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

Maximizing Quality of Life in Cancer Survivors

33rd Annual San Antonio Breast Cancer Symposium

Triple-negative Breast Cancer Proving to Be Genetically Diverse Genetic subtypes may be linked to prognosis. By Caroline Helwick

By Mary S. McCabe, RN, MA

he molecular deciphering of triple-negative breast cancer has become a strong research goal. Studies presented at the 33rd Annual San Antonio Breast Cancer Symposium moved the field forward, revealing distinct genetic subtypes within the triple-negative breast cancer classification and suggesting that not all triplenegative tumors may be unfavorable. The findings may help to individualize therapy some day—though they also suggest there will be no magic bullet.

Unique Gene Ontologies In a study that drew much attention at a poster discussion session, Brian Lehmann, PhD, and Joshua Bauer, PhD, from the laboratory of Jennifer Pietenpol, PhD, at the Vanderbilt-Ingram Cancer Center, Nashville, showed triple-negative breast cancer to be quite a heterogeneous disease based on the results of a tran-

SEE PAGE 38

Use your smartphone to view original abstracts from the 33rd Annual SABCS, including those discussed in this article (abstracts PD01-07, S5-5, and S5-4).

scriptome analysis in which six distinct biologic subtypes of triple-negative breast cancer were identified.1 Dr. Lehmann and his colleagues further linked these subtypes to potential therapeutic strategies. “We compiled an extensive triple-negative breast cancer transcriptome dataset from 21 independent breast cancer studies. We analyzed 386 triple-negative breast cancer gene-expression profile training sets and identified six stable clusters that display unique genecontinued on page 10

Health-care Policy

Containing the High Cost of Cancer Care Four experts examine the issue and offer solutions. By Jo Cavallo

hile the overall expenditure on cancer care in general has remained relatively steady over the past 2 decades—encompassing 4.8% of the total $513 billion spent on medical care in 1987, vs 4.9% of the average $979 billion spent annually from 2001 to 2005—the cost of oncology drugs has soared past all other classes of pharmaceutical agents (Cancer 116:3477-3484, 2010). According to the marketing firm IMS Health, sales of oncology drugs have skyrocketed from $5 billion in 1998 to $19.2 billion in 2008. Most of that increase is attributable to the newer anticancer agents on the market. According to Journal of the National Cancer Institute (see 2D barcode on page 6), 90% of cancer-fighting drugs or biologics approved by the FDA over the past 4 years cost more than $20,000 for a 12-week course of therapy, with many offering a survival benefit of only 2 months or less. The result of the rising cost of cancer treatment is threatening not just the financial solvency of patients—a poll by the American Cancer Society found that one in five families use up all of their savings paying for cancer treatment—but that of the country as well. With health-care spending projected to balloon

to $4 trillion by 2015, outpacing the growth in the gross domestic product by 20% (up from 17.3% in 2009), health-care industry experts and government agencies are looking for solutions to rein in costs without stifling drug Nancy E. Davidson, MD innovation or jeopardizing patient care. The ASCO Post explored some of the major issues confronting those who seek to ensure high-quality cancer care while reducing costs. For this article, we talked with Lowell E. Schnipper, MD, Chair of ASCO’s Cost of Cancer Care Task Force, Professor of Medicine at Harvard Medical School, and Chief of Hematology and Oncology at Beth Israel Deaconess Medical Center, Boston; Nancy E. Davidson, MD, Member of ASCO’s Government Relations Committee and Director of the University of Pittsburgh Cancer Institute; Antonio Tito Fojo, MD, PhD,

“The goal is to bring quality to the lives we fought so hard to keep.” —A lymphoma cancer survivor

ver the past 5 years, the lay press has heralded the rapidly growing number of cancer survivors in the United States, and the professional oncology literature has increasingly reported research results focused on issues specific to survivors. Now a number of key organizations (such as the Centers for Disease Control and Prevention and the American Cancer Society) and professional societies (such as the American Society of Clinical Oncology and the Oncology Nursing Society) have made survivorship a central part of their strategic plans. This organizational momentum is critical and focuses resources and attention on activities that will lead to greater knowledge about survivor needs during the post-treatment period, evidencebased interventions to reduce and/or ameliorate long term and late effects, evaluations of novel models of survivorship care, and health-care policy changes supporting appropriate surveillance continued on page 10

Ms. McCabe is Director of the Cancer Survivorship Initiative at Memorial Sloan-Kettering Cancer Center in New York.

