TAP Vol 2 Issue 7 by Harborside Press LLC

Metastatic melanoma 3

Non–small cell lung cancer 6

VOLUME 2, ISSUE 7

Breast implants and lymphoma 43

MAY 1, 2011 ASCOPost.com

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

Gastrointestinal Cancer

Everolimus Benefits in Pancreatic Neuroendocrine Tumors Sustained in Updated RADIANT Trials

Patient-centered Care vs Health-care Economics

Sunitinib demonstrates similar benefits, other studies find. By Caroline Helwick

By Richard J. Boxer, MD

n updated results from the RADIANT trials of treatment for advanced neuroendocrine tumors, everolimus provided a 2.4-fold increase in median progressionfree survival (PFS) for patients with pancreatic neuroendocrine tumors. Manisha H. Shah, MD In combination with the long-acting formulation of the somatostatin analog octreotide (Sandostatin LAR) in patients with carcinoid syndrome, however, the benefit was more questionable. The updates were reported at the 2011 Gastrointestinal Cancers Symposium. The phase III RADIANT-3 trial randomly assigned 410 patients with advanced pancreatic neuroendocrine tumors to everolimus (10 mg/d) or

Editor’s note: The Oncologic Drugs Advi-

sory Committee (ODAC) of the FDA recently recommended that everolimus (Afinitor) be approved for the treatment of advanced pancreatic neuroendocrine tumors. In a decision made that same day (April 12, 2011), the ODAC committee voted to recommend that the multikinase inhibitor sunitinib (Sutent) be approved for the treatment of unresectable pancreatic neuroendocrine tumors. ODAC’s unanimous decision to recommend approval of everolimus was based on data from the clinical trials described in this report showing a significant increase in median progressionfree survival for patients with pancreatic neuroendocrine tumors who received everolimus compared to those who received placebo and best supportive care.

continued on page 13

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End-of-life Care

Personalized Therapy in Advanced Cancer a Priority A conversation with Allen S. Lichter, MD By Ronald Piana

recently released policy statement by ASCO about end-of-life care? makes clear that individualized therapy is a When ASCO released its statement on barriers best practice throughout and recommendations the full course of treatto improving physicianment, encompassing the initiated conversations Oncologists across the diverse needs of patients regarding care options for country understand that diagnosed with advanced patients with advanced cancer. ASCO CEO Allen cancer, it received quite high-quality care does not S. Lichter, MD, spoke a bit of national attenend with a diagnosis of with The ASCO Post about tion. But in fact, providthe Society’s 15-year role ing quality care for paincurable disease. in advancing awareness tients at the end of life has —Allen S. Lichter, MD and knowledge in the adbeen a priority for ASCO vanced cancer setting. for many years. In 1997, ASCO President Robert Enhancing End-of-life Cancer Care Mayer, MD, made end-of-life care the focus of his What is some of the background that led to ASCO’s Presidency. This began a significant effort in endcontinued on page 12 statement on improving doctor-patient communication

he great American scientist and physician, Dr. Irving Selikof, said that “Statistics are people with the tears wiped away.” At this year’s ASCO Annual Meeting, we will be introduced to new ideas, discoveries that open windows of opportunity for improving our patients’ quality and quantity of life, and creative methods of reducing the ravages of disease. Data, statistics, facts, and erudite discussions will inundate our week. But we must realize that all of this new information and all the biotechnologic marvels that are displayed in the convention hall are meaningless to the person with cancer unless we are patient-focused.

Unapplied Research To paraphrase Dr. Otis Brawley, too many patients are dying, not because of a lack of research but because the research is not being applied to them. Translating continued on page 2

Dr. Boxer is Professor of Clinical Urology at the University of Miami and Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin.

MORE IN THIS ISSUE A Conversation with Larry Norton �� 7 Oncology Worldwide �� 11, 17 FDA Update �� 19, 33 Gastrointestinal Cancers �� 21 Direct from ASCO ��22 TAP on Technology �� 31 ACCC 37th Annual National Meeting ��36

A Harborside Press® Publication

The ASCO Post | MAY 1, 2011

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Opinion Policy

Health-care Economics continued from page 1

research and applying compassion will save more lives, bring greater comfort to our patients, and bring greater satisfaction to our professional lives.

Wrenching Decisions But how can our society pay for the scientific discoveries that may lead to cures, prolongation of life, or simply a slight delay of death? Like so many wrenching decisions being considered in the face of our nation’s debt, we need to consider economics when health care becomes too expensive and crushes other societal needs. And how shall we pay for the short- or long-term therapies, the potential cures, and the desired preventions? Should economics be further introduced into the decisionmaking of the care we render? If a patient and family were told that a therapy being offered has a 50% chance of prolonging life by 2 to 4 months, would the patient endure the further care? If that care were to cost the patient or his/her future estate $100,000, would that alter the decision? For patients who can afford such therapy, perhaps on a sliding scale, should society be asked to fund it, essentially funding the monies passed down to the patient’s heirs? At what point does society state that decisions impacting the economics of health care are no different than those involving the economics of other aspects of life? Where clinical studies have proven that a therapy (medication, radia-

tion, or surgery) clearly prolongs a quality productive life, particularly in the young, society should provide the care when insurance is not adequate. However, when the treatment is limited in its ability to improve life, the patient and his family should consider all the implications.

The Financial Burden on Family I will never forget the elderly patient with widely metastatic prostate cancer who came into my office with his wife of 50 years. He had Medicare, but no other insurance. He was

with his decision. Considering that a significant amount of one’s lifetime health-care expenditure occurs in the last year of life, and that there is not a limitless amount of money, personal healthcare economics may need to be considered as our nation struggles with controlling the debt.

The Impatient Patient Whether we are in research, clinical care, or both, our goals are to provide the best care for our patients. There is no reasonable method of determining whether a discov-

Scientists often say that one cannot predict what small finding will lead to major changes, and that is true. But there are limits to the logic, and with limited funds and a crushing debt, one must use common sense. faced with the decision of whether to continue his depot LHRH agonist because of the co-pay of several hundred dollars. He tearfully said that he could no longer live with the idea that the medication may prolong his life a few more months, but he believed his memory would be sullied in his wife’s mind because she would have less money to live on when he was gone. I tried to dissuade him and spoke to the manufacturer about obtaining the medication on a compassionate care basis, and the company responded favorably. The patient refused the medication, however, and he died soon thereafter satisfied

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

ery will lead to a cure, or better and longer health for patients. So the pursuit must continue with greater energy, enthusiasm, and funding. That is critical. The public has been convinced of the primacy of science and the real value of research. Our nation has made the decision to fund biomedical research at the expense of other less valued services and industrial output. But there seems to be a limit, and the ultimate consumer, the patient, is getting impatient. Some Americans believe that they are not getting their money’s worth. Science for the sake of sci-

ence may be peaking in its perceived value. Application and translation of science for the betterment of health has begun to take hold of the political (and the kitchen table) discussion. Is the country improved by funding remarkable discoveries that will have no chance of improving anyone’s health? Scientists often say that one cannot predict what small finding will lead to major changes, and that is true. But there are limits to the logic, and with limited funds and a crushing debt, one must use common sense.

Consider Risk-sharing Thus, we must continue advancing the discoveries, the exciting science, the exhilaration of lighting the darkness of the unknown, but we should consider risk-sharing. If projects are worthy and show the promise of translating into long-term therapies, preventions, or cures, the nation must promote them. But those who benefit—whether businesses or patients—and have the means must also be willing to cover the cost through risk-sharing, direct payment, or probate.

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

What’s Your Opinion? The ASCO Post wants to hear from you. Write to Editor@ASCOPost. com. All correspondence will be acknowledged. Selected letters will be published in future issues of The ASCO Post.

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

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

ASCOPost.com | MAY 1, 2011

PAGE 3

News

Phase III Trial Shows Increased Survival in Metastatic Melanoma Editorial Board James O. Armitage, MD Editor-in-Chief

William T. McGivney, PhD National Comprehensive Cancer Network

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

James L. Mulshine, MD Rush University Medical Center

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute

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

Paul F. Engstrom, MD Fox Chase Cancer Center

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

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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 Mary McCabe, RN Memorial Sloan-Kettering Cancer Center

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

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

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations; Artwork on page 31 by DNA Illustrations, Inc.

Financial disclosure information available at ASCOPost.com.

Genetics will be the key to better response, longer survival, and counteracting resistance. By Margot Fromer

antastic and “the next big thing” were how two of the principal investigators described the results of an interim analysis of the phase III trial of PLX4032, the harbinger of a significant breakthrough in the treatment of metastatic melanoma. PLX4032 works by inhibiting a protein produced by a gene mutation in melanoma cells. In phase I and II trials, many of the patients whose tumor cells manifested the BRAF V600 mutation responded to the drug with tumor shrinkage that lasted for an average of 6 months. Now, a controlled phase III trial pitting PLX4032 against dacarbazine showed that patients who received the investigational drug had a significant survival advantage, as well as increased time to disease progression when compared to standard therapy. How much extra survival? “We don’t know the answer to that yet,” said Keith Flaherty, MD, Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, and one of the principal investigators for the study. The data will be presented at the ASCO Annual Meeting.

Melanoma Treatments Not Effective Dacarbazine’s response rate in metastatic melanoma is 10% to 15%. In the prior phase I and II trials, more than 50% of the patients with melanoma who had the BRAF mutation responded to PLX4032. “We knew going into the phase III trial that the response rate to PLX4032 would be higher than to dacarbazine. We also knew that these responses were typically not long-lasting. The average duration of response observed in earlier studies suggested but did not prove that survival would be improved for PLX4032,” said Dr. Flaherty. Hence, a study with survival as the primary endpoint was clearly needed. Dr. Flaherty also noted that dacarbazine was approved more than 30 years ago. If it had been submitted for approval in today’s more stringent

regulatory environment, it would not have made the grade, he speculated. Prior to 2011, only two drugs (dacarbazine and high-dose interleukin-2 [Proleukin]) had been approved for treating metastatic melanoma, and neither one of these results in acceptable survival. A third, ipilimumab (Yervoy), was recently approved by FDA on March 25, 2011. Ipilimumab is a monoclonal antibody that inhibits the cytotoxic T lymphocyte–associated antigen 4 (CTLA-4). Several phase II studies have shown that ipilumumab can provide 1-year survival rates of nearly 50%. Ipilimumab has been associated with potentially lifethreatening toxicity, including gastrointestinal perforation and sepsis. In June 2010, The New England Journal of Medicine published a report1 of a phase III study of 676 patients with stage III or IV melanoma (which was initially presented at the Plenary Session of the 2010 ASCO Annual Meeting). They were randomly assigned to receive ipilimumab plus a glycoprotein 100 peptide vaccine (gp100), ipilimumab alone, or gp100 alone. Median overall survival was significantly better in patients who received either the combination or ipilimumab alone (10 and 10.1 months, respectively) compared to those on gp100 alone (6.4 months). However, it should be noted that 14 deaths were related to study drugs.

The Present Trial The BRIM3 trial, sponsored by Roche and Plexxikon, a biotech company in Berkeley, California, was begun in January 2010 with 675 patients with previously untreated melanoma who had the BRAF V600 mutation. (It was stopped only a year later—the shortest phase III trial on record.) It was randomized, controlled, openlabel, and multinational, with the primary endpoint of overall survival and secondary endpoints of time to disease progression and duration of response. Half the patients were given dacarbazine and half were given PLX4032. Patients continued on the continued on page 16

The ASCO Post | MAY 1, 2011

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News JCO Spotlight

ASCO Issues Provisional Clinical Opinion on EGFR Mutation Testing for Advanced Lung Cancer

SCO has issued a provisional clinical opinion on the clinical use of epidermal growth factor receptor (EGFR) mutation testing to identify patients with

advanced lung cancer who may benefit from treatment with EGFR tyrosine kinase inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva). The opinion,

which is based on the results of five recent randomized clinical trials, recommends that patients with advanced non–small cell lung cancer who are being consid-

ered for first-line therapy with an EGFR tyrosine kinase inhibitor should first have their tumor tested for EGFR mutations. Such testing is currently available both at academic medical centers and at some community medical centers. A panel convened by ASCO examined evidence compiled through a review of the medical research literature—in addition to suggestions by panel members—to develop its recommendation. The opinion was published online in the Journal of Clinical Oncology.1 “EGFR testing helps us move toward the goal of tailoring cancer treatments for each patient,” said Panel Cochair Vicki Keedy, MD, Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center. “We’ve learned over the years that non–small cell lung cancer is really a collection of genetically distinct diseases. We want to treat patients with drugs that target the molecular drivers of their specific tumors, rather than using a one-sizefits-all approach. But how this approach affects the patients’ overall outcome remains uncertain.”

IPASS Trial The major impetus for the opinion was the Iressa Pan-Asian Study (IPASS), a phase III SEE PAGE 47 multicenter trial comparing gefitinib with standard carboplatin and paclitaxel chemotherapy as firstline treatment in patients in East Asia who had advanced non–small cell lung cancer and were either nonsmokers or light smokers. The IPASS trial found that among patients with negative tests for EGFR mutation, progression-free survival and response rates were greater in patients treated with chemotherapy, while patients with mutated EGFR had better progression-free survival and higher response rates when treated with gefitinib. Four smaller studies examining the use of gefitinib (and in some cases, erlotinib) as first-line treatment reported similar results. None of the studies showed differences in overall survival between those who tested negative for EGFR mutations and those with mutations.

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Reference 1. Keedy VL, Temin S, Somerfield MR, et al: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol April 11, 2011 (early release online).

ASCOPost.com | MAY 1, 2011

PAGE 7

Expert’s Corner Translational Research

A Conversation with Larry Norton, MD

Tumor self-seeding may explain mysteries, expand possibilities. By Ronald Piana

Larry Norton, MD

he origin and journey of metastatic cancer cells is a perplexing process, often portending a dire prognosis for patients. The concept of tumor self-metastasis, or self-seeding, originated at Memorial Sloan-Kettering Cancer Center, based on work led by Joan Massagué, PhD, head of the Metastasis Research Center, and Larry Norton, MD, Deputy Physician-inChief of the MSKCC breast cancer programs. Dr. Norton spoke with The ASCO Post, shedding light on their ongoing research in tumor self-seeding and how this fascinating concept could influence the timing and nature of cancer treatment.

Early Publications What have you published describing your work on tumor self-seeding? In 2006, Dr. Massagué and I published a hypothesis paper on self-seeding in the journal Nature. It was based on reasoning from several points of view including biology and clinical observations. But proof of concept demands experiments. In the December 25, 2009 issue of the journal Cell, our colleagues and we published the findings of many studies not only demonstrating that self-seeding of tumors by circulating tumor cells (CTCs) occurs, but also showing how it enhances the growth of tumors by chemical signaling, including the induction of angiogenesis and recruitment of the microenvironment. The Cell paper has garnered a lot of attention and has already been cited numerous times in the literature.

Solving Mysteries What are some of the clinical applications of the self-seeding concept? Self-seeding might help solve a number of clinical quandaries. For instance,

in breast cancer, when you excise the primary tumor to clear margins, why is it that we still must irradiate the remaining breast tissue? That is, why does irradiation of the breast decrease not only the incidence of local recurrences, but also the incidence of systemic recurrences, even in patients who do not develop locally recurrent disease? This has been a mystery that self-seeding may help solve. CTCs that seed the tumor also seed the region near the tumor, and then might grow locally or seed other sites later if not eradicated by the radiation therapy. As another example, given that sentinel node mapping has shown that cancer cells use lymphatic flow patterns to reach the axillary lymph nodes, why do some patients without axillary nodal involvement still develop systemic metastases? And why do some patients with axillary nodal metastases not develop metastases elsewhere, even if those nodal metastases are not removed by surgery or irradiated? The answer may

treated, for a long time. Distant metastases become evident well after the primary tumor is eradicated, so CTCs would have had to be present but invisible at the time of initial diagnosis. Why didn’t they show up as gross disease in distant sites at the same time the primary tumor became apparent, or soon thereafter? An answer may be that these CTCs preferentially went to the primary site when it was still viable, going to and colonizing distant sites only when the primary site was no longer available. In other words: these tumors are metastatic, but they are metastatic to themselves! In this regard, it is interesting to note that in the early to mid 19th century, before patients with breast cancer were routinely treated by mastectomy, most women died of extensive local disease. Now that our surgical and radiotherapeutic procedures gain excellent local control, we have actually permitted the development of distant metastases because, basically, the CTCs have no other place to go.

Before patients with breast cancer were routinely treated by mastectomy, most women died of extensive local disease. Now that our surgical and radiotherapeutic procedures gain excellent local control, we have actually permitted the development of distant metastases. —Larry Norton, MD

be that metastases are site-specific, with the primary tumor being one of those specific sites, as are nodes and distant organs. The genetic tools that a cancer needs to self-seed may overlap but may not be the same as the ones that it needs to seed lymph nodes, which again may overlap but not be the same as the genetic tools needed to seed other parts of the body. So we are dealing with correlations rather than certainties regarding metastatic behavior. We are just beginning to elucidate the different gene sets that cancers use to accomplish their diverse behaviors. Another mystery: Why is it that so few patients—less than 5% in the developed world—present with metastatic disease, even when their tumors are large by virtue of growing in the breast, un-

Ongoing Research What other current areas of investigation focus on self-seeding? The concept of self-seeding has opened up many areas of investigation with clinical implications. Understanding—at the level of biology and not just clinical correlations—the gene sets responsible for all metastases, distant and self, is the most important goal. This should lead to the identification of new targets for targeted therapies. Some of the genes already identified by Dr. Massagué’s group are possible targets for drug therapy. This includes the actin cytoskeleton component fascin-1, which is an important factor for making cancer cells rigid and correlates with the clinical aggressiveness of tumors. Others are the two molecules that

are most important for attracting the seeds back to the primary site, the cytokines IL-6 and IL-8. We know that the relationship between inflammation and cancer is very real, and these cytokines are intrinsic to the inflammatory process. Inflammatory cytokines, after all, are important for attracting white blood cells to areas of infection. This is good regarding the body’s ability to contain and cure bacterial infections, but may be very bad regarding cancer. In addition, a unique new avenue is opening for us, seeking to exploit the phenomenon of cells returning to their home base. The tumor is acting as a sponge for soaking up CTCs. Can we make it a “poisoned sponge”? In other words, can we find ways to convert a tumor into a site to both receive and kill cancerous cells? We have a number of ongoing research projects in this area.

Better Use of Resources What is the future of this research? Obviously, the scientific field of oncology has made massive strides over the past few decades. The speed with which we are finding answers to questions with clinical relevance has been much faster than ever before. However, I think that we have reached a point in our history where we really need to reinvent the way we utilize those biologic answers in developing real medical advances. The system by which we develop new drugs needs to be constructively scrutinized. Perhaps smaller, more nimble biotechnology companies with stronger affiliations to academic centers would yield better results. Also, we would certainly benefit from more extensive international academic collaboration. But most important, the mechanics of converting discoveries into clinical advances need to be improved. This is not just about getting more money into oncologic research, which as an enterprise has always been underfunded; it’s about using our financial resources more wisely. Molecular pathology has changed the game, so now it is time to change the rules. In addition to laboratory and clinical science, this is another area that deserves thought and action over the next decade.

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

ASCOPost.com | MAY 1, 2011

PAGE 11

Global Perspective

Cancer in South Africa and the Role of the National Cancer Registry By Daniel A. Vorobiof, MD, and Paul Ruff, MD

Daniel A. Vorobiof, MD

he National Cancer Registry of South Africa, which publishes pathology-based cancer incidence data, was first established in 1986. Some 36,000 new cases were recorded in South Africa that year, and the National Cancer Registry currently receives information about 60,000 new cases annually. The main objective of the Registry is to monitor cancer burden in South Africa and report cancer incidence for each year, stratified by sex, age, and population group, as well as time trends over the past 20 years. Programs to control cancer need to be evaluated using accurate information on incidence, prevalence, and cancer patterns in different parts of the country. These parameters vary widely as a result of differences in access to health care, sociodemographics, lifestyle, and environmental factors. Most currently available information on cancer incidence is derived from developed countries. With the technical assistance of the International Agency for Research on Cancer, the number of cancer registries in Africa has recently increased. The major challenge facing cancer registries in developing countries is the implementation of World Health Organization-recommended, population-based cancer registries, to obtain accurate data that will better inform government policy. An added challenge is the need to overcome financial constraints and limitations imposed by a lack of trained personnel, to ensure long-term sustainability.

