out. “We felt there are people out there who have made tremendous advances in global health outside of oncology, and we should learn from and part-ner with them. We are try-ing to be inclusive and learn from each other.”

Closing the Gap in Survival RatesThe consortium called for an end to the assumption

that cancer is a “disease of the rich” and one that war-rants a back seat to infectious diseases, such as malaria and AIDS, in the developing world. Almost two-thirds of the 7.6 million cancer deaths per year occur in low-

Expert Panel Highlights Need to Intensify Cancer Care in Poorer Countries By Caroline Helwick

Julie Gralow, MD

Use your smartphone to view the original abstracts as presented at ASCO’s 2010 Annual Meeting.

See page 42 for more information about using 2D barcodes

Dr. Saijo is Professor in the Medical Oncology Division at Kinki University School of Medicine, Osaka, Japan, and a member of The ASCO Post’s International Edi-torial Advisory Board.

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ASCOPost.com | OCTOBER 2010 PAGE 3

Opinion

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

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

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

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

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

Michael P. Link, MD Stanford University Medical Center

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

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

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

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

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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

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

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

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

Conor Lynch, Executive Editor [email protected]

Cara H. Glynn, Director of Editorial [email protected]

Andrew Nash, Associate Director of Editorial [email protected]

Sarah McGullam, Assistant Editor [email protected]

Michael Buckley, Graphic Designer [email protected]

Wendy McGullam, Director of Production [email protected]

Leslie Dubin, Vice-President, Director of Sales [email protected]

Anthony Cutrone, President [email protected]

John A. Gentile, Jr., Chairman [email protected]

Editorial Board

Harborside Press Publishing Staff

Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Alice Goodman, Caroline Helwick, Larry Rosenberg, PhD, Matthew Stenger

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations

Financial disclosure information available at ASCOPost.com.

“Everyone is entitled to their own opinions, but not their own facts.” —Senator Daniel Patrick Moynihan

Few things can make a clinical physician’s blood boil more

rapidly, and with such intensity, as the cost—both in treasure and emotion—of medical malpractice. Nearly everyone pays insurance premiums, somewhat reluctantly, for a combination of policies cov-ering everything from life, health, and home, to disability, liability, and nearly 150 other insurable en-tities. But medical malpractice insurance strikes at the hearts of many physicians who believe that unscrupulous lawyers prey upon the medical profession. These law-yers facilitate frivolous lawsuits that entangle the courts and burden the health-care community and society at large. The result is often that doc-tors, especially those in specialties more prone to lawsuits, may refuse to care for patients in states where plaintiffs are favored. Moreover, many doctors may feel compelled to practice defensive medicine costing tens of billions of dollars per year.

Physicians rail against a public policy that they believe predatory lawyers have self-servingly main-tained under the guise of protect-ing patients’ rights, with profiteer-ing insurance companies complicit in their lenient policies. Further-more, many physicians believe that politicians, especially those be-holden to the trial bar, are willing to consider malpractice premiums as a tax to reduce state deficits. Wit-ness the Governor of Wisconsin grabbing over $200 million in a pa-tient compensation fund to plug a deficit, only to have the Wisconsin Supreme Court reverse the misap-propriation.

The generally accepted principle of medical malpractice lawsuits is to compensate victims of substan-dard care. Doctors and patients believe that all individuals deserve

the highest quality care; they nei-ther condone nor desire negligent or willful substandard care. The question is this: How does society compensate the true victims with-out making the innocent or, indeed, the entire health system suffer from abuse?

The Goal Is to Reduce Malpractice

As much as emotion seems to rule the debate, there are facts that need to be central in the discus-sion.1 Studies have demonstrated that the medical malpractice (tort) system is very inefficient. The Har-vard Practice Study2 demonstrated that only a very small percentage of patients injured by negligence even file a claim. Remarkably, there was no relationship between the pres-ence or absence of medical negli-gence and the outcome of malprac-tice litigation.

Arguments and FactsHere are some of the arguments

and the facts:

Medical liability premiums and law-suits are a major reason health-care costs are out of control. ■ In fact, the cost of medical li-

ability has risen at the same pace as medical price inflation,3 so it is a component, not a driving force. The actual costs are about $30 billion out of $2.7 trillion, although some researchers es-timate it to be twice as much.4 However, the greater amount—often quoted by the American Medical Association—does not allow for inflation, which would account for more than half the difference. This is an enormous amount of money, but only 1% to 1.5% of the health economy. That is one reason the politicians have not made it central to the health-care reform, ie, the Patient Pro-tection and Affordable Care Act (PPACA).


Ingredients of Tort Reform: Facts & Frustration, Emotion & Economy, and Public Policy & Physician PenaltyBy Richard J. Boxer, MD

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The ASCO Post | OCTOBER 2010

Best of ASCO®

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

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 [email protected]. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email [email protected] or fax (631) 692-0905.

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Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Domestic: $75 for the print or online edition; $125 for both editions. International: $125 for print or online edition; $175 for both editions. Contact [email protected].

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: [email protected].

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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.

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

Updated efficacy and safety results from a multicenter international

phase III trial indicate that compared to placebo, sunitinib (Sutent) provides significantly longer progression-free survival for patients with advanced, progressive, and well-differentiated pancreatic neuroendocrine tumors, according to a presentation at the 2010 ASCO Annual Meeting. In the trial, patients on sunitinib had a me-

dian progression-free survival of 11.4 months vs 5.5 months in the pla-cebo group (HR = 0.418, P = .0001). The trial closed

early because of more serious adverse events and deaths in the placebo arm, so Kaplan-Meier analysis of one of the planned endpoints, overall survival,

Sunitinib Delays Disease Progression in Patients with Advanced Pancreatic Neuroendocrine TumorsBy Barbara Boughton

■ An updated efficacy and safety analysis of an international multicenter phase III trial indicates that sunitinib improves progression-free survival in patients with low- to intermediate-grade advanced pancreatic neuroendocrine tumors.

■ The trial closed prematurely due to a greater number of adverse events and deaths in the placebo arm, but there was a trend toward improved overall survival in the sunitinib group.

■ Continuous daily dosing of sunitinib was well tolerated, and the drug could be given along with concomitant somatostatin analogs without added toxicities.

■ The trial indicates that sunitinib may be a new treatment possibility for some patients with advanced pancreatic neuroendocrine tumors, but how it might fit into treatment regimens is still not resolved.

Best of ASCO® San Francisco Best of ASCO® Boston

The ASCO Post presents reports from the Best of ASCO® meetings recently held in San Francisco and Boston. Watch for additional news and perspectives in future issues.

Sunitinib in Advanced Pancreatic Neuroendocrine Tumors

was not possible. Yet after a median follow-up of just under a year, there were 9 deaths in the sunitinib group and 21 in the placebo arm, as well as a trend toward improved overall survival in those who received sunitinib, with a hazard ratio of 0.409 (P = .0204), said lead investigator Patricia Niccoli, MD, who presented the results at the Annual Meeting.

Significant New Finding“This is a significant new finding and

an advance for patients with low-grade and intermediate-grade neuroendocrine tumors. As well as achieving increased progression-free survival across all the subgroups in the trial, sunitinib was fair-ly well tolerated, and the findings in this study may soon be applied to patients we see in our practices,” said James L. Abbruzzese, MD, Professor of Medi-

cine, and Chairman of the Department of Gastrointestinal Medical Oncology at The University of Texas M. D. Ander-son Cancer Center. Dr. Abbruzzese pre-

sented the study’s results at the Best of ASCO Meeting in San Francisco.1

Researchers with the sunitinib trial planned to accrue 340 patients with

Gastrointestinal Cancer

See page 42


Best of ASCO®

Although the results of the Iressa Pan-Asia study (IPASS) suggest-

ed that the oral agent gefitinib (Iressa) improved outcomes in patients with advanced non–small cell lung cancer (NSCLC)—particularly those with EGFR mutations—those benefits have

not been proven in other recent trials of patients with either early stage or locally advanced NSCLC. In fact, the results of the BR.19 trial presented at the 2010 ASCO Annual Meeting sug-gest that patients with local resected NSCLC disease do worse on gefitinib

Adjuvant Gefitinib Fails to Improve Survival in Post-resection Early Lung Cancer, Regardless of EGFR Mutation StatusBy Barbara Boughton

continued on page 6

Expert Point of View

Theodore Hong, MD, said the sunitinib (Sutent) study was well executed and may signal that this targeted medication could be a future option for

treatment of pancreatic neuroendocrine tumors. “I think it will be viewed as an unequivocally positive study, given that the primary endpoint was progres-sion-free survival (PFS) and they did demonstrate an improvement in PFS,” said Dr. Hong, Director of Gastrointestinal Radiation Oncology at Massa-chusetts General Hospital and Assistant Professor of Radiation Oncology at Harvard Medical School. Dr. Hong presented the sunitinib study results at the Best of ASCO meeting in Boston.

Pancreatic neuroendocrine tumors are often indolent and slowly progres-sive, so it can be difficult to demonstrate an improvement in overall survival through clinical trials in this patient group, Dr. Hong said. “Yet the investiga-tors of the sunitinib study impressively managed to produce an overall sur-vival benefit. They also demonstrated a response rate with this single-agent regimen—while there was no response in the placebo arm.”

“Given how well tolerated sunitinib is, and because it’s already used in oth-er malignancies such as renal cell carcinoma, I think it’s a very encouraging study,” he said. “Ultimately, it’s up to the FDA to decide what to do with these data—whether [sunitinib therapy] could be improved in terms of its use for pancreatic neuroendocrine tumors,” Dr. Hong added. ■

advanced pancreatic endocrine tumors, who had experienced disease progres-sion in the last 12 months, and were not amenable to curative treatment. When the trial closed in April 2009, 171 pa-tients had been randomly assigned to receive either 37.5 mg daily of sunitinib or placebo. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and many had nonfunctioning tumors (48.4% in the sunitinib arm and 51.8% in the pla-cebo group). Numerous patients had distant metastases, primarily in the liver. Yet patients in the placebo group were more heavily pretreated and the median time since their diagnosis was longer than in the sunitinib group.

Along with the trial’s premature closure, these factors made it difficult to reach definitive conclusions about the true efficacy of sunitinib, said Kjell

Oberg, MD, PhD, the discussant at the Annual Meeting. But the trial suggests that sunitinib “offers us a new possibility for treating pancreatic tumors,” he said.

Key ResultsIn the trial, the objective response

rate was 9% and there were no objec-tive responses in the placebo group. After closure of the trial, patients in the placebo group became candidates for open-label sunitinib, Dr. Niccoli said.

The most frequent grade 3 or 4 events on sunitinib were neutrope-nia, hypertension, and hand-foot syndrome, which affected 12%, 9.6%, and 6% of patients who received the medication, respectively. “Most of the toxicities were manageable,” said Dr. Abbruzzese. He also noted that al-most a third of patients on both arms of the study were receiving soma-tostatin analogs concurrently, which did not seem to add to toxicities.

Dr. Abbruzzese noted that most of the patients in the trial did not have high-grade tumors. And for patients with low- to intermediate-grade tumors, who are often asymptomatic, it may be challenging to make the decision of whether or not—and at what point— to introduce a treatment like sunitinib that has some toxicity, Dr. Abbruzzese

said. “The fact that there’s a survival benefit does give me some comfort about introducing this agent earlier rather than later,” he said. “Yet I think it’s going to take a little time and perhaps some additional studies to understand the best timing for intervention with an agent like sunitinib,” he added. ■

Reference1. Niccoli P, Raoul J, Bang Y, et al:

Updated safety and efficacy results of the phase III trial of sunitib versus placebo for treatment of pancreatic neuroendo-crine tumors. Best of ASCO Meeting San Francisco. Abstract 4000. Presented July 17, 2010, by James L. Abbruzzese, MD.

■ Although it was an underpowered study, the BR.19 trial adds to other recent data showing that gefitinib is not beneficial for patients with early stage or locally advanced NSCLC.

■ The IPASS trial showed improved outcomes for patients with advanced NSCLC who had EGFR mutations, but the BR.19 study indicated that in patients with locally advanced disease, maintenance gefitinib was worse than placebo, even in those patients with EGFR mutations.

■ Gefitinib and other targeted TKIs should be prescribed with caution—even for patients with EGFR mutations—outside of the setting of a clinical trial.

■ Chemotherapy is still the treatment of choice for NSCLC in the adjuvant setting, although upcoming results of trials with targeted agents may help inform treatment decisions.

Gefitinib for Locally Advanced NSCLC

than placebo, even if these patients have an EGFR mutation.1

Trial Halted Early“Although BR.19 was an underpow-

ered study, gefitinib in unselected as well as EGFR mutant patients was not beneficial,” said Heather A. Wakelee, MD, Assistant Professor of Oncology at Stanford University Medical Center, who presented the study’s results at the Best of ASCO Meeting in San Francis-co. “It has yet to be really demonstrated that a targeted agent improves survival in resected non–small cell lung cancer. I strongly recommend against giv-ing EGFR tyrosine kinase inhibitors (TKIs) in this setting even to patients with known EGFR mutations outside of a clinical trial,” she said.

Researchers conducting the BR.19 study, begun in 2002, planned to ran-domly assign at least 1,160 patients with completely resected stage IB-IIIA

NSCLC and a performance status of 0 to 2 to either gefitinib (250 mg daily) or placebo for 2 years. The primary endpoint was overall survival, and secondary outcomes included disease-free survival, toxicity, and evaluation of gefitinib’s efficacy in patients with KRAS mutations, EGFR gene expres-sion by FISH, and EGFR mutation sta-tus. Yet in 2004, the results of the ISEL (Iressa Survival Evaluation in Lung Cancer) trial showed a nonsignifi-

James L. Abbruzzese, MD

Heather A. Wakelee, MD

Lung Cancer


Best of ASCO®

cant improvement in survival—with a hazard ratio of 0.89—in advanced NSCLC patients treated with gefitinib.

The BR.19 trial was finally halted with 503 patients enrolled when the Southwest Oncology Group (SWOG) interim analysis of their 0023 trial in-dicated that maintenance gefitinib was worse than placebo in patients with lo-cally advanced disease. In the BR.19 trial, the median duration of treatment with gefitinib and placebo was less than 5 months, according to Glenn Goss, MD, of the Ottawa Hospital Regional Cancer Centre, who presented the study’s results at the ASCO Annual Meeting. Although the trial did not show that gefitinib had efficacy in local NSCLC, the treatment was well tolerated, Dr. Wakelee said.

Biomarker AnalysisDespite the negative conclusions of

the ISEL and SWOG 0023 studies, the results of the biomarker analysis in the BR.19 trial were eagerly anticipated, ac-

cording to Dr. Wake-lee. However, the BR.19 researchers found that neither the KRAS mutation, EGFR gene expres-sion by FISH, nor

EGFR mutation were prognostic of over-all survival. Only 21% out of the 357 pa-

tients tested had the EGFR mutation, but these patients fared worse on gefitinib (with a hazard ratio of 1.58) than those who were EGFR wild-type. “Although the results are not statistically significant because of small patient numbers, they’re very striking—especially when you con-sider the IPASS data we all heard so much about last year,” Dr. Wakelee said.

Dr. Wakelee noted that chemo-therapy is still the treatment of choice for NSCLC patients in the adjuvant setting, although the upcoming results of several studies—such as the RADI-ANT trial with erlotinib (Tarceva)—may provide further information about the use of EGFR TKIs and the targeted use of chemotherapy, she said. “There’s only a 5% to 10% benefit with chemo-therapy in NSCLC patients, so we have a long way to go toward improving treat-ments,” she said. “We need to look for-ward to information from new adjuvant trials, including some exciting ongoing biomarker studies involving markers of chemotherapy resistance and E1505 with adjuvant bevacizumab,” she said. ■Reference

1. Goss GD, Lorimer I, Tsao MS, et al: A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. Best of ASCO San Francisco. Abstract LBA7005. Presented July 17, 2010, by Heather A. Wakelee.

Adjuvant Gefitinib Fails to Improve Survival in Post-resection Early Lung Cancercontinued from page 6


Dr. Corey Langer of the University of Pennsyl-vania’s Abramson Cancer Study, said the results

of the ambitious BR.19 trial were not definitive but may sound a warning that gefitinib should still be re-garded as an investigational drug, he said. Dr. Langer, Professor of Medicine in the Hematology-Oncology Division and Director of Thoracic Oncology at the Abramson Cancer Center at the University of Penn-sylvania, presented the BR.19 study results at the Best of ASCO Meeting in Boston.

Dr. Langer noted several important limitations to the BR.19 study. As well as being halted early due to the ISEL and SWOG 0023 results, the BR.19 trial was begun before the widespread acceptance of platinum-based therapy for NSCLC in the adjuvant setting. The investigators amended the trial midway to allow adjuvant therapy in order to enhance ac-crual. “The trial was to some extent the victim of external circumstances,” he said. “Because patients were taken off gefitinib fairly early on—and the thera-py was truncated—the trial ended up being inconclusive.”

‘Disturbing’ ResultsYet the results of the BR.19 molecular analysis—particularly the trend toward

poorer outcomes in patients with EGFR mutations who received gefitinib com-pared to those on placebo—were disturbing, Dr. Langer said. Based on the IPASS trial results, many researchers and clinicians expected that patients with EGFR mutations in the BR.19 study would have more favorable outcomes, he said.

“The results of the study have to give us pause about the assumption that EGFR TKIs work in EGFR-mutated patients in all settings,” he said. “The only setting where they seem to have meaningful benefit is in advanced disease,” he said. Yet, Dr. Langer noted that only a small number of patients with EGFR mutations were included in the BR.19 molecular analysis, and negative out-comes with only a few could have skewed the results, he said. “It would be interesting to see if there were any prognostic features in EGFR-mutated pa-tients that distinguished those who did worse on gefitinib vs those who did not,” he added. ■

Corey Langer, MD

Coming in the November 2010 issue of ■ Comprehensive Coverage of Best of ASCO® 2010, Boston and San Francisco

■ News from the 35th ESMO Congress

■ Important Interviews and Expert Perspectives

■ TAP Caucus: Maintenance Treatment after First-line Therapy in NSCLC: Yes or No?

■ Plus, Direct from ASCO, Oncology Drug News, and much more

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

See page 42

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500,000 PATIENT YEARS Proven clinical profileEfficacy comparable to tamoxifen in head to head trials

ALREADY ACTIVEParent compound binds to and blocks estrogen receptors

UNIQUE METABOLISMMetabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTONNo known drug interactions with SSRI antidepressants

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

Please see full prescribing information on the following page.

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

Important safety information:

FARESTON® (toremifene citrate) tablets

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

and the molecular formula is C26

H28

CINO • C6H

8O

7. The molecular weight of toremifene citrate is

598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL.

FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied. Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European NordicTreatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40No. Patients 221 215 157 149 214 201ResponsesCR1 + PR2 14+33 11+30 7+25 3+28 19+48 19+56RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3Difference in RR 2.2 -0.4 -6.095% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1Time to Progression (TTP)Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2Hazard Ratio (TAM/FAR) 1.01 1.02 0.8095% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00Survival (S)Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7Hazard Ratio (TAM/FAR) 0.94 0.96 0.9495% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.221CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median

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

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

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly. There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended. Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum. Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice. Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses. Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS). Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS). Pediatric use: There is no indication for use of FARESTON in pediatric patients. Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

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

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%)CardiacCardiac Failure 2 (1) 1 (<1) - 1 (<1) 2 (1) 3 (1.5)Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) - 1 (<1)Arrhythmia - - - - 3 (1.5) 1 (<1)Angina Pectoris - - 1 (<1) - 1 (<1) 2 (1)Ocular*Cataracts 22 (10) 16 (7.5) - - - 5 (3)Dry Eyes 20 (9) 16 (7.5) - - - -Abnormal Visual Fields 8 (4) 10 (5) - - - 1 (<1)Corneal Keratopathy 4 (2) 2 (1) - - - - Glaucoma 3 (1.5) 2 (1) 1 (<1) - - 1 (<1)Abnormal Vision/Diplopia - - - - 3 (1.5) -ThromboembolicPulmonary Embolism 4 (2) 2 (1) 1 (<1) - - 1 (<1)Thrombophlebitis - 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5)Thrombosis - 1 (<1) 1 (<1) - 3 (1.5) 4 (2)CVA/TIA 1 (<1) - - 1 (<1) 4 (2) 4 (2)Elevated Liver Tests**SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17)Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15)Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5)Hypercalcemia 6 (3) 6 (3) 1 (<1) - - -

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm.** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.FARESTON Tablets are identified with TO 60 embossed on one side.FARESTON Tablets are available as:NDC 11399-005-30 bottles of 30NDC 11399-005-01 bottles of 100

Store at 25°C (77°F)excursions permitted to 15-30°C (59-86°F)[see USP Controlled Room Temperature].Protect from heat and light.