MORE IN THIS ISSUE Oncology Meetings Coverage 33rd Annual San Antonio Breast Cancer Symposium ��2, 33 52nd ASH Annual Meeting ��3, 19 2011 Gastrointestinal Cancers Symposium �� 8 Direct from ASCO �� 12 Future of Clinical Research �� 33

continued on page 6

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The ASCO Post | FEBRUARY 15, 2011

PAGE 2

33rd Annual San Antonio Breast Cancer Symposium 10 Newsmakers Reported from the 33rd Annual SABCS By Caroline Helwick

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

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University William T. McGivney, PhD National Comprehensive Cancer Network James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer,

s usual, news was plentiful at the San Antonio Breast Cancer Symposium, which was held December 8–12, 2010. While The ASCO Post will devote more space to key presentations in this and future issues, many other studies are worth a mention: 1. The phase III international AZURE trial, conducted in 3,360 women, failed to show a benefit for zolendronate (zoledronic acid) in improving disease-free survival when added to standard adjuvant chemotherapy and/ or hormonal therapy (abstract S4-5). The study contradicts earlier findings from the ABCSG-12 study in premenopausal women, where the addition of zolendronate improved disease-free survival by 32% (P = .0009). 2. The addition of capecitabine (Xeloda) to standard adjuvant chemotherapy did not significantly improve disease-free survival, though there was a suggestion of benefit in patients with triple-negative disease, according to the FinXX trial and US Oncology 01062 (abstracts S4-1 and S4-2). 3. Studies from the ATAC and BIG 1-98 trials of adjuvant endocrine therapy showed that CYP2D6 phenotypes that are associated with reduced enzyme activity in women receiving tamoxifen were not associated with worse disease-free survival (abstracts S1-7 and S1-8). 4. The presence of circulating tumor cells in both metastatic and early breast cancer patients was associated with worse breast cancer outcomes (abstracts S6-5 and S6-6). 5. The notion that obese women have worse breast cancer outcomes was modified somewhat by studies showing only some obese patients, in particular those with hormone receptor–positive, HER2-negative disease, had an increased risk for recurrence and death. In short, breast cancer subtype may matter, according to a multivariate analysis of several ECOG studies (abstract S2-1). 6. Aromatase inhibitors appear to increase the risk of cardiac events, according to a Canadian study that found a 26% increased risk except

Use your smartphone to view original abstracts from the 33rd Annual SABCS, SEE PAGE 38 including a selection of those discussed in this article.

among women treated with tamoxifen first, then switched to an aromatase inhibitor (abstract S2-7). 7. Despite the uproar over the U.S. Preventive Services Task Force recommendations in 2009, many women still do not get screened by mammography. In a study of more than 1.5 million women, annual mammography rates averaged only 50% in women aged 40 and older, despite the fact that most patients had continuous insurance coverage, a study from Medco Health Solutions showed (abstract S4-7). 8. Radiation therapy can be sandwiched between chemotherapy cycles without a loss of disease control. In fact, a 2% benefit in locoregional control was shown by a study from the United Kingdom in which radiotherapy was delivered between cycles 2 and 3 of CMF (cyclophosphamide, methotrexate, fluorouracil) or between cycles 5 and 6 of anthracycline/CMF chemotherapy. This approach shortens treatment time while maintaining the intensity of chemotherapy and only modestly increasing the risk of skin toxicity (abstract S4-4). 9. In two studies that examined data from the Women’s Health Initiative, hormone replacement therapy with estrogen alone (in women without a uterus) was shown to be protective against breast cancer, whereas combined estrogen/progestin therapy increased risk (abstracts P6-09-09 and S6-1). 10. In the first results of CALGB 40101, which is comparing chemotherapy with AC (doxorubicin, cyclophosphamide) to paclitaxel alone, a regimen of four cycles of chemotherapy (AC or paclitaxel) was not inferior to six cycles and was better tolerated (abstract S6-3). The comparison between the types of chemotherapy is not mature.