South African Data South Africa has a land area of 1.2 million km2, with the latest Na-

tional Census (1996) estimating a population of 42 million inhabitants (75% black, 14% white, 8.6% mixed race, 2.4% Asian). Cancer remains a major killer throughout the developed and developing world, including South Africa. Cancer incidence rates in South Africa are among the highest reported in Africa. According to the latest 2002 data from the National Cancer Registry, South African males have an overall age standardized incidence rate of cancer of 135.89 per 100,000 and a lifetime

diagnosed with cancer, with cancer of the breast (1 in 29) and cancer of the uterine cervix (1 in 36) predominating; cancers of an unknown primary site (1 in 91), corpus uteri (1 in 148), colon/rectum (1 in 158), and esophagus (1 in 199) followed.

Toward A More Accurate Picture In South Africa, lung cancer remains a growing health problem in both sexes. Although lung cancer risk in males (lifetime risk of 1 in 71) far exceeds that in females (life-

tests (alpha-fetoprotein)—without tissue diagnosis—but still remains among the top 15 most common cancers. Approximately 700,000 new cases yearly are diagnosed worldwide, especially in southern Africa and the Far East, which are endemic for hepatitis B virus. Future population-based registries, as well as better cancer diagnoses, especially in rural areas, will give us a more accurate picture of this usually fatal malignancy, as well as other pathologically underdiagnosed cancers. In considering cancers associated with HIV/AIDS, Kaposi’s sarcoma was the third most common cancer in South African males and females aged 15 to 29 years, comprising approximately 9% of all cancers in this group. Contrary to most cancers where the age standardized incidence rate peaks at older ages, the rate for Kaposi’s sarcoma showed a bimodal pattern in most racial groups, with the highest peaks at ages 25 to 29 in women and 35 to 39 in men.

Conclusions risk of developing cancer of 1 in 7, whereas South African females have an age standardized incidence rate of 115.53 per 100,000 and an lifetime risk of developing cancer of 1 in 8. In 2002, 28,126 males developed

time risk of 1 in 233), the long-term effects of smoking will result in increasing incidence of lung cancer in females as well as males for years to come. It will be decades before recent antismoking drives and legisla-

The major challenge facing cancer registries in developing countries is the implementation of World Health Organization-recommended, population-based cancer registries, to obtain accurate data that will better inform government policy. cancer; cancers of the prostate (1 in 23), unknown primary site (1 in 64), lung (1 in 71), esophagus (1 in 91), colon/rectum (1 in 99), and bladder (1 in 109) predominated. The same year, 28,430 women were

tion will reduce these figures. Some cancers are suboptimally reported because of a lack of tissue diagnoses. An important example is hepatocellular carcinoma, which is diagnosed clinically and by blood

Monitoring cancer incidence is important in detecting changes in cancer patterns that might occur as a result of environmental conditions or in association with other diseases (for example, HIV/AIDS). Such records are also essential for the detection of new cancers, and to measure effectiveness of cancer control programs. Future legislation in South Africa will make cancer a reportable disease by both pathologists and clinicians, enhancing the existing pathology-based registry while developing population-based registries.

■

Financial Disclosure: Dr. Vorobiof and Dr. Ruff reported no potential conflicts of interest.

Dr. Vorobiof is Oncology Director of the Sandton Oncology Centre, Johannesburg , South Africa, and a member of The ASCO Post’s International Editorial Board. Dr. Ruff is Professor of Medical Oncology at the University of the Witwatersrand, Faculty of Health Sciences, Johannesburg.

The ASCO Post | MAY 1, 2011

PAGE 12

End-of-life Care Policy

Personalized Therapy continued from page 1

of-life and palliative care, creating instructional materials to make this issue much more visible within the cancer community. Today, the “Art of Oncology” series published in the Journal of Clinical Oncology, addresses how oncologists deal with end-of-life issues. We’ve maintained our interest and efforts in evolving the quality of care in advanced disease for the past 15 years. So the release of the statement is a continuation of ASCO’s work in this area. Moreover, the recent health-care debate leading up to passage of the Affordable Care Act reinforced some of the misconceptions that surround end-of-life care. The politicized debate about these discussions demonized the act of providers engaging patients in these difficult, yet necessary conversations. As the world’s leading professional oncology society, we felt that we had a responsibility to reframe the issue from the perspective of professionals who deal with end-of-life care on a daily basis. That’s how we arrived at this point.

Impact on Public Perception What is the practical effect of an ASCO policy statement? ASCO’s goal is to ensure that cancer care planning throughout the trajectory of care remains a very active part of the current dialogue within the oncology community. The release of the ASCO statement provided much needed medical perspective on this

issue at the national level, and that is a positive step in helping patients and their families talk about the difficult issues patients face when diagnosed with advanced cancer. We intend to follow up with additional practice guidance and more educational materials to ensure that our members are informed, educated, and prepared to initiate these discussions with their patients. The ASCO statement recommends specific steps for physicians to conduct candid discussions about the full range of palliative care and treatment options soon after patients’ diagnosis

with cancer and how the experience was less than optimal. They encouraged us to continue with this work. So I think we are beginning to have a small, but meaningful influence on the public’s perception about the role of these honest discussions, and how timely doctor-patient communication is essential to optimal care during this difficult time.

A Learning Process What sort of research is being conducted in the terminal cancer setting? As with any aspect of care, we are learning, testing, and researching

Timely doctor-patient communication is essential to optimal care during this difficult time. — Allen S. Lichter, MD

with advanced cancer, which is defined as incurable disease. While ASCO’s efforts received broad news coverage among consumer media, we still have a long way to go in educating people about palliative care and hospice. However, this is the first time since I’ve been working at ASCO that I’ve received mail from the general public, saying “thank you for making this statement.” Some people shared stories of caregiving for family members

Caring for Patients with Incurable Disease

ey elements to individualizing advanced cancer care include the following considerations: ■■ Physicians should initiate frank discussions about prognosis with their patients soon after an advanced cancer diagnosis. Such conversations occur with less than 40% of patients. ■■ Quality of life should be a priority throughout the course of advanced cancer care. Physicians must help their patients fully understand their prognosis, the potential risks and benefits of available cancer treatments, and quality-oflife considerations. In cases where active treatment is unlikely to extend survival, palliative care should be discussed as a concurrent or alternate therapy. ■■ Clinical trial opportunities should be increased. Currently, very few patients with advanced cancer participate in trials because of strict eligibility criteria. Increasing opportunities for these patients to potentially benefit from trials and to contribute to improving cancer care should be a high priority.

■

to find ways to improve care for our patients at the end of their lives. In ASCO’s statement, Jeffrey Peppercorn, MD, and colleagues addressed ASCO’s vision for improved communication with patients who have been diagnosed with advanced cancer. One of the most important points of the paper is the need for more research to determine better ways to care for patients with terminal disease. For example, ASCO’s Conquer Cancer Foundation sponsored research about early initiation of palliative care in patients with non–small cell lung cancer that was published in The New England Journal of Medicine by Jennifer S. Temel, MD, and colleagues. They found that patients who received early palliative care integrated with standard care had better quality of life and longer median survival than those who received standard care alone. The Temel paper was provocative and will certainly lead to future studies that seek to replicate the results. An important question that will be asked in future studies is what are the special components of early palliative care intervention that lead to better outcomes? Once we have the answers to

that question, we will be able to better tailor our care in a more personalized manner.

Closing Thoughts How do political debates over physician reimbursement complicate these issues? Oncologists across the country understand that high-quality care does not end with a diagnosis of incurable disease. However, it is important to note that during the debate over the Affordable Care Act, the issue of payment for these cancer care planning discussions was a sticking point. Unfortunately, efforts to compensate oncologists for delivering this important aspect of cancer care were politicized, warping the important underlying message. Our current reimbursement system is heavily weighted toward procedures, and the highly complex cognitive services provided by oncologists go largely uncompensated. In fact, most public and private insurance plans provide little or no compensation for discussions with patients about palliative care options, despite their demonstrated value. Professionals such as lawyers are paid for their time spent speaking with and advising clients about estate planning, wills, and other end-of-life issues, and we accept that as common practice. But somehow policymakers feel that the very difficult and complex discussions doctors have with their patients surrounding their preferences and decisions for the future when diagnosed with advanced cancer should not be paid for. This attitude does a disservice to doctors and their patients whose quality of life would be greatly enhanced by these conversations Patients want and need information about optimal advance care planning. Oncologists have a responsibility to provide that information to their patients, and they should be appropriately compensated for the time it requires to have those necessary conversations. That said, our position statements, educational efforts, and work in this important patient care area is going to continue, regardless of whether there is a specific compensation mechanism in place for these valuable services.

■

ASCOPost.com | MAY 1, 2011

PAGE 13

News Gastrointestinal Cancers

Neuroendocrine Tumors

“The combination narrowly missed the prespecified boundary,” he noted. By local assessment, the same risk reduction was seen (HR = 0.78) but the P value was significant at P = .018. According to Dr. Yao, the lack of statistical significance can be attributed to the “informative censoring,” in which patients with progressive disease per investigator but who are later judged to have nonprogressive disease on central review are “informatively censored” in the central PFS analysis due to a change in therapy—and this can create bias. To correct for this, the RADIANT-2 investigators used an inverse probability of censoring weights (IPCW) analysis. This produces a “corrected treatment effect estimate” that, in this case, became statistically significant, he said (Table 1). “In all three analyses the hazard ratios favor everolimus, and the prespecified statistical analysis [inverse probability of censoring weights] adjusting for informative censoring, loss of power, and imbalances

continued from page 1

best supportive care, with crossover allowed upon progression. Median duration of exposure was 38 weeks for the active arm and 16 weeks for the placebo arm. Median PFS was 11.0 months with everolimus and 4.6 months with placebo, for a highly significant 65% reduction in risk (P < .0001). The 18-month PFS rates were 34% and 9%, respectively, reported Manisha H. Shah, MD, of Ohio State University Comprehensive Cancer Center in Columbus, Ohio.1 To control symptoms, 50% of patients on each arm had prior somatostatin analog use, and 40% used these drugs concomitantly with study treatment. Prior or concomitant use of somatostatin analogs was not associated with any detriment in efficacy. “Everolimus showed a consistent benefit in all subgroups regardless of the presence or absence of somatostatin analog treatment,” she said.

Table 1: RADIANT-2 Progression-free Survival Comparison Median PFS Assessment

Hazard Ratio

P Value*

Everolimus + Octreotide

Placebo + Octreotide

Local (investigator)

0.78

.018

12.0 mo

8.6 mo

Central

0.77

.026

16.4 mo

11.3 mo

IPCW (central)

0.60

.0014

13.8 mo

8.3 mo

*P value prespecified for statistical significance was P < .0246. IPCW = inverse probability of censoring weights; PFS = progression-free survival.

Everolimus Plus Octreotide LAR In RADIANT-2, which was conducted in 429 patients with advanced neuroendocrine tumors and a history of secretory symptoms, everolimus added to long-acting octreotide at 30 mg monthly “demonstrated a clinically meaningful prolongation of median PFS,” according to James Yao, MD, of The University of Texas MD Anderson Cancer Center, Houston.2 However, the 5.1-month prolongation of median PFS (HR = 0.77; P = .026) did not reach statistical significance by central review, according to the prespecified P value (P = .0246).

in baseline prognostics factors demonstrate a consistent benefit,” Dr. Yao reported.

Exploratory Analysis In an exploratory analysis, patients without prior somatostatin analog use had greater absolute and relative benefits, he added. In this group, median PFS with the combination was 25.2 months compared with 13.6 months for long-acting octreotide alone; in patients with prior use of these agents, PFS was 14.3 vs 11.1 months, respectively. The treatment was well tolerated, but more treatment-related adverse

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The ASCO Annual Meeting

Expert Point of View

ary F. Mulcahy, MD, of Northwestern University School of Medicine, Chicago, said that everolimus provided a “significant and durable benefit” in previously treated patients with pancreatic neuroendocrine tumors. Dr. Mulcahy was a discussant for the updated data from the RADIANT trials presented at this year’s Gastrointestinal Cancers Symposium. However, she had concerns about everoliMary F. Mulcahy, MD mus combined with long-acting octreotide in the broader neuroendocrine tumor population of RADIANT-2. “For the population studied, the benefit of everolimus with long-acting octreotide is undefined, and activity is demonstrated but is associated with significant adverse events,” she said. In particular, she questioned the large discrepancy in PFS by local assessment (12.0 months) vs central review (16.4 months). “I think this tells us that PFS may not be the right endpoint for evaluating disease with secretory symptoms. The clinician may think the patient is progressing, and the patient would be censored, while by radiologic review the disease is actually stable,” she pointed out.

Questionable Benefit Dr. Mulcahy noted that in the RADIANT-2 study 70% of the everolimus arm came off study due to progressive disease or adverse events, compared with 75% on the placebo arm. The median duration and range of exposure to everolimus was comparable in each arm. “Either way, this represents a failure of treatment,” she maintained. “I have concerns about the drug’s benefit. There is a signal, but it is not well-defined,” she said. She also noted that outcomes with the tyrosine kinase inhibitor sunitinib (Sutent) have been “strikingly similar” to those seen with everolimus, with nearly a 60% reduction in risk of progression as well. Future studies should determine how to sequence these classes of agents, she suggested. Regarding tolerability, she agreed with the investigators that the study arms of both trials showed acceptable toxicity, with little grade 3 or 4 toxicity, “but you can’t discount grade 1 and 2,” she added. “This can be concerning when you treat for 11 months.”

■

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

events were seen in the everolimus arm, especially stomatitis, which occurred (all grades) in 62% of everolimus patients vs 14% of placebo patients with the single agent; grade 3 or 4 stomatitis was seen in 7% and 0%, respectively. Rash, fatigue, and diarrhea were also greater with everolimus plus long-acting octreotide.

■

Financial Disclosure: Dr. Shah and Dr. Yao reported no potential conflicts of interest.

References 1. Shah MH, Ito T, Lombard-Bohas C, et al: Everolimus in patients with advanced pancreatic neuroendocrine tu-

mors: Updated results of a randomized, double-blind, placebo-controlled multicenter phase III trial (RADIANT-3). 2011 Gastrointestinal Cancers Symposium. Abstract 158. Presented January 21, 2011. 2. Yao JC, Hainsworth JD, Baudin E, et al: Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors: Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2). 2011 Gastrointestinal Cancers Symposium. Abstract 159. Presented January 21, 2011.

The ASCO Post Harborside Press

Booth 3039 Booth 13068

THE FIGHT IS CHANGING. It’s more personal than ever. Now, genetic biomarker tests may help deliver the right cancer treatment to the right patient. Bio-specific medicine is changing the way we treat cancer. In many instances, doctors can now test a tumor’s distinct profile with the goal of providing more targeted, more effective treatments with fewer side effects. The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

The ASCO Post | MAY 1, 2011

PAGE 16

News Targeted Therapy

Metastatic Melanoma

The Genetics of Melanoma

continued from page 3

Metastatic melanoma is associated with an average life expectancy of 8 months after diagnosis. Not only are there few treatment options, there has been no significant improvement in treatment for 30 years. Moreover, the incidence is expected to double over the next decade.

study until disease progression or until unacceptable toxicity. Although the final results from BRIM3 are currently unknown, in a phase I trial PLX4032 provided an average remission of approximately 7 months from initiation of treatment. The longest responders have been taking the drug for 2 years. Paul Chapman, MD, Attending Physician in the Melanoma-Sarcoma Services Department, Memorial Sloan-Kettering Cancer Center, said “This is the first-ever drug for melanoma that correlates improved survival with improved response rate. We had hoped this would happen, but we didn’t know until we did the trial.” Adverse events for PLX4032 included keratoacanthoma, a relatively common, benign skin lesion, increases in liver enzymes, rash, photosensitivity, joint pain, hair loss, and fatigue. Dr. Flaherty believes that PLX4032 will receive accelerated approval this year or early in 2012. This is the “next big thing,” he said, and until it is improved upon, it will become the standard treatment for metastatic melanoma.

mechanism of resistance and find other agents to combine with PLX4032.” Drs. Flaherty and Chapman agreed that all patients with melanoma should be tested for the BRAF mutation and other genetic characteristics at diagnosis, preferably as part of the original pathologic examination. To that end, a number of diagnostic tests have been developed, one of which is Roche’s cobas 4800 BRAF V600 Mutation Test.

What’s Next for PLX4032?

Paul Chapman, MD

Keith Flaherty, MD

About half of the 68,000 people diagnosed every year have the BRAF mutation, which results in increased cell proliferation and apoptosis. PLX4032 is designed to selectively inhibit the mutated form of the BRAF protein and has been shown to significantly delay growth in tumors harboring the BRAF V600 mutation. However, PLX4032 is not exempt from inevitable drug resistance. “Everyone develops resistance sooner or

Advocate Perspective

imothy Turnham, PhD, Executive Director of the Melanoma Research Foundation in Washington, commented about PLX4032. “The problem in withholding a drug such as PLX4032 is that it might be lifesaving—or at least life-extending. Does this affect the way research is done? Probably, which is why we desperately need a series of conversations among FDA, pharma, and researchers. We have got to find a way to improve and speed up the process of drug research. It is now way too slow and way too costly—and patients are dying in the meantime.”

■

Dr. Chapman agreed. “It’s fantastic. Now we have something solid to build on. For the first time, we know the mechanism of action of a drug that improves survival, and although single-drug treatments are never the most effective, PLX4032 has given us a huge leg up in the search for a successful combination.”

transduction alterations or activation of a parallel signal pathway,” said Dr. Flaherty. Meenhard Herlyn, DVM, DSc, Leader, Molecular and Cellular Oncogenesis Program, Wistar Institute, and his Wistar colleague, Jessie Villanueva, PhD, Staff Scientist, noted that even if inhibition of mutant

later,” said Dr. Flaherty. There might be a secondary mutation in the BRAF gene that prevents binding, but resistance can occur even in its absence. “Preliminary analyses of tumors collected from patients whose disease has progressed suggest something other than mutations in BRAF. It may be other mutations and/or signal

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Meenhard Herlyn, DVM, DSc

BRAF shuts down a major pathway, some cancer cells can use an alternate pathway and survive. Thus, resistant cells can reroute their signal around BRAF by switching to an alternate protein that promotes tumor cell growth. Combination therapies may overcome resistance. Drs. Herlyn and Villanueva have developed a model that allows melanoma cells to grow in vitro to determine which are vulnerable to various drug combinations. They also found that tissue samples taken from patients in phase I and phase II trials both before treatment and after they developed resistance show that an increased expression of one particular receptor is associated with resistance to BRAF inhibitors. And they noted an association between the loss of the tumor suppressor PTEN and resistance to BRAF inhibitors in melanoma cell lines. In fact, the relapsed tumor of one patient lost the PTEN gene even though it was present before treatment, suggesting that loss of PTEN could be an additional path to resistance. “BRAF mutations are probably necessary—but insufficient—to turn a cell into a melanoma,” Dr. Chapman added. “There are still a lot of unknowns—for instance, why some patients with the BRAF mutation responded to PLX4032 and some didn’t. But, we are racing to understand the

ASCOPost.com

Dr. Flaherty believes that PLX4032 has “blown the door off ” the barriers to therapeutic response to a melanoma drug. “PLX4032 will be used as a stepping stone to more trials with a variety of drug combinations, some perhaps with other MAP kinase pathway inhibitors and some with compounds that affect other mutated pathways.” PLX4032 is available through an expanded-access program from Roche, since the drug is currently investigational and not FDA approved. Dr. Flaherty is a proponent of this SEE PAGE 47 and other expandedaccess programs. “We’re in the business of finding drugs to treat people, and when we find one, they should be given access,” he said, but that doesn’t mean that patients with cancer should have access to any compound that comes down the pike. “It’s preposterous to give people an unproven drug. That’s the road back to the bad old snake oil days. But if there’s a drug that works and is on its way to approval, then of course, patients should have it.”