Distributed by GTx, Inc.Memphis, TN 38163, USAProduct covered by Orion Product Patents and related patent numbers.© 2004 GTx, Inc.All rights reserved.

1E Rev. 12/2004

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CH3

CH2

CH2COOH

CH2COOHCH2Cl

C CC COOHHO


Best of ASCO®

■ The Dutch multicenter phase III CROSS trial, the largest study to date of preoperative chemoradiotherapy (CRT) in advanced esophageal cancer, found that the combination of presurgical CRT with resection improves overall survival and complete response rate in primary tumors.

■ Patients who received CRT plus surgery were more likely to have R0 resection margins than those who received surgery alone.

■ The combination therapy of paclitaxel, carboplatin, and radiotherapy was well tolerated; just 6.8% of patients experienced major hematologic toxicities and 16%, nonhematologic toxicities of grade 3 or greater.

■ Preoperative CRT with surgery was most beneficial for patients with squamous cell carcinoma, although those with adenocarcinoma experienced improved outcomes as well.

Presurgical Paclitaxel/Carboplatin plus Radiotherapy for Esophageal Cancer

The largest study to date to look at the effects of preoperative chemoradio-

therapy in advanced esophageal cancer has found that a combination regimen of chemotherapy and radiation before resection is superior to surgery alone, according to an abstract presented at the 2010 ASCO Annual Meeting. In the phase III multicenter CROSS trial, in-volving 364 patients in the Netherlands with resectable esophageal adenocarci-noma or squamous cell carcinoma, the median survival of patients who received chemoradiation (CRT) and surgery was 49 months, compared to 26 months for those who received surgery alone. With a median follow-up of 32 months, 70 pa-tients had died in the CRT group vs 97 in the surgery-alone group, and 3-year over-all survival was superior in the CRT arm (HR = 0.67, P = .011)

Data Differed for Squamous Cell vs Adenocarcinoma

“This is a nicely performed trial that suggests that esophageal cancer patients with T2N1 or T3N0-1 tumors should be treated with chemoradiation followed by surgery,” said James L. Abbruzzese, MD, Professor of Medicine, and Chair-man of the Department of Gastrointesti-nal Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Dr. Abbruzzese presented the study’s re-sults at the Best of ASCO Meeting in San Francisco. “The trial supports the authors’ conclusions that chemotherapy with car-boplatin and paclitaxel, combined with radiotherapy does improve survival com-pared to surgery alone,” he said.

Dr. Abbruzzese pointed out that the CRT regimen used in the CROSS trial—paclitaxel with carboplatin and 41.4 Gy

Neoadjuvant Chemoradiation Improves Survival in Patients with Advanced Esophageal CancerBy Barbara Boughton


Theodore Hong, MD, said the CROSS study was notable because of its size and clean execution. The trial also helps establish preoperative chemoradio-

therapy (CRT) as a standard of care for certain patients undergoing resection for esophageal tumors. “It will be viewed as the definitive study of preoperative chemoradiation for advanced esophageal cancer,” said Dr. Hong, Director of Gastrointestinal Radiation Oncology at Massachusetts General Hospital and As-sistant Professor of Radiation Oncology at Harvard Medical School. Dr. Hong presented the CROSS study results at the Best of ASCO Meeting in Boston.

Dr. Hong noted that results of previous studies on preoperative chemora-diotherapy in esophageal cancer have been conflicting—with some showing a benefit for CRT plus surgery, while others have not. Yet all these studies had clear flaws, Dr. Hong said.

Doubly Impressive BenefitWorking with a group of patients representative of those most often treated

for esophageal cancer by oncologists today, the authors managed to meet the primary endpoint of improving median survival. They also showed a signifi-cant 3-year overall survival benefit for CRT, Dr. Hong noted. These findings correlated with a decrease in positive margin rates—a thesis that formed the hypothesis for the trial, Dr. Hong said.

The surgery-alone treatment in the CROSS trial resulted in outcomes that outperformed any results from preoperative chemoradiation in previous stud-ies. So the benefit of CRT in the phase III CROSS study was doubly impres-sive, Dr. Hong said.

Dr. Hong noted that many medical centers have moved toward treating ad-vanced esophageal cancer patients with preoperative chemoradiation, although that choice had been based on conflicting data. “I think this trial removes a lot of the controversy about what should be the standard of care,” he said. ■

radiotherapy—was well tolerated, prob-ably more so than regimens with fluo-rouracil. “I’m impressed with the results of combining carboplatin and paclitaxel with radiation in this patient group,” he said.

Yet Dr. Abbruzzese also noted that CRT with surgery improved outcomes most for patients with squamous cell carcinoma (HR = 0.34), who comprised 23% of patients treated in both arms of the trial. By contrast, those with adeno-carcinoma derived less benefit from CRT combined with surgery (HR = 0.82).

“These results highlight the difficulty of treating patients with adenocarci-noma of the esophagus. In fact, patients with squamous cell carcinomas can be cured with chemoradiation alone with-out surgery,” Dr. Abbruzzesse said. He noted that more research needs to delve into how to improve outcomes for ad-enocarcinoma patients, and that to better understand the impact of various treat-ments, adenocarcinoma patients should be separated from those with squamous cell carcinoma in clinical trials. Combin-ing these two groups in a clinical trial has the potential to confound results, Dr. Ab-bruzzesse said.

Typical U.S. Esophageal Cancer Population

In the CROSS trial, patients had esophageal squamous cell or adeno-carcinoma T1N1 or T2-3Nx, M0. The greatest numbers of patients in the trial had T3N0 or T3N1 tumors, followed by T2N0 or T2N1 tumors. Patients with T1N0 or metastatic disease were excluded. Most patients (74% in both arms) had adenocarcinoma, and the great majority also had distal tumors.

“This really mirrors the population that we’re likely to see in the United States at this time,” Dr. Abbruzzesse said. In the CRT arm, patients received weekly paclitaxel at 50 mg/m2 plus car-boplatin at AUC2 as well as concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy. Patients on the intervention arm underwent surgery within 6 weeks of completion of their CRT regimen. Most patients—85% to 90%—were able to have surgery, even if they had re-ceived prior CRT.

Results indicated that 67% of those on the surgery-alone arm had R0 re-section margins—defined as no tumor within 1 mm of resection margins—while 92.3% in the CRT arm achieved R0 resection margins. Using 158 avail-able resection specimens, the investiga-tors found that 32% of patients on the CRT arm had a pathologic complete response in their primary tumors. The 2-year and 3-year survival rates were 52% and 48% in the surgery-alone arm vs 67% and 59% in the CRT arm. Post-operative morbidity and mortality rates

were similar in both groups, with the greatest percentage due to pulmonary complications or anastomotic leakage.

In the CRT arm, all major toxicities of grade 3 or greater were nonhemato-logic, affecting 16% of patients. Just un-der 7% of patients who received CRT experienced hematologic toxicities. Most toxicities were grade 3, and only two patients experienced grade 4 or 5 toxicities. “These numbers reflect the excellent tolerability of the preop program,” Dr. Abbruzzese said. ■Reference

1. Van Der Gaast A, van Hagen P, Hulshof M, et al: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esopahageal or esophagograstic junction cancer: Result from a multi-center randomized phase III study. Best of ASCO Annual Meeting San Francisco. Abstract 4004. Presented July 17, 2010, by James L. Abbruzzese, MD.

Gastrointestinal Cancer

See page 42


Global Perspective

However, a subsequent placebo-controlled randomized phase III trial named the Iressa Survival Evaluation in Lung Cancer—or ISEL study—did not stratify patient populations ac-cording to Asian vs non-Asian. With an enrollment of 1,692 advanced or metastatic non–small cell lung cancer (NSCLC) patients who had under-gone prior chemotherapy, the ISEL study was designed to investigate the effect on survival of gefitinib as a second- or third-line therapy. Over-all survival was not statistically sig-nificantly different among the entire population (HR = 0.89, P = .087) or among patients with adenocarcinoma (HR = 0.84, P = .089).

Among the 342 patients of Asian origin, however, the median survival was significantly different from that of non-Asian patients (HR = 0.66, P = .01). On the other hand, the sur-vival curves of EGFR tyrosine kinase inhibitor and placebo groups were completely superimposable in Cauca-

arm.) A clear advantage was observed in the gefitinib group among EGFR mutation–positive patients.4 In two other Japanese randomized controlled trials comparing gefitinib vs standard chemotherapy in EGFR mutation–positive patients, gefitinib produced a significantly better PFS than chemo-therapy.5,6

Based on these data, new algorithms for the treatment of NSCLC have been established. The frequency of EGFR mutation is 35% to 40% among East Asian populations vs less than 10% among Caucasian populations. There-fore, the strategy for treating NSCLC differs considerably between East Asians and Caucasians.

Anti-EGFR Antibody: Cetuximab in NSCLC

The First-Line in Lung Cancer with Erbitux (FLEX) trial was designed to demonstrate the effect of first-line cetuximab (Erbitux) combined with cisplatin plus vinorelbine in patients with NSCLC. Cetuximab significantly improved the overall survival (HR = 0.871, P = .0441) of patients with ad-

ever, the criteria were not quantita-tive. A more definitive biomarker is essential for patient selection. How will future clinical trials of cetuximab in Asian patients be conducted? The FDA has not approved the use of ce-tuximab because no useful biomarker for selecting a target population for the drug exists, even though cetux-imab had positive benefits on overall survival. There is, at this moment, no rationale for conducting another clinical trial of cetuximab in Asian patients because post-study subset analysis showed completely negative results in the Asian population.

Bevacizumab in Gastric Cancer

The Avastin in Gastric Cancer (AVAGAST) trial was a random-ized, double-blind, placebo-con-trolled phase III study of first-line capecitabine (Xeloda) and cisplatin plus bevacizumab (Avastin) or place-bo in patients with advanced gastric cancer. The primary endpoint of this study was not met. Heterogeneous efficacy results were obtained in both treatment arms across geographic regions.8 In both arms, the median survival times (for chemotherapy alone and chemotherapy plus beva-cizumab) were better in Asia (12.1 and 13.9 months, respectively) than in Europe (8.6 and 11.1 months, re-spectively) and the Americas (6.8 and 11.5 months, respectively). The hazard ratios for the chemotherapy-plus-bevacizumab group were 0.97 (0.75–1.25), 0.85 (0.63–1.14), and 0.63 (0.43–0.94) in Asian, European, and American patients, respectively.

In Asian patients, the tumor was mainly located in the gastric fundus, and tumors of the gastroesophageal junction accounted for only 6%. The frequency of liver metastasis was higher among Asian patients. The majority (66%) of Asian patients re-ceived second-line therapy. On the other hand, only 31% and 21% of Eu-ropean and pan-American patients, respectively, received second-line therapy. The reason for the difference in the treatment strategy was related to the tumor burden, patient status, medical practice patterns, and phar-macogenomics.

Based on the AVAGAST data, bev-acizumab will not be tested in further clinical trials in Asian countries against gastric cancer, although such trials re-main a possibility in Europe and the Americas.

SummaryRecent large cooperative multina-

tional clinical trials have clarified un-investigated factors that can influence drug effects. Some of these factors can clearly be explained by pharma-cogenomic differences. However, the reasons for these pharmacogenomic differences remain unexplained. Oth-er ethnic differences also cannot yet be clearly explained. Various factors must be kept in mind when conduct-ing multinational trials, and stratify-ing patients according to region is likely to be necessary for the effec-tive use of results pertaining to ethnic differences. ■References

1. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase III trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 Trial). J Clin Oncol 21:2237-2246, 2003.

2. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib on inhibitor of the primary epidermal growth factor receptor tyrosine kinase, in symptomatic patients with NSCLC. A randomized trial. JAMA 290:2149-2158, 2003.

3. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in pre-viously treated patients with refractory ad-vanced NSCLC: Results from a random-ized placebo-controlled, multicenter study (IRESSA Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005.

4. Mok TS, Wu Y-L, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.

5. Maemond M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for NSCLC with mutated EGFR. N Engl J Med 365:2380-2388, 2010.

6. Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with NSCLC harboring muta-tions of the EGFR (WJOG 3405): An open label randomized phase III trial. Lan-cet Oncol 11:121-128, 2010.

7. Pirker R, Pereira JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label ran-domised phase III trial. Lancet 373:1525-1531, 2009.

8. Kang Y-K, Ohtsu A, Van Cutsem E, et al: AVAGAST: A randomized, double-blind placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). J Clin Oncol 28(18S):LBA4007, 2010.

The frequency of EGFR mutation is 35% to 40% among East Asian populations vs less than 10% among Caucasian populations. Therefore, the strategy for treating NSCLC differs considerably between East Asians and Caucasians.

Multinational Trials Reveal Striking Regional Differencescontinued from page 1

sians.3 Although the analysis was pre-planned, these data represent a post-study stratification. Thus, the data were regarded as preliminary in many countries with regard to the approval of regulatory affairs.

The reason the response rate to gefitinib is higher among Asian popu-lations has been explained pharma-cogenomically as the presence of a higher EGFR mutation rate in this population.

The Iressa Pan-Asia Study (IPASS), comparing gefitinib vs standard che-motherapy, including carboplatin and paclitaxel, was conducted only in Asian patients with adenocarcinoma who had not received prior chemo-therapy. These patients were either never-smokers or light smokers. The progression-free survival (PFS) period was significantly longer in the gefitinib arm, although the PFS crossed over at 6 months. (PFS before 6 months was better in the standard chemotherapy

vanced NSCLC when added to plati-num-based chemotherapy.7 A planned subgroup analysis showed a remark-able difference in outcomes between Asian and Caucasian patients, with Asian patients living longer. The medi-an overall survival period among 121 Asian patients was 17.6 months with cetuximab and 20.4 months with che-motherapy alone. On the other hand, the median overall survival periods of these treatment groups were 10.5 and 9.1 months, respectively, among 946 Caucasians.

Although the Asian population had better prognostic factors, such as higher percentages of adenocarcino-ma, females, and never-smokers, this huge difference is difficult to explain. In addition, Asian patients were more often treated with an EGFR tyrosine kinase inhibitor after the protocol treatment. In this study, the use of cetuximab was restricted to patients whose tumors expressed EGFR; how-


News

more efficacious than the results we quote from traditional chemotherapy studies to justify the use of neoadju-vant treatment,” Dr. Ellis said.

The breast-conservation rate was 83% for women considered marginal for breast-conserving surgery at baseline, and successful breast conservation was seen even in patients deemed inoperable

The study evaluated an ER-rich population (Allred score* of 6–8) with stage II/III breast cancer and median tumor size of 4.0 cm. The 374 women were randomly assigned to 16 weeks of daily exemestane, 25 mg; letrozole (Femara), 2.5 mg; or anastrozole, 1 mg. In the intent-to-treat analysis, clinical response rates were 60.5% for exemes-tane, 70.9% for letrozole, and 66.7% for anastrozole; per-protocol response rates were 69%, 79.3%, and 77%, respectively. Differences between the agents were not considered clinically significant, based on equivalent surgical outcomes, Dr. El-lis said.

These response rates are clearly higher than those achieved in other neoadjuvant studies, which may be due to better patient selection.

so impressive, although the interesting thing is that we still saw wide variation in response,” he said. “ER level alone is an insufficient predictive biomarker.”

Using Ki67 to DifferentiateIt appears that Ki67, the prolif-

eration index, may be another piece to the puzzle. In another study pre-sented at ASCO’s Annual Meeting (the GEICAM/2006-03 trial), Spanish inves-tigators concluded that chemotherapy is more effective than endocrine therapy in women with localized luminal breast cancer—particularly those with “luminal B” disease, as indicated by high Ki67 lev-els. This conclusion was based on clinical response rates of 66% with chemother-apy (epirubicin/cyclophosphamide/docetaxel) vs 48% with endocrine ther-apy (exemestane plus goserelin [Zola-dex] for premenopausal women).3 Rates of breast-conserving surgery were 51% with chemotherapy and 65% with hor-monal therapy. Grade 3/4 toxicity was significantly more common with chemo-therapy—47% vs 9%—reported Emilio Alba, MD, of the Hospital Universitario Virgen de la Victoria, Málaga, Spain.

Dr. Ellis, who was familiar with the GEICAM/2006-03 study, pointed out, however, that its eligibility criteria differed from ACOSOG Z1031 because of the inclusion of premenopausal women. Re-

hort B). Patients will receive 2 weeks of endocrine therapy, and then have tumors biopsied to measure Ki67. Those with a Ki67 level of 10% or less will continue on preoperative endocrine therapy, whereas those with a Ki67 greater than 10% will switch immediately to neoadjuvant che-motherapy or undergo surgery, as this is considered a marker of early treatment resistance (Fig. 1).

“We presented data at San Antonio last year4 showing that if you successfully suppress Ki67 at 2 weeks, you enrich for endocrine therapy responders, but if the proliferation index is still high despite the use of a potent aromatase inhibitor, you identify nonresponders,” he said.

He added that his group has found that patients with a node-negative, small, persistently ER-positive tumors with a fully suppressed Ki67 after neoadjuvant endocrine therapy have extremely low rates of recurrence and resemble patients with a complete pathologic response to chemotherapy.5 This subset of the Co-hort B study, therefore, will not receive adjuvant chemotherapy.

Using this approach, he predicted that treatment decisions could be straightfor-ward for about half the ER-positive clini-cal stage II/III population with a group of about 25% who definitely do not need chemotherapy and 25% who definitely do. “By assessing the patient’s respon-siveness to endocrine therapy using a

simple algorithm based on pathologic stage, ER, and Ki67, sensible decisions regarding the need for further systemic therapy can be made,” he said. ■References

1. Ellis MJ, Buzdar A, Unzeitig GW, et al: ACOSOG Z1031: A randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer. 2010 ASCO Annual Meeting. Abstract LBA513. Presented June 7, 2010.

2. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmeno-pausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12:1527-1532, 2001.

3. Alba E, Calvo L, Albanell J, et al: Chemotherapy versus hormone thera-py as neoadjuvant treatment in luminal breast cancer: A multicenter, randomized phase II study (GEICAM/2006-03). 2010 ASCO Annual Meeting. Abstract 500. Pre-sented June 6, 2010.

4. Ellis MJ, Luo J, Tao Y, et al: Tumor Ki67 proliferation index within 4 weeks of initiating neoadjuvant endocrine therapy for early identification of non-responders. 2009 Annual CTRC-AACR San Antonio Breast Cancer Symposium. Abstract 78. Presented December 12, 2009.

5. Ellis MJ, Tao Y, Luo J, et al: Outcome prediction for estrogen receptor–positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 100:1380-1388, 2008.

Fig. 1: Design of Cohort B in ongoing study Z1031. AI = aromatase inhibitor; CR = complete response; PEPI = preoperative endocrine prognostic index. Courtesy of Matthew J. Ellis, PhD, MB, BChir, ACOSOG Z1031 Study Chair.

Exemestane

Letrozole

Anastrozole

2-4 weekbiopsy for

Ki67 testing

Ki67 = 10%Continue Al

therapy

Ki67 > 10%Chemotherapyor immediate

surgery

PEPI score 0Path stage 1/0No chemotherapy

PEPI > 0Path stage > 1treatmentdiscretionary

Adherence withrecommendation forno chemotherapy on

PEPI score 0 stage 1?SURGERY

FOLLOW

Path CR rate?

SURGERY

FOLLOW

■ For ER-rich tumors, endocrine therapy may be a more effective neoadjuvant approach than chemotherapy.

■ In ACOSOG Z1031, clinical response rates exceeded 60%, and the breast-conserving surgery rate was 51%.

■ Ki67 > 10% after 2 weeks of endocrine therapy may predict for endocrine-resistant tumors, and chemotherapy may be more beneficial.