■

Alice Goodman, Caroline Helwick, Ronald Piana, Matthew Stenger, Marian Wiseman

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

Visit The ASCO Post website at: ASCOPost.com

ASCOPost.com | FEBRUARY 15, 2011

PAGE 3

52nd ASH Annual Meeting High-dose Cytarabine plus Pretransplant Myeloablative Induction Benefits Young Patients with Mantle Cell Lymphoma By Alice Goodman

antle cell lymphoma, an aggressive form of B-cell non-Hodgkin lymphoma, has been associated with a poor prognosis and a median overall survival of 3 to 4 years. A study reported at the 52nd American Society of Hematology (ASH) Annual Meeting demonstrated that the addition of high-dose cytarabine to induction

chemotherapy that includes R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) improved outcomes compared with six courses of R-CHOP and chemoradiotherapy when given prior to autologous stem cell transplantation (ASCT) in younger patients with newly diagnosed mantle cell lymphoma.1

Expert Point of View

ccording to Gilles Salles, MD, Professor of Hematology at the Université Claude Bernard and Hospices Civils de Lyon, France, these clinical results are in line with those achieved with regimens such as HyperCVAD1 and others2 that have included intermediate- to high-dose cytarabine. “The merit of the present study is to demonGilles Salles, MD strate the benefit of a high-dose cytarabine–containing regimen in a randomized trial,” Dr. Salles explained. Although no overall survival benefit has been achieved with current follow-up, these results taken together indicate that R-CHOP cannot be considered standard of care for young patients with mantle cell lymphoma who are in need of therapy.3 “An alternative regimen containing cytarabine therefore constitutes the basis for the evaluation of the benefit of new targeted therapies developed in this lymphoma subtype,” Dr. Salles stated. Andrew Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York, said that several studies from The University of Texas MD Anderson Cancer Center, the Nordic Lymphoma Group, and the Andrew Zelenetz, MD, PhD GELA have suggested that the inclusion of cytarabine in initial therapy for mantle cell lymphoma can improve outcome. “The study presented by Dr. Hermine on behalf of his colleagues in the European MCL Network is a very important study, because it prospectively evaluates the role of cytarabine in mantle cell lymphoma. There is a clear improvement in progression-free survival but not yet overall survival in the high-dose cytarabine–containing arm. However, the follow-up is limited,” Dr. Zelenetz stated. “One drawback in the study design is the inability to determine what was the most important change, since both the induction chemotherapy and the high-dose therapy were changed in the experimental arm compared to the control arm. Nonetheless, the experimental regimen appears to be highly effective and tolerable,” Dr. Zelenetz noted.

■

References 1. Romaguera JE, Fayad LE, Feng L, et al: Ten-year follow-up after intense chemoimmunotherapy with rituximab-HyperCVAD alternating with rituximab-high dose methotrexate/cytarabine and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol 150:200-208, 2010. 2. Geisler CH, Kolstad A, Laurell A, et al: Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivopurged stem cell rescue. Blood 112:2687-2693, 2008. 3. Martin P, Chadburn A, Christos P, et al: Outcome of deferred initial therapy in mantle cell lymphoma. J Clin Oncol 27:1209-1213, 2009.

Cytarabine plus R-CHOP–based Induction Therapy ■■ A prospective trial showed that intensified induction therapy

incorporating high-dose cytarabine improves progression-free survival in younger patients with mantle cell lymphoma.

■■ No overall survival advantage has emerged for the addition of high-dose cytarabine, but longer follow-up is needed to assess this possibility.

At the time of the ASH meeting, the primary endpoint of the trial—time to treatment failure—had not been reached in the high-dose cytarabine arm (which also included cytarabine in the transplant conditioning regimen). Time to treatment failure was 49 months in the R-CHOP arm. Overall survival was similar between the two arms, and median survival had not yet been reached. Both arms had comparable safety. “Results of this study confirm that there is a new standard of care for the treatment of younger patients with previously untreated mantle cell lymphoma,” commented lead author Olivier Hermine, MD, PhD, who is Professor and Head of the Hematological Department at Necker Hospital in Paris. “High-dose cytarabine should be part of induction therapy along with R-CHOP prior to autologous stem-cell transplant, in order to improve outcomes without increased toxicity,” he said.

Study Rationale and Design The European MCL Network initiated the present study to evaluate the superiority of a high-dose cytarabine– containing regimen with R-CHOP and R-DHAP vs R-CHOP followed by chemoradiotherapy and ASCT. The study was conducted in four European countries and randomly assigned 497 patients to treatment for newly diagnosed mantle cell lymphoma from July 2004 to May 2010; 391 patients were evaluable for the primary analysis. Patients were randomly assigned to the control arm (six courses of R-CHOP followed by myeloablative chemoradiotherapy and ASCT) or the experiUse your smartphone to view original abstracts from the 52nd ASH Annual Meeting, including SEE PAGE 38 the one discussed in this article (abstract 110).

mental arm (alternating three courses of R-CHOP and R-DHAP followed by the high-dose cytarabine–containing myeloablative regimen that included radiotherapy and melphalan followed by ASCT).