■

Financial Disclosure: Dr. Chapman reports serving as a consultant for Roche Pharmaceuticals. Dr. Flaherty reports serving as a consultant for GlaxoSmithKline and Roche Pharmaceuticals. Dr. Herlyn reported no potential conflict of interest. Dr. Turnham is an employee of the Melanoma Research Foundation. Dr. Villanueva reported no potential conflict of interest.

Reference 1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.

ASCOPost.com | MAY 1, 2011

PAGE 17

OncologyWorldwide From Cairo to Brussels: An International Perspective Hatem Azim, MD, discusses cancer care abroad. By Ronald Piana

Hatem Azim, MD

he worldwide oncology community shares a common language based on evidence, clinical trials, and shared anecdotal results of the dayto-day care of patients with cancer. However, diverse political, economic, and cultural issues in different geographic regions present varying challenges to the delivery of oncology services. This column kicks off an ongoing series of articles, Oncology Worldwide, which will explore those similarities and differences on an occasional basis. Hatem Azim, MD, an oncologist from Cairo, Egypt, now working in Brussels, Belgium, recently spoke with The ASCO Post about his experience as an international oncologist.

Career Choices Why did you choose a career in oncology? In my last 2 years of medical school, I was fortunate enough to

be offered an internship at the University of Nebraska Medical Center (UNMC). I worked closely with experts in the field of lymphoma at the UNMC Eppley Institute for Research in Cancer and Allied Diseases and became impressed with the challenges and potential in the field of hematologic malignancies, on the clinical as well as the research side. I believe my experience in the United States was a pivotal point in my decision to become an oncologist. In addition, observing the progress of my father, who is a successful Egyptian

Because of a number of cultural awareness and barriers-to-access issues, Egyptian patients with cancer usually present at a relatively advanced stage in their disease. oncologist, and being close to him on the personal level, unsurprisingly provided an extra nudge to seal my decision.

Cancer Care in Egypt Your career choice was influenced by your experience in the United States, a country with vast resources. What challenges did you face as a practicing oncologist in Egypt? In Cairo, I was working at the National Cancer Institute, which is

Egyptian Cancer Epidemiology at a Glance

here is no population-based cancer registry in Egypt; however, based on hospital-based registries, the leading cancers in Egypt are those of the urinary bladder (32.67%), gastrointestinal tract (22.24%), and breast (13.15%), followed by lymphoma (9.8%). Egyptian patients have some features in common with those observed in developed countries, including a high incidence of breast and gastrointestinal cancers. Currently, the most distinct cancer patterns in Egypt are liver cancer secondary to endemic hepatitis C virus (around 15% of the population) and mesothelioma due to the wide use of asbestos in the local industry. Bladder cancer secondary to schistosomiasis was common in Egypt over the past 2 to 3 decades, but with the proper treatment of schistosomiasis, the incidence of bladder squamous cell carcinoma secondary to this disease is significantly declining.

■

the largest cancer center in Egypt, seeing around 20,000 newly diagnosed cancer cases per year. I was a resident in the Department of Medical Oncology for 3 years; then I spent 1 year as an assistant lecturer. During this period, I faced several challenges that are endemic in the Egyptian cancer care system, where the number of accumulated patients with cancer represents about three times the amount of new patients, and the patient load is expanding. Naturally, access to care in Egypt is an issue. We have extremely busy out-

patient clinics; at times, I used to see 40 to 50 patients a day! The demand on patient admissions always exceeded the available resources. That shortage was also true in chemotherapy, especially expensive drugs and newer targeted agents. Moreover, we lacked a systematic way of discussing cancer cases in the outpatient clinic, which was compounded by an absence of multidisciplinary meetings and tumor boards. Because of a number of cultural awareness and barriers-to-access issues, Egyptian patients with cancer usually present at a relatively advanced stage in their disease, which has a negative impact on treatment results. Adding to that dilemma, patients also face long waiting lists to get basic radiologic and other diagnostic examinations, presenting significant delays in treatment initiation.

Policy Problems How does the political machine in Egypt affect cancer care? Health-care policies as they pertain to managing patients with cancer were very poorly addressed at the time I was practicing oncology in Egypt.

When someone is diagnosed with cancer, it takes their insurance provider an inordinate amount of time to cover health costs, and in most cases, the coverage did not exceed 20% to 30% of the patient’s real costs. This situation forces patients to start and stop therapy until they can sort out the problem with the insurance carrier. Consequently, we spent a lot of time writing reports for patients, requesting increased coverage from their insurance provider. This compromises the quality of medical care patients receive and places a huge administrative burden on providers. It is a major barrier to the delivery of cancer care, especially since many patients in Egypt are resourcechallenged.

On to Brussels You are currently in Brussels. Could you briefly explain your work there? I moved to Brussels in 2009 to work as a fellow in the Department of Medical Oncology at Institut Jules Bordet, working exclusively in the field of breast cancer. My main task was acting as a medical advisor for large, international phase III clinical trials conducted by the Breast International Group (BIG). In addition, I was involved in writing, discussing, and developing new clinical and translational research protocols in breast cancer. At the same time, I was enrolled in the PhD program of the Université Libre de Bruxelles. In 2010, I earned a translational research grant from the European Society for Medical Oncology (ESMO) and moved to the Breast Cancer Translational Research Laboratory in the same institute. There I am developing my PhD project on the biology and prognosis of breast cancer diagnosed during pregnancy, using gene expression profiling, while continuing to do my clinical research work as well.

U.S. vs European Practice What about the European oncology experience is different from how oncology is practiced in the United States? continued on page 18

The ASCO Post | MAY 1, 2011

PAGE 18

Oncology Worldwide

From Cairo to Brussels continued from page 17

I have worked in two large cancer institutes in Europe: the European Institute of Oncology in Milan (2008) and where I now work, the Institut Jules Bordet in Brussels. I also had the opportunity to visit

a couple of cancer centers in the United States—the University of Nebraska Medical Center and Beth Israel Deaconess Teaching Hospital in Boston. In my opinion, the quality of cancer care is actually quite comparable in the United States and Europe.

In my experience at various institutes, I did not witness significant differences in the quality of the multidisciplinary discussions. Likewise, I found a universal appreciation of the importance of conducting highquality research that translates into clinical benefits. Any differences in

approach between Europe and the United States might be determined more by cultural and political environments, but I found the quality of research and cancer care to be on the same level.

■

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

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief email: Editor@ASCOPost.com Cara H. Glynn Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

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TREANDA® is his chemo.

This is his therapy.

B:17.

T:15

S:14

.25”

5.5”

4.5”

ASCOPost.com | MAY 1, 2011

PAGE 19

FDA Update

Vandetanib Approved for Medullary Thyroid Cancer

he FDA recently approved vandetanib, a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, local-

ly advanced, or metastatic disease. The use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease should be carefully considered because of the

treatment-related risks of vandetanib. The approval was based on an international, multicenter, randomized, double-blind trial conducted in patients with unresectable locally advanced or metastatic medullary

thyroid carcinoma. Patients were randomly assigned (2:1) to receive either vandetanib, 300 mg/d orally, (n = 231) or placebo (n = 100). The primary objective was demonstration of improvecontinued on page 20

Single-agent TREANDA produced a 74% ORR* in patients with indolent B-cell NHL that had progressed

ORR*: INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA (NHL) THAT HAS PROGRESSED

57%

PR (n=57)

17%

CR/CRu (n=17)

74%

Total ORR

(95% CI†: 64.3, 82.3)

100

Patients responding (%) *Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm. † CI=confidence interval.

• TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles • TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176) • The most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

LEARN MORE AT TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

B:11.125”

Discover the elements of efficacy and safety

S:10”

Selected Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

T:10.5”

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

The ASCO Post | MAY 1, 2011

PAGE 20

FDA Update

Thyroid Cancer continued from page 19

ment in progression-free survival with vandetanib compared to placebo. Other endpoints included evaluation of overall survival and objective response rate. A central, independent blinded review of the imaging data was used

in the assessment of progression-free survival and objective response rate. Upon objective disease progression, patients were given the option of receiving open-label vandetanib.

Key Data An improvement in progression-

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

free survival was observed for patients randomly assigned to receive vandetanib (HR = 0.35; 95% CI = 0.24– 0.53; P < .0001). Analyses in the subgroups who were either symptomatic or who had disease progression within 6 months prior to enrollment showed similar progression-free survival re-

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

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

sults: hazard ratios of 0.31 (95% CI = 0.19–0.53) and 0.41 (95% CI = 0.25– 0.66), respectively. At the primary progression-free survival analysis, 15% of the patients had died; no significant overall survival difference was noted. The objective response rate was 44% vs 1% for patients randomized to receive vandetanib or placebo, respectively. All objective responses were partial responses. QT prolongation, torsades de pointes, and sudden death are included in a boxed warning. Because of vandetanib’s prolonged half-life of 19 days, ECGs and levels of serum potassium, calcium, magnesium, and TSH should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment, and subsequently every 3 months. Electrolytes and ECGs may require more frequent monitoring in patients experiencing diarrhea. Only prescribers and pharmacies certified through the Vandetanib Risk Evaluation Mitigation Strategy Program, a restricted distribution program, are able to prescribe and dispense vandetanib.

Adverse Effects The most common (≥ 20%) grade 1–4 adverse reactions included diarrhea/colitis, rash, dermatitis acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Laboratory abnormalities in > 20% of patients included decreased calcium, increased ALT, and decreased glucose. The most common (≥ 5%) grade 3/4 adverse reactions were diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Adverse reactions resulting in death in patients receiving vandetanib (n = 5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. In addition, two deaths in patients receiving vandetanib (one sudden death and one death from cardiopulmonary arrest) were noted after data cutoff. “Vandetanib’s approval underscores FDA’s commitment to approving treatments for patients with rare and difficult to treat diseases,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. Vandetanib is marketed by AstraZeneca Pharmaceuticals LP of Wilmington, Delaware. There is no trade name established for the drug at this time.

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ASCOPost.com | MAY 1, 2011

PAGE 21

News Gastrointestinal Cancer

Sorafenib Given Differently by Oncologists and Nononcologists in Global Investigation of Hepatocellular Carcinoma Treatment By Barbara Boughton

he first interim results of the GIDEON registry trial, in which patients with unresectable hepatocellular carcinoma were treated with sorafenib (Nexavar),

Alan Venook, MD

revealed that oncologists use this treatment much differently from other specialists. Results in 479 patients indicate that oncologists were more likely to treat patients

with advanced cancer, yet were also less likely than hepatologists or gastroenterologists to use a full 800-mg starting dose, and also used sorafenib for a shorter time (11.7 vs 13.1 weeks for gastroenterologists and hepatologists). The first interim results of the GIDEON study were presented in January at the Gastrointestinal Cancers Symposium in San Francisco.1 “Hepatologists use a higher dose of sorafenib on average in patients with hepatocellular carcinoma than do medical oncologists, but this is not explained by a difference in toxicities,” said lead researcher Alan Venook, MD, Professor in the Department of Medicine at the University of California, San Francisco. “Toxicities among these patients appear to be comparable across specialties, including handfoot syndrome and hematologic toxicities.”

Interspecialty Differences in Treating Liver Cancer ■■ The initial results in 479 patients with hepatocellular carcinoma from the

GIDEON trial indicate that hepatologists and gastroenterologists are more likely to use a full starting dose of sorafenib than medical oncologists, and to treat patients with this therapy for a longer period of time.

■■ Medical oncologists in the study were more likely to treat patients with

advanced disease, but they were also more likely to use a lower dose of sorafenib throughout treatment.

■■ Although treatment patterns with sorafenib clearly varied among

hepatologists/gastroenterologists and medical oncologists, toxicity rates (eg, for hand-foot syndrome and hematologic toxicities) were similar among all three specialties.

Child-Pugh Score

hild-Pugh score1,2 is a prognostic measurement used in patients with chronic liver disease. The Child-Pugh score is determined by five clinical measures, including total bilirubin level; serum albumin level; prothrombin time expressed by international normalized ratio (INR), presence of ascites (none, mild, severe); and presence of hepatic encephalopathy (none; grade I-II; grade III-IV). Each clinical measure is assigned 1 to 3 points ranging from least severe (1 point) to most severe (3 points). A total score based on the five clinical measures is used to determine Child-Pugh Class of disease (A, B, or C). Child-Pugh Class A is associated with 1- and 2-year survival rates of 100% and 85%, respectively; Class B is associated with 1- and 2-year survival rates of 81% and 57%, and Class C is associated with 1- and 2-year survival rates of 45% and 35%, respectively.

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References 1. Child CG: Surgery and portal hypertension, in Child CG (ed): The Liver and Portal Hypertension, pp 50-72. Philadelphia, WB Saunders, 1964. 2. Pugh RN, Murray-Lyon IM, Dawson JL, et al: Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646-649, 1973.

Expert Point of View

he findings from the first interim analysis of the GIDEON trial are significant because they point out the different approaches to treatment of hepatocellular carcinoma by oncologists and hepatologists/ gastroenterologists, said Morton Kahlenberg, MD, a surgical oncologist and Medical Director of the Baptist Cancer Center in San Antonio, Texas. Compared with hepatologists or gastroenterologists, medical oncologists have very different training Morton Kahlenberg, MD and experience in treating patients with hepatocellular carcinoma, Dr. Kahlenberg noted. “Because of their background and experience in dealing with adverse events and toxicities, medical oncologists may have a bit more concern about starting at a higher dose of sorafenib,” he said. “Medical oncologists are more likely to build their way up to the full dose of sorafenib to make sure the patient is tolerating the dose adequately,” he said.

‘It’s Good to Be Cautious’ Gastroenterologists, hepatologists, and medical oncologists worldwide are treating hepatocellular carcinoma, but the specialties have different viewpoints and experience with the efficacy and toxicities of this cancer treatment, he said. The final results of the GIDEON trial should be illuminating, because they will detail toxicities as well as efficacy of sorafenib among patients treated by hepatologists, gastroenterologists, and medical oncologists, Dr. Kahlenberg said. Dr. Kahlenberg did not think that medical oncologists are overly wary of sorafenib at higher doses for treatment of hepatocellular cancer. “I think it’s good to be cautious,” he said. “It will be interesting to see what kind of outcomes will result from treatment of patients by the different specialties in the G IDEON trial,” he noted.

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

Real-world Patterns The GIDEON trial researchers aim to evaluate the use of sorafenib in real-life circumstances, and have the goal of accruing 3,000 patients from over 400 sites in 40 countries. In previous studies, treatment with sorafenib has produced a marked improvement in overall survival for patients with hepatocellular carcinoma, and it is the only systemic therapy indicated for treatment of the disease. The GIDEON trial was designed to explain differences in outcome with sorafenib seen in previous studies, ie, less favorable outcomes in Asia-Pacific regions than Western countries, where patients tend to have a lower incidence of hepatitis B and less advanced disease, Dr. Venook said. “We designed GIDEON to look at the global use patterns of sorafenib and to give us a look at how it is used in the real-world setting. We’re hoping that the results of the trial may explain the differences in outcome we’ve seen in previous studies,” he added.

The initial results in 479 patients indicate that there are clear differences among countries as to which specialists are more likely to treat hepatocellular carcinoma, as well as their use of sorafenib. About half of patients in the United States were cared for by medical oncologists, but two-thirds of those in Europe were treated by hepatologists and gastroenterologists. On the whole, medical oncologists were more SEE PAGE 47 likely to treat patients with stage IV hepatocellular carcinoma and less likely to treat patients with ChildPugh B disease than hepatologists and gastroenterologists. In Asia, hepatologists usually used full doses of sorafenib (800 mg/d) at the start of therapy. Medical oncologists from the same region as well as those in the United States were most likely to start therapy at about 500 to 530 mg/d, however. “In the U.S., medical oncologists used the starting continued on page 25

The ASCO Post | MAY 1, 2011

PAGE 22

Direct from ASCO

ASCO Offers Mobile Apps for Meeting Navigation, Member Content

o assist ASCO Annual Meeting attendees who use their smartphones and iPads to plan and enhance their Meeting experience, ASCO offers two free Meetingrelated apps. iPlanner allows users to browse sessions, personalize a Meeting schedule, and locate session rooms and exhibits/booths on an interactive McCormick Place map. iMeeting allows users to play purchased Mobile Meeting content (videos captured at Annual Meeting and thematic symposia sessions) on Web-enabled devices. ASCO also offers apps that allow convenient on-the-go access to the Membership Directory, Society publications, patient information on Cancer.Net, and the Conquer Cancer Foundation. ASCO’s complete suite of apps is detailed below.

MEETING APPS iPlanner Free; available for iPhone, iPad, Android, and BlackBerry. Search “ASCO” in App Store, iTunes Store, or Google Marketplace.

iMeeting Free app; available for iPhone and iPad. Search “ASCO” in App Store or iTunes Store.

■■ Get directions to a contact’s address from your location, or view nearby colleagues on a list or map view ■■ Read the ASCO Twitter feed

iLibrary Free; available for iPad. Search “ASCO” in App Store or iTunes Store. Members-only; sign in with ASCO.org username and password for access. Highlights: ■■ View Mobile Meeting content (videos) captured at 2011 ASCO meetings. Content can be purchased during Registration, online at the ASCO University Bookstore (university.asco.org/ store), or onsite at ASCO University Bookstore locations ■■ Access Meeting presentations where and when you want, without being tethered to a computer

MEMBER-ONLY APPS iDirectory Free; available for iPhone, iPad, and Android. Search “ASCO” in App Store, iTunes Store, or Google Marketplace. Members-only; sign in with ASCO.org username and password for access.

Conquer Cancer Foundation Free; available for iPhone and iPad. Search “Conquer Cancer Foundation” in App Store or iTunes Store. Highlights: ■■ Read full-text ASCO publications, including the Journal of Clinical Oncology ( JCO), Journal of Oncology Practice ( JOP), ASCO Connection, The ASCO Post, ASCO Daily News ■■ Browse Annual Meeting and thematic symposia resources, blogs, and videos ■■ Sync to the last page you read so you can pick up where you left off, or re-read from your list of recently viewed media

OTHER ASCO APPS Cancer.Net ■■ ■■ ■■ ■■ ■■

Highlights: Browse sessions by date, time, speaker, and track Add selected sessions to a personalized schedule Syncs with the Web-based ePlanner (accessible by computer), so your itinerary is always available Locates your session room with an interactive map of McCormick Place Browse exhibitor list and locate specific booths

Free; available for iPhone, iPad, and iPod Touch devices. Search “Cancer.Net” in App Store or iTunes Store. Highlights: ■■ Search for ASCO members by name, institution, city, state/ province, country, or specialty ■■ Add contacts to your Favorites list or send a colleague’s public contact information to a patient by e-mail

Selected portions reprinted from ASCO Connection. © American Society of Clinical Oncology. “Journals Adopt New Technology to Augment Impact of Research.” ASCO Connection, April 2011:25. All rights reserved.

Highlights: ■■ Oncologist-approved mobile companion for patients ■■ Comprehensive information on cancer types ■■ Organizational tools for personal medical data

Highlights: ■■ Interactive content and easy access to online resources and videos

Journal Apps (upcoming) Apps for JCO and JOP for iPhone and iPad are planned for release later this year. Mobile versions of JCO (jco.ascopubs.org) and JOP (jop. ascopubs.org) websites are available now and optimized for viewing on any mobile device, including iPhone, Android, and BlackBerry.