Neoadjuvant Endocrine Therapy for Breast Cancer

Neoadjuvant Endocrine Treatment Makes Sense for Estrogen Receptor–rich Breast Tumorscontinued from page 1

*Allred score = percent-staining score (0–5 scale) + intensity-of-staining score (1–3 scale).

Visit The ASCO Post website at:

ASCOPost.com

New!

gardless, he added, the findings were not contradictory. “If you drill down on the GEICAM data and just look at the post-menopausal subset (54% of patients) you see that those with a low baseline Ki67 have similar outcome for chemotherapy vs endocrine therapy,” he noted.

In fact, he added, Ki67 may prove to aid in personalizing neoadjuvant treat-ment, a hypothesis that is being tested in a follow-up of ACOSOG Z1031 (Co-

“One thing we learned from the pre-vious P024 trial of letrozole2 is that clini-cal response is clearly related to ER level. We therefore set an Allred score of 6 to 8 as criteria for eligibility, so Z1031 was a strongly ER-rich group. We think this explains why our surgical outcome is


Global Perspective

Expert Panel: Need to Intensify Cancer Care in Poorer Countriescontinued from page 1and middle-income countries, making cancer a leading cause of mortality in these as well as more entitled areas, the authors noted.

In addition to preventing new can-cers, much more needs to be done to close the gap in cancer survival rates between developed and developing countries. Case fatality from cancer is estimated to be 75% in countries of low income, vs 46% in countries of high in-come, they said.

Dr. Farmer and colleagues noted that in developing countries, awareness of cancer risk factors is growing but atten-

tion to early detec-tion and screening remains low. In addi-tion, cancer still car-ries a social stigma, and financial barriers to prevention and

treatment remain formidable. “Thus, the world faces a huge and largely unper-ceived cost of inaction around cancer in developing regions, which merits an im-mediate and large-scale global response,” the report stated. “Yet, only a small pro-portion of global resources for cancer are spent in countries of low and middle income…an estimate of 5%. By contrast, these countries together account for al-most 80% of the disability-adjusted life-years lost worldwide to cancer.”

“GTF.CCC calls for immediate ac-tion in the face of existing needs,” the report stated. To skeptics, the report contended, “Successful examples of programs show that effective diagnosis and treatment can be introduced even in rural areas of low-income countries in which specialized services are absent.”

Three Changes ProposedThe focus, they asserted, should be

on cancers that can be prevented, cured or, if nothing else, palliated. To this end, three changes were formally proposed: ■ Simultaneous implementation of

large-scale demonstration programs to define and build new infrastructure, train health professionals and para-professionals, and harness technol-ogy and telecommunications to over-come on-site limitations in resources;

■ Design and implementation of re-gional and global pricing and procure-ment mechanisms to facilitate collec-tive negotiation of reduced prices for essential services, drugs, and vaccines;

■ Implementation of innovative fi-nancing mechanisms, which should decisively expand the financial re-sources available for the mission. Mary Gospodarowicz, MD, Pro-

fessor and Chair of Radiation Oncol-ogy at the University of Toronto, noted the partnership between the global task force and the Union for International Cancer Control (UICC), a consortium of 300 member organizations from 100 countries for which Dr. Gospodarow-

A Case Model from Fred Hutchinson Cancer Research Center

The next mission for the global task force is to develop models that will be vehicles for accomplishing the goals set by the committee, said Julie

Gralow, MD, who is involved in a model being exercised at Fred Hutchin-son Cancer Research Center, Seattle. The goals include not only health-care delivery but training of providers, negotiations for cheaper drugs, and other components of cancer care.

In developing countries, oncologists are in very short supply. “Just a few years ago I was told there was just one practicing medical oncologist for the whole country of Uganda,” Dr. Gralow said. “We know that in rural areas, therefore, much of the cancer care will have to be delivered by nononcolo-gists. It may be that a few oncologists will be used for making treatment deci-sions for a given city or even country, but others will actually deliver the care in the villages. Models for this will need to be developed.”

Fred Hutchinson is in the fourth year of a program, led by infectious dis-ease expert Corey Casper, MD, upon which one model will be based. The center partners with the Uganda Cancer Institute to train physicians who have some internal medicine training but little oncology experience. After a year spent in Seattle, the physicians return to Uganda but their relationship with Fred Hutchinson continues.

“The Hutchinson Center recently obtained a grant for monthly teleconfer-ences in which oncologists on both ends discuss topics about how this tumor would be treated here, and also over there,” Dr. Gralow said. “What are the minimum standards of treatment, and what else would we do if we had the resources? We believe this can be a model for adapting cancer care to available resources, which will be an important aspect of this mission,” she added. ■

ress) that discusses concrete ways these goals can be accomplished. “We are developing a plan of action that out-lines evidence, tools, and innovative strategies for presentation to and use by policymakers, Ministers of Health, and the global health community, with examples of programs that have worked in other settings. We understand that each country makes its own decisions about allocation of resources, and the idea is not to focus on cancer to the ex-clusion of other diseases and compete for the same pool of money, but to raise awareness about health issues across the spectrum. We don’t want to single out cancer. Our hope is to strengthen health systems across the board.”

Dr. Gospodarowicz added that there is a need to ensure that the pro-gram is “scalable,” ie, fits the needs of the individual countries.

“The need is huge and we must in-crease access, but Western countries cannot just go into these countries and provide the care,” she said. “We need to build whole cancer systems within these countries so that they can man-age their own care.” ■

Reference1. Farmer P, Frenk J, Knaul FM, et al:

Expansion of cancer care and control in countries of low and middle income: A call to action. Lancet. August 13, 2010 (epub ahead of print).

We need to build whole cancer systems within these countries so that they can manage their own care.

– Mary Gospodarowicz, MD

Dr. Julie Gralow with pediatric patients at Uganda Cancer Institute. Courtesy of Julie Gralow, MD.

See page 42

Global Task Force OrganizedThis “5/80 cancer disequilibrium”

prompted several Harvard faculty members to initiate the Global Task Force on Expanded Access to Cancer Care and Control in Developing Coun-tries (GTF.CCC). Its mandate is to de-sign and implement global and regional initiatives for financing and procure-ment of affordable cancer drugs, vac-cines, and services, and, through local partners, to develop and apply innova-tive service delivery models.

icz is President-Elect (2012). The aims of the task force fit nicely with those of the UICC, and were presented recently during the World Leaders Summit at the UICC semiannual global meeting in Shenzhen, China, she said. (An in-terview with Dr. Gospodarowicz on the UICC agenda will appear in a future is-sue of The ASCO Post.)

Moving ForwardDr. Gralow said the next step is to

complete a white paper (now in prog-

Supportive care: The most common initial MDS treatment90% of patients with newly diagnosed myelodysplastic syndromes (MDS) present with anemia, and most patients eventually become red blood cell (RBC) transfusion dependent.1 For years, MDS was treated with best supportive care—RBC or platelet transfusions and antibiotics.2 With the advent of hematopoietic growth factor therapy, supportive care expanded to include erythropoiesis-stimulating agents (ESAs), with or without G-CSF,† which were used to reduce the need for transfusions.3,4

Survival decreases with increasing transfusion requirements5

Therefore, it is critical to achieve transfusion independence in patients with transfusion- dependent MDS. While ESAs can effectively relieve the symptoms of anemia, they may not be sufficient to provide RBC transfusion independence in all MDS patients.6-9 Some of your patients with lower-risk MDS may need treatment other than growth factors (GFs).

Use baseline serum erythropoietin (sEPO) levels to guide treatment decisionsBecause the response to ESAs declines with increasing baseline sEPO levels, it is critical to measure endogenous levels of erythropoietin before initiating treatment with ESAs. As many as 85% of patients with MDS have elevated baseline sEPO levels,10 making them less likely to respond to growth factors. Patients with high sEPO levels (>500 U/L) and high transfusion needs (≥2 RBC units/month) have a low chance of response to erythropoietin.3 Current treatment guidelines recommend that the determination of baseline sEPO levels should be a required part of the initial evaluation of patients with cytopenias.11

©2010 Celgene Corporation 07/10 CELG10174T

* MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk MDS per International Prognostic Scoring System (IPSS).

† G-CSF, granulocyte colony-stimulating factor. Growth factor therapy includes ESA ± G-CSF or granulocyte/macrophage (GM)-CSF.3

Clinical challenge: Treatment selection for patients with lower-risk MDS*

23%Chance of

responding to ESAs‡

74% 7%

References: 1. Italian Cooperative Study Group For rHuEpo in Myelodysplastic Syndromes. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998;103:1070-1074. 2. Nimer SD. ASH 50th anniversary review: Myelodysplastic syndromes. Blood. 2008;111(10):4841-4851. 3. Sekeres MA, Fu AZ, Maciejewski JP, Golshayan A-R, Kalaycio ME, Kattan MW. A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer. 2007;109(6):1125-1132. 4. Fenaux P, Kelaidi C. Treatment of the 5q- syndrome. American Society of Hematology Education Program–Myelodysplastic Syndromes. Hematology. 2006;192-198. 5. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica. 2006;91(12):1588-1590. 6. Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106(3):803-811. 7. Miller KB, Kim HT, Greenberg P, et al. Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone in the treatment of myelodysplastic syndromes (MDS): results of the ECOG-CLSG trial (E1996). Blood. 2004;104(11):24a. Abstract 70. 8. Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2004;128(2):204-209. 9. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120(6):1037-1046. 10. Hofmann W-K, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16. 11. National Comprehensive Cancer Network®. Myelodysplastic Syndromes. V.2.2010. NCCN Clinical Practice Guidelines in Oncology ™.

If your patients have a predicted intermediate or poor response to ESAs, it may be appropriate to consider non-growth factor therapies.3

‡ The Hellström-Lindberg study defined complete erythroid response as an increase in hemoglobin (HgB) to ≥11.5 g/dL. Partial response was defined as an increase in HgB of ≥1.5 g/dL in patients with anemia who are not transfusion dependent, and for RBC transfusion-dependent patients, a stable HgB level for ≥4 weeks and transfusion independence.9

Consider baseline sEPO levels and transfusion burden when determining treatment options for your RBC transfusion-dependent patients with lower-risk MDS. It is also important to continually evaluate these patients.

Low (<2 units/month)

Low (≤500 U/L)

High (≥2 units/month)

Low (≤500 U/L)

High (≥2 units/month)

High (>500 U/L)

Two variables can be used to help predict response to growth factor therapy: Baseline sEPO levels and RBC transfusion burden9

Low (<2 units/month)

High (>500 U/L)

POORINTERMEDIATEGOOD

sEPO Level

Transfusion Requirement

Adapted from Hellström-Lindberg et al (2003).9

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The Ascot Post


Direct from ASCO

The ASCO Cancer Foundation® recently announced three re-

cipients of the 2010 Advanced Clini-cal Research Award (ACRA). Each award provides a 3-year, $450,000 grant to fund investigators who are committed to clinical cancer research and who wish to conduct origi-nal research not currently funded. Grant funds, paid in increments of $150,000 each year, are directed to the sponsoring institution and used toward salary support, supplies, equipment, and travel necessary for the continued pursuit of the recipi-ent’s research project.

Breast CancerIsabelle Bedrosian, MD,

FACS, was awarded the ACRA in Breast Cancer for her research on “Oncogene activation of DNA damage response [DDR] as a bio-marker of breast cancer risk and possible target for prevention.” Dr. Bedrosian, who is Assistant Profes-sor in the Department of Surgical Oncology, Division of Surgery, at The University of Texas M. D. An-derson Cancer Center, and her team will conduct a nested case-control study to determine the association between DDR pathway biomark-ers in normal breast tissue and the development of sporadic invasive

breast cancer. The data from the study, along with epidemiologic risk factors, will be used to con-struct a preliminary risk-prediction model and compare its discrimina-tory power with that of the widely used Gail Model risk-assessment

2010 Advanced Clinical Research Awards AnnouncedSarcoma

The 2010 ACRA in Sarcoma re-cipient, David Kirsch, MD, PhD, is Associate Professor at Duke Uni-versity Medical Center. Dr. Kirsch collaborated with Ralph Weissleder, MD, PhD, to use novel molecular im-

cause of positive margins. The ACRA in Sarcoma grant is supported by the Sarcoma Foundation of America and the Capon family.

Colorectal CancerSanjay Goel, MD, MS, of the Albert

Einstein College of Medicine, Monte-fiore Medical Center won the ACRA in Colorectal Cancer with his project “A Novel Pharmacogenomic-based Therapeutic Approach for Patients with K-ras–mutant Metastatic Colorectal Cancer (mCRC) Using an Oncolytic Reovirus.” With significantly limited therapeutic options for 40% of patients with metastatic colorectal cancer whose disease is mutated, Dr. Goel is hoping to expand options beyond the current two lines of therapy by uncovering the anti-cancer activity of a reovirus/irinotecan combination. Eight colorectal cancer cell lines that demonstrate synergistic cytotoxicity have been identified, and investigators have identified in vitro activity of the reovirus in K-ras mutant cells through clinical research. Dr. Goel is looking to determine whether the combination of reovirus with iri-notecan is clinically valid. The ACRA in Colorectal Cancer is supported by Genentech BioOncology™. ■© 2010. American Society of Clinical Oncology. All Rights Reserved.

Isabelle Bedrosian, MD, FACS Sanjay Goel, MD, MSDavid Kirsch, MD, PhD

tool. They will also investigate the effect of oncogene-induced DNA damage on the transformation of normal mammary epithelial cells, study the role of DNA repair in mitigating this risk of malignant transformation, and attempt to uncover whether the presence of oncogene-induced DNA damage in mammary epithelial cells sensitizes these cells to therapy-inhibiting DNA repair pathways. This award is supported by The Breast Cancer Research Foundation (BCRF).

aging techniques to detect sarcoma in genetically engineered mice during surgery. With the grant, he hopes to bring into the operating room a de-vice that detects microscopic residual disease remains with greater sensitiv-ity and a wider field of view. To do so, he will conduct clinical trials to test the safety and efficacy of the device in humans. If successful, this technology could help surgeons avoid prescrib-ing unnecessary radiation treatment for patients and reduce the number of reoperations and reexcisions be-

As part of ASCO’s Leadership Development Program, the 10

early-career oncologists selected for the inaugural class of 2009–2010 split into three teams to work on as-signed projects designed to address specific challenges facing ASCO. The teams presented preliminary reports to the ASCO Board of Directors in June, and their findings and recom-mendations will be reviewed by the relevant committees before they are approved.

Team 1: Effectively Addressing Young Oncologists’ Learning Styles

To help ensure that ASCO re-mains in the forefront as the provider of oncology education for genera-tions to come, the team researched how learning styles are changing

and conducted a survey of oncology fellows.

Currently, 30% of ASCO mem-bers are younger than 40 years of age—part of Generation X. They were raised with technology, value social and professional interaction with peers, and prefer straightfor-ward, factual information. Future ASCO members, ages 10–28, are the Millennial Generation—team-ori-ented, comfortable with technology and multitasking, and easily bored.

Younger oncologists’ learning modes call for personal contact (networking) and increased guid-ance in sifting through and critically analyzing information. According to the team, incorporating more tech-nologic innovations and increasing audience participation at meetings could enhance education. The team

suggested gradually increasing the use of social media, including devel-oping an “ASCOpedia”—a wiki web-site that has information about can-cer sites, reviews and updates from leaders, an interactive chat feature, and weekly or monthly case presen-tations. They suggested increasing social media applications that could be used to query fellows, involve in-ternational oncologists in real time, have ASCO Facebook pages by dis-ease site, and provide immediate clinical case feedback.

Team 2: Improving Cancer Care in Developing Countries

After researching the cancer bur-den and barriers to cancer care in low- and middle-income countries (LMCs)—defined by the World Bank as having an income per cap-

New Ideas/Tactics for ASCO Proposed by Future Leadersita between $976 and $3,855—this leadership development team out-lined action steps to be taken in three areas:

Awareness: Offer a session every year at ASCO’s Annual Meeting on challenges in cancer care in LMCs and publish a manuscript based on this session in the ASCO Education-al Book.

Practice: Publish resource-ap-propriate guidelines (beginning with cervical cancer guidelines), create educational curricula for midlevel providers, and partner with govern-ment and nongovernment organiza-tions to increase the trained work-force.

Innovation: Establish an ASCO grant for innovation in cancer con-trol in LMCs, and create a cross-functional ASCO Global Health


Direct from ASCODirect from ASCO

Direct your patients to Cancer.Net (www.cancer.net), ASCO’s

patient information website, to learn what the research highlighted at the 2010 Breast Cancer Symposium means for patients. Also, encourage them to read Cancer.Net’s Guide to Breast Cancer (www.cancer.net/breast), which provides compre-

Help Your Patients Understand Research from the Breast Cancer Symposium

Task Force that could link various ASCO committees to coordinate these efforts strategically.

Team 3: Increasing ASCO Membership Recruitment and Retention

This team analyzed the recruit-ment methods ASCO uses and attri-tion rates of ASCO members within several categories: (1) member type, (2) subspecialty, (3) practice type, and (4) ASCO grant recipients. They suggested recruitment tactics such as making brochures, grants, and aware-ness campaigns more oriented to subspecialties and possibly bundling registration fees for ASCO’s Annual Meeting and subspecialty meetings.

The team found that although ASCO’s overall membership reten-tion is very high (96.3%), retention among Active-Junior members is lower (88%), with the highest attri-tion being among academic hema-tologists/oncologists.

Specific steps suggested to address retention of Active-Junior members are to survey them about how ASCO can serve them better, increase their opportunities for active participa-

tion in ASCO through committee appointments, and increase their awareness of the career development track at the Annual Meeting.

The team concluded that Active-Junior members need more opportu-nities to serve on ASCO committees; ASCO needs to increase activities to address issues specific to early-career oncologists (with a focus on the aca-demic basic science community); and subspecialists need to be made aware that they will be well served by participating in ASCO, includ-ing having opportunities to obtain grants.

Participants in the yearlong Lead-ership Development Program are selected from applicants who have completed their subspecialty fellow-ship between 5 and 10 years ago. In addition to the team projects, the program includes networking with ASCO leaders and staff, a leadership boot camp where participants gain skills in communication and conflict resolution, and experience in politi-cal advocacy. ■© 2010. American Society of Clinical Oncology. All rights reserved.

1. Population-Based Longitudinal Study of Follow-Up Care for Breast Cancer Survivors Eva Grunfeld, et al 6(4):174

2. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer M. Elizabeth H. Hammond, et al 6(4):195

3. Practice and Productivity of Physician Assistants and Nurse Practitioners in Outpatient Oncology Clinics at National Comprehensive Cancer Network Institutions Jennifer M. Hinkel, et al 6(4):182

4. ASCO Clinical Practice Guideline on Uses of Serum Tumor Markers in Adult Males With Germ Cell Tumors Timothy D. Gilligan, et al 6(4):199

5. Capecitabine and Temozolomide: Design, Implementation, and Preliminary Outcomes From a Pilot Project to Ensure Safe Prescribing of Oral Chemotherapy Aminah Jatoi, et al 6(4):210

What’s Hot in JOP Top 5 most-accessed articles recently published in

Journal of Oncology Practice

jop.ascopubs.org

Filling the Gap: Development of theOncology Nurse PractitionerWorkforce

“Developing new strategies for oncology care delivery by increasing thenumbers and expanding the roles of nonphysician practitioners, such asnurse practitioners (NPs) and physician assistants (PAs), is criticallyimportant to meet the current and potential cancer care needs of theUS population.”

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

Ensuring Quality Cancer CareThrough the OncologyWorkforce“There is a crisis in the oncology workforce. Health professionals . . . areexperiencing significant workforce shortages . . . because of the rapidlygrowing population of Americans requiring cancer care, an aging oncologyworkforce, and inadequate numbers of newly trained workers. This mis-match between supply and demand for cancer care could threaten patientcare, safety, and quality.”