Key Results Following induction chemotherapy, the overall response rate was high in both arms: 90% for controls and 94% for the cytarabine-containing arm. Complete remission and unconfirmed complete remission rates were higher in the experimental arm: 26% vs 39% (P = .012) and 41% vs 60%, respectively (P = .0003). The percentage of patients able to undergo transplant was similar in both arms (97% for both), and complete remission rates after ASCT were comparable: 63% vs 65%, respectively. At a median follow-up of 27 months, the experimental arm was superior for the primary endpoint of time to treatment failure: 49 months vs not yet reached (P = .038) due to fewer relapses in the experimental arm (20% vs 10%). Both arms had comparable safety, with the exception of increased grade 3/4 hematologic toxicity, more renal toxicity, and more patients reporting grade 1/2 nausea in the experimental arm. Toxicities for both myeloablative conditioning regimens were similar, but there was more grade 3/4 mucositis with the high-dose cytarabine regimen and more liver toxicity and constipation in the control arm.

■

References 1. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3× CHOP and 3× DHAP plus rituximab followed by a highdose ARA-C containing myeloablative regimen and autologous stem cell transplantation is superior to 6 courses CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma. 52nd ASH Annual Meeting. Abstract 110. Presented December 5, 2010.

The ASCO Post | FEBRUARY 15, 2011

PAGE 4

Expert’s Corner

A Conversation with Siddhartha Mukherjee, MD, PhD

Examining the history of cancer with The Emperor of All Maladies author By Jo Cavallo The ASCO Post talked with Dr. Mukherjee, Assistant Professor of Medicine, Division of Medical Oncology at Columbia University Medical Center in New York, about the book’s success and how his exploration of the history of cancer has influenced his approach to both treating patients and conducting research.

Popularity of the Book Siddhartha Mukherjee, MD, PhD

ast November, The Emperor of All Maladies: A Biography of Cancer (Scribner) by Siddhartha Mukherjee, MD, PhD, hit the bookstores and immediately made it onto The New York Times best-seller list, later garnering additional acclaim when it was named one of the Top Ten Books of 2010 by the Times and Time magazine, among others. To raise public awareness of cancer even further—and increase funding for research—the charitable organization Stand Up To Cancer has acquired the TV and film rights to the book and plans productions for television, the Internet, and release on DVD. The Emperor of All Maladies chronicles the history of cancer over 5,000 years, detailing the seminal events that led to a better understanding of the biology of the disease from the earliest evidence of cancerous tumors found in skeletal remains in Egypt to the development of the first clinical trials and chemotherapeutic agents.

Given that cancer is such a frightening disease, why do you think your book has been so embraced by the lay public? Dr. Mukherjee: Cancer might be a frightening diagnosis, but it’s also a reality for each and every one of us, in the sense that we will all face cancer in our lifetimes, either in ourselves or in a loved one. In light of that prevalence, it amazed me while I was writing the book that for the most part, this history had never been written, although there had been attempts to tell pieces of it. So I think part of the response to the book is precisely because people want sophisticated information, they want to know the history of cancer, and they want to know its future. I hope the book demystifies cancer in some fundamental ways and that the act of demystification itself provides some solace. Are you surprised by the success of the book? Dr. Mukherjee: Absolutely. Based on the critical response, it’s very hard to know which way book sales will go, but I am surprised by the depths of the reading and the fact that people from

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.

really diverse fields approach me to talk about the book. The best kind of comment for me is when a patient or someone who has a loved one with cancer says, ‘You have told a piece of my story.’ That’s been the most gratifying thing about writing this book.

Impact of History on Practice What has the examination of the history of cancer taught you about the disease, and how has it influenced the way you treat patients and your approach to research? Dr. Mukherjee: I think the history of cancer is very humbling. It tells us that for every step forward, there have been three steps backward. It’s a reminder of the importance of serendipity in this history and the importance of direction and purpose. But most importantly, it’s a reminder to me of the fact that at the end of the day, it’s about the incredible resilience of the patients. Time and time again through the centuries, that fact has really defined this disease and has allowed us to make progress. There have been important scientists and physicians, but ultimately the people who drove the progress were patients. Does having that perspective influence the way you treat your patients? Dr. Mukherjee: It absolutely does. I think that I’m able to explain the level of uncertainty and the level of complexity of the disease better. In some ways, I’m able to tell patients about exactly where they sit in this long history of the disease. Relating that story has