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Help Your Patients Understand News Emerging from the 2011 Annual Meeting

n May 19, direct your patients to Cancer.Net, ASCO’s patient website, where they will find easy-to-read summaries of studies, released in advance of this year’s Annual Meeting (www.cancer.net/canceradvances). In addition, encourage them to listen to a

panel discussion and Q&A session about these latest cancer advances in a recording of a teleconference for patient advocates (www.cancer. net/podcasts).

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ASCOPost.com | MAY 1, 2011

PAGE 23

Direct from ASCO

ASCO Launches New Quality Department

Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al

o promote quality, value, and accountability in cancer care, ASCO recently formed a department focused solely on quality measurement, tools for practice improvement, and using information technology as a key to advancing quality. This new department is tasked with preparing ASCO’s clinical practice guidelines, leading efforts to assist oncology practices in adopting electronic health records and other health information technology, and expanding ASCO’s Quality Oncology Practice Initiative (QOPI). This enhanced focus on quality initiatives is built on more than a decade of investment in advancing the quality of cancer care. Through expanding clinical practice guidelines and related tools for physicians, promoting electronic health records (EHR) adoption and standards, and enhancing quality measurement, ASCO has steadily increased its efforts in this arena. In 2006, ASCO launched QOPI, the first national program to certify quality of care provided in outpatient oncology offices. Since implementation of QOPI, more than 50 practices have received certification and nearly 700 practices have enrolled to participate. As health reform continues to unfold, value and accountability have be-

Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al

come higher priorities among cancer patients and the health-care community as a whole. A major component of The Patient Protection and Affordable Care Act involves improving quality of care and enhancing participation by patients in selecting and assessing their own treatment. The rapidly evolving practice environment, growing concerns over health-care costs, and provisions in the health reform legislation prompted ASCO’s Board of Directors to form the new department. Through this department, ASCO will be able to collect, integrate, and analyze its quality initiatives in ways that best leverage quality efforts to help practices and the patients they serve. ASCO is currently engaged in a national search for a permanent Senior Director of the Quality Department. Deborah Kamin, RN, PhD, is serving in this capacity in the interim, until that position is filled. Dr. Kamin has served as Senior Director of ASCO’s Cancer Policy and Clinical Affairs Department since 1998 but will devote the time needed to establish the Society’s Quality Department and launch its efforts.

■

Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

www.jco.org

What’s Hot in

JCO

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

JCO.org 1. Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214) R. Timothy D. Oliver, et al 29(8): 957 2. Carboplatin in Clinical Stage I Seminoma: Too Much and Too Little at the Same Time George J. Bosl, et al 29(8): 949 3. Clinical Research: Show Us the Data Alberto Ocana 29(9): 1099 4. Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value Howard West 29(9): 1095 5. Bevacizumab for Advanced Breast Cancer: All Tied Up With a RIBBON? Harold J. Burstein 29(10): 1232

For more information vist asco.org

6. Is It Good or Bad to Find a BRAF Mutation? Keith T. Flaherty 29(10): 1229 7. Life After Adjuvant Chemotherapy for Breast Cancer: The News Is Mostly Good Belinda E. Kiely, et al 29(9): 1092 8. Biology-Driven Phase II Trials: What Is the Optimal Model for Molecular Selection? Fabrice Andre, et al 29(10): 1236 9. Big Costs for Little Gain in Ovarian Cancer Martee L. Hensley 29(10): 1230 10. Providing Protocol Information for Journal of Clinical Oncology Readers: What Practicing Clinicians Need to Know Daniel G. Haller, et al 29(9): 1091

The ASCO Post | MAY 1, 2011

PAGE 24

News Genitourinary Cancer

Genomic Test for Newly Diagnosed Prostate Cancer By Alice Goodman

genomic test to distinguish between clinically indolent and aggressive prostate cancer may soon become a reality, suggests a study presented at the Genitourinary Cancers

Symposium held in Orlando, Florida, in February.1 Once the target genes are identified and the test is validated, it could be used to identify patients who can safely opt for active surveil-

lance and those who should undergo primary treatment with surgery or radiation. The test is being developed by Genomic Health Inc—the same company that developed the Onco-

type DX assays for breast cancer and colon cancer, two commercially available tests performed by the Genomic Health laboratory, which is regulated and certified under the Clinical Laboratory Improvement Amendments (CLIA) program of the Centers for Medicare & Medicaid Services.

Prognostic Uncertainty and Treatment Choice Developing a genomic test for prostate cancer that predicts need for therapy is important, explained Eric A. Klein, MD, Chairman and Professor of Surgery at the Glickman Urological and Kidney Institute, Cleveland Clinic. Dr. Klein was first author of a prospectively designed study to measure gene expression in prostate cancer specimens obtained from radical prostatectomy and to link gene expression to outcomes. “The biggest challenge facing men with newly diagnosed prostate cancer is uncertainty about the biologic potential of their disease,” Dr. Klein said. “About 90% of men with newly diagnosed low-grade cancer opt for treatment with radical prostatectomy or radiation therapy, but many of them have indolent disease and could be spared primary therapy.” Dr. Klein pointed out that autopsy studies show that a substantial number of older men who die have clinically silent prostate cancer and die of other causes. These men have indolent disease and don’t need treatment, he emphasized. The study he presented at a poster session was based on 501 archived tumor samples from men who had radical prostatectomy at the Cleveland Clinic between 1987 and 2004 analyzed so as to be representative of all 2,600 men operated on during this period. Of the 501 samples, 127 had clinical recurrence and 374 had no recurrence during a long follow-up interval. A total of 51 tumor samples were excluded for insufficient tissue. The expression pattern of 732 genes previously suggested to be important drivers of prostate cancer progression were tested in these samples using an RT-PCR–based technique. The results indicated that the expression signatures of about 300 genes had SEE PAGE 47 the ability to predict

ASCOPost.com | MAY 1, 2011

PAGE 25

News

whether or not a patient’s disease had recurred, Dr. Klein explained. Another important finding is that the genes associated with clinical recurrence appear to be similar in both the predominant and the highest Gleason pattern from an individual patient’s biopsy, indicating that sampling tissues on biopsy would not limit the usefulness of the test, Dr. Klein noted.

ing genes that are predictive for important clinical outcomes in prostate cancer, Dr. Klein said. “There is a tight correlation between gene expression and recurrence,” Dr. Klein emphasized. “The gene expression patterns we ob-

conduct, reflecting the difficulty of doing a genomic study in prostate cancer. “This study provides new biologic information that may help us better understand the biologic mechanisms that drive prostate cancer growth, and identify which genes

Evolving Test “This was a wonderful marriage of tissue samples and quantitative gene expression linked to outcomes. We started with 732 genes, analyzing the results to identify the smaller number of genes that gives us the best test performance. We expect to end up with a range of 10 to 25 genes,” said Steven Shak, MD, Chief Medical Officer of Genomic Health.

Steven Shak, MD

Oliver Sartor, MD

served reveal an underlying biology that overcomes apparent heterogeneity by Gleason grading on biopsy,” he added.

Gene Expression Profiling for Prostate Cancer ■■ Gene expression analysis identified a large number of genes that

are strongly associated with clinical recurrence of prostate cancer after radical prostatectomy, in both the primary and highest Gleason pattern.

■■ This information is being used to develop a biopsy-based assay that distinguishes indolent vs aggressive disease.

Once the final number of genes needed for the test is determined, future studies will be done to validate the test. The study reported at the Genitourinary Cancers Symposium lays the groundwork for determin-

Another important observation was that genes predicting clinical recurrence are involved in multiple pathways that drive prostate cancer metastasis. This study took almost 5 years to

Hepatocellular Carcinoma

some questions,” he said. Differences in treatment patterns might be explained by the extent of cancer or liver dysfunction among patients as well as physician expectation or patient preferences, according to Dr. Venook. “Our hope is to mine the mature data from GIDEON to see if we can get to the bottom of why the drug is used differently among specialists,” he said.

continued from page 21

dose of 800 mg/d only half the time, while in the Asia-Pacific, gastroenterologists and hepatologists almost always used the full dose at the start of treatment,” Dr. Venook said. The median dose of sorafenib was also lower for treatment by medical oncologists than by hepatologists, at 570 vs 770 mg/d, he said.

■

Study Limitations

Financial Disclosure: Dr. Venook reported that he has received research funding from Bayer.

Dr. Venook noted that GIDEON trial was limited by the lack of specified follow-up intervals and assessments, as well as details on dose adjustments. “All of this was at the discretion of the treating physician,” he said. Dr. Venook also acknowledged that the difference in sorafenib use patterns among physicians in the GIDEON trial may have been due to selection bias. “However, the data do generate

Reference 1. Venook AP, Lencioni R, Marrero JA, et al: First interim results of the global investigation of therapeutic decisions in hepatocellular carcinoma (HCC) and of its treatment with sorafenib (GIDEON) study: Use of sorafenib by oncologists and nononcoloogists in the management of HCC. Gastrointestinal Cancers Symposium. Abstract 157. Presented January 21, 2011.

Nicholas Vogelzang, MD

or pathways are appropriate targets for developing therapies,” Dr. Klein explained. The study was supported by Genomic Health.

Tempered Enthusiasm “Many people are working hard on developing gene signatures for prostate cancer, but I think the systems we have are pretty good. That includes using devices such as the Kattan nomogram, the Partin nomogram, and the Memorial Sloan-Kettering Cancer Center risk assessment that use clinical and laboratory measurements to determine whether a newly diagnosed patient has aggressive disease,” explained Oliver Sartor, MD, Director of the Prostate Cancer Program at Tulane University.

“To convince me that a genomic test is useful, the investigators would have to compare the test to the best nomograms that utilize readily available clinical and laboratory parameters,” he said. “Show me the data that this test is superior at risk stratification compared to nomograms as they are used at centers of excellence.” A genomic test is a good step forward, said Nicholas Vogelzang, MD, US Oncology, Las Vegas. According to Dr. Vogelzang, even if a test can identify which prostate cancers are more aggressive, the “tool chest” has only a limited number of treatments for nonmetastatic prostate cancer. “We don’t have many options for these patients,” he stated. “A test like this should be linked to improved outcome,” Dr. Vogelzang said. “On the other hand, it could spare people from needless therapy and overtreatment.”

■

Financial Disclosure: Dr. Klein disclosed direct research support from Genomic Health to support tissue processing and data extraction. Dr. Sartor and Dr. Vogelzang reported no potential conflicts of interest. Dr. Shak is the Chief Medical Officer of Genomic Health.

Reference 1. Klein EA, Falzarano SM, Maddala T, et al: Use of quantitative gene expression in primary and highest Gleason pattern cancers to identify genes associated with clinical recurrence after radical prostatectomy. Genitourinary Cancers Symposium. Abstract 39. Presented February 17, 2011.

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In the treatment of advanced RCC

When prognostic risk is high —let evidence chart the course

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.

• 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.

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

• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received 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.

• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.

• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.

• 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. • 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.

Powerful 1st-line evidence— TORISEL significantly extended overall survival in poor-risk patients

Powerful evidence

Overall survival (OS)* results—TORISEL vs IFN 1

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

• Studied 1st-line in patients with ≥3 of 6 preselected prognostic risk factors1II • 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 arm1

TORISEL has a Category 1 NCCN recommendation specific to poor-risk patients as 1st-line treatment in advanced renal cell carcinoma (RCC)2 TORISEL is indicated for the treatment of advanced renal cell carcinoma.1

• 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%). • 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. RCC=renal cell carcinoma. IFN =interferon alpha. CI=confidence interval. NCCN=National Comprehensive Cancer Network. * Time from randomization to death. † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths). ‡ Based on log-rank test stratified by prior nephrectomy and region. § Based on Cox proportional hazard model stratified by prior nephrectomy and region. II Prognostic risk factors included: <1 year from time of initial RCC diagnosis to randomization, Karnofsky Performance Status of 60 or 70, hemoglobin <lower limit of normal, corrected calcium >10 mg/dL, lactate dehydrogenase >1.5 x upper limit of normal, >1 metastatic organ site. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Kidney Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2011. TRS00216/282520 All rights reserved.

TORISEL® Kit

[tor-a<sel] (temsirolimus) injection

% only FOR INTRAVENOUS ADMINISTRATION Brief Summary of Prescribing Information This product’s label may have been revised after this insert was used in production. See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our Medical Communications Department toll-free at 1-800-934-5556. INDICATIONS AND USAGE TORISEL is indicated for the treatment of advanced renal cell carcinoma. CONTRAINDICATIONS TORISEL is contraindicated in patients with bilirubin >1.5 x ULN. WARNINGS AND PRECAUTIONS Hepatic Impairment The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline bilirubin ≤1.5 x ULN when treated with TORISEL. The overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, were greater in patients with baseline bilirubin >1.5 x ULN. TORISEL is contraindicated in patients with bilirubin >1.5 x ULN due to increased risk of death. Use caution when treating patients with mild hepatic impairment. Concentrations of temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week (see USE IN SPECIFIC POPULATIONS, Hepatic Impairment). Hypersensitivity Reactions Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TORISEL. An H1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H1-receptor antagonist (such as diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). Hyperglycemia/Glucose Intolerance The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89% of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and 26% of patients reported hyperglycemia as an adverse event. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum glucose should be tested before and during treatment with TORISEL. Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination. Infections The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections (see ADVERSE REACTIONS). Interstitial Lung Disease Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic with infiltrates detected on computed tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics, while some patients continued treatment without additional intervention. Patients should be advised to report promptly any new or worsening respiratory symptoms. Hyperlipemia The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum cholesterol value and 83% had at least one elevated serum triglyceride value. This may require initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL. Bowel Perforation Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain,

metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools. Renal Failure Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis. Wound Healing Complications Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should be exercised with the use of TORISEL in the perioperative period. Intracerebral Hemorrhage 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. Co-administration with Inducers or Inhibitors of CYP3A Metabolism Agents Inducing CYP3A Metabolism: Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, and rifampicin may decrease exposure of the active metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should be considered. St. John’s Wort may decrease TORISEL plasma concentrations unpredictably. Patients receiving TORISEL should not take St. John’s Wort concomitantly.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the Phase 3 randomized, open-label study of interferon alfa (IFN- ) alone, TORISEL alone, and TORISEL and IFN- , a total of 616 patients were treated. Two hundred patients received IFN- weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN- weekly. Treatment with the combination of TORISEL 15 mg and IFN- was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN- alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN- alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN- alone arm are shown for comparison. Table 1—Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Adverse Reaction

Agents Inhibiting CYP3A Metabolism: Strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be administered, a dose adjustment should be considered.

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

139 (67)

199 (100)

155 (78)

Asthenia

106 (51)

23 (11)

127 (64)

52 (26)

Edemaa

73 (35)

7 (3)

21 (11)

1 (1)

Pain

59 (28)

10 (5)

31 (16)

4 (2)

Pyrexia

50 (24)

1 (1)

99 (50)

7 (4)

Weight Loss

39 (19)

3 (1)

50 (25)

4 (2)

Headache

31 (15)

1 (1)

30 (15)

0 (0)

Chest Pain

34 (16)

2 (1)

18 (9)

2 (1)

17 (8)

1 (1)

59 (30)

3 (2)

General disorders

Chills

Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Gastrointestinal disorders

Pregnancy Pregnancy Category D Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine toxicities in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications.

Mucositisb

86 (41)

6 (3)

19 (10)

0 (0)

Anorexia

66 (32)

6 (3)

87 (44)

8 (4)

Nausea

77 (37)

5 (2)

82 (41)

9 (5)

Diarrhea

56 (27)

3 (1)

40 (20)

4 (2)

Abdominal Pain

44 (21) 42 (20)

34 (17) 36 (18)

3 (2)

Constipation

9 (4) 0 (0)

Vomiting

40 (19)

4 (2)

57 (29)

5 (3)

Infectionsc

42 (20)

6 (3)

19 (10)

4 (2)

Urinary tract infection d

31 (15)

3 (1)

24 (12)

3 (2)

Pharyngitis

25 (12)

0 (0)

3 (2)

0 (0)

Rhinitis

20 (10)

0 (0)

4 (2)

0 (0)

28 (14)

7 (4)

1 (1)

Infections

In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer patients at the recommended human dose). Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL therapy has stopped. Temsirolimus can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Musculoskeletal and connective tissue disorders Back Pain

41 (20)

Arthralgia

37 (18)

2 (1)

29 (15)

2 (1)

16 (8)

1 (1)

29 (15)

2 (1)

Myalgia

6 (3)

Respiratory, thoracic and mediastinal disorders

Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to starting treatment. Men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for 3 months after the last dose of TORISEL.

Dyspnea

58 (28)

18 (9)

48 (24)

11 (6)

Cough

53 (26)

2 (1)

29 (15)

0 (0)

Epistaxis

25 (12)

0 (0)

7 (4)

0 (0)

Skin and subcutaneous tissue disorders

Monitoring Laboratory Tests In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion. ADVERSE REACTIONS The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label (see WARNINGS AND PRECAUTIONS).

The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

All Grades* n (%)

Any

Concomitant use of TORISEL with sunitinib The combination of TORISEL and sunitinib resulted in dose-limiting toxicity. Dose-limiting toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization) were observed in two out of three patients treated in the first cohort of a phase 1 study at doses of TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days 1-28 followed by a 2-week rest).

Hypersensitivity Reactions Hyperglycemia/Glucose Intolerance Interstitial Lung Disease Hyperlipemia Bowel Perforation Renal Failure

IFN- n=200

Rash e

97 (47)

10 (5)

14 (7)

0 (0)

Pruritus

40 (19)

1 (1)

16 (8)

0 (0)

Nail Disorder

28 (14)

0 (0)

1 (1)

0 (0)

Dry Skin

22 (11)

1 (1)

14 (7)

0 (0)

Acne

21 (10)

0 (0)

2 (1)

0 (0) 0 (0)

Nervous system disorders Dysgeusiaf

41 (20)

0 (0)

17 (9)

Insomnia

24 (12)

1 (1)

30 (15)

0 (0)

9 (4)

0 (0)

27 (14)

4 (2)

Depression

* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. a

Includes edema, facial edema, and peripheral edema

b Includes

aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis

Includes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster

d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary

tract infection

Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash

Includes taste loss and taste perversion

The following selected adverse reactions were reported less frequently (<10%). Gastrointestinal Disorders – Fatal bowel perforation occurred in 1 patient (1%). Eye Disorders – Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%). Immune System – Allergic/Hypersensitivity reactions occurred in 18 patients (9%). Angioneurotic edema-type reactions have been observed in some patients who received TORISEL and ACE inhibitors concomitantly. Infections – Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred in 14 patients (7%). General Disorders and Administration Site Conditions – Impaired wound healing occurred in 3 patients (1%). Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5 patients (2%), including rare fatalities. Vascular – Hypertension occurred in 14 patients (7%); venous thromboembolism (including deep vein thrombosis and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis occurred in 2 patients (1%). Table 2—Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN- in the Randomized Trial TORISEL 25 mg n=208 Laboratory Abnormality

IFN- n=200

All Grades* n (%)

Grades 3&4* n (%)

All Grades* n (%)

Grades 3&4* n (%)

208 (100)

162 (78)

195 (98)

144 (72)

Hemoglobin Decreased

195 (94)

41 (20)

180 (90)

43 (22)

Lymphocytes Decreased**

110 (53)

33 (16)

106 (53)

48 (24)

Neutrophils Decreased**

39 (19)

10 (5)

58 (29)

19 (10)

Platelets Decreased

84 (40)

3 (1)

51 (26)

0 (0)

Leukocytes Decreased

67 (32)

1 (1)

93 (47)

11 (6)

Alkaline Phosphatase Increased

141 (68)

7 (3)

111 (56)

13 (7)

AST Increased

79 (38)

5 (2)

103 (52)

14 (7)

Creatinine Increased

119 (57)

7 (3)

97 (49)

Glucose Increased

186 (89)

33 (16)

Phosphorus Decreased

102 (49)

Any Hematology

Agents Inhibiting CYP3A Metabolism Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus Cmax or AUC; however, sirolimus AUC increased 3.1-fold, and Cmax increased 2.2fold compared to TORISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered. (see Dosage and Administration in full Prescribing Information). Interactions with Drugs Metabolized by CYP2D6 The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of TORISEL was co-administered. No clinically significant effect is anticipated when temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D (see WARNINGS AND PRECAUTIONS, Pregnancy). Nursing Mothers It is not known whether TORISEL is excreted into human milk, and due to the potential for tumorigenicity shown for sirolimus (active metabolite of TORISEL) in animal studies, a decision should be made whether to discontinue nursing or discontinue TORISEL, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of TORISEL in pediatric patients have not been established. Geriatric Use Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Renal Impairment No clinical studies were conducted with TORISEL in patients with decreased renal function. Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous dose of [14C]labeled temsirolimus in healthy subjects. Renal impairment is not expected to markedly influence drug exposure, and no dosage adjustment of TORISEL is recommended in patients with renal impairment. TORISEL has not been studied in patients undergoing hemodialysis. Hepatic Impairment TORISEL was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Table 3—Adverse Reactions in Patients With Advanced Malignancies Plus Normal or Impaired Hepatic Function Hepatic Function*

TORISEL Dose Range

Adverse Reactions Grade ≥ 3** n (%)

Death*** n (%)

Normal (n=25)

25 – 175

20 (80.0)

2 (8.0)

Mild (n=39)

10 – 25

32 (82.1)

5 (12.8)

2 (1)

Moderate (n=20)

10 – 25

19 (95.0)

8 (40.0)

128 (64)

6 (3)

Severe (n=24)

7.5 – 15

23 (95.8)

13 (54.2)

38 (18)

61 (31)

17 (9)

1 (50.0)

0 (0)

16 (8)

2 (1)

25 (13)

4 (2)

Total Cholesterol Increased

181 (87)

5 (2)

95 (48)

2 (1)

Triglycerides Increased

173 (83)

92 (44)

144 (72)

69 (35)

43 (21)

11 (5)

15 (8)

0 (0)

Chemistry

Total Bilirubin Increased

Potassium Decreased

* NCI CTC version 3.0 ** Grade 1 toxicity may be under-reported for lymphocytes and neutrophils. DRUG INTERACTIONS Agents Inducing CYP3A Metabolism Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus Cmax by 65% and AUC by 56% compared to TORISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered (see Dosage and Administration in full Prescribing Information).