By Laura Levit, JD, et al

Role of Advanced Nurse Practitionersand Physician Assistants inWashington State

By Jonathan C. Britell, MD

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

Physician Assistant Perspective on theASCO Workforce Study Regarding theUse of Physician Assistants andNurse Practitioners

By Maura Polansky, MS, PA-C, et al

Georgia Society of Clinical OncologyForms a Patient Navigator Affiliate

Basic Steps to Building a ResearchProgram

By Allison Baer, RN, BSN, et al

A m e r i c a n S o c i e t y o f C l i n i c a l O n c o l o g y

Journal ofOncology

PracticeT H E A U T H O R I T A T I V E R E S O U R C E F O R O N C O L O G Y P R A C T I C E S

V O L U M E 6 I S S U E 1 J A N U A R Y 2010

http://jop.ascopubs.org

hensive information about risk fac-tors, diagnosis, staging, treatment, side effects, and current research, among other topics. In addition to the online guide, printed versions are available through the ASCO Book-store (www.cancer.net/ordermateri-als), along with one-page fact sheets about breast cancer. ■© 2010. American Society of Clinical Oncology. All Rights Reserved.

How to ApplyFor application forms and complete application criteria for all three awards, visit The ASCO Cancer Foundation website at www.ascocancerfoundation.org

and click on “Awards.” For further information about the Diversity in Oncology Initiative, please e-mail [email protected].

© 2010. American Society of Clinical Oncology. All Rights Reserved.

Application Period Loan Repayment Program (LRP) . September 16 – December 16, 2010 Resident Travel Award (RTA) October 31, 2010 – January 31, 2011 Medical Student Rotation (MSR) October 31, 2010 – January 31, 2011

The ASCO Diversity in Oncology Initiative, funded by Susan G. Komen for the Cure®


Direct from ASCO

Multidisciplinary, international, the latest clinical and trans-

lational research. These are terms used by Program Committee Chair Mitchell Posner, MD, to describe the Gastrointestinal Cancers Sym-posium to take place January 20–22 at the Moscone West building in San Francisco. Asked to name the most compelling reason for someone to at-tend this meeting, Dr. Posner replied, “It provides the most up-to-date sci-entific and clinical advances in the treatment of gastrointestinal (GI) cancer—it marries the science to the clinical management of patients.”

ASCO joins its Symposium co-sponsors, the American Gastroen-terological Association Institute, the American Society for Radiation On-cology, and the Society of Surgical Oncology in inviting professionals interested in GI cancers to attend the 2011 Symposium.

Interaction among Participants a Hallmark

Audience participation in ses-sions: The Program Committee has created a meeting structure that features ongoing opportunities for attendees to network, share experi-ences, and ask questions and provide feedback about the relevance of the material to clinical management. More educational sessions than ever will include audience interaction technology, through either audience

response systems to poll the attend-ees about key areas, or e-Q&A, which allows participants to submit text or e-mail questions and comments.

Tumor board: Professor David Cunningham of The Royal Mars-den Hospital, London, will chair the case presentation, “How Should Histology Influence the Selection of Treatment in Esophageal Cancer?” A multidisciplinary panel including a medical oncologist, a radiation on-cologist, and a surgeon will discuss two cases contrasting the manage-ment of squamous cell carcinoma and adenocarcinoma.

Meet the Professor: The Sympo-sium will have two Meet the Profes-sor sessions, where four different topics will be presented concurrently. On Friday morning, session options

2011 Gastrointestinal Cancers Symposium to Present Advances in Treatment from World ExpertsJanuary 20–22, 2011, in San Francisco

will be transplantation in hepatocel-lular cancer, chemoradiation therapy and the role of intensity-modulated radiotherapy (IMRT) in pancreatic cancer, treatment of carcinoma of the anal canal, and treatment options for GI stromal tumor (GIST). Friday afternoon offerings are chemopre-vention for colorectal cancer, imag-ing for esophageal cancer, adjuvant therapy in cholangiocarcinoma, and GIST (repeated from the morning).

Research Integrated with Multispecialty Clinical Guidance

If submissions from the last 3 years’ symposia are any guide, re-searchers will submit close to 600 ab-stracts for consideration by the Sym-posium’s review committee. (As The

ASCO Post went to press, abstract submissions were still open.) From these submissions, the Symposium’s poster sessions and abstract oral pre-sentations will present the most cut-ting-edge and relevant research.

In the educational sessions, faculty from around the world will present discussion-based sessions covering prevention, screening, diagnosis, translational research, and multidis-ciplinary treatment of GI cancers. Each of the three days of the Sympo-sium focuses on specific types of GI cancers: ■ January 20: esophagus and

stomach ■ January 21: pancreas, small

bowel, and hepatobiliary tract ■ January 22: colon and rectum

The Gastrointestinal Cancers Symposium is the premier meeting for professionals in this field. Dr. Pos-ner noted, “There are very few places where you can gather the world’s ex-perts who are focused on the treat-ment and optimization of manage-ment of GI cancers. For those who care for patients, it’s the perfect forum for interacting with your col-leagues and learning about present and future strategies.”

For more information and to reg-ister for the Symposium, visit www.gicasym.org/2011. ■© 2010. American Society of Clinical Oncology. All rights reserved.

The Moscone West Building, San Francisco

The ASCO Cancer Foundation®, with support of The Breast Can-

cer Research Foundation (BCRF), has awarded the Comparative Ef-fectiveness Research Professorship (CERP) in Breast Cancer to Patricia A. Ganz, MD, Professor of Medicine and Public Health at the University of California, Los Angeles (UCLA). This award is given to outstanding re-searchers who have made significant strides in their field and are dedicated

This 5-year, $500,000 grant will fund her work, “Improving Outcomes for Breast Cancer Sur-vivors: Measuring the Compara-tive Effectiveness of Survivorship Care Programs within the UCLA-LIVESTRONG Survivorship Cen-ter of Excellence.” Dr. Ganz and her two mentees, a doctoral student and an early-career physician scientist, will examine how well survivorship program interventions align with

The ASCO Cancer Foundation®/BCRF Grant Promotes Comparative Effectiveness Research

to mentoring the next generation of researchers.

ASCO’s recommendations for breast cancer surveillance.

Real-world OutcomesBy focusing on creating and

combining evidence that compares the benefits and risks of alternative treatment methods to prevent, di-agnose, treat, and monitor a clinical condition to improve care, compara-tive effectiveness research examines outcomes in a real-world setting.

Patricia A. Ganz, MD


Direct from ASCODirect from ASCO

Randomized clinical trials, however, examine the efficacy of treatment un-der rigorous and exacting controls. Comparative effectiveness research studies may compare similar compet-ing treatments, different therapeutic approaches, or new interventions with usual care or best practices, Dr. Ganz noted.

This type of research also may in-volve clinical- and population-level registries, outcome data derived from electronic health records, and clinical decision modeling (including cost-effectiveness analyses). Compara-tive effectiveness is being identified as an important part of oncology research, and Dr. Ganz believes it essential that clinical oncology play an active role in defining key clini-cal questions, determining relevant comparative therapeutic strategies, and selecting appropriate outcomes for use in comparative effectiveness research in oncology. “Comparative effectiveness research is important in helping ensure that people with cancer receive the most appropriate therapy,” stated Joseph Bailes, MD, Past-Chair of The ASCO Cancer Foundation Board of Directors.

Dr. Ganz will strive to assist practitioners, patients, and fami-lies in making informed decisions to improve health care with her re-search. “The research planned will examine the quality of post-treat-ment surveillance and survivor-ship care—using ASCO guidelines as the benchmark—by looking at outcomes before and after the survivorship care programs were introduced.”

Diverse Care SettingsThe UCLA-LIVESTRONG Sur-

vivorship Center of Excellence was established in 2006 with funding from the Lance Armstrong Founda-tion. The Center includes four diverse care settings: ■ a matrix-type, NCI-designated

comprehensive cancer center ■ a university-affiliated public hospital ■ a community hospital ■ a large, managed-care medical group

Breast cancer survivors and pa-tients undergoing treatment are the focus and recipients of improved survivorship care in each of these set-tings.

“What we learn from these real-world experiences can translate into knowledge about how best to deliver

care for patients,” Dr. Ganz noted. “I’m thrilled to have the opportunity to carry out this work and honored to be selected by The ASCO Cancer Foundation.” ■© 2010. American Society of Clinical Oncology. All Rights Reserved.

Genitourinary Cancers SymposiumProgress in Multidisciplinary Management

Registration is now open for the GU Cancers Symposium, February 17–19, 2011, in Orlando, Florida.

For more information and to register, visit www.gucasym.org/2011.

(Stimulating Targeted Antigenic Responses To NSCLC)

EMD Serono, Inc. is anaffiliate of Merck KGaA,Darmstadt, Germany


Direct from ASCO

The Oncology Slide Library is now a reality. In response to requests

from members, ASCO has created the Slide Library, which is hosted on the ASCO University website (at www.university.asco.org/slides). The Slide Library contains a growing ar-chive of slides that members can use for patient education, teaching, tu-mor boards, or community presenta-tions. ASCO launched the resource at the 2010 Annual Meeting.

The Slide Library contains tumor images, signaling pathway figures, medical illustrations, and more. The Library has two categories of slides available: a collection of slides drawn from ASCO materials and a collection of slides that users have uploaded.

ASCO-created content: Slides in this category come from ASCO’s vast repository of peer-reviewed con-tent. ASCO’s Education Products Subcommittee selects and keeps the slides current. Updated monthly with additional slides, this collection currently has about 700 slides.

User-created content: Presenters at ASCO meetings and oncologists who have created slides for use in other settings are invited to upload their slides for use by others. By fa-cilitating this clearinghouse of slides, ASCO has created a platform for

ASCO University® Offers Oncology Slide Libraryoncologists to share their expertise and research findings. All the slides added to this collection must be from educational presentations, not com-mercial promotion.

Slides Have Multiple Uses in Practice

One of the early users of the Slide Library is Thomas H. Davis, MD, the Hematology/Oncology Fellowship Director at Dartmouth-Hitchcock Medical Center, who became a sub-scriber at the Annual Meeting. “So far I’ve just downloaded about 20 slides in my specialty area—head and neck

cancer—mostly for education of my own fellows,” Dr. Davis said in July. “It’s a great opportunity to grab some background material. It gives me ac-cess to visual teaching tools that I

can very quickly share by turning my computer around.”

Davis had not yet used the slides with patients, but he thinks they would be very useful for educating patients, for example, about anatomy.

How to Use the Slide LibraryOnce they are logged in to the

website (www.university.asco.org/

slides), ASCO members can browse the slides by topics established in the library’s built-in taxonomy and by meeting content, such as all the slides presented at the Breast Can-cer Symposium. In addition, a search function is available to find slides us-ing a keyword or phrase. The search function identifies and returns slides from both the ASCO content and the user-created content.

While browsing, users can select slides to create one or more of their own personalized slide sets. They can select an entire category of slides at once—such as the 40+ slides under “leukemia”—or they can select slides individually.

ASCO members can browse the slides without subscribing but must subscribe in order to download slides for personal use. A 1-year sub-scription fee is $50, and subscribers may download slides anytime dur-ing that period.

The user-uploaded slides are marked as being from an external source and are downloadable as Pow-erPoint files. The slides drawn from ASCO’s resources are marked as copy-righted by ASCO and are available as an unchangeable fixed image. ■© 2010. American Society of Clinical Oncology. All rights reserved.

Vol 28, No 20 July 10, 2010

OURNAL OFLINICALNCOLOGY

Official Journal of the American Society of Clinical Oncology www.jco.org

JCO

JCO

Comments and Controversies: Research on Early-Stage Carcinogenesis: Are WeApproaching Paradigm Instability? S.G. Baker et al

Editorial: Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: AMismatch? K. Ng et al

Editorial: Defective Mismatch Repair in Colon Cancer: A Prognostic orPredictive Biomarker? D.J. Kerr et al

Editorial: Wrestling With the High Price of Cancer Care: Should We ControlCosts by Individuals’ Ability to Pay or Society’s Willingness to Pay? J.L. Malin

Confirmation of Defective Mismatch Repair As a Predictive Marker for Lack ofEfficacy of FU-Based Adjuvant Therapy in Colon Cancer. D.J. Sargent et al

Comparison of Anticancer Drug Coverage Decisions in the United States andUnited Kingdom. A. Mason et al

Randomized Phase III Trial of Ixabepilone Plus Capecitabine VersusCapecitabine in Patients With Metastatic Breast Cancer Previously TreatedWith an Anthracycline and a Taxane. J.A. Sparano et al

EGFR Inhibitor Gefitinib Added to Chemoradiotherapy in Locally AdvancedHead and Neck Cancer. E.E.W. Cohen et al

Review Article: Emerging Targeted Therapies for Breast CancerR.H. Alvarez et al

Biology Of Neoplasia: Clinical Relevance of Microsatellite Instability inColorectal Cancer. A. de la Chapelle et al

ASCO Special Article: American Society of Clinical Oncology 2009 ClinicalPractice Guideline on Uses of Serum Tumor Markers in Adults With Germ CellTumors. T. Gilligan et al

What’s Hot in JCOTop 10 most-accessed articles recently published in Journal of Clinical Oncology

JCO.org

1. American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer Harold J. Burstein, et al 28(23):3784

2. Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Long-Acting Methylphenidate for Cancer-Related Fatigue: North Central Cancer Treatment Group NCCTG-N05C7 Trial Amanda R. Moraska, et al 28(23):3673

3. Physician As Typist Alok A. Khorana 28(24):3899

4. Phase III Study Comparing Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105 Nobuyuki Yamamoto, et al 28(23):3739

5. Challenge of Managing Cancer-Related Fatigue Eduardo Bruera, et al 28(23):3671

6. Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ Udo Rudloff, et al 28(23):3762

7. Early Warning: An Ailing Canary in the Mine David M. Dilts 28(24):3799

8. Emerging Targeted Therapies for Breast Cancer Ricardo H. Alvarez, et al 28(20):3366

9. Time to Activate Lung Cancer Clinical Trials and Patient Enrollment: A Representative Comparison Study Between Two Academic Centers Across the Atlantic Andrea Wang-Gillam, et al 28(24):3803

10. Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure Michel Duval, et al 28(23):3730

Direct from ASCO

THE 5-YEAR SURVIVAL RATEIS 17% FOR PATIENTS WITHMETASTATIC SOFT TISSUE SARCOMA,YET SIGNIFICANT THERAPEUTICADVANCEMENTS ARE LAGGING.1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. 21003100(5)-ARI

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE

46323Alt_M06DR_Tab_v1 1 5/12/10 10:46 AM


JCO Spotlight

Multivitamin supplementation dur-ing or after adjuvant chemothera-

py failed to improve outcomes in patients with stage III colon cancer who under-went surgical resection. These findings persisted after adjusting for household income, number and amount of multi-vitamins consumed per week (dose ef-fect), consistency of multivitamin use, and selected components of multivita-mins. However, an interaction between multivitamin use and age was found; patients aged 60 or younger appeared to derive benefit from the supplements. Moreover, less fatigue was observed in multivitamin users than nonusers.

evidence to support this practice.2 The present cohort study was part

of a prospective NCI-sponsored Can-cer and Leukemia Group B (CALGB 89803) randomized trial comparing two different adjuvant chemotherapy combinations in patients with stage III colon cancer. The study found no dif-ference in outcomes between the two adjuvant chemotherapy arms.

Vitamin use was determined by self-reports on two questionnaires. For the cohort study, 518 (49.9%) of 1,038 pa-tients reported multivitamin use during adjuvant chemotherapy on the first ques-tionnaire (Q1). Six months after adjuvant chemotherapy, 416 (51.4%) of 810 can-cer-free patients reported multivitamin use on the second questionnaire (Q2).

At a median follow-up of 7.3 years, of the 1,038 patients who completed Q1 shortly after starting adjuvant chemo-therapy, 351 had experienced a disease recurrence and 314 died (Fig. 1). At a median follow-up of 6.5 years, of the 810 patients who completed Q2, 190 had faced a recurrence and 169 died.

No significant difference was seen for the primary endpoint—disease-free survival—or for recurrence-free or overall survival between users of multivitamins and nonusers, either during or after adjuvant chemothera-py. These results remained the same af-ter the investigators adjusted for other predictors of cancer recurrence.

Exploratory AnalysisIn an exploratory analysis, multivita-

min use was associated with improved disease-free survival in younger patients (≤ 60 years), but not in older patients. This effect was not related to family history or to the presence of microsatellite instabil-ity. Additionally, obese multivitamin us-ers (body mass index [BMI] ≥ 30 kg/m2) had significantly improved disease-free survival compared with nonusers, but this effect was not seen in overweight patients (BMI = 25.0–29.9 kg/m2).

“The interactions of multivitamin use with younger age and higher body mass index require confirmation in other studies,” Dr. Ng said.

Multivitamin use was safe and pro-duced no detrimental effects. Further-more, multivitamin use did not increase the frequency of the common grade 3 and higher toxicities associated with chemotherapy, including leukopenia,

Multivitamins Do Not Prevent Recurrence or Death in Patients with Established Colon CancerBy Alice Goodman

Multivitamin use

Log-rank P = .18

NoYes

0.10.20.30.40.50.6

10 2 3 4 5 6 7 8 9 10

Time (years)

C

Ove

rall

surv

ival

(pro

porti

onal

) 0.70.80.91.0

Time (years)

Multivitamin use

Log-rank P = .25

NoYes

0.10.20.30.40.50.6

10 2 3 4 5 6 7 8 9 10

B

Rec

urre

nce-

free

surv

ival

(pro

porti

onal

) 0.70.80.91.0

Time (years)

Multivitamin use

Log-rank P = .26

NoYes

0.10.20.30.40.50.6

10 2 3 4 5 6 7 8 9 10

A

Dis

ease

-free

sur

viva

l(p

ropo

rtion

al) 0.7

0.80.91.0

Fig. 1: (A) Disease-free survival, (B) recurrence-free survival, and (C) overall survival by multivitamin use reported during adjuvant chemotherapy (questionnaire 1). Reprinted with permission from Ng et al.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

Kimmie Ng, MD, MPH

neutropenia, nausea, vomiting, and di-arrhea. As previously noted, an inverse association was found between grade 3 and higher fatigue and multivitamin use.

Dr. Ng noted that advantages of using a cohort within an NCI-sponsored clini-

cal trial included homogeneity of disease stage, standardized treatment and follow-up, routine data collection on prognostic factors, and prospective recording of date and nature of cancer recurrence. Never-theless, selection bias is a potential con-

Colon Cancer

“To our knowledge, this is the first study to examine the impact of multi-vitamin use on survival among patients with established colon cancer. No ben-efit on patient outcome was seen for multivitamin supplementation in this large prospective study of patients with stage III colon cancer. These results are consistent with the National Institutes of Health 2006 conference statement concluding that there is insufficient evidence to recommend for or against use of multivitamins for prevention of chronic diseases,” stated the study’s lead author, Kimmie Ng, MD, MPH, of Dana-Farber Cancer Center, Boston.

Dr. Ng noted that despite these find-ings, further study of the utility of in-dividual vitamins (such as vitamin D) in patients with established colorectal cancer is warranted. The study was published online ahead of print in the Journal of Clinical Oncology.1

Big Business, Little EvidenceAccording to the authors of this study,

multivitamin supplementation is big business in the United States, account-ing for annual sales of more than $20 bil-lion. An estimated 26% to 77% of cancer survivors reported multivitamin use in a systematic review in 2008, despite little


JCO Spotlight


According to Emily Chan, MD, PhD, Assistant Professor of Medicine, GI Oncology, at

Vanderbilt University in Nashville, Tennessee, the multivitamin study by Ng and colleagues does not provide practice-changing new information and has some limitations.

First, studies based on questionnaires have a built-in potential for recall bias with self-reports. “Patients may not remember accurately, and their responses may not be reliable,” she said.

Second, it is not known why these patients were taking multivitamin supplements. Some patients may take supplements be-cause they are eating poorly or have a poor diet; others may take multivita-mins because they are more health conscious and believe that the vitamins are health-promoting, she continued.

Interpreting the Results“On the basis of this study, patients with colon cancer should be aware

that taking multivitamins does not affect cancer outcome. However, they may want to take a multivitamin or specific vitamin supplements if they are defi-cient in certain vitamins,” Dr. Chan said.