an enormous importance to patients. People want to feel connected to their history. They want to know how their disease has changed in the past and what will happen in the future. I think that’s very important. There’s a real hunger for this information. Patients and their loved ones want the information in all its complexity; they don’t want a simplified thesis about cancer. They want to know that the discovery of tamoxifen originated with a rumor that a Scottish surgeon heard while walking across the Highlands—about how removing the ovaries of cows changed their lactation—and how that led to the surgeon performing ovarian operations to treat breast cancer. The role of serendipity in that kind of story is very important to patients. Patients want to know how, through a series of dedicated studies on the one hand, but also through a series of serendipitous events, imatinib was discovered. People want to know the history of surgery and how anesthesia was developed. All these things play an important role informing the evolution of cancer, and it’s changed the way that I think about the disease.

Jigsaw Puzzle Many turning points in cancer research have led to more effective therapies, but was there one pivotal discovery that altered researchers’ understanding of the biology of cancer? Dr. Mukherjee: No. I think the biology of cancer is going to be solved

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 | FEBRUARY 15, 2011

PAGE 5

Expert’s Corner

piece-by-piece, or as NCI Director Dr. Harold Varmus suggested to me, almost like a jigsaw puzzle. When you solve one piece of the puzzle, you say this must be the pivotal piece. That’s what the experience of puzzle-solving looks like, but, in fact, when you take a step back, it turns out that every piece is pivotal. There is no single key piece. And obviously, there is no single type of cancer. It’s a family of diseases. Even within the same cancer there is an enormous degree of heterogeneity. As I point out in the book, there has never been and there is unlikely to ever be a single magical solution. For example, the mortality of breast cancer will be driven down by a combination of prevention, treatment, and early diagnosis. It’s unlikely that we will be able to prevent chronic myelogenous leukemia, but mortality will be reduced by targeted therapy. Likewise, it’s unlikely that we will ever prevent testicular cancer, but it might be possible to successfully treat it with a combination of traditional chemotherapy like cisplatin and something else. Every cancer presents at a somewhat different phase and, therefore, the treatment and the pivotal advance are different.

Dr. Mukherjee: I think it is very unlikely that we will ever eradicate cancer. Even in the ideal world, as Dr. Varmus recently said, some cancers are part of our genetic heritage. The genes that release cancer are stitched into our chromosomes. That said, I think the ability to convert some cancers into chronic diseases or to prevent them from arising

in the body, represents a great frontier. Even that, as I say in the book, will be an incredible technologic and medical victory. Many cancers are being converted into chronic diseases, but isn’t the goal still to find a cure? Dr. Mukherjee: The goal might be to cure, but it may be impossible

to cure every form of cancer. One of the lessons that this book teaches us is that there is a cycle in which scientists, clinicians, and others have optimistic hopes about the future, which leads to a phase of nihilism and defeat when those hopes are not met. As an oncologist, I hope I’m eventually put continued on page 6

Cancer Research Today The chemotherapy agents you describe in the treatment of childhood leukemia in the 1950s and 1960s were toxic, but some of today’s chemotherapies are equally toxic. Many of the new targeted drugs have been disappointing in their long-term effectiveness, and they have troubling side effects as well. Where is cancer research now in terms of developing better-targeted drugs? Dr. Mukherjee: The challenge lies in figuring out what’s driving various forms of cancer. When imatinib was discovered, the idea that cancers could become addicted to certain genes was itself a novel idea. But that’s a very important concept because it gives us the opportunity to intervene on those genes or on the pathways encoded by those genes. Yes, it’s absolutely true that some targeted therapies have not lived up to their hype, but they are just the harbingers of a much newer set of drugs, which will actually get more and more refined in their ability to target cancer cells. In the beginning of your book, you ask whether it’s possible to eradicate cancer from our bodies. Given what you know about the history of cancer and the advances being made in research now, do you have an answer to that question?

Y1467ALT_7x10NB_v1 1

1/17/11 2:04 PM

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

Oncogenic BRAF: A new potential therapeutic target1,2

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2:

~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6

In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

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

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Expert’s Corner

Siddhartha Mukherjee continued from page 5

out of my job, but I think that converting some of these cancers into chronic diseases will actually be an enormous victory in and of itself.