TRS00216/282520

Liver Transplant (n=2)

* Hepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3 x ULN; severe = bilirubin >3 x ULN; liver transplant = any bilirubin and AST. ** Common Terminology Criteria for Adverse Events, version 3.0, including all causality. *** Includes deaths due to progressive disease and adverse reactions. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic Impairment). OVERDOSAGE There is no specific treatment for TORISEL intravenous overdose. TORISEL has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of TORISEL greater than 25 mg. This brief summary is based on TORISEL Prescribing Information W10524C011 ET01, revised 09/10. © 2010, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101

Printed in USA/April 2011

The ASCO Post | MAY 1, 2011

PAGE 30

Quality of Care Patient-centered Treatment

Research Supports the Value of Patients Being More Involved in Cancer Treatment Planning Bringing patients into the decision-making process is not easy, but it is essential. By Margot Fromer

n the April 15 issue of The ASCO Post, we began a two-part report on a recent workshop, “Patient-centered Cancer Treatment Planning: Improving the Quality of Oncology Care,” hosted by the National Coalition of Cancer Survivorship (NCCS) and the Institute of Medicine (IOM) National Cancer Policy Forum. Participants focused on the need to incorporate patient perspectives in the treatment planning process and best practices for improving communication and decision-making in oncology care. In addition to examining the obstacles to patient-centered care and offering recommendations for overcoming those barriers, speakers addressed research illustrating differences in perception between patients and physicians, the challenges involved in bringing patients into the complex decision-making process, and the importance of initiating discussions about advance directives.

1,154 women eligible for either mastectomy or breast-conserving surgery, 71% said that their surgeons discussed both treatments. However, the surgeons said they had discussed both treatments with 82% of the women. “One-third of the time, patients and surgeons disagreed about whether both treatments were discussed,” said Dr. Keating. It’s true that knowledge confers a certain amount of power, and more to the point, it can help women choose between mastectomy and breast-conserving surgery. Dr. Sepucha reported on a prospective study of 125 patients who all received a video decision aid before seeing their surgeon to discuss treatment options for breast cancer. Patients completed a questionnaire at three time points that examined their knowledge, goals and concerns, and decision-making.3 Most of the women understood that mastectomy and breast-conserving surgery have a similar survival benefit

Fear of the ‘D Word’

homas Smith, MD, Professor of Palliative Care Research, and Medical Director of the Thomas Palliative Care Unit at Virginia Commonwealth University-Massey Cancer Center said that most patients want to know the truth, and they want their oncologist to be realistic and compassionate, and to stay with them throughout the course of the illness. But this is often not what happens. The Cancer Outcomes Research and Surveillance Consortium Thomas Smith, MD (CanCORS) looked at 1,517 patients with non– small cell lung cancer.1 Half had not discussed hospice care 2 months before death. However, those who expected to live less than 2 years were much more likely to have discussed hospice, and 70% of patients who had such a discussion used hospice within a year of diagnosis compared with 26% who did not. Why don’t providers bring up the “D word”? It’s complicated, said Dr. Smith. For instance, a study of 75 patients reported that 41% had an advance directive that no one knew about.2 Only 7% had discussed advance directives with their oncologist, 86% were willing to, and 95% thought it was important. But only 16% wanted to. Of the 75, only 2 had an oncologist who brought up the subject. “We must educate patients about why an advance directive is beneficial, and we have to train all physicians—especially oncologists—to initiate these discussions. Or let another caregiver do it. But somebody has to.” And somebody has to talk about death, he added. “Advance directives have never been associated with worse survival. In fact, in bone marrow transplant, they are associated with a 2.2-fold better survival. What’s more, being overoptimistic about survival is not associated with longer life and, in fact, results in worse end-of-life care. “People who discuss dying with their physicians do not worry more, they don’t have poorer mental health, they don’t die sooner—but they do have better quality of life at the end of it.”

■

Financial Disclosure: Dr. Smith reported no potential conflicts of interest. Nancy Keating , MD, MPH

Jeffrey Peppercorn, MD, MPH

Theory and Research in Patient-centered Care Even when physicians and patients do talk about treatment, there can be problems, said both Nancy Keating, MD, MPH, Associate Professor of Medicine and Health Care Policy, Harvard Medical School, and Karen Sepucha, PhD, Director of the Health Decision Sciences Center at Massachusetts General Hospital. Much of their research reveals dichotomies in perception. One study, published in the Journal of Clinical Oncology,1 showed that only half of 1,081 patients with early-stage breast cancer reported involvement in decision-making that matched their desired level of involvement. These women were more satisfied with their treatment than were patients who had no role. Another, from Breast Cancer Research and Treatment,2 reported that of

Karen Sepucha, PhD

and that breast-conserving surgery is associated with a slightly higher recurrence rate, yet about one third of these well-informed patients still chose mastectomy. Dr. Sepucha reported that certain goals such as removing the breast to gain piece of mind, avoiding radiation, and desire to keep the breast clearly discriminated between patients choosing mastectomy or breast-conserving surgery, providing evidence that providers were tailoring treatment to patients’ goals. The use of a video decision aid or other informational tools before surgery can help women make informed value-based decisions and be more comfortable with those decisions.

What Ought to Be and What Is Jeffrey Peppercorn, MD, MPH, Associate Professor, Division of Medical Oncology, Duke Cancer Institute,

References 1. Huskamp HA, Keating NL, Malin JL, et al: Discussions with physicians about hospice among patients with metastatic lung cancer. Arch Intern Med 169:954-962, 2009. 2. Dow LA, Matsuyama RK, Ramakrishnan V, et al: Paradoxes in advance care planning: The complex relationship of oncology patients, their physicians, and advance medical directives. J Clin Oncol 28:299-304, 2010.

noted that even with the best of intentions and despite promises about patient-informed decisions, this is not always how treatment options are selected. “Bringing patients into the process isn’t easy. You have to take many factors into consideration: respect for autonomy, various costs and trade-offs, patient satisfaction, symptoms and morbidity, and the possibility of death,” he said. “The reality of making decisions about surgical, chemotherapeutic, and endocrine treatments is even more complex and is based on the prognosis, likely benefit from treatment, and

various toxicities. And this is just for first-line treatment.” He added that when the disease progresses, more decisions have to be made, for example, about further disease-directed therapy, palliative care alone or combined with disease-directed treatment, or entry into a clinical trial. The options and variables are fewer than the first time around, but the emotional impact is far greater. “The challenges at all stages of disease treatment are enormous,” Dr. Peppercorn continued. “We need to provide information and assess all aspects of the continued on page 32

ASCOPost.com | MAY 1, 2011

PAGE 31

TAP on Technology Nanotechnology

Nanofluidic Proteomic Immunoassay for Measuring Oncoprotein Expression and Phosphorylation By Matthew Stenger

Glossary ■■ CML: Chronic myelogenous leukemia

■■ ERK: Extracellular signal-related kinase

■■ FACS: Fluorescence-activated cell sorter

■■ HRP: Horseradish peroxidase ■■ JNK: c-Jun N-terminal kinase ■■ MAPK: Mitogen-activated protein kinase

■■ MEK: Mitogen-activated kinase 1 ■■ NIA: Nanofluidic proteomic immunoassay

■■ STAT3: Signal transducer and activator of transcription protein 3

■■ STAT5: Signal transducer and activator of transcription protein 5

Clinical Trials

ancers are frequently associated with the abnormal expression and phosphorylation of oncogenes, and the ability to detect specific oncoproteins and their activated forms is a major goal in efforts to develop new treatments and methods for assessing response to treatments. Current methods for protein detection are relatively insensitive to small changes in oncoprotein activation underlying cancer signaling processes, and serial tumor sampling for assessing response to treatments is often precluded by the need for large numbers of cells for analysis. Alice C. Fan, MD, and Dean W. Felsher, MD, PhD, at Stanford School of Medicine, recently developed a nanofluidic proteomic immunoassay (NIA) that is capable of quantifying total and low-abundance protein isoforms in nanoliter volumes, allowing collection of samples through minimally invasive blood draws or fine-needle aspirates. “NIA is an exciting new technology for rapidly measuring proteins in minimal amounts of clinical materials,” Dr. Felsher, Associate Professor, Medicine-Oncology, at Stanford, told The ASCO Post. “The method has been automated to incorporate a charge-based separation of proteins with a microfluidic platform and antibody-based detection. To date, we have used this method for nanoscale

Fig. 1: Capillary isoelectric focusing separation in the nanofluidic proteomic immunoassay.

analysis of blood, bone marrow, and fine-needle aspirates. Eventually, this approach will also enable the direct assessment of targeted treatments that will assist in personalized cancer therapy.”

Technique The NIA test developed and used in studies by Drs. Fan and Felsher (NanoPro 1000 Instrument, Cell Biosciences™) is capable of using samples as small as 25 cells to generate information on the post-translational status of signaling proteins. NIA uses a standard 384-well microplate and can analyze up to 96 samples with each run. As with the Western blot technique, proteins in samples are separated, immobilized, and probed with antibodies. However, the NIA system uses capillary isoelectric focusing separation to resolve phosphorylation states of signaling proteins, with the separated proteins being immobilized to the capillary wall and probed with primary and secondary antibodies. The secondary antibody is HRP-labeled, permitting ultrasensitive chemoluminescence detection of proteins present in even low quantities.

Findings The NIA has been shown to detect oncoprotein expression and oncoprotein phosphorylation in clinical specimens. Initial studies of specimens from normal controls and patients with solid and hematopoietic tumors showed that the immunoassay can detect phosphoprotein profiles in tumor cells that distinguish tumor from normal cells. Moreover, investigators determined that patient tumors could be grouped based on different patterns of percent ERK and MEK phosphorylation. In particular, the NIA has been shown to be able to quantify amounts of MYC oncoprotein and B-cell lymphoma protein 2 in Burkitt’s and follicular lymphomas and identify changes in activation of ERK1 and ERK2, MEK, STAT3 and STAT5, c-JNK, and caspase 3 in imatinib (Gleevec)-treated chronic myelogenous leukemia cells. The immunoassay also has been able to measure an otherwise unanticipated change in the phosphorylation of an ERK2 isoform in patients with chronic myelogenous leukemia responding to imatinib and detect a decrease in STAT3 and STAT5 phosphorylation in patients with lymphoma treated with atorvastatin (Lipitor).

In the clinical trial setting, NIA has been used alone and in conjunction with multicolor flow cytometry (fluorescence-activated cell sorter, or FACS) to monitor changes in phosphorylation profiles among patients receiving novel agents for hematopoietic cancers. For example, NIA has been used to measure changes in MAPK and cell-cycle proteins in serially sampled leukocytes during a study of a new cell-cycle inhibitor in patients with myelodysplastic syndrome. NIA was highly complementary to FACS for the detection of signaling changes in tumor cells, monocytes, and T cells in a trial of atorvastatin in nonHodgkin lymphoma patients. Pathways initially activated in tumor cells showed reduced activation with atorvastatin treatment, with reductions in phosphoSTAT3 and phospho-STAT5 of up to 70% being observed, whereas pathways that were initially suppressed in tumor cells (including phospho-phospholipase Cγ) were normalized during treatment. Moreover, expression levels of proteins in apoptotic pathways (including p38) increased with treatment, and changes in signaling associated with atorvastatin treatment were found to be cell-specific, with effects on tumor cells being distinct from effects on nontumor T cells and monocytes.

Conclusions These findings show that nanoscale proteomic technology can be used to identify and quantify changes in cell signaling and identify responses to therapeutic intervention in different cell populations using small clinical specimens that can be collected serially from patients with minimal invasiveness. These results suggest that this technology may allow identification of previously unidentified changes in signaling patterns in tumor cells that may prove important in development of targeted therapies or that may serve as response markers. Overall, nanoscale analysis appears to be a promising approach to identifying and measuring diagnostic markers of disease and assessing and monitoring markers of therapeutic response. “NIA is an example of how new technologies might help us develop better ways to detect tumors earlier and make continued on page 32

The ASCO Post | MAY 1, 2011

PAGE 32

TAP on Technology

Nanofluidic Proteomic Immunoassay continued from page 31

decisions more quickly,” commented Dr. Fan, Instructor, Medicine-Oncology, at Stanford. “It’s amazing that I can take a fine-needle aspirate from a patient, and within a few hours, know the levels of tumor signaling proteins in their cells. Developing the use of new technologies is an exciting collaborative effort among physicians, bench scientists, and our patients. Together, our goal is to complete clinical trials that show these analyses can help us optimize new treatments.”

■

Financial Disclosure: Dr. Fan reported no potential conflicts of interest. Dr. Felsher has previously served on the science advisory board for Cell Biosciences.

Resources Cell Biosciences™ NanoPro 1000 system. Available at http://www.cellbiosciences.com/nanopro-1000.html. Fan AC, Deb-Basu D, Orban MW, et al: Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens. Nature Med 15:566-571, 2009. Fan AC, Dermody J, Kong C, et al: Nano-immunoassay profiling of ERK and MEK isoforms in fine-needle as-

Patient-centered Treatment continued from page 30

situation. This takes time and skill.” There is, of course, no one answer to solving these problems, but core competencies are critical. Dr. Peppercorn stressed the need for: ■■ Knowledge and understanding about prognosis, options, and potential consequences ■■ Ability to translate information to patients from all educational levels, ages, sexes, and cultures ■■ Empathy and efficiency

■

Financial Disclosure: The speakers at the NCCS/IOM workshop reported no potential conflicts of interest. Dr. Sepucha receives research and salary support from the Foundation for Informed Medical Decision Making.

References 1. Keating NL, Guadagnoli E, Landrum MB, et al: Treatment decision making in early-stage breast cancer: Should surgeons match patients’ desired level of involvement? J Clin Oncol 20:1473-1479, 2002. 2. Keating NL, Weeks JC, Borbas C, et al: Treatment of early stage breast cancer: Do surgeons and patients agree regarding whether treatment alternatives were discussed? Breast Cancer Res Treat 79:225231, 2003. 3. Collins ED, Moore C, Clay K, et al: Can Women Make an Informed Decision for Mastectomy? J Clin Oncol 27:519-525, 2009 [Epub 2008 Dec 29].

pirates of solid tumors. J Clin Oncol 28(15s):Abstract 2564, 2010. Fan AC, Dermody JL, Kong C, et al: Nanoscale approaches to define biologic signatures and measure proteomic response to targeted therapies in hematologic and solid tumors. Presented at the Fourth American Association for Cancer

Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development, 2010. Abstract PR6. Available at http://www.aacr.org/Uploads/DocumentRepository/2010_conf/ MD/moldia10_abstracts_proffered.pdf. Fan AC, Orban MW, Shirer AE, et al: Nanoscale analysis of changes in signaling

INDICATIONS XELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defined as progressive disease while on treatment, with or without initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen. XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

proteins in patients treated with single agent atorvastatin for low-grade or refractory NHL. J Clin Oncol 27(suppl):Abstract 11011, 2009. Seetharam M, Tran M, Fan AC, et al: Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Blood 116(21):Abstract 4010, 2010.

y Assista nc e Co-payC o-pa Card RxBIN:

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XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with hyperbilirubinemia. Other adverse reactions, including serious fluoropyrimidine therapy alone is preferred. XELODA was nonadverse reactions, have been reported. inferior to 5-fluorouracil and leucovorin (5-FU/LV) for diseaseGENEXL-1043_Card_FM.indd 1 11/30/10 Important Safety Information – Monotherapy in MBC free survival (DFS). Although neither XELODA nor combination In a single arm study of XELODA monotherapy in metastatic chemotherapy prolongs overall survival (OS), combination breast cancer, serious adverse events (grade 3/4) occurring in therapy has been demonstrated to improve disease-free ≥5% of patients receiving XELODA (%) were lymphopenia (59), survival compared to 5-FU/LV. Physicians should consider diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia these results when prescribing single-agent XELODA in the (11), fatigue (8), stomatitis (7), and dehydration (5). The most adjuvant treatment of Dukes’ C colon cancer. common adverse events for all grades occurring in ≥30% of Boxed WARNING and Additional Important Safety Information patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), Boxed WARNING fatigue (41), dermatitis (37), and vomiting (37). Warfarin Interaction—Coagulopathy Important Safety Information – Combination Therapy with >> Patients receiving concomitant capecitabine and oral Docetaxel in MBC coumarin-derivative anticoagulant therapy should have In a phase 3 study of XELODA combination therapy (XELODA their anticoagulant response (INR or prothrombin time) plus docetaxel) in metastatic breast cancer, serious adverse monitored frequently in order to adjust the anticoagulant events (grade 3/4) occurring at a ≥2% higher incidence in patients dose accordingly. receiving XELODA plus docetaxel vs docetaxel alone (%;%) were >> A clinically important XELODA-Warfarin drug interaction lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis was demonstrated in a clinical pharmacology trial. (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail >> Altered coagulation parameters and/or bleeding, disorder (2;0). The most common adverse events for all grades including death, have been reported in patients taking occurring at a ≥5% higher incidence in patients receiving XELODA concomitantly with coumarin-derivative XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), anticoagulants such as warfarin and phenprocoumon. stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), >> Clinically significant increases in prothrombin time (PT) thrombocytopenia (41;23), vomiting (35;24), abdominal pain and INR have been observed in patients who were (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia stabilized on anticoagulants at the time XELODA was (14;8), lacrimation increase (12;7), and appetite decrease (10;5). introduced. These events occurred within several days Important Safety Information – Monotherapy in Adjuvant and up to several months after initiating XELODA Colon Cancer therapy, and infrequently within 1 month after stopping XELODA. These events occurred in patients with and In a phase 3 study of XELODA monotherapy in colon cancer without liver metastases. in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/ >> Age greater than 60 and a diagnosis of cancer LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome independently predispose patients to an increased risk (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), of coagulopathy. decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5). Contraindications The most common adverse events for all grades occurring in XELODA is contraindicated in patients with known ≥30% of patients receiving either XELODA or 5 FU/LV were hypersensitivity to capecitabine or to any of its components or hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), to 5-fluorouracil. XELODA is also contraindicated in patients and stomatitis (22;60). A total of 18 deaths due to all causes with known dihydropyrimadine dehydrogenase (DPD) occurred either on study or within 28 days of receiving study deficiency, or severe renal impairment. drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV Most Common Adverse Reactions The most common adverse reactions (≥30%) reported with XELODA were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and

Please see following brief summary of full Prescribing Information, including Boxed WARNING, for additional Important Safety Information.