The only way to establish the role of multivitamins in this setting is to con-duct a prospective, randomized, placebo-controlled trial, but that is unlikely to be done. “If multivitamins were a real home run, then there would have been a strong consistent signal in this study,” Dr. Chan stated. It is also pos-sible that specific vitamins are beneficial, while others are not, and that a posi-tive signal is not evident because these authors explored multivitamin supple-mentation rather than specific vitamin supplementation. ■

■ Multivitamin supplementation in patients with stage III colon cancer either during or after adjuvant therapy does not influence outcomes.

■ Multivitamin use had no detrimental effects but also did not reduce the frequency or occurrence of chemotherapy-related side effects.

■ This study provides no support for a recommendation for or against use of multivitamins in patients with colon cancer who undergo surgery and adjuvant chemotherapy.

Multivitamins and Colon Cancer

Emily Chan, MD, PhD

founder, because patients who consume supplements often have other health-promoting behaviors.

Further Studies?“We are not planning any further stud-

ies on multivitamins and colorectal cancer survival,” Dr. Ng noted. “However, other dietary lifestyle interventions have shown promise in improving cancer outcomes, including vitamin D, physical activity, and minimization of a Western dietary pat-tern. Further research on these factors is

currently ongoing.”Dr. Ng specu-

lated that it is pos-sible that vitamin D may, in fact, provide real benefit in this

setting. “Standard multivitamin supple-ments contain only a low dose of vita-

min D, and that low dose is usually not sufficient to raise an individual’s blood level of vitamin D to the range believed to be necessary for a beneficial impact on colorectal cancer recurrence and sur-vival,” she commented. ■This study was partially funded by a 2008 ASCO Cancer Foundation Young Investiga-tor Award to Kimmie Ng.

References1. Ng K, Meyerhardt JA, Chan JA, et

al: Multivitamin use is not associated with cancer recurrence or survival in patients with stage III colon cancer: Findings from CALGB 89803. J Clin Oncol. August 30, 2010 (early release online).

2. Velicer CM, Ulrich CM: Vitamin use and mineral supplementation among US adults after cancer diagnosis. J Clin Oncol 26:665-673, 2008.

JCO News

See page 42

A new study of nearly 8,800 women with early-stage breast cancer

found that fewer than half—approxi-mately 49%—completed their full regimen of hormone therapy accord-ing to the prescribed schedule. Inves-tigators found that younger women were particularly likely to discontinue treatment. The findings underscore the need to both better understand the reasons behind such treatment non-compliance and also develop interven-tions to reduce it.

“We were surprised to see that so many young women stopped treat-ment early, despite the fact that the therapy has a proven track record of reducing breast cancer recurrence,” said Dawn Hershman, MD, Associate Professor of Medicine and Epidemiol-ogy at Columbia University Medical Center, New York, who led the study. “Perhaps we need to do a better job of making patients aware that to get the full benefit of treatment, they need to take their medications on time and for the full duration.”

Adherence an Issue in Hormonal Therapy for Breast Cancer, Study Finds

Pharmacy Records ExaminedUp to 5 years of oral hormone ther-

apy (such as tamoxifen and aromatase inhibitors) is frequently prescribed for hormone-sensitive breast cancers, to re-duce the risk of cancer recurrence and death. However, previous small studies have indicated that only approximately 40% to 60% of women finish their rec-ommended course of therapy. In order to provide a more comprehensive perspec-tive, Dr. Hershman and her colleagues examined automated pharmacy records of 8,769 women diagnosed with stage I, II, or III hormone-sensitive breast can-cer between 1996 and 2007. They used the records to identify hormonal therapy prescriptions and refill dates. Each wom-an filled at least one prescription for hor-monal therapy within 1 year of diagnosis. Women used tamoxifen (43%), aroma-tase inhibitors (26%), or both (30%).

The researchers found that women un-der age 40 had the highest risk of discon-tinuing therapy early. By 4.5 years, 32% of all patients in the study had stopped tak-ing their hormone therapy, and of those

who did not stop, only 72% finished on schedule (meaning they took their medi-cation more than 80% of the time).

They found that among women younger than 40 and women older than 75, those who had lumpectomy as opposed to mastectomy and those with other medical illnesses were more likely to discontinue hormonal therapy early. Asian/Pacific Islander ethnicity, a history of prior chemotherapy, being married, and longer prescription refill intervals were associated with com-pleting 4.5 years of hormonal therapy. Longer refill intervals meant fewer chances to not refill prescriptions.

Increasingly Important Problem

“Physicians are often unaware of patient compliance, and this is becom-ing an increasingly important issue in cancer,” Dr. Hershman said. “It’s very disturbing that patients under 40 had the highest discontinuation and non-adherence rates, because those patients have the longest life expectancy. If we

can better un-derstand the is-sues surround-ing compliance with hormonal therapy, this might help us understand why patients don’t adhere to other treatments that are moving out of the clinic and into the home, such as oral chemotherapy, as of-ten as we would like.”

She added that there are several pos-sible reasons for halting therapy early, noting that 13% of the women delayed getting their first prescription refilled. These factors can include the side ef-fects of the therapy, such as joint pain, hot flashes, fatigue, a lack of under-standing of the benefit of the therapy, and high costs of medications and/or insurance copayments. ■This article was published online June 28, 2010, in the Journal of Clinical Oncology.

For a full copy of the article, view this 2D barcode.

See page 42

TORISEL—Significant overall survival benefit as first-line therapy1

Kaplan-Meier curves for overall survival (OS)*—TORISEL vs IFN�1

• Live vaccinations and close contact with those who received live vaccines should be avoided.• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL

therapy has stopped.• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%),

nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).

• In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion.

• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).

• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.

• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the brief summary of the full Prescribing Information on the next page.

References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. Data on file, Pfizer Inc. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

Change expectations

• Studied first-line in patients with ≥3 of 6 preselected prognostic risk factors1

The advanced RCC pivotal study included patients with2

• Clear-cell or non–clear-cell tumor histologyII • Any nephrectomy status

Median duration of treatment was 17 weeks (range 1-126 weeks) for the TORISEL arm and 8 weeks (range 1-124 weeks) for the IFN� arm.1

Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

mTOR=mammalian target of rapamycin.IFN�=interferon alpha.CI=confidence interval.* Time from randomization to death.1† A comparison is considered statistically significant

if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1

‡ Based on log-rank test stratified by prior nephrectomyand region.1

§ Based on Cox proportional hazard model stratified by prior nephrectomy and region.1

II 82% and 82.5% of patients had known clear-cell histology for TORISEL and IFN�, respectively.2

¶ NCCN Category 1 recommendations are based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.3

# TORISEL was approved by the FDA in 2007.1

• Category 1 NCCN recommendation—first-line for poor-prognosis patients3¶

• >3 years experience since FDA approval#

Important Safety Information• TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild

hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN.

• Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.

• Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in

the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of

infections, including opportunistic infections.• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented

with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic

acidosis, bloody stools, diarrhea, and/or acute abdomen.• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred

in patients who received TORISEL.• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy

may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

portant Safety Information

Change expectationsfor overall survival

With the fi rst and only IV mTOR inhibitor indicated for advanced renal cell carcinoma (RCC)1...

TUP100027_ASCO Post_Tabloid_FNL.indd 1-2 8/12/10 4:38 PM

TUP100027_ASCO Post_Tabloid_FNL.indd 3-4 8/12/10 4:38 PM


Psychosocial Oncology

Because of the relatively significant incidence of both clinical de-

pression and debilitating hot flashes (20%–30%), clinicians caring for women with breast cancer who are taking tamoxifen for the treatment or prevention of cancer recurrence are often faced with the need to prescribe antidepressant medications concur-rently with tamoxifen. Over the past 5 years, a growing number of studies have raised questions regarding the interaction of antidepressants and

Do Antidepressants Reduce the Effectiveness of Tamoxifen?By William Breitbart, MD

tamoxifen, particularly the follow-ing question: “Do antidepressants reduce the effectiveness of tamoxi-fen treatment?” At issue is the extent of the clinical impact of cytochrome P450 2D6 (CYP2D6) inhibitors, in the form of several antidepressants (particularly several of the serotonin reuptake inhibitors, or SSRIs) on the effectiveness of tamoxifen.

Tamoxifen and Breast CancerTamoxifen is a selective estrogen

receptor modulator (SERM) used as adjuvant therapy for early-stage, estrogen receptor–positive (ER+) breast cancer in premenopausal wom-en. Other uses for tamoxifen include treatment of metastatic ER+ breast cancer in pre- and postmenopausal women, as well as chemoprevention in women at risk for breast cancer.1,2

The Early Breast Cancer Trialists’ Collaborative Group3 demonstrated

that early-stage breast cancer patients with ER+ disease given tamoxifen for 5 years had a significant reduction in recurrence (an almost 47% propor-tional reduction) and in new breast cancers in the opposite breast (also a 47% proportional reduction). The in-vestigators observed fewer deaths in tamoxifen recipients than in women who did not receive the drug (26% proportional reduction). The survival advantage for women treated with tamoxifen continues to increase up to at least 10 years. In a large chemopre-vention trial4 involving 13,175 women who were determined to be at high risk for breast cancer, tamoxifen signifi-cantly reduced the incidence of inva-sive and noninvasive breast cancer, es-pecially ER+ tumors in both pre- and postmenopausal women.

Tamoxifen and MetabolismClinical benefit in this setting re-

quires conversion of the prodrug tamoxifen into its active metabolites—4-hydroxytamoxifen and endoxifen (4-hydroxy-N-desmethyltamox i-fen)—by cytochrome P450 enzymes, the most clinically relevant of which is CYP2D6. These active metabolites bind to the estrogen receptor 100-fold more readily than tamoxifen,5 and the higher affinity for the recep-tor correlates with cell growth inhibi-tion.6 Decreased CYP2D6 activity, and therefore decreased conversion of tamoxifen to its active metabolites, may be related to allelic (genetic) phenotype variation, or exogenous competitive inhibition of CYP2D6 by medications (eg, antidepressants).

Allelic phenotype variation can be seen in 5% to 20% of the population. More that 80 different alleles of CY-P2D6 have been identified, and many are associated with decreased CYP2D6 activity. These individuals would thus be poorer metabolizers of tamoxifen, and studies have shown that such ge-netically poor metabolizers have sig-nificantly lower serum levels of tamox-ifen than good genetic metabolizers.7 Several subsequent studies examining outcomes in tamoxifen trials for poor genetic metabolizers have been mixed, with some showing increased risk of recurrence and shorter relapse-free survival and others showing no effect or opposite effects.8,9 Clearly, the ques-tion as to whether exogenously coad-ministered CYP2D6 inhibitors, such

as antidepressant medications, signifi-cantly impact the clinical efficacy of tamoxifen is complicated by the fact that the population of women receiv-ing tamoxifen are quite genetically diverse in their innate capacity to me-tabolize tamoxifen.

Many antidepressants are inhibi-tors of the CYP2D6 enzyme system, and thus have the potential to interfere with the metabolism of tamoxifen to its active metabolites (particularly en-doxifen). Table 1 lists the antidepres-sants that are “strong,” “moderate,” or “weak” inhibitors of CYP2D6, or “noninhibitors.” A growing amount of literature has demonstrated that strong CYP2D6 inhibitor antidepressants not only reduce the serum levels of tamox-ifen’s active metabolite endoxifen, but may also significantly interfere with the clinical efficacy of tamoxifen. Mul-tiple studies have demonstrated low levels of serum endoxifen in women on tamoxifen who take strong 2D6 inhibitor antidepressants such as par-oxetine and fluoxetine, and interme-diate levels of serum endoxifen with mild 2D6 inhibitors such as sertraline and citalopram.10-12 The mean plasma concentration of endoxifen was more than twofold higher in women not taking a CYP2D6 inhibitor drug than in women taking a CYP2D6 inhibi-tor drug.7 Thus, the question becomes whether such reductions in endoxifen caused by antidepressants that inhibit CYP2D6 translate into poorer out-comes for women with breast cancer being treated with tamoxifen.

Tamoxifen and Antidepressants

In a 2009 review of the literature on interactions between tamoxifen and antidepressants via CYP2D6, 13 the au-thors found consistent evidence that paroxetine and fluoxetine have large effects on the metabolism of tamoxifen and recommended that these drugs should not be used in conjunction with tamoxifen treatment in breast cancer. Indirect evidence suggests that bupropion also has considerable effects on the metabolism of tamoxi-fen because it is a potent CYP2D6 inhibitor. Safer choices, according to the authors, given a lack of CYP2D6 inhibition, include venlafaxine (Ef-fexor), desvenlafaxine (Pristiq), and mirtazapine. The question remains as to whether these inhibitory effects on

A Woman with Depression on Tamoxifen Therapy

S.M. is a 41-year-old divorced premenopausal woman who was diag-nosed with estrogen receptor–positive, invasive ductal carcinoma,

treated with surgery, adjuvant chemotherapy, and radiotherapy. Tamoxifen therapy was begun to reduce chances of breast cancer recurrence. S.M. tol-erated tamoxifen therapy poorly, primarily complaining of severe depres-sive symptoms. These depressive symptoms were so severe that she con-templated discontinuation of tamoxifen therapy after 3 months.

The patient had a history of recurrent depressive episodes. The first oc-curred 12 years earlier during the postpartum period after the birth of her daughter, and the second occurred after a bitter divorce and custody battle 2 years ago. Both prior episodes of depression had been successfully treated with antidepressant therapy. The first episode resolved with fluoxetine at 20 mg/d, which she continued to take for 18 months. The second episode was successfully treated with sustained-release bupropion at 300 mg/d. Pri-or to the bupropion, trials of mirtazapine and venlafaxine were stopped be-cause of side effects (increased anxiety/agitation and unacceptable weight gain, respectively).

S.M. had stopped taking bupropion approximately 6 months prior to her cancer diagnosis. Upon psychiatric examination, she met criteria for a major depressive syndrome and was thought to be having a recurrent epi-sode of her depressive illness. A mood disorder—depression, secondary to tamoxifen therapy—was also considered. She had clearly responded to fluoxetine and bupropion in the past. However, both of these antidepres-sants are potent CYP2D6 inhibitors and posed a significant risk of inter-fering with the efficacy of tamoxifen therapy. Good CYP2D6 noninhibitor alternative antidepressants (venlafaxine and mirtazapine) had been tried in this patient in the past but were not well tolerated.

The patient was started on escitalopram, a selective serotonin reuptake inhibitor similar in antidepressant action to fluoxetine, which has very mild CYP2D6 inhibitory action. The patient’s depression remitted in 3 weeks with an escitalopram dosage of 20 mg/d. ■

Breast Cancer

William Breitbart, MD



tamoxifen metabolism translate into poorer clinical outcomes.

Several small and large clinical trials over the past few years have examined the issue of antidepressant drug treat-ment effects on the efficacy of tamoxi-fen, in terms of risk of breast cancer re-currence and survival. The results have been primarily mixed, but the major-ity of studies tended to not support a negative impact of CYP2D6 inhibitor use—particularly for SSRIs with mild CYP2D6 inhibition—on breast can-cer recurrence and mortality in women using tamoxifen.14-18

A 2008 retrospective study (N = 368) using data from the Danish Breast Cancer Cooperative Group15 suggested that premenopausal and postmenopausal women with ER+ tumors who used citalopram while on tamoxifen did not have a higher rate of recurrence than women who never used citalopram while on tamoxifen. In this study, citalopram exposure was defined as the use of citalopram or its S-stereoisomer escitalopram. The data also supported the conclusion that citalopram does not directly affect risk of breast cancer recurrence in estrogen receptor–negative (ER–) and tamoxi-fen-naive or ER+ and tamoxifen-treat-ed breast cancer patients.

In 2010, Lash and colleagues16 conducted a population-based, case-


controlled study in Denmark and found no increased risk of breast can-cer recurrence in women on tamoxi-fen and concomitant citalopram or escitalopram. A recently published Dutch study, presented at the 2009 ASCO Annual Meeting,18 found no association between the CYP2D6 in-hibitors paroxetine and fluoxetine and

breast cancer recurrence in patients on tamoxifen. This study was based on a small sample of only 18 cancer pa-tients and suffers from the same small sample size and power issues common to several other negative trials noted above.14,17

By contrast, several studies have re-ported a higher rate of breast cancer re-

currence and mortality among women re-ceiving SSRIs, which are potent CYP2D6 inhibitors. In a 2010 Canadian popula-tion-based cohort study of 2,430 women treated with tamoxifen,19 paroxetine use was associated with increased breast can-cer mortality, which increased further with more prolonged concurrent use. A

Jimmie Holland, MD, Guest Editor

Providing care beyond medical treatment, the interdisciplinary field of psychosocial oncology addresses the psychological, social, and emotional health of the patient with cancer. On an occasional basis, The ASCO Post will explore the realm of psychosocial oncology with a column guest edited by Jim-mie Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center, New York.

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U.S. population study by Aubert and col-leagues20 presented at the 2009 ASCO Annual Meeting found an increased risk of breast cancer recurrence among wom-en concurrently taking tamoxifen and the more potent CYP2D6 inhibitor SSRIs paroxetine, fluoxetine, and sertraline. No such increase in breast cancer recurrence was found for SSRIs that are less potent inhibitors of CYP2D6, including citalo-pram, escitalopram, and fluvoxamine.

Although not specifically exam-ined in many of these studies, it is im-portant to note that several non-SSRI antidepressants, such as bupropion, are known to be strong CYP2D6 in-hibitors, and antidepressants such as venlafaxine, desvenlafaxine, and mir-tazapine are in fact noninhibitors of the CYP2D6 enzyme system.21 Theoreti-cally, noninhibitors of CYP2D6 may be safer, or at least as safe as the milder in-hibitors (citalopram and escitalopram), whereas strong CYP2D6 inhibitors such as bupropion may, in fact, pose a safety problem. Interestingly, although investigators have observed a benefit with venlafaxine in the treatment of hot flashes, bupropion has not been shown to be helpful in this setting.22,23

Summary and Recommendations

A growing and evolving literature has legitimately raised concerns about the potential for antidepressant medica-tions, particularly those that are potent CYP2D6 inhibitors, to decrease the clinical efficacy of tamoxifen when used concurrently in women with breast can-

cer. It has been established that tamoxi-fen (a prodrug) must be metabolized by the CYP2D6 enzyme system in order to be converted into its active metabo-lites (eg, endoxifen). Furthermore, the use of antidepressants that are potent CYP2D6 inhibitors has been demon-

ing CYP2D6 genotyping in premeno-pausal ER+ women with breast cancer before initiating tamoxifen therapy. Given the potential for diminished metabolism of tamoxifen to endoxifen as a result of both endogenous (geno-typic variability) and exogenous fac-

11. Borges S, Desta Z, Li L, et al: Quanti-tative effect of CYP2D6 genotype and inhibi-tors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61-74, 2006.

12. Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concen-trations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758-1764, 2003.

13. Desmarais JE, Looper KJ: Interac-tions between tamoxifen and antidepressants via cytochrome P450 2D6. J Clin Psychiatry 70:1688-1699, 2009.

14. Lehmann D, Nelsen J, Ramanath V, et al: Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibi-tion. J Clin Pharmacol 44:861-865, 2004.

15. Lash TL, Pedersen L, Cronin-Fenton D, et al: Tamoxifen’s protection against breast cancer recurrence is not reduced by concur-rent use of the SSRI citalopram. Br J Cancer 99: 616-621, 2008.

16. Lash TL, Cronin-Fenton D, Ahern T, et al: Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncologica 49:305-312, 2010.

17. Chubak J, Buist DS, Boudreau DM, et al: Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat 112:123-132, 2008.

18. Dezentje VO, van Blijderveen NJ, Gelderblom H, et al: Effects of concomitant CYP2D6 inhibitor use and tamoxifen adher-ence on breast cancer recurrence in early stage cancer: A pharmacologic study. J Clin Oncol 27(suppl 18):Abstract CRA509, 2009.

19. Kelly CM, Juurlink DN, Gomes T, et al: Selective serotonin reuptake inhibitors and breast cancer mortality in women receiv-ing tamoxifen: A population based cohort study. BMJ 340:c693, 2010.

20. Aubert RE, Stanek EJ, Yao J, et al: Risk of breast cancer recurrence in women initi-ating tamoxifen with CYP2D6 inhibitors. J Clin Oncol 27(suppl 18):Abstract CRA508, 2009.