Looking Ahead Where do you think the next big breakthrough in cancer research will come from? Could it be the study of cancer stem cells? Dr. Mukherjee: I think how generalizable cancer stem cells are remains a big question. Do they apply only to certain leukemias, or are they generalizable to all forms of cancer? I certainly think the study of cancer stem cells is important. The role of the immune system in controlling certain cancers such as melanoma is also a major avenue of research. The understanding and sequencing of cancer genomes is similarly important, as is the role of metabolism in the development of cancer. There are also other important

Cost of Cancer Care continued from page 1

Senior Investigator and Head of the Experimental Therapeutics Section of the National Cancer Institute; and Peter B. Bach, MD, MAPP, Director of the Center for Health Policy and Outcomes and Attending Physician at Memorial Sloan-Kettering Cancer Center, New York, and former Senior Advisor to the Administrator of the Centers for Medicare and Medicaid Services.

Major Challenges What are some of the greatest challenges facing oncologists in the future? Dr. Schnipper: The key issue is how best to enable people afflicted with cancer to live as long as possible with the disease and function in the healthiest way possible. What’s happened over the past 5 to 10 years is that advances in the basic biology of cancer have given us insights into how cancer cells work at a level of detail we’ve not had before. As a result, pharmaceutical Use your smartphone to view the papers discussed in this article (Fojo T, et al: J Natl Cancer SEE PAGE 38 Inst 101: 1044-1048, 2009; and Tangka FK, et al: Cancer 116:3477-3484, 2010. )

frontiers to explore, such as an integrated approach to prevention that involves using our molecular understanding of cancer and finding more subtle ways of finding carcinogens— not just using epidemiology, which is a valuable tool, but also using laboratory techniques to discover carcinocompanies and innovative scientists have been able to develop therapies targeting the various cellular circuits that seem to be abnormally activated in cancer. A few magnificent examples of success have included imatinib for CML, trastuzumab (Herceptin) for HER2-overexpressing breast cancer, and rituximab (Rituxan) for B-cell lymphomas, but we have seen very few other home runs. That brings us to the focus on cost. The little bit of improvement patients get out of some of the newer drugs comes at an enormous cost, both emotionally and financially. Does the drug cure the patient or just give the patient a few extra months until the disease progresses again? The magnitude of the impact of the drug on the patient is not taken into consideration in pricing. Oncologists often discuss the treatment of advanced cancer with a patient who has heard about a novel therapy that holds promise. Frequently, the medication being considered will have a minimal impact on longevity at the expense of sometimes very unpleasant toxicity and substantial financial consequences to the patient. It is the oncologist’s responsibility to help patients understand the magnitude of potential benefit—small or large— and whether there are less costly but equally effective alternatives.

gens before they become detectable epidemiologically. Are you optimistic about the future of cancer research and treatment? Dr. Mukherjee: Yes, and my optimism is based on history. There has been steady progress in many cancers over the past few decades. People will look back on this time and say this was an amazing decade of cancer research. It’s been a time when we took a disease that was poorly understood at every level— politically, publicly, and biologically—and converted it into a disease whose face we can begin to recognize. We understand its heterogeneity, some of its growth patterns, and its dependencies, so this is an enormous advance. But now all of this has to be converted into clinical realities, and that’s what makes me optimistic. There’s an enormous glut of knowledge, and the convergence of that knowledge into clinical reality will change the way we think about cancer in the future.

Closing Thoughts

Seeking Solutions

integrate this information into their discussion with patients. Dr. Davidson: I helped establish ASCO’s Cost of Care Task Force with ASCO’s CEO Allen Lichter, MD, and it is based on a several-point plan. The first point is to put the cost of cancer care into the conversation we have with our patients. Talking about the cost of their care is the same as talking about other kinds of side effects of care that we provide. We need to make that a routine part of the conversation. The second part of the plan is to stress that oncologists need to be engaged in generating the kind of evidence we need to make good health-care decisions. And then we need to put that information into evidence-based guidelines. The last part of this plan is to encourage a conversation that we all have to engage in, both as oncologists and as citizens, about what our priorities are and what we want to do as a society regarding health care. The issue of cost isn’t just about high-priced drugs; it’s also about the very expensive devices we use as well as the cost of general health care. We have to consider end-of-life health care and how we can use resources most wisely to make sure that individuals in that situation are comfortable and get all the care they need but are not overtreated. Our obligation as physicians is to talk about all aspects of care with our patients. These days, that means the economic