2:11 P

ASCOPost.com | MAY 1, 2011

PAGE 33

FDA Update

FDA Investigating Risk of New Malignancies with Lenalidomide

n a recent Drug Safety Communication, the FDA informed the public that it is aware of results from clinical trials showing that patients treated with lenalidomide (Revlimid) may be at an increased risk of developing new

types of cancer compared to patients who did not take the drug. The Agency is reviewing all available information on this potential risk and will communicate any new recommen-

dations once it has completed its review. Lenalidomide (Revlimid) is approved for use, in combination with dexamethasone, for the treatment of patients with mul-

The XELODA Co-pay Card helps reduce eligible patient out-of-pocket costs—up to $4000 a year Program benefit

Pays up to 80% of XELODA co-pay toward each prescription and refill.

Program limit

Up to $4000 in XELODA co-pay support, which must be used within 1 year after card activation. There is a coverage limit for each 30-day supply. Enrolled patients whose annual household income is $100,000 or more can receive only up to $1500 in benefits per calendar year. (Proof of income is required.)

Eligibility

>> Covered by a private (nongovernmental) insurance >> 18 years of age or older

Patients covered under Medicare, Medicaid, Medigap, VA, DoD, Tricare, or any other government-funded health care program, patients currently residing or receiving services in Massachusetts, and patients who are already participating in Genentech® Access to Care Foundation (GATCF) are not eligible.

For full terms and conditions, questions regarding enrollment, claim transmission, patient eligibility or other issues, contact XELODA ASSIST:

Call 1-877-344-7774, from 8 AM–8 PM (EST), Monday–Friday, or visit www.XELODAASSIST.com.

REACH OUT TO YOUR PATIENTS ON XELODA THERAPY TODAY. Terms and conditions No person or entity may seek reimbursement from any third-party payer for any amount provided using the card program. Genentech USA, Inc. reserves the right to deny payment under the card to anyone deemed ineligible in accordance with the stated program criteria. For full terms and conditions, questions about enrollment in other XELODA patient support programs, including nurse call support, call 1-877-987-2487 or visit www.xelodasupport.com. If your patients are not eligible, they may qualify for support offered by XELODA Access Solutions. To learn more call 1-888-249-4918.

tiple myeloma who have received at least one prior therapy. The drug is also approved for treatment of patients with transfusion-dependent anemia due to low- or intermediate-1–risk myelodyscontinued on page 34

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MAY 1, 2011

PAGE 34

FDA Update

Lenalidomide Malignancies continued from page 33

plastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

Benefits Outweigh Risks FDA believes the benefits of

lenalidomide continue to outweigh the potential risks. At this time, there is no recommendation to delay, modify, or restrict the use of lenalidomide for patients being treated according to the FDA-approved indications. The announcement adds that health-care professionals should carefully weigh

the benefits and risks of the drug when prescribing it. Preliminary data derived from evaluation of outcomes after longer-term exposure to lenalidomide and from controlled clinical trials shows an increased incidence of some second primary malignancies, particularly acute

myelogenous leukemia and B-cell lymphoma malignancies, compared to controls. Since lenalidomide is an analog of thalidomide (Thalomid), FDA is also currently reviewing all available information on this potential risk for thalidomide.

â&#x2013;

ASCOPost.com | MAY 1, 2011

PAGE 35

Awards

Association of Community Cancer Centers Honors Former NCI Director

T John E. Niederhuber, MD

he Association of Community Cancer Centers (ACCC) recently awarded John E. Niederhuber, MD, its Annual Achievement Award for his long-standing advocacy, dedication, and

commitment to the study and treatment of cancer. The award was presented at ACCC’s 37th Annual National Meeting. Dr. Niederhuber served as Director of the National Cancer Institute from

2006 until 2010. He recently joined Inova Health System in Fairfax, Virginia, as Executive Vice President and CEO of the Inova Institute for Translational Research and Personalized Medicine.

■

The ASCO Post | MAY 1, 2011

PAGE 36

ACCC 37th Annual National Meeting Preparation Needed for New Trends and Payment Models By Ronald Piana

presentation on legislative and regulatory issues at the recent 37th Annual National Meeting of the Association of Community Cancer Centers (ACCC) in Washington, DC,

offered attendees an overview of the changing health-care landscape, and a glimpse of things to come. Speaker Matthew Farber, Director, Provider Economics & Public Policy for ACCC,

said that although numerous components of the Affordable Care Act were still in political flux, it is important for the oncology community to start preparing for inevitable reforms such

Matthew Farber

as exchanges, Medicaid updates, highrisk pools, and new payment models and trends in community oncology.

Trends to Watch Despite efforts by the House of Representatives to stall or kill parts of the Act, the sweeping law still exists and some of the bill’s initiatives have the power to alter the delivery of cancer care. Everyone agrees that exorbitant care spending must be curbed; however, the problem is how to make significant cuts without reducing access or quality. To that end, the administration is studying ways to increase efficiency in our delivery system, such as the creation of Accountable Care Organizations (ACOs). Mr. Farber said that the Centers for Medicare & Medicaid Services defines an accountable care organization as an organization of health-care providers that agrees to be accountable for the quality, cost, and overall

Questions about Accountable Care Organizations ■■ How is this different from programs designed to reduce costs?

■■ How will new payment models fit into the program?

■■ How much will the shared savings be?

■■ Will ACOs be able to use

newfound market power to negotiate higher prices with private payers?

■■ What will this look like/ mean to patients?

■■ Will this actually save

$5 billion, like the Congressional Budget Office thinks?

ASCOPost.com | MAY 1, 2011

PAGE 37

ACCC 37th Annual National Meeting care of Medicare beneficiaries who are enrolled in the traditional fee-for-service program who are assigned to it. “But really, what exactly is an ACO?” asked Mr. Farber. He speculated as to whether an accountable care organization will be a real entity or exist only virtually. He continued, “There seems to be, even now, a good deal of disagreement on what these proposed organizations will look like and what they will mean to the way we deliver patient care.” The Affordable Care Act states that accountable care organizations will still be paid fee-for-service, but they will be able to “share savings” if they deliver care to Medicare beneficiaries more efficiently.

Proposed Rule Published, Questions Remain Mr. Farber noted that since his ACCC presentation, the proposed rule for establishing accountable care organizations was published in the April 7 Federal Register, calling for a 60-day public comment period. “Our first goal is to make sure that our members are educated so that if they intend to create or become part of an accountable care organization, they’ll understand the challenges from the business and clinical side,” said Mr. Farber. “Since ACCC members are both hospital- and physician’s office–based, we are represented across the spectrum of cancer care delivery. Some members are already prepared to implement an ACO model and may be able to send their applications to CMS as soon as the final rule is published. However, we also have a lot of members with a number of concerns—for one, the very high start-up costs CMS estimates it will take to launch an accountable care organization,” said Mr. Farber. Mr. Farber mentioned that many oncologists are also concerned about legal issues regarding accountable care organizations. Such issues include contract negotiations and the establishment of network relationships that are responsible for coordinating all aspects of care including the sensitive is-

sue of sharing of patient information. “In addition to the unanswered questions and logistical issues involved in setting up an accountable care organization, another concern is how the collective aspect of accountable care organizations might shift the site-of-service availability to care for our patients,” said Mr. Farber. He added that “ACCC is in the process of crafting a comment letter expressing concerns about how accountable care organizations are structured and how the process might affect the delivery of cancer care.”

Comparative (Cost) Effectiveness Research Another initiative on the oncology community’s radar is comparative effectiveness research, an evaluation instrument purportedly designed to determine the effectiveness of similar therapies or drugs. “Even though we

Shared Savings ■■ Model 1: Providers would obtain up to 60% of any savings beyond 2% of budget, and would face the potential downside risk if their actual costs exceed the projected expenses by 2%. Providers would have to provide proof they could repay up to 1% of total costs.

■■ Model 2: Providers would obtain only 50% of savings beyond 2% to

3.9% of budget depending on size, and would transition to upside and downside risk as of year 3.

fective therapy. “We support efforts to determine the most cost-effective therapies, but with the highly personalized nature of oncology, we want to ensure that physicians are not constrained from giving the best care to their patients regardless of cost.”

Another Initiative to Cut Costs Another cost-control entity of the accountable care organization is the Independent Payment Advisory Board (IPAB) charged with reducing

Even though we know that cost is not supposed to be part of the comparative effectiveness research discussion, that doesn’t mean that it’s possible to separate out costs from the larger discussion. —Matthew Farber

know that cost is not supposed to be part of the comparative effectiveness research discussion, that doesn’t mean that it’s possible to separate out costs from the larger discussion,” said Mr. Farber. Mr. Farber stressed that ACCC’s overriding goal is to make sure that cancer patients receive the most ef-

the growth of Medicare spending, ostensibly without affecting coverage or quality. According to Mr. Farber, the initial focus of the Board will be the Medicare Advantage Plan and Prescription Drug Plans. “Our central concern with the Independent Payment Advisory Board is that it is basically going to be yet an-

Independent Payment Advisory Board ■■ 15-member board nominated by the President and confirmed by the Senate

■■ Members serve 6-year staggered terms: Who will serve? ■■ Beginning in 2013, if the Medicare actuary projects the per capita growth rate to exceed spending targets for the following year, IPAB will submit proposals to reduce such spending

■■ At least $3 billion a year in cuts

other bureaucratic body that is going to suggest cuts to Medicare reimbursement and, unlike members of Congress, the Board is not going to be accountable to our members,” said Mr. Farber. He continued, “The questions we need answers to are these: What is this Independent Payment Advisory Board going to cut, and who is going to constitute the 15-member board that will be nominated by the President?” Mr. Farber explained that for the first 5 years the Board has specific limitations on what they can cut, but after that pretty much all of Medicare is fair game, including outpatient services and drug reimbursement. “The confirmation process of setting up the Independent Payment Advisory Board will undoubtedly move at a very slow pace, but it is another initiative that ACCC will follow,” said Mr. Farber. “We are also paying close attention to several other issues that could affect the delivery of cancer care, such as the movement to create new payment systems. Obviously CMS wants to move away from the “buy and bill” payment model that community oncologists depend on,” noted Mr. Farber. In fact, CMS has been allotted $10 billion over 10 years to study innovation and new ways of paying doctors. Some of the models under review will be episodic care, increased bundling, more use of guidelines, pathways, and benchmarks, and comparative effectiveness research. “ACCC is working for our members with CMS and Congress, testifying before panels and lobbying for issues that affect our ability to continue to deliver highvalue care for our patients,” concluded Mr. Farber.

■

Financial Disclosure: Mr. Farber reported no potential conflicts of interest.

The ASCO Post | MAY 1, 2011

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Expert’s Corner Spotlight on Research

A Conversation with Rafat Abonour, MD

Indiana investigator discusses B-cell cancer research and funding. By Jo Cavallo research plans and how his award will help him further his goals.

Research Objectives

Rafat Abonour, MD

he research efforts of Rafat Abonour, MD, Professor of Medicine in the Division of Hematology/Oncology and Associate Dean for Clinical Research at Indiana University School of Medicine, Indianapolis, and a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center, focus on finding less toxic and more efficacious remedies to fight B-cell malignancies, especially in such incurable cancers as multiple myeloma. Last year, Dr. Abonour became Chairman of the Hoosier Oncology Group, an organization whose goal is to bring together researcher/clinicians from academic institutions and community hospitals and patients to make personalized medicine a reality for every patient with cancer. The NCI named Dr. Abonour one of its recipients of the Cancer Clinical Investigator Team Leadership Award. The 2-year award provides $50,000 in funding for cancer research programs and clinical trials at NCI-designated cancer centers. The ASCO Post talked with Dr. Abonour about his current and future

Much of your research centers on gene therapy in B-cell cancers, specifically in multiple myeloma. What are you hoping to achieve? What we are trying to do is twofold. One goal is to identify the marker of the disease that will help us better assign the right treatment for our patients. Today, one of the obstacles in the treatment of patients with multiple myeloma is the one-size-fits-all approach. But the disease is quite heterogeneous, so one of our efforts is to identify biomarkers, specifically those that will help identify patients at in-

smoldering multiple myeloma have no standard treatment, and we’re not addressing the issue of bone disease and the potential for developing pathologic fractures in these folks. So our goal is to try to prevent this morbidity and improve quality of life.

Role of Bisphosphonates Isn’t the potential for bone disease ameliorated by the use of bisphosphonates? Bisphosphonates are not a home run. They have helped reduce the occurrence of bone disease by 50% in symptomatic disease, however, their role in smoldering disease is less clear. And one of the issues with these medications is that they work on one path-

One of our efforts is to identify biomarkers, specifically those that will help identify patients at increased risk of bone disease. creased risk of bone disease, which is the major morbidity of these patients. We’re also trying to find molecules that will help change the behavior of the disease and prevent the development of bone lesions and destruction of the bone. That’s the area that we’re focusing on at this point. Finding these molecules will allow you to extend the length of remission, making the disease more chronic? Yes. Although patients are living longer, there is still no cure for multiple myeloma. In addition, those with

way, which really only inhibits osteoclast activity against the bone. Also, they have some risk of renal toxicity and osteonecrosis of the jaw, so it will be important to come up with a molecule that will not only enhance osteoclast activity, but also improve bone building and remodeling and have less toxicity. And we’re exploring some of these molecules in the clinic.

Impact of Funding How will you use the NCI Cancer Clinical Investigator Team Leadership Award to achieve your research priorities?

The ASCO Post

Wants to Hear from You

Last year, I became Chairman of the Hoosier Oncology Group, which has been around for 25 years. The group started with the collaboration between clinicians in the community and academics in Indiana University School of Medicine, and it’s been successful in trying to bring new molecules to patients across Indiana and beyond. But my goal as Chairman is to transform the organization from another phase II or phase III trial-driven organization to one that is driven by a more molecular-specific plan, to achieve personalized medicine. What I’d like to be able to do is start looking at the biomarkers of all types of cancer and investigate why certain cancers respond to certain treatments and others don’t, as well as why certain patients develop toxicities while they’re receiving treatment and other patients don’t. The $50,000 in funding from the award provides me with the protected time I need to coordinate these efforts. I’m reaching out to oncologists across Indiana and working with our investigators at the Simon Cancer Center to come up with the tools to recruit patients, collect tissue samples for biomarkers, and help design the clinical research needed to facilitate those goals. I’m excited about the activity that we have at our institution, and I’m really excited about the buy-in from the community oncologists to participate in this kind of research, to both help reduce drug toxicities and increase the efficacy of our current chemotherapies for all cancers.

■

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

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

ASCOPost.com | MAY 1, 2011

PAGE 39

JNCI Spotlight Patient-centered Treatment

Quality-of-life Measures Show Increased Acceptance of the ‘Patient’s Voice’

n updated review of quality-of-life (QOL) measures in clinical trials among patients with breast cancer found that these measures were most useful for clinical decisions in trials using nonbiomedical interventions, such as psychosocial interventions and physical activity, in which QOL is often the primary outcome. Published in the Journal of the National Cancer Institute, the review of 190 randomized clinical trials of breast cancer interventions updates an earlier review of 66 trials published in 2003. “For trials of biomedical interventions, QOL influenced decisions about use of the intervention studied in 30.1% of the trials in this review compared with 15.2% of the trials in the previous review,” the authors reported. Biomedical interventions included those for primary management, adjuvant treatment, metastatic disease, follow-up, or symptom control. “Corresponding numbers for trials of nonbiomedical interventions were 63.2% and 95%, respectively,” the authors continued. “However, it must be noted that there were only 20 trials testing nonbiomedical interventions in the previous review, and there were 89 such trials in this update. Also, studies used a greater variety of interventions in this update, including many trials of physical activity interventions.”

Growing Number of QOL Studies In an accompanying editorial, Patricia A. Ganz, MD, of the Jonsson Comprehensive Center at UCLA, wrote, “The large increase in the number of published studies identified in this high-quality systematic review reflects the increased acceptance of the patient’s voice in assessing the outcome of trials as well as the participation of expert QOL investigators in the design, conduct, and analysis of clinical trials.” She concluded, “Inclusion of well-validated measures of relevant symptoms should be a high priority for assessing the burden of breast cancer treatments, whether in survivors of breast cancer or in women with advanced disease receiving palliative care.” The results of the study led the investigators to make several suggestions. QOL should be included as a secondary endpoint in adjuvant therapy trials, they stated, only for equivalence or noninferiority studies (since QOL may play a greater role in decision-making if SEE PAGE 47 the medical outcome

is expected to be about the same); for studies focusing on a vulnerable population such as the elderly; or for tests of new interventions. The investigators also suggested including QOL in metastatic breast cancer trials when a minimal sur-

vival difference is expected or treatments have substantial differences in toxicity. When QOL is not the primary endpoint of a trial, the authors asserted, “QOL results should ideally appear in a companion article published at the same

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time as the traditional medical outcomes article.”

■

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Lemieux J, et al: J Natl Cancer Inst 103:178-231, 2011. Ganz PA: J Natl Cancer Inst 103:196199, 2011.

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The ASCO Post | MAY 1, 2011

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In the Literature

Emerging Clinical Data on Cancer Management and Epidemiology BREAST CANCER Multiple Childbirths May Raise the Risk of Triple-negative Breast Cancer Factors related to a woman’s reproductive history that lower the risk for estrogen receptor (ER)-positive breast cancer may raise the risk for triple-negative breast cancers. These cancers not only lack estrogen receptor, but progesterone receptor and HER2 expression as well, and have a poorer prognosis. Investigators from several cancer centers and research institutes nationwide analyzed data from 155,723 women enrolled in the Women’s Health Initiative, including 307 women with triple-negative breast cancer and 2,610 women with ER-positive breast cancers. “Specifically, we found that nulliparity was associated with a 39% lower risk of triple-negative breast cancer but a 35% higher risk of ER-positive disease in postmenopausal women. Among parous women, we found that having multiple children was associated with greater risk of triple-negative breast cancer but with lesser risk of ER-positive breast cancer,” the investigators reported in the Journal of the National Cancer Institute.

Qualifying Remarks “Age at menarche was modestly inversely associated and age at menopause was modestly positively associated with risk of ER-positive breast cancer; these associations were not evident for triple-negative breast cancer,” the researchers wrote, but “breastfeeding and oral contraceptive use were not associated with either subtype.” They acknowledged, however, that the older age and postmenopausal status of women in the Women’s Health Initiative study could be why no association was found between breastfeeding and the risk of triple-negative, or ER-positive breast cancer or between the use of oral contraceptives and the risk of triple-negative breast cancer. The JNCI editors also noted that the postmenopausal status of women in the study population could mean the findings may not apply to younger women and should be confirmed with a larger population of women with triple-negative breast cancer. “Given the poor prognosis associ-

ated with triple-negative breast cancer, it remains important to identify the factors that influence a woman’s risk of developing this subtype of disease and to further characterize if and how such factors differ from risk factors for the more predominant ER-positive breast cancer subtype that has a better prognosis,” the authors concluded. Phipps AI, et al: J Natl Cancer Inst 103:470-477, 2011.