21. Geotz MP, Kamal A, Ames MM: Tamoxifen pharmacogenomics: The role of CYP2D6 as a predictor of drug response. Na-ture Clin Pharm Ther 3:12-16, 2007.

22. Loprinzi CL, Kugler JW, Sloan JA, et al: Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 356:2059-2063, 2000.

23. Perez DG, Loprinzi CL, Sloan J, et al: Pilot evaluation of bupropion for the treat-ment of hot flashes. J Palliative Medicine 9:631-637, 2006.

Dr. Breitbart is Chief of the Psychiatry Service and Vice-Chairman of the Department of Psy-chiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York.

Table 1: Antidepressants Classified by Potency of CYP2D6 Inhibition

Strong CYP2D6 Inhibitors

■ Fluoxetine

■ Paroxetine

■ Sertraline

■ Bupropion

Moderate CYP2D6 Inhibitors

■ Duloxetine

Mild CYP2D6 Inhibitors

■ Citalopram

■ Escitalopram

Noninhibitors of CYP2D6

■ Venlafaxine

■ Desvenlafaxine

■ Mirtazapine

Antidepressants and Tamoxifencontinued from page 29

An emerging consensus suggests that antidepressants that are potent inhibitors of CYP2D6 used concurrently with tamoxifen may reduce the clinical efficacy of tamoxifen.

strated to result in lower serum levels of endoxifen. The question that remains is whether lower levels of endoxifen in women with breast cancer taking tamoxifen and antidepressants (spe-cifically those that are potent CYP2D6 inhibitors) concurrently results in in-creased risk of breast cancer recurrence or increased mortality.

Studies to date have reported mixed findings, but there appears to be an emerging consensus that antide-pressants that are potent inhibitors of CYP2D6 (ie, fluoxetine, paroxetine, and sertraline) used concurrently with tamoxifen therapy for women with breast cancer may reduce the clinical efficacy of tamoxifen. Furthermore, evidence suggests that antidepres-sants that are either milder inhibitors of CYP2D6 (citalopram, escitalopram, duloxetine) or noninhibitors (venla-faxine, mirtazapine) are in fact safer choices, with less potential to decrease the clinical efficacy of tamoxifen.

In clinical practice (see case example), it is therefore reasonable to avoid potent 2D6 inhibitor antidepressants (parox-etine, fluoxetine, sertraline) for the treat-ment of depression or hot flashes while a woman is receiving tamoxifen therapy for breast cancer. Clinicians are advised to preferentially use antidepressants with lower CYP2D6 inhibition properties (citalopram, escitalopram, duloxetine) or CYP2D6 noninhibitor antidepres-sants (venlafaxine, mirtazapine). If pa-tients are already on a potent CYP2D6 inhibitor and are unable to be cross-tapered or unable to tolerate non–2D6 inhibitor options, the breast cancer treat-ment team, including the oncologist, surgeon, and psychiatrist, can collabora-tively work to optimize a safe plan, which may include one of these drugs perhaps for a limited period of time.

One interesting question that re-mains concerns the utility of conduct-

tors (medications), such testing could prove to be a practical approach. ■ References

1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 97:1652-1662, 2005.

2. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998.

3. Early Breast Cancer Trialists’ Collabor-ative Group (EBCTCG). Tamoxifen for early breast cancer: An overview of the random-ized trials. Lancet 351:1451-1467, 1998.

4. Day R, Ganz PA, Costantino JP: Tamoxifen and depression: More evidence from the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention (P-1) Randomized Study. J Natl Cancer Inst 93:1615-1623, 2001.

5. Malet C, Gompel A, Spritzer P, et al: Tamoxifen and hydroxyl-tamoxifen isomers vs estrodiol effects on normal human breast cells in culture. Cancer Res 48:7193-7199, 1988.

6. Coezy E, Borgna JL, Rochefort H: Tamoxifen and metabolites in MCF-7 cells: Correlation between binding to estrogen re-ceptor and inhibition of cell growth. Cancer Res 42:317-323, 1982.

7. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005.

8. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metab-olism in women receiving adjuvant tamoxi-fen. Breast Cancer Res Treat 101:113-121, 2007.

9. Henry NL, Stearn V, Flockhart D, et al: Drug interactions and pharmacogenomics in the treatment of breast cancer and depres-sion. Am J Psychiatry 165:1251-1255, 2008.

10. Borges S, Desta Z, Jin Y, et al: selective serotonin reuptake inhibitors, but not venla-faxine, decreased endoxifen plasma concen-tration. Clin Pharma Therapeutics 79:P13, 2005.

From the preface:

In addition to providing treat-

ment, oncologists need to re-

spond to the very personal and

human needs of patients and

their loved ones. How does an

oncologist honestly, yet com-

passionately, tell patients and

their families that things are not

going well; that there is no lon-

ger any useful anticancer thera-

py left to give; that it is time to

focus on symptom control rather

than anticancer therapy? How

do physicians, who are trained to

treat disease, instead talk about

death and loss? And, for those

fortunate enough to survive,

how do doctors discuss the

long-term consequences of

treatment? Additionally, how do

oncologists deal with their own

emotions and grief?

A strength of the collection is its potential to allow patients to better understand

issues faced by their oncologists.

-Dr. L. James Maher III, Mayo Clinic

These writings present voices of the physician experience that are sadly not heard often

enough–perspectives that are authentic, sensitive, and truly focused on thoughtful

delivery of patient care.

-Germaine Tupper, Senior Biotechnology Manager

At a time when the science of oncology is burgeoning with new information and practice-

changing advances, it is easy to overlook the importance of the art of oncology, the

focus on the meaning of the cancer and the experience to the patient as well as the

importance of the relationship between doctor and patient.

-Cynthia Chauhan, Patient Advocate

Art of Oncology is a collection of 30 brief articles that address

issues related to end-of-life care, symptom control, ethics,

and communication with patients. The essays

collected in this volume first appeared in the

monthly Art of Oncology section of Journal of

Clinical Oncology (JCO), the world’s leading

peer-reviewed journal for doctors who treat

patients with cancer.

Just Published on KindleArt of Oncology:Honest and Compassionate Responses to the Daily Struggles of People Living with Cancer-Edited by Charles L. Loprinzi, MD, Regis Professor of Breast Cancer Research, Mayo Clinic

Available for purchase at www.jco.org/kindle.


News

Administering an intensified regi-men of BEACOPP chemother-

apy (bleomycin, etoposide, doxoru-bicin, cyclophosphamide, vincristine, procarbazine [Matulane], and pred-nisone) to patients with interim PET-positive advanced Hodgkin lymphoma (HL) after treatment with two courses of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) may be superior to continuing treatment with four additional courses of ABVD, ac-cording to results of a phase II (non-randomized) trial presented at the 2010 ASCO Annual Meeting.1 Use of escalated BEACOPP in this high-risk group boosted 2-year progres-sion-free survival (PFS) compared to historical data.

Is BEACOPP Superior to ABVD in Patients with Advanced Hodgkin Lymphoma Who Are PET-positive after Initial ABVD?By Alice Goodman

powerful prognostic tool for advanced HL in predicting treatment outcome. Our study sought to address whether we could change the destiny of PET-positive patients after two courses of ABVD by giving them BEACOPP. In other words, we wanted to see if there is an advantage in this cohort of giving intensified chemotherapy,” said senior author of this paper, Andrea Galla-mini, MD, of Santa Croce Hospital in Cuneo, Italy.

Dr. Gallamini added, “Another question posed by our study was this: Could the overall PFS of this entire co-hort of advanced-stage HL patients—among whom a small subset of interim PET-positive patients received intensi-fied chemotherapy with BEACOPP—be improved by this strategy, as com-pared with historic ABVD-treated control patients? The answer is prob-ably yes, because the 2-year PFS of advanced-stage, ABVD-treated histori-cal control patients was 80% to 85%, as opposed to about 91% in our study. However, longer follow-up is needed to confirm these results.”

Some physicians reserve the use of BEACOPP for high-risk patients because it is highly myelotoxic. In this study, a less toxic regimen of ABVD was given up front to patients with advanced HL, and esca-lated BEACOPP was given to those with interim PET-positive scans but not to those with PET-negative scans. This approach spared the PET-negative patients from the short- and long-term toxicity associated with BEACOPP, Dr. Gallamini explained.

Study DetailsThe investigation was based on

pooled patients (n = 162) from eight

centers in Italy and one in the United States. All patients enrolled in the trial had advanced-stage HL, and all were treated initially with two cours-es of ABVD followed by an interim PET scan. Less than 25% of these patients had high-risk advanced-stage disease (ie, International Prog-nostic Index score > 3). The interim PET-positive patients (n = 27) were given four courses of escalated BEA-COPP and then four courses of stan-dard BEACOPP, followed by con-solidation radiotherapy. The interim PET-negative group (n = 135) was treated with four additional courses of ABVD followed by consolida-tion radiotherapy.

The investigators found no differ-ences in pretreatment patient charac-teristics between the two arms. At a mean follow-up of 26 months, 2-year PFS in 158 evaluable patients was 92.5% in the PET-negative group vs 64% in the PET-positive group. Some discordance arose in interpreting the interim PET scans in six patients

whose initial classification as positive or negative by the local PET reviewer changed upon cen-tral review. Thus, these six patients were incorrectly treated according to the study proto-col. Taking these six patients out of the analysis, 2-year PFS was 96.2% in the PET-negative group vs 60.5% in the PET-positive group.

“This approach [in PET-positive patients] is now being studied pro-spectively in multiple trials that are running worldwide,” Dr. Gallamini told listeners. ■Reference

1. Fiore F, Patti K, Viviani S, et al: Effect of early intensification with BEA-COPP in high-risk interim-PET posi-tive, advanced-stage Hodgkin lymphoma on overall treatment outcome of ABVD. 2010 ASCO Annual Meeting. Abstract 8006. Presented June 5, 2010.

■ BEACOPP given after an interim PET-positive scan following two courses of ABVD appears to increase progression-free survival in patients with high-risk advanced Hodgkin lymphoma in this phase II trial.

■ Patients with advanced Hodgkin lymphoma who are PET-negative after two courses of ABVD can continue on ABVD.

■ Although PET is prognostic, it may not be predictive (able to select optimal treatment).

■ This study is hypothesis-generating; randomized controlled trials are needed.

BEACOPP vs ABVD for Hodgkin Lymphoma


Formal discussant of this trial, Ralph Meyer, MD, Queen’s University in Kingston, On-

tario, Canada, said that the study raises two ques-tions: whether BEACOPP is superior to ABVD in PET-positive patients with advanced HL, and whether a PET-positive scan is predictive (ie, can be used to select the best treatment) in this group of patients in addition to being prognostic.

The study was hypothesis-generating, according to Dr. Meyer. He said that both of these issues need to be addressed by randomized controlled trials. At present, he continued, the weight of evidence from randomized controlled trials suggests that BEACOPP provides superior disease control as compared with ABVD for advanced HL, but these results, while suggestive, are less con-sistent for intermediate disease. He concluded by stating that as BEACOPP is associated with greater toxicity, its use is thus associated with trade-offs.

“BEACOPP is associated with more short-term toxicity, including neu-tropenia and febrile neutropenia, and greater use of antibiotics,” Dr. Meyer said. “BEACOPP also has more frequent and serious late-term toxicity than ABVD and in particular, is associated with very important problems of gonadal failure and infertility. However, BEACOPP probably achieves superior disease control. The reason oncologists have been slow to adopt BEACOPP is because of these trade-offs. Choice of therapy for advanced HL has to balance the side effects with patient preferences.” ■

Lymphoma

See page 42

In this study, 64% of PET-positive patients were alive and progression-free at 2 years, presumably because they received escalated BEACOPP.

The 2-year PFS rate in patients with advanced HL who remain PET posi-tive after ABVD has been suggested to be around 10% to 12%. In this study, 64% of PET-positive patients were alive and progression-free at 2 years, presumably because they received es-calated BEACOPP.

“Interim PET-positive scans af-ter two courses of ABVD is the most

Ralph Meyer, MD


FDA Update

AstraZeneca recently announced that the FDA has approved the

500-mg dose of fulvestrant (Faslodex) injection, replacing the previously ap-proved monthly dose of 250 mg, for the treatment of hormone receptor–positive metastatic breast cancer in postmeno-pausal women with disease progression following antiestrogen therapy. The FDA approval of the new dose was based on results from CONFIRM (COmparisoN of FASLODEX In Recurrent or Meta-

static breast cancer), a phase III study demonstrating that fulvestrant at 500 mg significantly reduced the risk of disease progression in patients with metastatic breast cancer, compared with the 250-mg dose. Safety and tolerability profiles of both doses were comparable.

“This approval is an important ad-vancement for women with metastatic breast cancer, where the treatment ap-proach is centered on delaying disease progression,” said Gershon Locker, MD, Medical Director for AstraZen-eca. “Faslodex at 250 mg has been an important treatment option for many women, and we now have data to show

FDA Approves New Dosing for Fulvestrant in Treatment of Metastatic Hormone Receptor–positive Breast Cancer

that the new 500-mg dosing regimen can improve progression-free survival compared with the 250-mg dose.”

Fulvestrant at 500 mg should be administered intramuscularly into the

buttocks as two 250-mg injections, one in each buttock, on days 1, 15, and 29, and once monthly thereafter. A dose of 250 mg is recommended in patients with moderate hepatic impairment.

The 500-mg dose will be supplied as 2 × 250 mg/5 mL packaged togeth-er, in early fourth quarter 2010. Dur-ing this time, fulvestrant at 250 mg will still be available. ■

FDA Extends Review Period for Bevacizumab

Genentech announced that infor-mation submitted to the FDA

during the review of the supplemen-tal Biologics License Applications (sBLAs) for bevacizumab (Avastin) for previously untreated (first-line) ad-vanced HER2-negative breast cancer has been deemed a major amendment. In accordance with FDA guidelines, the agency has extended the review period for the sBLAs by an additional 90 days. The company now anticipates FDA action on the sBLAs by Decem-ber 17, 2010. At this time, bevacizu-mab remains under accelerated ap-proval in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. ■ © sanofi -aventis

174, Avenue de France75635 Paris, France

sanofi -aventis U.S. www.sanofi -aventis.usUS.XON.10.04.049

There are thousands of ways to show you care:working to improve health is one of them.

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to help improve the lives of patients and their families.

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

9891320.4.28.lb.indd 1 5/4/10 12:16:54 PM


News

According to William Kevin Kelly, DO, of Thomas Jefferson

University, the addition of bevaci-zumab (Avastin) to the combination of docetaxel and prednisone offers no survival advantage compared with docetaxel and prednisone alone in men with metastatic castrate-resistant prostate cancer (CRPC). Dr. Kelly presented final survival results of the CALGB 90401 trial at the 2010 ASCO Annual Meeting.1 CALGB 90401 was a randomized, double-blind, placebo-controlled phase III trial conducted in collaboration with the Cancer and Leukemia Group B (CALGB) and Eastern Cooperative Oncology Group (ECOG).

Previous studies had demonstrated that plasma vascular endothelial growth factor (VEGF) levels were predictive of survival in CRPC, providing the ra-tionale for therapeutic targeting of this

protein.2 Results of a subsequent CALGB phase II trial sug-gested that in che-monaive patients with CRPC, the addition of bevaci-

zumab to a docetaxel-based regimen produced more favorable responses than chemotherapy alone.3 CALGB 90401 was designed to confirm these findings and evaluate whether the ad-dition of bevacizumab to docetaxel/prednisone could significantly improve survival in patients with CRPC.

Bevacizumab Added to Docetaxel/Prednisone Provides No Increase in Overall Survival in Metastatic Castrate-resistant Prostate Cancer By Larry Rosenberg, PhD

disease progression, progression by bone scan, or prostate-specific an-tigen (PSA) progression, despite a recent change in therapy, including antiandrogen withdrawal. Because bevacizumab was used, eligibility cri-teria also included no history of signifi-cant bleeding events within the past 6 months or deep-vein thrombosis/pulmonary embolism within the past year, no serious nonhealing wound, ul-cer, or bone fracture within 12 months, and no uncontrolled hypertension. No prior cytotoxic chemotherapy or anti-angiogenic therapy was allowed.

Patients were stratified by 24-month predicted survival (< 10%, 10%–29%, ≥ 30%) using the Halabi nomogram. Treatment consisted of docetaxel at 75 mg/m2 IV every 3 weeks plus pred-nisone at 10 mg daily and either beva-cizumab, 15 mg/kg IV every 21 days, or placebo, following docetaxel. Both groups received oral dexamethasone, 8 mg, at 12 hours, 3 hours, and 1 hour prior to docetaxel therapy. The prima-ry endpoint was overall survival (OS), with secondary endpoints of progres-sion-free survival (PFS), response rate, and PSA response. The study was pow-ered to detect an increase in OS from 19 to 25 months (α = 0.05).

Patients were well balanced with respect to baseline characteristics. A median of eight cycles of therapy was administered on both arms. Although a statistically significant increase was shown in median PFS with the beva-

rum alkaline phosphatase.Toxicity was significantly greater

with the addition of bevacizumab. Treatment-related adverse events of grade 3 or higher occurred in 74.8% of patients who received bevacizumab compared with 55.3% of patients on the control arm (P < .001). The propor-tion of patients who died while on study (mainly due to infection) was greater with bevacizumab (3.8% vs 1.1%).

Unanswered QuestionDr. Kelly noted that the OS of 21.5

months in the control arm exceeded the 19.2 months previously observed in the TAX327 trial.4 This suggests the possibility of stage migration in the cur-rent study, which is supported by the increased percentage of good-risk pa-tients in the CALGB 90401 trial (47% of men had a 24-month predicted sur-vival > 30%). Although the addition of bevacizumab to docetaxel and predni-sone increased PFS, response rate, and PSA decline ≥ 50%, it did not improve OS and was associated with greater morbidity and mortality. “This may in-dicate that subsequent treatments may have an effect on the primary outcome of the study,” concluded Dr. Kelly. ■References

1. Kelly WK, Halabi S, Carducci MA, et al: A randomized, double-blind, place-bo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resis-tant prostate cancer (mCRPC): Survival results of CALGB 90401. 2010 ASCO Annual Meeting. Abstract LBA4511. Pre-sented June 6, 2010.

2. George DJ, Halabi S, Shepard TF, et al: Cancer and Leukemia Group B 9480. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 7:1932-1936, 2001.

3. Picus J, et al: Cancer. In press.4. Tannock IF, de Wit R, Berry WR, et

al: TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus predni-sone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.

■ In chemonaive men with metastatic castrate-resistant prostate cancer (CRPC) who have evidence of disease progression, addition of bevaci-zumab to a regimen of docetaxel and prednisone provides no signifi-cant increase in overall survival compared with docetaxel and predni-sone alone.

■ Patients on the bevacizumab arm did experience statistically significant increases in median PFS, objective response rate, and PSA response.

■ Severe toxicity, including the incidence of treatment-related death, was higher with bevacizumab.

■ These results do not support the findings of an earlier phase II trial of bevacizumab plus a docetaxel-based regimen, and indicate that further study is needed to define the role of antiangiogenic agents in the treat-ment of metastatic CRPC.

Bevacizumab plus Docetaxel/Prednisone in CRPC

Prostate Cancer

See page 42

cizumab regimen (9.9 vs 7.5 months; HR = 0.77; P < .0001), this was not the case for median OS (22.6 vs 21.5 months; HR = 0.91, P = .181). Objec-tive response was greater on the bevaci-zumab arm (53.2% vs 42.1%; P = .0113), as was decrease in PSA (≥ 50% decline in PSA: 69.5% vs 57.9%; P = .0002). Sub-group analysis revealed that patients who may have a more favorable benefit on the bevacizumab regimen include those with low hemoglobin, increased LDH, low testosterone levels, and elevated se-

Although a statistically significant increase was shown in median progression-free survival with the bevacizumab regimen, this was not the case for median overall survival.

Study Design and ResultsThe study randomly assigned,

in a 1:1 fashion, 1,050 chemona-ive men with metastatic CRPC who had evidence of progressive disease despite castrate testosterone levels (< 50 ng/ mL) and antiandrogen with-drawal. Eligibility criteria included ECOG performance status ≤ 2 and adequate bone marrow, hepatic func-tion, and renal function. Eligible pa-tients must have demonstrated recent disease progression, ie, measurable

Visit The ASCO Post

website at:

New!