What is ASCO doing to help solve the problem? Dr. Schnipper: ASCO is taking a series of steps to alert our membership to the impact that the rising cost of cancer care is having on both patients and society. We are encouraging physicians to be very open to communicating with their patients about cost and its relationship to the quality of available treatments. Patients need to understand that “more expensive” and “newer to the market” does not necessarily equate with “better.” There is a need for oncologists to recognize the implications of cost for individual patients, understand its practical dimensions, and increasingly integrate this information into treatment discussions, such that medical decisions can be optimized. ASCO is committed to the development and dissemination of clinical support tools to help prepare oncologists to engage in cost discussions with their patients. ASCO’s Cost of Cancer Care Task Force is identifying ways to help guide oncologists on the practical application of scientific evidence as it not only pertains to clinical benefit and risk, but also to cost. Specifically, the Task Force is identifying how oncologists can obtain access to up-to-date, comprehensive information about the clinical benefit, toxicity, and cost of the treatment regimens they prescribe such that they may

Do you have advice for medical students considering oncology as their specialty? Dr. Mukherjee: First, oncology is a vital profession. The population is aging, and some cancers are age-related. We need to find a way to take care of both older and younger people who are developing cancer. Second, I would encourage all oncologists to do research. It’s the only way we will move forward. Part of the reason we’ve had such great success in treating pediatric cancers is because nearly every child with cancer in the 1960s and 1970s who came into a hospital was treated on a pediatric cancer research protocol. That model needs to be followed in adult cancers as well, so that everyone is contributing to the knowledge base. Part of the responsibility lies with physicians. We need to gain the trust of patients to be able to provide this kind of infrastructure, but we also need to devise trials that ask important questions and give patients the capacity to contribute to our knowledge.

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Health-care Policy

consequences, including the cost of drugs and costs in terms of time—for example, time away from work. All aspects of care should be part of the dialogue. There isn’t any one part of the system that is responsible for driving up the costs of care. I think that we’re all equally responsible, so it behooves all of us to try and carry out the high-quality research that’s necessary to establish the value, or lack thereof, for new therapies. We also need to figure out how best to apply them and then police ourselves so that we use these new therapies appropriately. At the University of Pittsburgh Medical Center, we’ve put a pathways program in place, in which a large consortium of academic and community practitioners work together. We have self-assembled into a dozen or more disease-specific groups. On a regular basis, each group reviews the existing medical literature for its disease and then puts together pathways that can help physicians and patients understand the most appropriate therapy for a particular disease, at a particular stage.

Antonio Tito Fojo, MD, PhD

Practical Considerations How can the cost of cancer drugs be reduced while still providing the most effective care for patients, and without limiting drug development innovation? Dr. Fojo: I don’t have the answers, but I’ll give you my bias. A big deal has been made regarding personalized medicine, but unfortunately this has yet to become a full-fledged reality. We’re heading there, but we’re not there yet, not even close. When we do get there

and can identify the small percentage of patients who benefit from a specific drug, then the problem of drug costs will basically solve itself. And by that I mean that practically every drug that is tried and every drug that is approved has activity in some patients. When you think about all the rigor that goes into drug development, when the drug “fails” to bring benefit to patients in a clinical trial, it’s a disappointment and also in many ways a surprise. Usually it has been demonstrated to have activity in too few patients to be considered a valuable option. But, in fact, the majority of drugs do have some activity, and the challenge is to find the individuals in whom that drug is effective. Once drug development is linked hand-in-hand with biomarkers and we are able to determine whether a patient’s tumor will or will not respond to the drug, then we’ll be able to narrow down the number of patients we give these expensive drugs to by identifying those in whom we know the agetns will be effective. At that point the drugs won’t look so expensive. When you charge $80,000 for a drug that gives a patient an average of 1.2 months survival advantage, that just doesn’t make sense. At some point, we should become smart enough to identify that small percentage of patients in whom the drug would be really effective. Then we’ll be giving these expensive drugs to patients who are getting not 1.2 months, but at least 1 to 2 years’ benefit from them. The other thing that should worry us is that these drugs aren’t harmless. We refer to many of our “novel agents” as “targeted therapies.” The implication here is that they target the tumor and not normal tissues. But it turns out that every target these drugs have is also present in normal tissues. Consequently, they all have toxicities, often as bad or even worse than those of cytotoxic agents. So we’re giving these drugs to too many patients, including

many patients who experience no benefit, and we are in fact causing them harm. We have to reprogram ourselves and recognize that these agents are like all our previous drugs—they have side effects that we need to think about. We can’t expect that a patient will either have benefit or suffer no consequences. It actually comes down to benefit or harm. And the harm can either be a case of no activity and some level of toxicity or, as we are finding in an increasing number of examples, these drugs may actually worsen the disease they are intended to treat. The solution in the long term is to know ahead of time the tumor’s genetic and epigenetic composition and whether it is likely that a given drug will work. As a medical community, we’ve got to stress that 1.2 months is a marginal benefit. Furthermore, we ought to recognize that a majority of patients are not deriving this marginal benefit but are nevertheless suffering toxicities and are thus being harmed. We ought to say as a community to pharmaceutical companies, “We were all hoping your drug would perform better, but, unfortunately, it has not, and a 1.2-month survival benefit just isn’t worth $80,000.” It is also not worth conducting additional large trials to extend the indications for these drugs. We need to move forward. We need to do better for our patients. We need better drugs.