LYMPHOMA Pralatrexate Induces Durable Responses in Patients with Peripheral T-cell Lymphoma The novel antifolate pralatrexate (Folotyn) produced durable responses in patients with refractory or relapsed peripheral T-cell lymphoma (PTCL) regardless of patient age, histologic subtype, and prior therapy, autologous stem-cell transplantation, and prior methotrexate. In the Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PROPEL) study, the overall response rate (the primary endpoint) was 29%, with an 11% complete response rate. The median duration of response was 10.1 months. The median overall survival was 14.5 months, with a range of 1 to 24 months, and the median progression-free survival was 3.5 months, with a range of 1 day to 23.9 months. “These data form the basis for the [FDA’s] approval of pralatrexate, the first drug approved for this disease,” the investigators stated in their report in the Journal of Clinical Oncology. Trial participants were required to have PTCL with documented disease progression after one or more prior treatments. Most patients had more, with a range of 1 to 12 and a median of 3 among the 109 evaluable patients. “Of the 69 patients who did not have any evidence of response to their most recent prior therapy, 17 (25%) responded to pralatrexate,” the investigators reported. “Of the 26 patients who did not have evidence of response to any prior conventional therapy, 5 (19%) responded to pralatrexate.” Earlier clinical experience in patients with relapsed or refractory Bcell or T-cell non-Hodgkin lymphoma established the tolerability and efficacy of a weekly schedule of pralatrexate with vitamin B12 supplementation

and daily oral folic acid to ameliorate mucositis. Treatment was continued until progressive disease or unacceptable toxicity, or at patient/physician discretion.

Key Findings “The majority of patients in this study tolerated pralatrexate,” the investigators reported, although 76 patients (68%) had one or more dose omissions due to adverse events. Mucositis was the most common adverse event, the most common cause of dose modification, and the most common reason cited by the 26 patients (23%) who withdrew from treatment. Other common grade 3/4 adverse events were thrombocytopenia, neutropenia, and anemia. Eight patients (7%) died within 30 days of their last dose of pralatrexate, seven due to progressive disease. The other patient had a cardiopulmonary arrest approximately 3 weeks after the last dose and while hospitalized for mucositis and febrile neutropenia. “This death was deemed possibly related to pralatrexate,” the researchers stated. The consistency in the response rate among the patients of different ages and with different PTCL subtypes and prior treatments “suggests pralatrexate has broad activity across the spectrum of features that often characterize this heterogeneous disease,” the investigators commented. They also noted that 10 of 12 patients who attained a complete response “continue in remission, suggesting a lack of cross-resistance to conventional chemotherapy,” and 4 patients who received autologous stem cell transplant following pralatrexate remain in remission, “suggesting that pralatrexate could be a potential bridge to definitive [stem cell transplant].”

O’Connor OA, et al: J Clin Oncol 29:1182-1189, 2011.

COLORECTAL CANCER Use of Bisphosphonates for More Than 1 Year Associated with Reduced Risk of Colorectal Cancer “The use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in

breast cancer risk,” according to the Molecular Epidemiology of Colorectal Cancer study. This northern Israel population–based, case-control study assessed long-term use of bisphosphonates in 933 pairs of postmenopausal women diagnosed with colorectal cancer and matched controls. The association between the use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, remained statistically significant after adjustment for factors associated with colorectal cancer risk. These included family history of colorectal cancer, vegetable consumption, sports activity, body mass index, and use of low-dose aspirin, statins, vitamin D, and postmenopausal hormones. The results were reported in the Journal of Clinical Oncology. The median age of patients was 71.1 years, and the median age of controls was 72 years. Potential controls and patients were excluded if they had a history of colorectal cancer. Using computerized pharmacy records from Israel’s largest healthcare provider, researchers identified bisphosphonate users who filled at least three prescriptions before diagnosis of colorectal cancer (97 patients or 10.4%) and the controls (138 people or 14.8%), as well as the duration of use and type of medication. Most (94.7%) used alendronate, 60% of them at 10 mg daily and 40% at 70 mg weekly.

Bisphosphonate/Statin Combination “Compliance with daily use was estimated at 89%, and compliance with use of weekly agents was estimated at 96%. A significant negative association with colorectal cancer risk was demonstrated only in those who used bisphosphonates for more than 1 year,” the researchers reported. “Because bisphosphonates and statins both act through blocking the same mevalonate pathway, we studied the effects of concomitant use of both drugs on risk of colorectal cancer,” they added. “Although bisphosphonate use and statin use each demonstrated a strong negative association, the combined use was not associated with further risk reduction.” The authors noted that the adverse effects profile of bisphosphonates, although not fully clear, “is of major importance if bisphospho-

ASCOPost.com | MAY 1, 2011

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In the Literature

nates are to be recommended for cancer prevention in healthy people. Similar to the case with breast cancer, the protective effect of bisphosphonates in our study was demonstrated after only 1 year of use and did not change meaningfully with extended periods of use. Because this class of medications is known to be stable in the bone for many years after its administration, further research should focus on the optimal length of intervention needed to achieve cancer risk reduction.” Rennert G, et al: J Clin Oncol 29:11461150, 2011.

PANCREATIC CANCER Heavy Drinking Linked to Increased Risk of Death from Pancreatic Cancer Drinking three or more glasses of liquor a day is associated with an increased risk of death from pancreatic cancer, according to a report in the Archives of Internal Medicine. “Alcoholic beverage consumption—a modifiable lifestyle factor—is causally related to several cancers, including oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast,” the authors noted. “Heavy alcohol consumption causes acute and chronic pancreatitis but has never been linked definitively to pancreatic cancer.”

Prospective Study Using data from the Cancer Prevention Study II (CPS-II), a longterm prospective study of U.S. adults aged 30 years and older, Susan M. Gapstur, PhD, MPH, and colleagues from the American Cancer Society examined the association between alcohol intake and pancreatic cancer. Based on alcohol consumption data initially gathered in 1982, with follow-up through 2006, there were 6,847 pancreatic cancer deaths among 1 million participants (453,770 men and 576,697 women). Among the men, 45.7% were nondrinkers, as were 62.5% of the women. The analyses of men only and of men and women combined showed a statistically significant increased risk of pancreatic cancer death for consumption of three drinks per day and four or more drinks per day, whereas the analyses of women only showed the estimated risk of death from pancreatic cancer was statistically sig-

nificant for consumption of four or more drinks per day.

Smoking History and Other Variables Compared with nondrinkers, consuming three or more drinks of liquor per day was associated with an increased risk of pancreatic cancer death in the total study population, and consumption of two or more drinks of liquor per day was associated with an increased risk in those who never smoked and in those who had ever smoked. This association was observed for liquor consumption but not for beer or wine. Among study participants who never smoked, there was a 36% higher risk of pancreatic cancer death associated with consuming three or more drinks a day compared with nondrinkers for men and women combined. In those who had ever smoked, there was a 16% higher risk of death from pancreatic cancer after adjustment for smoking history and other variables. The authors concluded that the findings from the prospective study “strongly support the hypothesis that alcohol consumption, in particular heavy intake, also is an independent risk factor for pancreatic cancer, the fourth most common cause of cancer mortality in the United States.”

Gapstur SM, et al: Arch Intern Med 171:444-451, 2011.

LUNG CANCER

and declined to 102 per 100,000 by 2007.” While pack-a-day consumption was typical throughout much of the early history of cigarette smoking in the United States, there has been a major decline in smoking prevalence since the first surgeon general’s report on smoking and health in 1964. During this period, California has consistently led the United States in using public policies to reduce cigarette smoking, with faster declines in smoking prevalence, as well as in lung cancer rates, according to background information in the article.

Two Large Surveys John P. Pierce, PhD, of the University of California San Diego, La Jolla, and colleagues examined trends in smoking intensity for both California and the other states using two large population-based surveys with state estimates: National Health Interview Surveys, 1965–1994; and Current Population Survey Tobacco Supplements, 1992–2007. There were 139,176 total respondents for California and 1,662,353 for the remaining states. In 1965, the prevalence of high-intensity smoking among California adults was slightly higher (23.2%) than adults in other states (22.9%), but by 2007 had declined to 2.6% in California vs 7.2% in the remaining states. For moderate-intensity smoking (10 to 19 cigarettes per day), the prevalence was 11.1% in California

and 10.5% in the other states in 1965, compared with 3.4% in California and 5.4% in the remaining states in 2007. For low-intensity smoking (9 or fewer cigarettes per day), the population prevalences in 1965 were 7.1% in California and 7.0% in the other states, and by 2007, 5.3% in all states. In 2007, 11.3% of California adults were smokers, 23% of them high-intensity smokers, and 17.9% of adults in other states were smokers, 40% of them high-intensity smokers.

Continued Widening of Difference in Rates Moderate and high-intensity smoking “declined across successive birth cohorts,” the authors reported. “As it now appears that less than 10% of young Californians and less than 20% of young residents in the remaining United States will ever reach these high-intensity levels of cigarette consumption, lung cancer rates should continue to decrease, with a continued widening of the difference in rates between California and the remaining United States.” The researchers stated that further study of “these changes in the intensity of smoking patterns should assess the relative importance of changes in initiation, cessation, and reduced consumption in the documented decline of health consequences of smoking in the United States.”

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Pierce JP, et al: JAMA 305:1106-1112, 2011.

California Leads the Pack in Reducing Prevalence and Intensity of Smoking High-intensity smoking, defined as 20 or more cigarettes per day, “had declined markedly in both California and the remaining United States from 56% of all smokers in 1965 to 23% of smokers in California and 40% of smokers in the remaining United States in 2007,” according to a study in The Journal of the American Medical Association. “As expected, the large decline in the prevalence of pack-a-day smoking has been reflected in declines in lung cancer,” the researchers reported. “Lung cancer death rates peaked in California in 1987 at 109 per 100,000 and declined continuously to 77 per 100,000 in 2007. In the remaining United States, lung cancer deaths peaked in 1993 at 117 per 100,000

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ASCOPost.com | MAY 1, 2011

PAGE 43

In the News Risk Factors

Possible Link between Breast Implants and Rare Lymphoma Should Raise Vigilance for Many, Red Flag for Some By Charlotte Bath

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

or most women with breast implants and for health professionals, the FDA’s announcement of “a possible association” between saline and silicone breast implants and anaplastic large cell lymphoma (ALCL) should serve to raise awareness about symptoms of ALCL in the breast. These symptoms include pain and swelling in the breast. For women who develop symptoms, the FDA announcement “should raise a red flag, and these women should make sure that they follow up with their doctors,” advised Jasmine Zain, MD, Assistant Professor, Division of Hematologic Malignancies and Medical Oncology, and Director of the Bone Marrow Transplant Program and at NYU Institute and NYU Langone Medical Center in New York.

Jasmine Zain, MD

Numbers Difficult to Verify “Data reviewed by the FDA suggest that patients with breast implants may have a very small but significant risk of ALCL in the scar capsule adjacent to the implant,” the FDA announced.1 These data came from a review of scientific literature, published from January 1997 through May 2010, that “identified 34 unique cases of ALCL in women with breast implants throughout the world,” according to an FDA Medical Safety Communication.2 “In total, the FDA is aware of approximately 60 case reports of ALCL in women with breast implants world-

wide,” the communication continued, but acknowledged that the number is “difficult to verify.” Not all cases were published in the scientific literature, and some identified by other sources may be duplicates of those cited in the literature. “Most patients were diagnosed when they sought medical treatment for implant-related symptoms such as pain, lumps, swelling, or asymmetry that developed after their initial surgical sites were fully healed,” the FDA reported. “These symptoms were due to collection of fluid (persistent seroma), hardening of breast area around the implant (capsular contracture), or masses surrounding the breast implant. Examination of the fluid and capsule surrounding the breast implant led to the ALCL diagnosis.”2

Rare and Unpredictable Currently, there is no way to predict which of the estimated 5 to 10 million women with breast implants might develop ALCL, Dr. Zain said. ALCL is a rare T-cell lymphoma, and ALCL in the breast is rarer still, with approximately 3 in 100 million women diagnosed each year in the United States. Despite the rarity of ALCL in the breast, Dr. Zain has had experience with patients who had ALCL in the breast. Those cases occurred while Dr. Zain was at the City of Hope in Duarte, California, and were reported by Popplewell et al in 2004.3 That report is part of the published data reviewed by the FDA. “There is no uniform way of treating this,” Dr. Zain told The ASCO Post. Patients with ALCL that arises in the skin only “can be treated locally, with radiation or even very mild chemotherapy,” but patients with ALCL that arises in deeper tissues and in lymph nodes “need to be treated with chemotherapy,” she explained. “The patients I saw actually had advanced disease. They had systemic symptoms. One of them even needed a bone marrow transplant.” “The treating physician really has to get into the details of how the ALCL is presented and where it is found, to try to make a decision whether this is systemic anaplastic large cell lymphoma or cutaneous anaplastic large cell

Expect Questions from Your Patients

he FDA announcement of the “possible association” between breast implants and anaplastic large cell lymphoma in the breast was widely reported by major media, including The New York Times, The Washington Post, The Wall Street Journal, Los Angeles Times, and ABC World News. Internet advertisements from several law firms offering a free consultation for women to discuss their legal options as a result of the announcement also suggest that the issue will continue to generate interest. What should health professionals do? The FDA recommendations for health-care professionals include the following actions: ■■ Report confirmed cases of ALCL in women with breast implants to Medwatch, the FDA’s Safety Information and Adverse Event Reporting Program online at https://www.accessdata.fda.gov/scripts/medwatch/ medwatch-online.htm, or at 1-800-332-1088. ■■ Consider the possibility of ALCL in a patient with late-onset, persistent fluid around the implant. ■■ When testing for ALCL, collect fresh seroma fluid and representative portions of the capsule, and send for pathology tests. ■■ For patients diagnosed with ALCL in the breast, develop an individualized treatment plan in coordination with the patient’s multidisciplinary care team. What should women who have breast implants do? For women with breast implants, the FDA recommends that they: ■■ Continue routine medical care and follow-up. ■■ Monitor their breast implants and contact their doctors promptly if they notice pain, swelling, or any changes in or around their breast implants. What should women who are considering having breast implants do? The FDA also recommends that women who are considering breast implant surgery discuss the risks and benefits of the procedure with their doctors. Dr. Zain said that women considering breast implants should be made aware of the possible association with ALCL. “This is certainly one of the risks that you would consider,” she said. “Obviously, if someone has a previous history of lymphoma, my recommendation would be to not do it in that particular situation because lymphoma predisposes to more lymphoma. But in an otherwise healthy woman, she should be made aware of this risk and the numbers, and then she can make a decision about what she wants to do. This is an individual decision.”

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lymphoma, because the treatments are very different. If it is in the deeper tissues, this is a systemic disease and can progress to other parts of the body as well. But it is treatable and even curable,” Dr. Zain explained. “Every case has to be looked at on an individual basis—the extent of the lesion, where it is found, how compromised the tissue barriers were, and whether there was any systemic involvement—and then a decision has to be made about treatment.”

Among the 34 cases reviewed by the FDA, “treatment was reported for 20 patients,” according to the FDA preliminary findings and analyses.4 “Most had the imSEE PAGE 47 plants removed, and some went on to receive treatment with radiation and/or chemotherapy. Overall, the outcomes appeared to be more favorable than would continued on page 44

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In the News

Breast Implants and Lymphoma continued from page 43

typically be expected for systemic ALCL,” according to the report. Among 19 patients whose outcomes were reported, 14 had no evidence of disease at last follow-up. “However, most cases were diagnosed with early-stage disease, and follow-up on many cases was limited. At present, it cannot be determined if these patients have a different prognosis than patients who present with ALCL at other sites unassociated with breast implants.”4

ALK Status and Prognosis Whether ALCL expresses the protein anaplastic lymphoma kinase (ALK-positive) or it does not (ALKnegative) can influence prognosis. In the data reviewed by the FDA, “the 26 reports of ALCL in women with breast implants that included ALK status were all ALK-negative.” Among patients with systemic ALCL, those with ALK-positive disease tend to have a better prognosis than those with ALK-negative disease. Anaplastic large cell lymphomas that arise from skin tissue, however, “are always ALK-negative and still have an excellent prognosis,” Dr. Zain said. “Anaplastic large-cell lymphomas in general, as a group—even ALKnegatives—have a better prognosis

than other T-cell lymphomas,” Dr. Zain added. “ALK-positive ALCL has the best prognosis, but ALK-negative disease also has a good prognosis compared to other T-cell lymphomas.”

Table 1: Characteristics of 34 Unique Cases of ALCL in Women with Breast Implants Age

Registry Being Established To obtain more data about the possible association between breast implants and ALCL in the breast, the FDA is asking health-care professionals to report confirmed cases to its Medwatch program (see “Expect Questions from Your Patients” for details) and is working with the American Society of Plastic Surgeons and others to establish a breast implant patient registry. “I think this is an important step,” Dr. Zain said, “because this will give us the information we need. If we collect all these cases together, especially going forward prospectively, we may be able to make some connection about why we think this is occurring. We may be able to pick out risk factors that may predict these particular cases. I don’t think it has any treatment implications at the moment, but certainly it would provide a lot of useful information, and in the end it may help us guide treatment.” The FDA reported that it also will be working with breast implant manufacturers in the coming months to update their product labeling materials for patients and health-care professionals.

■

Type of Implant

Texture of Implant

Time from Implant to ALCL Diagnosis

Reason for Implant

Median

51 yr

Range

28–87 yr

No age specified

Silicone

Saline

No implant type specified

Textured

Smooth

No surface texture specified

Median

8 yr

Range

1–23 yr

No time to diagnosis specified

Reconstruction

Augmentation

No reason specified

ALCL = anaplastic large cell lymphoma. Source: FDA.

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

References 1. U.S. Food and Drug Administration: FDA review indicates possible association between breast implants and a rare cancer. Press release, January 26, 2011. Available at www.fda.gov. 2. U.S. Food and Drug Administration: Reports of anaplastic large cell lymphoma (ALCL) in women with breast implants. Medical device safety commu-

nication, January 26, 2011. Available at www.fda.gov. 3. Popplewell L, Chang K, Olevsky O, et al: Primary anaplastic large cell lymphoma of the breast occurring in patients with silicone breast implants. Blood 104:Abstract 4563, 2004. 4. U.S. Food and Drug Administration, Center for Devices and Radiological Health: Anaplastic large cell lymphoma (ALCL) in women with breast implants: Preliminary FDA findings and analyses. January 2011. Available at www.fda.gov. JOP Spotlight

Updated Guidelines on Bone-modifying Agents in Metastatic Breast Cancer

he “monumental task of updating” the ASCO guideline on the role of bone-modifying agents in metastatic breast cancer “is an important service to the community of patients and physicians alike,” according to a commentary in the Journal of Oncology Practice by Gabriel Hortobagyi, MD, Professor and Chair, Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in HousSEE PAGE 47 ton. As Dr. Hortobagyi notes in his commentary: “Bone is the most frequent target of metastatic breast cancer, and although bone metastases are not life-threatening, some of the complications (spinal cord compression, hypercalcemia) can be.

More important, bone metastases and their complications can be substantially disabling, require multiple interventions, and are costly to the patient and the health-care system.”