ASCOPost.com


Lessons Learned

We live in an amazing information age. In the medical world, we now

have the technology that allows us to see how fast a tumor grows and, in some types of cancer, whether it is genetically programmed to respond to our therapy. We have computers that can tell us where a specific tumor is located, its size, and even its metabolic rate. We can watch a tumor grow and watch it shrink.

However, we have become so accus-tomed to taking advantage of the latest state-of-the-art technology to treat our patients, we sometimes discount the importance of the human quality of the practice of medicine.

Physical ContactDuring my early training at Wayne

State University School of Medicine, my mentor, Dr. Vainutius Vaitkevicius, stressed the importance of having physi-cal contact with patients. Each time he left the examining room or discharged a patient, he would gently place his hand on the patient’s arm or forehead and reassure him that everything was going to be okay.

The importance of making a human connection with patients was a lesson I learned early in my career and one that I’ve always tried to remember, although I haven’t always been successful.

Important ReminderA few years ago, I had just completed

a follow-up examination, and I told my patient that everything was fine. As I was leaving the exam room, she showed me her arm—which had a skin lesion on it—and asked me what she should do. I looked at the cherry angioma and dismissed the problem with a quick, “There’s nothing to worry about.”

The next day, the patient called me to ask for a referral to a dermatologist. When I asked her why, she said, “I don’t feel like you really examined me yesterday. You just looked at my arm and never even touched my skin, and you said ‘it was nothing.’”

That was a reminder to me about the importance of using all the physi-cal techniques I had been taught to ex-amine a patient: inspection, palpation, percussion, and auscultation. In the case of that patient, I had failed to use the tool of palpation.

Wisdom QuestionedI recently read an article that ques-

tioned the wisdom of routinely per-forming a physical exam and to depend instead on MRI, PET, and CT scans to

Staying in Touch: The Value of Physical Contact By Stanley Winokur, MD

diagnose disease. That prompted me to think about the basics we learned in med-ical school and about the importance of touch and the human connection made by the simple act of “laying on of hands.”

Of course, technology plays a cru-

cial role in how we care for our pa-tients. But it will never replace the comfort or the bond between doctors and patients that touch provides. ■Dr. Winokur is a retired oncologist.

Stanley Winokur, MD

Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter

A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial

A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

Trial Currently Recruiting

Trial Currently Recruiting


News

José Carreras, one of the greatest tenors of all time, appeared on stage

earlier this month at La Scala after a 14-year absence, in a concert to raise funds for the fight against cancer. The occasion was the 35th Congress of the

ESMO’s 35th Congress Features Performance by José Carreras at Milan’s La Scala

European Society for Medical Oncol-ogy (ESMO), October 8-12, 2010, in Milan.

“You can return to live as you did before,…, before the tumor, before the illness, and with the same deter-

mination and the same energy,” Mr. Carreras said. “In 1987, I was attacked by leukemia. I spent 11 months in a hospital and had a marrow transplant. People who survive cancer change; they become more mature, and their

priorities change. I’ve become more ready to listen to others, more able to talk to people and communicate. And you can see this change when I perform because the artist and the man cannot be separated. The mes-sage I want to transmit to others who are fighting against cancer is to hold on to those you love and your friends, because even the smallest glimmer of hope can help you to fight with more determination. Cancer leaves deep wounds but you can win.” ■

José Carreras

35th ESMO Congress October 8–12, 2010, Milan

Look for coverage of the 35th Congress of the European Society for Medical Oncology (ESMO) in future issues of The ASCO Post.

Comprehensive meeting news will include coverage of the ESMO and ASCO joint symposium on “The future of antiangiogenesis therapy,” featuring ESMO and ASCO Presidents, David Kerr and George Sledge, with speakers Peter Carmeliet (Belgium), Robert S. Kerbel, (Canada), and Lee M. Ellis (United States).

Access and Quality of Care

The ASCO CAnCer FOundATiOn®

To help us make a difference, visit www.ascocancerfoundation.org or call 571-483-1700.

Making a World of Difference in...

Cutting-Edge Cancer Research

Patient and Family Support

Advancing Physician Education

ASC_101200 Foundation General AdV5.indd 1 9/1/10 2:44:01 PM


In the News

A review of data on 123,934 men with newly diagnosed prostate

cancer from the Surveillance, Epide-miology, and End Results (SEER) system found that most men diag-nosed as having prostate cancer with a prostate-specific antigen (PSA) level below 4.0 ng/mL had low-risk disease but underwent aggressive local treat-ment. Published in the Archives of Internal Medicine,1 the study was cov-ered by the medical and mainstream press, including Reuters and The New York Times as well as CNN and Wall Street Journal blogs, drawing public at-tention once again to the continuing controversy about whether prostate cancer is being overdiagnosed and overtreated.

Is Prostate Cancer Being Overdiagnosed and Overtreated? The Controversy ContinuesBy Charlotte Bath

In the News focuses on media re-ports that your patients may have questions about at their next visit. This continuing column will pro-vide summaries of articles in the popular press that may prompt such questions, as well as com-ments from colleagues in the field.

that if you biopsy men with low PSA, you will find some men with high-grade disease,” Dr. Stein noted. “If it wasn’t for that, it would be very straightforward.”

Studies on prostate cancer also un-derline the need for better molecular markers and other screening tools, ac-cording to Dr. Stein. “That is why it is so important to participate in clinical trials. One hopes that we can ultimate-ly move beyond a PSA number and a Gleason score. We need to be able to do a lot better. Major decisions are still being made with relatively crude in-struments.”

Considering ComorbiditiesThe investigators found that 14%

of the men in the SEER database had a PSA level of 4.0 ng/mL or lower. Among these men, 54% had low-risk disease (stage < T2a, Gleason score < 6), but more than 75% of them received radical prostatectomy or radiation therapy. “The PSA levels documented in the SEER data are the highest laboratory values prior to diagnostic biopsy or treatment,” the authors wrote. All of the men had prostate cancer that was newly diagnosed from 2004 to 2006. De-mographic and clinical features were stratified by PSA level, but comor-bidities were not.

Comorbidities, however, should be considered when choosing ap-propriate treatment options for men with prostate cancer, according to Anthony D’Amico, MD, Professor and Chief of Genitourinary Radiation Oncology at Dana-Farber Cancer In-stitute and Brigham and Women’s Hospital in Boston. “Clearly a man of 60 who has had a prior heart attack, may have diabetes, be obese, maybe is a smoker—if he is diagnosed with low-risk prostate cancer, there is no question that that man’s risk of dy-ing of prostate cancer, whether he is treated or not, is very small, if not 0, because of his other health issues,” Dr. D’Amico said. “But if you have a man who has no past medical history, or maybe hypercholesterolemia man-aged with a statin, and he is 60 years old, has longevity in his family, and has a low-risk prostate cancer, there is no way, based on all of the world’s literature that we have right now, that

we can say that man is overdiagnosed, or if he is treated, overtreated, be-cause we have no database that tracks people by comorbidity and life expec-tancy with low-risk prostate cancer. It just doesn’t exist.”

Dr. Stein acknowledged that co-morbidity is “another issue that clearly needs to be tackled and quantified.”

Long-term Data Lacking“Most databases for men diagnosed

with prostate cancer in the PSA era do not go beyond 10 years, and only a few go beyond 15 years.” Dr. D’Amico said. “But in order to claim that a man with low-risk prostate cancer will not live long enough to benefit from any treat-ment, requires a database that goes well beyond the person’s life expectan-

cy, which for a man of 60 in otherwise excellent health would be 20 years or longer,” he added.

“To talk about overtreatment or overdiagnosis is speculative until we have databases with much lon-ger follow-up and those that account for underlying health issues,” Dr. D’Amico said. “Until that informa-tion is available, I think we have to be careful not to undertreat people who are in excellent health and in their 60s or 70s with low-risk disease, but also to be careful about not over-treating people who have other seri-ous health issues like cardiovascular disease.”

Dr. D’Amico is collaborating on a long-term database with cooperative groups in this country as well as in

Expect QuestionsBy the time a patient with prostate cancer sees

an oncologist, the question is usually “How should I be treated?” not “Should I be treated?” Dr. D’Amico noted. And while most patients have been put through several rounds of testing, and are concerned more about their own health than whether prostate cancer is generally overdiag-nosed or overtreated, they are “willing to listen,” he said.

Dr. Stein concurred and said that during the past few years, “the number of men who are open to the idea of active surveillance certainly has increased. There is an in-creased awareness that not everyone with prostate cancer necessarily needs treatment right off the bat,” he said. “There certainly has been an evolution in that direction. But it is slow.” Patients more likely to choose surveillance are those who “realize that there are some ambiguities,” Dr. Stein added.

Difficult Emotional Process“They are going through a process that is emotionally very difficult,” Dr.

D’Amico noted. The process from abnormal blood test to biopsy to diag-nosis might have taken months. At this point, the patient probably doesn’t want to hear that although he has cancer, he may not need treatment, but it’s hard to be certain.

“When I have a conversation with a man who has a lot of comorbidity and low-risk disease, it can take me more than an hour to get him to un-derstand without becoming upset that his heart disease, diabetes, or kidney problem is much more significant than this prostate cancer,” Dr. D’Amico said. He also explains the side effects of various treatment options at this point.

“If the patient is in good health, the conversation is a little easier,” Dr. D’Amico said. You basically say, “You are in excellent health. We don’t know exactly what your life expectancy is, and this cancer could run a natural course of 20 years. You may or may not benefit from treatment, but here is what treatment involves if you decide to go that route. ■


Mark N. Stein, MD

Anthony D’Amico, MD

Mark N. Stein, MD, a member of the team of investigators who con-ducted the study at the Cancer Insti-tute of New Jersey in New Brunswick and Assistant Professor of Medicine, Division of Medical Oncology there, said the results correlated with his clinical experience. “When they are diagnosed with cancer, men tend to want treatment.” So while he was not surprised by the results of the study, he said he was “intrigued that there might be a possibility of trying to de-crease the number of men with low-risk disease who don’t really need to be treated.” The challenge remains of determining just who these men are. “Some large-scale trials have shown

Prostate Cancer


In the News

Canada, Europe, and Australia. That database includes comorbidities and collects information on cancer out-comes and other outcomes on an on-going basis.

“The ongoing collection and ascer-tainment of long-term data on cancer outcomes following various forms of treatment or surveillance, stratifying for underlying health issues, is essen-tial to answering whether overtreat-ment or overdiagnosis really exists,” Dr. D’Amico stressed.

Lowering Biopsy ThresholdIn their conclusions, the investiga-

tors cautioned: “Lowering the biopsy threshold but retaining our inability to distinguish indolent from aggressive

cancers might increase the risk of over-diagnosis and overtreatment.”

Dr. D’Amico cited a Swedish pop-ulation-based study published in the Lancet Oncology,2 which showed “a huge benefit” for PSA screening with a threshold of 3 ng/mL. He noted that

Prostate Cancer Overdiagnosed?continued from page 37

Phase III Trial Compares Active Surveillance to Radical Treatment

The conclusive determination of whether active surveillance of prostate cancer is associated with an increase in cancer mortality compared to

radical treatment at diagnosis of favorable-risk disease is the goal of the phase III Surveillance Therapy Against Radical Treatment (START) trial. Eligible patients are those with a Gleason score < 6, PSA < 10 ng/mL, stage T1b–T2b cancer, and a minimum life expectancy > 10 years. Patients are randomized between active surveillance and radical treatment as chosen by the patient—surgery, radical radiotherapy consisting of three-dimension-al conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or brachytherapy. Patients reclassified with higher-risk disease over time have the opportunity for selective delayed intervention.

Website VideoThe study is available to patients through the National Cancer Institute

of Canada Clinical Trials Group (NCIC CTG PR.11). A video explaining the trial is available at www.startstudy.ca. ■

the median age of men in that study was only 56 years old. “The place where you would expect a lower-threshold PSA for biopsy to be use-ful—and this study supports it—is in men less likely to have the major confounder of PSA, which is benign prostatic hypertrophy (BPH). That happens with advancing age. So if you go to a younger cohort like the Swed-ish did, where the median age was 56, and use a lower cut-point, you actu-ally see a substantial benefit in cancer death reduction,” he explained.

In whom should a threshold of 2.5 or 3 ng/mL be considered? “In younger men,” Dr. D’Amico suggest-ed. “In older men, above 60 or 65, the prevalence of BPH is very high. It would probably be wisest to stratify men by comorbidity as to whether they should be screened or not, and then use age or the presence or ab-sence of BPH, which would even be better, to determine whether or not you use a cutpoint of 2.5 or some-thing higher like 4, to determine whether they are referred for a biopsy or not,” he said. ■

References1. Shao Y-H, Albertsen PC, Roberts

CB, et al: Risk profiles and treatment pat-terns among men diagnosed as having prostate cancer and a prostate-specific an-tigen level below 4.0 ng/mL. Arch Intern

Med 170:1256-1261, 2010. 2. Hugosson J, Carlsson S, Aus G, et al:

Mortality results from the Göteborg ran-domised population-based prostate-can-cer screening trial. Lancet Oncol 11:725-732, 2010.

Promise MeBy Nancy G. BrinkerWith Joni Rodgers

Promise Me is Nancy G. Brinker’s poignant memoir of unshakable com-mitment to her late sister, Susan G. Ko-men, and the phe-

nomenal global impact that she has had in pursuing her life’s purpose—to end breast cancer. Nancy embarked on her quest to change the way the world thought about, spoke about, and treated breast cancer, a quest that took on added urgency when she her-self was diagnosed with the disease in 1984. Through it all, she was aided by

Ambassador Nancy Brinker Publishes Memoir ‘Promise Me’

her husband, Norman Brinker, whose dynamic approach to business be-came Nancy’s model for running her foundation, Susan G. Komen for the Cure.

Promise Me weaves a host of other elements into the compelling story of Brinker’s personal and professional life, including a historical overview of breast cancer and its treatment; a timeline of major developments in breast cancer detection and treat-ment; short, inspiring profiles of women who have survived breast can-cer; a primer in advocacy and cause-marketing; and an extensive list of re-sources for people living and dealing with breast cancer.

Nancy G. Brinker is the founder and CEO of Susan G. Komen for the Cure. She has served as Ambassador to Hungary and White House Chief of Protocol and as Global Ambassador for Cancer Control for the World Health Organization.

Joni Rodgers is a New York Times bestselling author.

353 pages; Publisher: Crown Ar-chetype; www.crownpublishing.com; Komen.Org

Henry Kaplan and the Story of Hodgkin’s DiseaseBy Charlotte DeCroes Jacobs, MD

Henry Kaplan and the Story of Hodgkin’s Disease explores the life of this multifac-eted, internationally known radiation on-cologist. Kaplan’s pas-

sion to cure cancer dominated his life and helped him weather the controver-sy that marked each of his innovations, but it extracted a high price, leaving ca-sualties along the way.

Charlotte Jacobs gives us the first account of a remarkable man who changed the face of cancer therapy and the history of a once fatal, now curable, cancer. She presents a dual drama —the biography of this renowned man who called cancer his “Moby Dick” and the history of Hodgkin’s disease, the malignancy he set out to annihi-late. The book recounts the history of Hodgkin’s disease, first described in 1832: the key figures, the serendipi-tous discoveries of radiation and che-motherapy, the improving cure rates, the unanticipated toxicities. The lives

Nancy G. Brinker

of individual patients bold enough to undergo experimental therapies lend poignancy to the successes and failures.

Charlotte Jacobs, MD, is Ben and A. Jess Shenson Professor of Medicine at Stanford University.

444 pages; Stanford General Books, Stanford University Press; www.sup.org

What are you reading? Write to [email protected] to share your recommenda-tions of books for health professionals.

Noteworthy Books

October is Breast Cancer Awareness Month


Meetings Calendar

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 (see below), scan these codes with your camera phone, and see where they bring you.

Getting the ApplicationThere are three ways to download the ScanLife applicatiton:

Scanning 2D codesWhen you see a code 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 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.

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).

1

2

3

October is Breast Cancer Awareness MonthBreast Cancer Meetings, October – December 2010

OCTOBER Expert Perspectives: Integrating New Data Into Best Practices for Breast Cancer October 1 • National Harbor, Maryland For more information: www.cancerlearning.com

2010 Breast Cancer Symposium October 1-3 • National Harbor, Maryland For more information: breastcasymposium.org

9th Annual Controversies in Breast Cancer: Adjuvant and Neoadjuvant Therapy October 8-10 • New York, New York For more information: www.cancerlearning.com

12th Annual Lynn Sage Breast Cancer Symposium October 28-31 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

NOVEMBER 2010 School of Breast Oncology November 11-14 • Atlanta, Georgia For more information: www.cancerlearning.com

DECEMBER CTRC-AACR San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

What’s this?

NOW OPEN: MeMbers Only HOusing and registratiOnMark your calendar now for the 2011 ASCO Annual MeetingJune 3-7, 2011, McCormick Place, Chicago, illinois

Take full advantage of all that your ASCO membership offers by registering

for the 2011 Annual Meeting and reserving your housing early.

Available exclusively to ASCO members from now until early December, visit

chicago2011.asco.org to secure advance access to hotel accommodations

and register for your first-choice of ticketed sessions.

Know a colleague who does not belong to ASCO yet? Share this information

on early Annual Meeting registration and housing advantages, only

available to ASCO members.

June 3-7, 2011 | McCormick Place | Chicago, il

to register and make housing reservations,

visit chicago2011.asco.org

to become an asCO member, visit benefits.asco.org


TAP Caucus

Do Patients with Limited-stage Hodgkin Lymphoma Require Radiotherapy?


CONThe clinician treating a patient with limited-stage Hodgkin lymphoma

has two very important but competing responsibili-ties: First, the treatment chosen must have the high-est likelihood of curing the lymphoma. Second, it should have the least probability of inducing major permanent toxicity such as infertility, cardiac in-jury, or induction of a secondary neoplasm. Stated simply, the goal is cure with the least harm.

Historically, limited-stage Hodgkin lymphoma was first reliably cured with wide-field radiation. However, once multiagent chemotherapy had been

shown to cure advanced-stage disease it became logical to explore its role in limited-stage disease. At first the role of chemotherapy was to eliminate highly invasive staging with laparotomy and later to reduce the size of the field of radiation. Thus, combined brief chemotherapy plus involved-field radiation became the treatment of choice and has been repeatedly demonstrated to be able to cure at least 90% of patients with limited-stage Hodgkin lymphoma.1

The success of this approach and the demonstration that the radiation field can be reduced to a very small size2 opened the question as to whether any radiation is needed at all if highly effective chemotherapy is employed. False starts with older chemotherapy such as MOPP (mechlorethamine, vincris-tine, procarbazine, prednisone) or newer but inferior regimens like EVE (eto-poside, vincristine, epirubicin) and EBVP (epirubicin, bleomycin, vinblastine, prednisone) demonstrated that one must be careful to use the most effective

chemotherapy, which is currently ABVD (doxorubicin, bleomycin, vinblas-tine, dacarbazine). In the pivotal trial addressing this issue, the experimental arm—ABVD alone—demonstrated that at least 80% of patients can be cured with just chemotherapy.3

The final task, then, became how to recognize the small minority of pa-tients whose lymphoma required radiation. The current leading contender for that role is functional imaging, namely FDG-PET scanning, and the definitive trials to test that question are in progress.

Success Bar Raised HigherAs the treatment of limited-stage Hodgkin lymphoma evolves, the success

bar is raised higher and higher. Today we expect to cure at least 95% of pa-tients, and death from lymphoma should be rare.1 With almost all patients being cured, minimization of late major toxicity becomes essential. Undoubt-edly, reduction of field size and greater sophistication of dosimetry have re-duced cardiac injury and second neoplasms. However, no dose of radiation is completely safe, and it should be eliminated if excellent disease control can be maintained without it.

Guided by PET scanning, since 2004 we have offered all patients with

PRO This past summer, a flurry of infor-mation from mature and ongoing

large, randomized studies has made it easier for me to state the following: Removing radiotherapy (RT) from the treatment of patients with favorable- or unfavorable-prognosis early-stage Hodgkin lym-phoma is ill-advised.