Key Recommendations These are the key recommendations of the updated guidelines for bone-modifying agents: ■■ Bone-modifying agents (eg, denosumab [Xgeva], pamidronate, zoledronic acid) are recommended for patients with metastatic breast cancer with evidence of bone destruction. ■■ One bone-modifying agent is not recommended over another. ■■ In patients with creatinine clearance > 60 mL/min, no change in dosage, infusion time, or interval is

Journal of Oncology Practice

American Society of Clinical Oncology

THE AUTHORITATIVE RESOURCE

VOLUME 6

ISSUE 1

FOR

ONCOLOGY PRACTICES

JANUARY 2010

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

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

Ensuring Quality Cancer Care Through the Oncology Workforce

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

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

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

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

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

By Laura Levit, JD, et al

http://jop.ascopubs.org

required; monitor creatinine level with each IV bisphosphonate dose. ■■ In patients with creatinine clearance < 30 mL/min or on dialysis who may be treated with denosumab, close monitoring for hypocalcemia is recommended. ■■ All patients should have a dental exam and preventive dentistry before

receiving a bone-modifying agent. ■■ At onset of cancer bone pain, provide standard of care for pain management and start bone-modifying agents. ■■ Use of biochemical markers to monitor bone-modifying agent use is not recommended for routine care. “The fate of patients with bone metastases has improved significantly over the past couple of decades thanks to bone-modifying agents,” Dr. Hortobaygi concluded. “Our choices are becoming more complex, and we must make sure we use these drugs most effectively while limiting the risks of chronic and serious adverse effects.”

■

Hortobagyi GN: J Oncol Pract 7:121123, 2011.

ASCOPost.com | MAY 1, 2011

PAGE 45

TAP Caucus Pro/Con

Does Removing the Primary Breast Cancer in Patients with Metastatic Disease Prolong Survival? By Seema A. Khan, MD, and Blake Cady, MD

PRO

About 5% of new breast cancer diagnoses in the United States are made when there are already clinically detectable metastases to distant sites, amounting to about 10,000 women annually. The primary therapeutic approach for this problem consists of systemic therapy. The underlying assumption is that systemic therapy will control the distant sites and will control the primary tumor sufficiently well for the remainder of the paSeema A. Khan, MD tient’s life, so that specific local therapy for the primary tumor is not beneficial. This concept needs to be reevaluated because of the lengthening survival of patients with stage IV disease, the tendency toward decreasing metastatic disease burden at diagnosis, and accumulating data that local therapy for the primary site may be beneficial.

Robust Association Retrospective data on over 30,000 women have now been published from a variety of settings in North America and Europe, showing a robust association between surgical treatment or radiotherapy for the primary tumor and prolonged survival.1 It is possible, of course, that these findings are explained by a consistent selection bias favoring the surgical group, who tend to be younger and more prosperous, with smaller tumors and more indolent disease.

Data on over 30,000 women show a robust association between surgical treatment or radiotherapy for the primary tumor and prolonged survival. There are also negative studies, two of which are relatively small.2,3 The third, large study matched women receiving surgery to those who did not. Despite the interpretation by the authors that this is a negative study, the data in fact show a consistent benefit for the use of surgery in multiple subsets, including those with more than one metastatic site. The exception was the group of women with visceral-only metastases, where the trend favored the surgical group, with a P value of .09 in 100 women.4

Further Considerations A separate factor that has been difficult to control for relates to the fraction of women in published studies who underwent surgery prior to the diagnosis of metastatic disease, and therefore may have had a smaller disease burden than those diagnosed with metastases preoperatively. However, the apparent benefit of primary site resection or radiotherapy persists across a dozen or more studies, with a remarkably consistent reduction in the hazard of death by 30% to 50% despite statistical adjustment for known prognostic factors. Another important aspect of the use of primary site local therapy in this setting relates to the quality of local control. When the primary tumor is treated only with systemic therapy, about 30% of women require surgery or radiation for palliation. The palliative success of surgery or radiotherapy once the tumor is symptomatic is only modest. Three separate studies (albeit small) have now shown that symptomatic chest wall disease is far less likely among women who receive specific local therapy for the primary site.5-7

CON

The concept that breast surgery might increase survival in patients with stage IV breast cancer seems illogical: The horse is already out of the barn! While retrospective studies have shown significantly improved survival in patients with stage IV disease undergoing resection of the primary breast cancer, differences must also be biologically plausible and define causality, not mere coincidence. Blake Cady, MD Survival prolongation after primary breast surgery with demonstrable metastasis could be causally related by only a few possible mechanisms: (1)The primary cancer produces growthpromoting hormonal substances that, when reduced by excision, slow metastatic growth. (2) Continued cell shedding producing further metastases from the primary cancer is eliminated. (3) Decreased tumor burden by primary cancer removal allows more effective systemic therapy. (4) Some case selection process promotes primary site surgery selection in patients with a better prognosis.

Selection for Surgery Patient or tumor factors leading to selection for breast surgery might include: (1) Patients initially treated with systemic chemotherapy or hormone blockage who have a substantial response (favorable prognosis) are preferentially selected for breast surgery. (2) Patients with favorable prognostic features (estrogen receptor–positive, bone predominant disease, oligometastases, long disease-free interval, young age) are preferentially selected for breast surgery. (3) Patients with supraclavicular node metastases or T4 primary cancers (classified by AJCC before 1997 as stage IV, but now classified stage III) are preferentially selected for breast surgery. (4) Patients are misclassified as stage IV because of erroneous radiologic study interpretations. (5) Registry misclassification of biopsy procedures as therapeutic surgery or vice versa leads to erroneous conclusions.

While retrospective studies have shown improved survival in patients with stage IV disease undergoing resection of the primary, differences must also be biologically plausible and define causality, not mere coincidence. Registry-based Study

Nevertheless, many uncertainties remain, including questions about the role of selection bias in explaining the results of primary site surgery, whether specific

Our report of 622 stage IV cases in a large hospital consortium cancer registry were studied by matched-pair analysis comparing patients with similar prognostic features with and without primary breast surgery. Favorable prognostic criteria described above were present more often in patients selected for breast surgery, which decreased or eliminated the apparent better survival. Surgery following initial systemic therapy was associated with better survival than when exactly similar systemic therapy was given after surgery or without surgery, implying that systemic therapy response led to primary breast surgery, while failure to respond did not. We also performed detailed actual chart review of all 5-year survivors with registry-classified stage IV disease. This assessment indicated significant selection bias or misclassification favoring primary breast surgery, including the following findings in these long survivors: 87% had estrogen receptor–positive cancers; 72% had bone-predominant disease; 26% had oligometastases; 25% had incorrect staging (not M1); 25% had errors in surgical definition (biopsy vs therapeutic procedures); and patients were younger, all factors with statistically significantly

continued on page 46

Uncertainties Remain

The ASCO Post | MAY 1, 2011

PAGE 46

TAP Caucus

PRO: Observed Benefits Warrant Further Evaluation continued from page 45

biologic subsets would derive greater benefit, and the appropriate timing and extent of local therapy (ie, whether axillary clearance and radiotherapy provides benefit). These can only be definitively

addressed in a randomized trial. Two trials are open in India and Turkey; a third was recently activated in the United States (ECOG 2108). Given the importance of this question for the approximately 10,000 women who are diagnosed with stage IV breast cancer in the United States, and the many more world-

wide, it is hoped that the U.S. trial will receive strong support from breast cancer physicians, and from our patients.

■

References 1. Ly BH, Nguyen NP, Vinh-Hung V, et al: Loco-regional treatment in metastatic breast cancer patients. Breast Cancer Res

Treat 119:537-545, 2010. 2. Bafford AC, Burstein HJ, Barkley CR, et al: Breast surgery in stage IV breast cancer. Breast Cancer Res Treat 115:7-12, 2009. 3. Leung AM, Vu HN, Nguyen KA, et al: Effects of surgical excision on survival of patients with stage IV breast cancer. J Surg Res 161:83-88, 2009. 4. Cady B, Nathan NR, Michaelson JS, et al: Matched pair analyses of stage IV breast cancer with or without resection of primary breast site. Ann Surg Oncol 15:3384-3395, 2008. 5. Carmichael AR, Anderson ED, Chetty U, et al: Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol 29:17-19, 2003. 6. Hazard HW, Gorla SR, Scholtens D, et al: Surgical resection of the primary tumor, chest wall control, and survival in women with metastatic breast cancer. Cancer 113:2011-2019, 2008. 7. Neuman HB, Morrogh M, Gonen M, et al: Stage IV breast cancer in the era of targeted therapy. Cancer 116:1226-1233, 2010. Financial Disclosure: Dr. Khan reported no potential conflicts of interest.

Dr. Khan is Bluhm Family Professor of Cancer Research and Professor in Surgery and Surgical Oncology at the Northwestern University Feinberg School of Medicine, Chicago.

CON: Prognostic Features Lead to False Assumptions continued from page 45

better prognosis than all 622 patients or patients without breast surgery. Accepting registry staging, which has numerous possibilities for error, is not sufficient for sophisticated clinical studies or conclusions. Actual charts must be examined, and only M1 cases classified as stage IV.

Conclusions Thus, favorable case selection bias was the only plausible cause for better apparent survival following therapeutic breast surgery in stage IV (M1) cancer presentation. Other possible casual relationships described involve unproven assumptions or illogical biologic processes. Therapeutic primary breast cancer surgery does not cause the apparent improved survival in M1 disease, but is utilized more often in patients with a variety of more favorable prognostic features or misclassifications (selection bias), leading to false assumptions.

■

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

Dr. Cady is Professor Emeritus of Surgery at Harvard Medical School and Brown Medical School, and is currently staff surgeon at the Breast Center at Cambridge Hospital, Cambridge, Massachusetts.

ASCOPost.com | MAY 1, 2011

PAGE 47

Perspective Spiritual Care

A Conversation with Sister Elaine Goodell, PBVM, DMA, BCC Bringing comfort to believers and nonbelievers alike By Jo Cavallo years of teaching music and I’ve now worked about 30 years as a chaplain. Two weeks after coming to New York and starting work at Memorial SloanKettering Cancer Center, I knew I had found my niche.

Sr. Elaine Goodell

or over 25 years, Sister Elaine Goodell, PBVM, DMA, BCC, has brought spiritual comfort to thousands of patients with cancer at Memorial Sloan-Kettering Cancer Center in New York. As staff chaplain, Sister Elaine ministers to patients of all faiths as well as nonbelievers, to help ease their fears and anxieties about their illness and even provide a laugh or two. In 1944, Sister Elaine joined the order of the Sisters of the Presentation of the Blessed Virgin Mary in Aberdeen, South Dakota, and there taught music to students from grade school through college age for over 30 years. Although Sister Elaine found teaching fulfilling, she was drawn to hospital work. At the time, clinical pastoral education came into prominence, and she thought a chaplaincy career in a hospital would satisfy her need to give support and solace to seriously ill patients. After earning her credentials as a board-certified chaplain, Sister Elaine moved to New York and went to work for HealthCare Chaplaincy, which manages chaplaincy services for 12 health-care institutions. Last year, Memorial Sloan-Kettering selected Sister Elaine as its Wholeness of Life Award honoree. At age 85, Sister Elaine shows no signs of slowing down. The ASCO Post caught up with Sister Elaine for a conversation about her work.

Helping Hospital Patients You’ve had a long career, first as a convent-based nun and then as a music teacher. Why were you interested in becoming a hospital chaplain? I always had a hankering to work in a hospital. I thought if I got training in clinical pastoral education, I could work in a hospital. So I gave up 30

my prayers,” so as not to alienate anyone. I also want the family to know that I’m there to give them support as well.

Helping Nonbelievers

and there’s sadness. Acceptance is the crux of life. I think that we cannot have peace without acceptance. The point is we are not in control. There are so many things in life that we have to accept. But for those of us with a belief system, we may be angry with God and that’s okay—He can take care of Himself—but we are fortunate because God is with us all the time. I tell patients, “We are only assured of this moment right now, and we go on to the next moment and that’s all we can be sure of. We do not know what is going to happen to us.” When you have cancer you have time to tell people how you feel about them and to fix broken relationships. I suggest to patients that they write letters to their loved ones, which is so meaningful to the people left behind.

Are nonbelievers receptive to you? Yes, 99% of the time. One time I introduced myHow do you self to a patient, approach patients When people get a and he said, “I’m with cancer who an atheist and I are going through cancer diagnosis, all don’t need anysurgery or chemothe existential issues of thing.” I said, therapy? What “That’s fine. All I do you say to help life pour down at that wanted to do is to them? moment, and then the wish you well. Is Some people that okay?” I also have an agenda, ultimate question is, sometimes say, “I but my only “Am I going to die? just want to wish agenda is to be you healing.” It’s with the patient all in how you in whatever is say it. You have to see what the vibe is happening. Life is about relationships, for each patient, but I don’t mention connections, and the state of being What can oncologists do to help their prayer if it’s not appropriate. interested in another person. In our patients overcome fear and anxiety? work, it could be called presence. PresA recent survey of chaplains, nurses, Is it easier for a patient with faith to ence is attentiveness, concentration, and patients ranked talking and listenface death than it is for a nonbeliever? and focusing on what the patient is ing as the number 1 spiritual intervenOn one level, it’s easier if you have saying and not anticipating your next tion. Talking and listening is intrinsic a belief system, but it’s still a struggle remark. Those are also the qualities of to human existence. a good listener. Some times it’s really hard to go into a patient’s room. I’m the preop chaplain on the floor for head and neck cancers, and in some cases paThe 2D barcodes found in this issue of The ASCO Post will tients aren’t able to speak. I say a litconnect readers to further information about the articles they tle prayer and then I just go into the are reading using the ScanLife application. room. You have to treat patients as normal people.

■ Using 2D Barcodes

Facing Terminal Illness In your experience, what is the greatest fear of patients with cancer? I would say it’s the fear of suffering. Patients need pain management. But there’s also the fear of death. When people get a cancer diagnosis, they may be shocked and stunned. Even if the patient has a deep faith system, that faith system can be shattered. All the existential issues of life pour down at that moment, and then the ultimate question is, “Am I going to die?” How are you able to bring comfort to patients who are terminally ill? You have to go to the patient and ask how he or she is doing. I just say, “I’m Sister Elaine. Don’t panic; I want you to know that you’re in my thoughts and best wishes.” I don’t say “you’re in

Getting the Application

There are three ways to download the ScanLife application:

1 2

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

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

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

Live:10.75”

Zometa® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL patient albumin (g/dL)). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 μmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 μmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy Zometa should not be used during pregnancy. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose if 4 mg based on an AUC comparison) resulted in pre- and postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Patients Studied Total No. of Patients Studied Total No. of Patients with any AE Body as a Whole Fever Progression of Cancer Cardiovascular Hypotension Digestive Nausea Constipation Diarrhea Abdominal Pain Vomiting Anorexia Hemic and Lymphatic System Anemia Infections Moniliasis Laboratory Abnormalities Hypophosphatemia Hypokalemia Hypomagnesemia Musculoskeletal Skeletal Pain Nervous Insomnia Anxiety Confusion Agitation Respiratory Dyspnea Coughing Urogenital Urinary Tract Infection

Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

86 (100) 81 (94)

103 (100) 95 (92)

38 14

(44) (16)

34 21

(33) (20)

(11)

(2)

25 23 15 14 12 8

(29) (27) (17) (16) (14) (9)

28 13 17 13 17 14

(27) (13) (17) (13) (17) (14)

(22)

(18)

(12)

(4)

11 10 9

(13) (12) (11)

2 16 5

(2) (16) (5)

(12)

(10)

13 12 11 11

(15) (14) (13) (13)

10 8 13 8

(10) (8) (13) (8)

19 10

(22) (12)

20 12

(19) (12)

(14)

(15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4 1Grade

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

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Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%)

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Patients Studied Total No. of Patients 1031 (100) Total No. of Patients with any AE 1015 (98) Blood and Lymphatic Anemia 344 (33) Neutropenia 124 (12) Thrombocytopenia 102 (10) Gastrointestinal Nausea 476 (46) Vomiting 333 (32) Constipation 320 (31) Diarrhea 249 (24) Abdominal Pain 143 (14) Dyspepsia 105 (10) Stomatitis 86 (8) Sore Throat 82 (8) General Disorders and Administration Site Fatigue 398 (39) Pyrexia 328 (32) Weakness 252 (24) Edema Lower Limb 215 (21) Rigors 112 (11) Infections Urinary Tract Infection 124 (12) Upper Respiratory Tract Infection 101 (10) Metabolism Anorexia 231 (22) Weight Decreased 164 (16) Dehydration 145 (14) Appetite Decreased 130 (13) Musculoskeletal Bone Pain 569 (55) Myalgia 239 (23) Arthralgia 216 (21) Back Pain 156 (15) Pain in Limb 143 (14) Neoplasms Malignant Neoplasm Aggravated 205 (20) Nervous Headache 191 (19) Dizziness (excluding vertigo) 180 (18) Insomnia 166 (16) Paresthesia 149 (15) Hypoesthesia 127 (12) Psychiatric Depression 146 (14) Anxiety 112 (11) Confusion 74 (7) Respiratory Dyspnea 282 (27) Cough 224 (22) Skin Alopecia 125 (12) Dermatitis 114 (11)

Pamidronate 90 mg n (%)

Placebo

556 (100) 548 (99)

455 (100) 445 (98)

175 83 53

(32) (15) (10)

128 35 20

(28) (8) (4)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

50 82

(9) (15)

41 30

(9) (7)

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

(62) (16) (16) (9) (11)

(17)

(20)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

(11) (13) (16) (8) (10)

95 73 39

(17) (13) (7)

49 37 47

(11) (8) (10)

155 129

(28) (23)

107 65

(24) (14)

80 74

(14) (13)

36 38

(8) (8)

n (%)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8. Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 3 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg n/N (%) 7/529 6/973 115/973 19/971 1/971

(1%) (<1%) (12%) (2%) (<1%)

Pamidronate 90 mg n/N (%) 4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

Placebo n/N 4/241 0/415 14/415 8/415 1/415

1Grade 3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2Grade 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L)

(%) (2%) — (3%) (2%) (<1%)

Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg n/N (%) 2/529 7/973 5/973 0/971 2/971

Pamidronate 90 mg n/N (%)

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

Placebo

(<1%) (<1%) — — (<1%)

n/N

(%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenzalike illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Normal Abnormal Total Solid Tumors Normal Abnormal Total Prostate Cancer Normal Abnormal Total

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

27/246 2/26 29/272

(11%) (8%) (11%)

23/246 2/22 25/268

(9%) (9%) (9%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

17/154 1/11 18/165

(11%) (9%) (11%)

10/143 1/20 11/163

(7%) (5%) (7%)

Zometa 4 mg

Placebo

n/N

(%)

n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

8/68 2/10 10/78

(12%) (20%) (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include: CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials.

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7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zometa did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Zometa should not be used during pregnancy. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia. 8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman.

8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. 16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Manufactured by Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2011-01 ©Novartis

Indication ZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Important Safety Information ZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient. Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary. In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit profile before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose. Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby. In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, and a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. Insufficient data exist on how to safely use ZOMETA in HCM patients with hepatic impairment. Live:13.5”

Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported. The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain. Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs. Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily. Please see full Prescribing Information. Please see brief summary of full Prescribing Information on the following pages. References: 1. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 2. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 4. Boniva Prescribing Information. Roche Laboratories Inc. 5. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 6. Fosamax Prescribing Information. Merck & Co. 7. Skelid Prescribing Information. sanofi-aventis US LLC. 8. Xgeva Prescribing Information. Amgen Inc.

March 2011

ZOM-1011311

Proven efficacy across multiple malignancies1 Indicated across more advanced malignancies than any other approved bone-remodeling agent1-8 FDA-approved indications Bone metastases from solid tumors including Breast cancer Castration-resistant prostate cancer (CRPC)* Nonsmall cell lung cancer Renal cell carcinoma Multiple myeloma Hypercalcemia of malignancy *ZOMETA should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy.

Across multiple advanced malignancies, helps reduce and delay multiple SREs1 • Pathologic fracture • Spinal cord compression • Surgery to bone • Radiation to bone • Hypercalcemia of malignancy SRE=skeletal-related event.

Highlights from the Important Safety Information • There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose • Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status • A causal relationship between bisphosphonate use and ONJ has not been established Please see full Prescribing Information. Please see brief summary of full Prescribing Information on the following pages.

Visit www.zometa.com for more information.