In trying to understand why this debate con-tinues, and why some of my esteemed colleagues are not yet convinced by the abundance of data that favor a “mini” combined-modality approach,

I can only offer one explanation. They may be confusing the radical RT of the past with the “mini” low-dose RT of today. These treatments are worlds

apart, just as the MOPP (mechlorethamine, vincristine, procarbazine, pred-nisone) toxicity profile is dissimilar to that of ABVD (doxorubicin, bleomy-cin, vinblastine, dacarbazine).

Not Your Grandmother’s Radical Maxi-RTThe main argument for avoiding RT stems from its reputation for increas-

ing the risk of long-term morbidity from second cancers and coronary heart disease, decades after Hodgkin lymphoma was cured. The problem with this line of thinking is that this was relevant to patients who were treated 3 to 5 decades ago with “radical radiotherapy” to all involved and uninvolved nodal sites, and often to normal organs, with doses that are almost twice what we use today. The pioneers who cured Hodgkin lymphoma had only one effective treatment—RT—and they used it at the highest tolerated doses and volumes to maximize cure. They were not aware of long-term effects and had little alternative.

Today, with more weapons, we can afford to be smart; we use a short course of ABVD and supplement it with mini-RT. The field size is often 10% of what it was, and the dose is often halved. Most of the time, the breasts and lungs are avoided and the coronary exposure is minimal. A long list of publica-tions document a significant reduction in second cancers with mini RT (most recently, a paper by De Bruin et al in the Journal of Clinical Oncology).1 Unfor-tunately, many patients receive information about RT that sounds frightening and is irrelevant to current RT risks.

When RT is avoided, the compensation is more chemotherapy: two cycles of ABVD become four (or more) and four become six (for less fa-vorable prognoses). We were told ABVD (and even more of it) is safe. But just as with the older RT regimen, more chemotherapy generates more risk to the heart and lungs. A large population-based British study surprisingly documented an eightfold increased risk of death from myocardial infarction in patients with Hodgkin lymphoma who were treated with ABVD alone.2 The “safety” of avoiding RT is replaced by new risks that we are just starting to recognize.


Pro/Con

In the pivotal trial addressing this issue, the experimental arm—ABVD alone—demonstrated that at least 80% of patients can be cured with just chemotherapy.

Most Patients with Limited-stage Hodgkin Lymphoma Do Not Require RadiotherapyBy Joseph M. Connors, MD, FRCPC

Less Is More: Less ABVD with Mini-RT Is a Clear Winner in Hodgkin LymphomaBy Joachim Yahalom, MD

Joachim Yahalom, MD

Joseph M. Connors, MD, FRCPC

Those who are unconvinced by the data favoring a ‘mini’ combined-modality approach may be confusing the radical RT of the past with the ‘mini’ low-dose RT of today.


TAP Caucus

Most Patients Do Not Require Radiotherapycontinued from page 43

Less ABVD with Mini-RT Is a Clear Winnercontinued from page 43

limited-stage Hodgkin lymphoma in British Columbia treatment with an initial two cycles of ABVD. If the PET scan is negative after those two cycles, treatment continues with two more (for a total of four). We switch to radia-tion instead of ABVD if that PET scan is positive. Following this algorithm, 80% of patients avoid radiation. With 120 patients treated and more than 80% followed for longer than the maximum time to relapse, we have seen a progres-sion-free survival of 95%, and no patient

has died from Hodgkin lymphoma.With optimal chemotherapy (pres-

ently ABVD), the large majority of patients with limited-stage Hodg-kin lymphoma can be cured using brief chemotherapy alone. Radiation should be reserved for a carefully cho-sen small minority—no more than 20% of patients. In this way, we can meet our responsibility to achieve cure with the least harm. Most patients with limited-stage Hodgkin lymphoma do not require radiotherapy. ■References

1. Engert A, Diehl V, Pluetschow A, et

al: Two cycles of ABVD followed by in-volved field radiotherapy with 20 gray (Gy) is the new standard of care in the treatment of patients with early-stage Hodgkin lym-phoma: Final analysis of the randomized German Hodgkin Study Group (GHSG) HD10. Study supported by the Deutsche Krebshilfe and in part by the Competence Network Malignant Lymphoma. Ameri-can Society of Hematology Annual Meet-ing. Abstract 716. Presented December 7, 2009.

2. Campbell BA, Voss N, Pickles T, et al: Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin’s lymphoma:

A question of field size. J Clin Oncol 26:5170-5174, 2008.

3. Meyer RM, Gospodarowicz MK, Connors JM, et al: Randomized com-parison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lym-phoma: National Cancer Institute of Can-ada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin On-col 23:4634-4642, 2005.

Dr. Connors is Clinical Director, Centre for Lymphoid Cancer, BC Cancer Agency, and Clinical Professor, University of British Co-lumbia, Vancouver.

Disease Control and Overall Survival Inferior without RT

Every single randomized study that compared combined modality to chemotherapy alone showed a sig-nificantly better rate of freedom from treatment failure for the RT-contain-ing arm. Two studies were even pre-maturely closed, because of higher-than-tolerated failure rates without RT. A single study (from Memo-rial Sloan-Kettering Cancer Center) showed only a trend in favor of RT but had no power to detect a differ-ence smaller than 20%. Indeed, most of those studies were not powered as noninferiority studies and had short follow-up periods. Thus, the advan-tage in disease control did not trans-late for each individual study into a significant overall survival advantage.

About half of patients experienc-ing treatment failure can be salvaged or live with disease for an extended period of time. The poor quality of life associated with relapse and stem cell transplantation is not measured in our survival curves. Still, a very recent sys-. Still, a very recent sys-tematic review including a meta-anal-ysis of randomized controlled trials comparing chemotherapy alone with combined-modality therapy docu-mented not only better disease control with combination therapy in early-stage Hodgkin lymphoma, but also a significantly better overall survival (HR = 0.40) for the RT-containing arms.3 The risk of failure without RT is not insignificant in the context of the expected success rate for Hodgkin lymphoma. Doubling the failure rate (roughly from 10% to 20%) by avoid-ing RT seems unacceptable to me.

The Crystal Ball Has Disappointed Us

RT could be excluded in some cases if we had an interim predictive test to guide therapy. For the past 5 years, we hoped that PET would do it for us. Many have already discard-ed RT if PET became negative after ABVD. They probably should have waited for the results of H10, a large, randomized intergroup (EORTC/GELA/IIL) study that examined whether interim negative PET obvi-ates the need for RT. Over 1,300 pa-tients with early-stage Hodgkin lym-phoma participated, and all had PET scans after two cycles of ABVD. Pa-tients in the standard-treatment arm with favorable prognoses received an additional cycle of ABVD followed by a reduced RT field (involved-node RT) of 30 Gy, regardless of PET results. In the experimental arm, those who became PET-nega-tive received two additional cycles of ABVD and no RT. PET-positive patients were switched to two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophos-phamide, vincristine, procarbazine, prednisone) plus involved-node RT. Patients on the standard arm with an unfavorable prognosis received two additional ABVD courses and involved-node RT regardless of PET status. On the experimental arm, PET-negative patients received four additional cycles of ABVD (total of six) and no RT. Positive patients were switched to escalated BEA-COPP plus involved-node RT.

After an interim analysis and careful review of its implications, all investigators were instructed to im-mediately cease treating patients on chemotherapy-only arms and send

all those who had just completed che-motherapy to receive involved-node RT. We are waiting for the detailed analysis that led to this dramatic de-velopment. It seems reasonable to assume that, even for patients who achieved a PET-negative status after chemotherapy, forgoing RT would be a mistake.

Well Established Standard of Care

Two major studies conducted by the German Hodgkin Study Group (GHSG) were published this sum-mer. Each of these investigations in-cluded more than 1,300 patients and was performed at over 300 centers in five countries. The HD10 study ad-dressed favorable early-stage Hodgkin lymphoma and established that a mini-mal combined-modality treatment of only two cycles of ABVD followed by 20 Gy of involved-field RT results in a 5-year freedom from treatment failure rate of 91% and an overall survival of 97%.4 The twin study, HD11, addressed patients with unfavorable early-stage disease. It showed that four cycles of ABVD followed by involved-field RT of 30 Gy is a very effective therapy, with a 5-year freedom from treatment failure of 85% and overall survival of 95%.5

These publications establish that the standard of care for early-stage Hodgkin lymphoma is a short course of combined-modality treatment that should include a small reduced-dose RT component. The H10 in-terim analysis suggests that avoiding RT even in PET-negative patients is wrong; hopefully more details will be available soon.

Thus, with these utterly straightfor-ward, convincing data collected from thousands of patients in randomized

controlled studies, is it not time to say goodbye to historical controls, personal series, and anecdotal experiences of the past? Even in its mini form, RT provides protection from devastating relapses, allows shorter (and therefore safer) chemotherapy, reduces the need for fre-quent imaging, and is very likely to im-prove long-term cure and safety, rather than reduce it. With mini-RT, more con-trol is achieved with less toxicity. ■References

1. De Bruin ML, Sparidans J, van’t Veer MV, et al: Breast cancer risk in female sur-vivors of Hodgkin’s lymphoma: Lower risk after smaller radiation volumes. J Clin On-col 27:4239-4246, 2009.

2. Swerdlow AJ, Higgins CD, Smith P, et al: Myocardial infarction mortality risk after treatment for Hodgkin disease: A col-laborative British cohort study. J Natl Can-cer Inst 99:206-214, 2007.

3. Herbst C, Rehan FA, Brillant C, et al: Combined modality treatment improves tumor control and overall survival in pa-tients with early stage Hodgkin’s lympho-ma: A systematic review. Haematologica 95:494-500, 2010.

4. Engert A, Plütschow A, Eich HT, et al: Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363:640-652, 2010.

5. Eich HT, Diehl V, Görgen H, et al: In-tensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin’s Lympho-ma: Final Analysis of the German Hodgkin Study Group HD11 Trial. J Clin Oncol Au-gust 16, 2010 (e-pub ahead of print).

Dr. Yahalom is Attending Radiation Oncolo-gist and Member, Memorial Sloan-Kettering Cancer Center, and Professor of Radiation Oncology, Weill Cornell Medical College, New York.


Appointments

Dr. Maurie Markman is the new Vice President of Patient Oncol-

ogy Services and National Director for Medical Oncology at Cancer Treat-ment Centers of America (CTCA). Dr. Markman will also serve patients as a medical oncologist at the hospital net-work’s Philadelphia location.

Dr. Maurie Markman Joins Cancer Treatment Centers of Americaactive participants in their care; our entire team is excited to have him on board.”

CTCA has provided innovative cancer treatment for almost 30 years with a fully integrated model of can-cer care that focuses on what cancer

patients value most. This translates into merging state-of-the-art clini-cal treatments and technologies for fighting cancer (such as surgery, ra-diation, and chemotherapy), along with scientifically supported comple-mentary therapies (such as nutrition,

naturopathic medicine, mind-body medicine, oncology rehabilitation, pain management, spiritual support, and others), which help mitigate side effects of treatment and maintain the immune system to improve each pa-tient’s quality of life. ■

Maurie Markman, MD

Dr. Markman has more than 20 years of experience in cancer treat-ment and gynecologic research. He joins an expanding team of special-ized oncology physicians and clini-cians at CTCA to implement new research and find innovative ways to fight cancer.

“From the beginning of my career, I recognized the importance of prac-ticing medicine as a ‘people’s doc-tor’” said Dr. Markman. “All of my research and work has been motivat-ed by the thought of giving patients every option to beat their disease. I look forward to working as part of a truly integrated team that personal-izes care to meet each patient’s indi-vidual needs.”

Previously, Dr. Markman served as the Vice President for Clinical Research and Chairman of the De-partment of Gynecological Medi-cal Oncology at M.D. Anderson, and Chairman of the Department of Hematology/Oncology at The Cleveland Clinic Foundation. He earned his medical degree from New York Medical University School of Medicine and holds a Master of Sci-ence degree in health policy and management from New York Uni-versity Graduate School of Public Administration.

“Beyond his professional cre-dentials, we recognized how greatly Dr. Markman’s treatment philoso-phy aligns with our approach,” said Edgar D. Staren, MD, PhD, MBA, Senior Vice President for Clinical Affairs and Chief Medical Officer at CTCA. “Dr. Markman shares our commitment to empower patients as

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Opinion

Tort Reformcontinued from page 3 ■ The number of malpractice claims

has been constant over the past 20 years, even though health-care costs have doubled. Furthermore, studies have shown that there are a fixed number of errors per hospital-ization over that period.5,6 Thus, the percentage of lawsuits per patient visit has declined.

The vast majority of lawsuits are frivolous. ■ Actually, the studies quoted in

the seminal work by the Institute of Medicine, “To Err Is Human,” found that of those patients in-jured, only 4% to 7% filed a law-suit. Over the past 20 years the real number of injuries has in-creased (based on the constant percentage of errors and the greater number of patients), and yet the lawsuits remain the same. Thus, the rate of lawsuits is really decreasing.

■ The facts indicate that the vast ma-jority of lawsuits are not frivolous.7

Doctors are practicing “defensive medi-cine,” which is a major driver of increased health-care costs. ■ Defensive medicine is the natural

outcome of doctors feeling assault-ed by lawyers and their litigious patients. A 1996 study on cardio-vascular disease in Florida (a haven for plaintiffs’ lawyers) found that defensive medicine may account for up to 5% to 7% of costs.8 Within a few years of managed care taking hold, however, the costs were re-duced by half.9

■ A study just released in September 2010 in Health Affairs demonstrates that in 2008 dollars, the cost of medical liablity is approximately $55.6 billion or 2.4% of all spend-ing on health care.10 Eighty percent ($45.6 billion) of the costs are for “defensive medicine.”

■ In a study reported in JAMA, 93% of Massachusetts physicians report-ed practicing defensive medicine.11 Imaging accounted for nearly half of all acts of defensive medicine.

Malpractice awards are rising. ■ There does not appear to be evi-

dence that awards are rising.3

Caps on non-economic damages reduce the costs of malpractice. ■ Only 5% of all malpractice claims

go to trial, and less than 1% of these

claims end in a jury trial. Caps may be beneficial, but they do not address the major goal of patient safety.

■ However, a RAND study demon-strated that caps did reduce awards by 30% in California12

■ Another example of proactively re-ducing errors and improving qual-ity is the University of Michigan ex-perience where the medical system reduced suits by 50%.13

As physicians, our practices are ruled by the Hippocratic Oath and the edict primum non nocere, or “first, do no harm.” Errors will always happen. This is regrettable and possibly compensa-ble through the legal system. However, our first and most important approach must be to eliminate malpractice, and that will improve our patient’s health and our professional lives. ■References

1. Localio AR, Brennan TA, Laird NM, et al: Relation between malpractice claims and adverse events due to negli-gence. Results of the Harvard Medical Practice Study III. N Engl J Med 325:245-251, 1991.

2. Brennan TA, Sox CM, Burstin HR: Relation between negligent adverse events and the outcomes of medical-malpractice lit-igation. N Engl J Med 335:1963-1967, 1996.

3. Chandra A, Nundy S, Seabury SA: The growth of physician medical malprac-tice payments: Evidence from the National Practitioner Data Bank. Health Aff (Mill-wood) Jan-Jun(suppl); Web exclusives: W5-240–W5-249, 2005.

4. Baicker K, Fisher ES, Chandra A: Malpractice liability costs and the prac-tice of medicine in the Medicare program. Health Aff (Millwood) 26:841-852, 2007.

5. Baker T: The Medical Malpractice Myth. Chicago, University of Chicago Press, 2007.

6. Kohn LT, Corrigan JM, Donaldson MS (eds): To Err Is Human, Building a Safer Health System. Committee on Qual-ity of Health Care in America, Institute

of Medicine. Washington, DC, National Academy Press, 2000.

7. Studdert DM, Mello MM, Gawande AA, et al: Claims, errors, and compensa-tion payments in medical malpractice. N Engl J Med 354:2024-2033, 2006.

8. Kessler DP, McClellan MB: Do doctors practice defensive medicine? NBER working paper no. 5466. Q J Econ 111:356-390, 1996.

9. Kessler D, McClellan M: Medical li-ability, managed care, and defensive medi-cine. J Public Econ 84(2):175-197, 2002.

10. Mello MM, Chandra A, Gawande AA, et al: National costs of the medical liability system. Health Aff (Millwood) 29(9):1569-1577, 2010

11. Studdert DM, Mello MM, Sage WM, et al: Defensive medicine among high-risk specialist physicians in a vola-tile malpractice environment. JAMA 293:2609-2617, 2005.

12. Pace NM, Golinelli D, Zakaras L: Capping non-economic awards in medical malpractice trials: California jury verdicts under MICRA. RAND, MG-234-ICJ, 2004

13. Klein E: The medical malpractice myth. Accessed from Slate, http://www.slate.com/id/2145400/. Posted July 11, 2006.

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

© Kim Warp/The New Yorker Collection/www.cartoonbank.com

Our first and most important approach must be to eliminate malpractice.

SolutionsHere are some of the possible

solutions:

Institute medical courts and no-fault in-surance. ■ Medical courts with experts have

been proposed and would be par-tially or wholly dependent upon evidence-based medicine. These courts would screen lawsuits to re-duce frivolous claims.

■ More clearly define standard of care, although presently standard of care and the community standard may not be the same.

■ New Zealand and Scandinavia use a no-fault system. There is a prompt predetermined payment to an in-jured patient. No blame is assessed, somewhat akin to automobile liability.

Reduce malpractice. ■ Immediate disclosure of errors,

apologies, and aggressive efforts to remediate mistakes and settle may stem the number of patients seeking compensation through the courts. These efforts were tried at a veteran’s hospital in Kentucky, resulting in an average claim paid that was one-sixth that of the national average.

■ Reducing medical errors has been proven to reduce medi-cal malpractice claims and im-prove patient safety. Nearly 30 years ago, the American Society of Anesthesiologists (ASA) re-sponded to the enormous num-ber of malpractice lawsuits against their members by analyzing all past claims. By understanding the cause of the claims, the ASA suc-cessfully brought new measures of safety to the patients and reduced the number of lawsuits—truly a win/win result.

Solution for intravenous infusion Initial U.S. Approval: 2004

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

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.1.3 Metastatic Breast Cancer (MBC)Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.1.4 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]1.5 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]5.2 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]5.3 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]5.4 Non-Gastrointestinal Fistula FormationSerious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]5.6 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]5.9 Infusion ReactionsInfusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.6).][See Dosage and Administration

(2.4), Warnings and Precautions (5.7).][See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.Surgery and Wound Healing ComplicationsThe incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound

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

were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic

gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]Venous Thromboembolic EventsThe incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving

venous thromboembolic event. Among these patients, an additional thromboembolic event

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients

Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in

placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of

neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus

also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.ProteinuriaGrade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart FailureThe incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence

paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior

to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving

Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2

(n = 396) (n = 392)

NCI-CTC Grade 3-4 Events 74% 87%

Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra-Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving

Grade 1–4 adverse events were collected for the first approximately 100 patients in each of

was discontinued.

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1

Arm 1 Arm 2 Arm 3

(n = 98) (n = 102) (n = 109)

Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19%

Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second-line mCRCOnly Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence

(17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition

Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a

α) plus Avastin α plus placebo arm were fatigue (13% vs. 8%),

asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

α plus α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9

α α + Placebo)

α α + Avastin Preferred term* (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions

Investigations

Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

*Adverse events were encoded using MedDRA, Version 10.1.

α plus α alone and not represented in Table 4: gingival bleeding

(13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications,

with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLSDigestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the

bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

Manufactured by: 7453214Genentech, Inc. 4835706

94080-4990 © 2009 Genentech, Inc

70072ha_a:70072ha_a 3/8/10 5:59 PM Page 2

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

To reach beyond convention…To reach beyond convention…

IndicationsAvastin 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 informationGastrointestinal (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 beendetermined. 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 vaginalbleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events amongpatients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp ofred 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 fistulaformation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverseevents for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posteriorleukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurredin 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 reactionsIn NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treatedpatients 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-abdominalthrombosis (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% vs5%), 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.

©2010 Genentech USA, Inc. All rights reserved. 9146401 (01/10) Printed in USA. www.avastin.com

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