Whys and Wherefores Why is the cost of cancer drugs so high? Dr. Bach: It’s pretty simple, actually. The drug manufacturers in the United States essentially have no downward pressure on the cost of cancer drugs. They can choose to charge whatever they like. There’s been this long period where manufacturers are getting increasingly bold in terms of the prices they’re willing to charge. One of them comes on the market with a drug with a high price, and no one flinches. Then the next one has no hesitation to charge a

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Peter B. Bach, MD, MAPP

similar price. So we see this almost lockstep progression in the rise of the cost of cancer drugs and no check on that. With our medical care system as it works today, can anything really be done to substantially lower the cost of cancer care? Dr. Bach: There’s no question that the challenges ahead are sizable. But the reality is that anything that drives down the cost of drugs or decreases utilization will decrease the incentive for innovation, and if the incentives are decreased, it will tamp down on the total amount of beneficial innovation. That’s the expectation at least. How big an effect that will have in a negative direction, or how large the changes have to be to reimbursement, payment, and costs to really suppress pharmaceutical innovation, and even technologic innovation— that’s harder to know, but that is one tension here. Everyone would agree that the rising cost of health care is economically unsustainable in the United States. Whether cancer is itself the big problem or a little problem is hard to know. I can’t look at the problem in isolation. I actually think that the cost problem we have in cancer care is just a reflection of the broader ills we have in our health-care system.

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Financial disclosure: No potential conflicts of interest were reported by Peter B. Bach, MD, MAPP; Nancy E. Davidson, MD; Antonio Tito Fojo, MD, PhD; and Lowell E. Schnipper, MD. Editor’s note: Several pharmaceutical companies declined to be interviewed for this story when contacted by The ASCO Post.

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2011 Gastrointestinal Cancers Symposium French Study Supports Cetuximab in Esophageal Cancer But phase III data awaited By Caroline Helwick

etuximab (Erbitux) may be an active addition to chemoradiation and chemotherapy for the treatment of locally advanced esophageal cancer, according to the final results of an open-label, single-arm multicenter phase II study conducted in France by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR).1

Aimery de Gramont, MD

“The threshold for efficacy was reached,” Aimery de Gramont, MD, of the Hospital Saint-Antoine in Paris, announced at the 2011 Gastrointestinal Cancers Symposium, held January 20– 22 in San Francisco. The lead investigator of the study was Gerard Lledo, MD, of the Hôpital Privé Jean Mermoz in Lyon. Dr. de Gramont noted that oxaliplatin has proven superior to cisplatin in esophageal cancer, which is why GERCOR investigators chose FOLFOX (leucovorin, fluorouracil [5‑FU], oxaliplatin) as the chemotherapy backbone, in combination with radiotherapy. Cetuximab was added, based on its demonstrated synergy with both radiotherapy and platinum-based chemotherapy. The ERaFOX trial, therefore, evaluated the safety and efficacy of adding cetuximab to chemoradiotherapy with FOLFOX.

Study Details The study included 80 patients with untreated stage III squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Tumor was located in the esophagus in 74 persons and the cardia in 5. The treatment

was two cycles of FOLFOX induction therapy plus cetuximab, followed by radiotherapy at 50.4 Gy with FOLFOX. Cetuximab, 250 mg/m2, was given weekly during induction and during the three cycles of chemoradiotherapy. Tumors were evaluated after chemoradiotherapy, and the primary endpoint was overall response, with a 50% threshold for efficacy. Complete responses by endoscopic ultrasound and tumor biosies were also assessed. The intent-to-treat analysis included 79 patients, and the full analysis set included 67 patients. Approximately three-quarters of patients received at least 90% of the planned doses of cetuximab, oxaliplatin, and 5-FU. Approximately 10% of patients received less than 60% of the cetuximab and oxaliplatin doses, whereas just 5% received less than 60% of 5-FU.

Key Results Responses were observed in 61 patients (77.2%) in the intent-to-treat analysis, which more than met the study’s primary endpoint, Dr. de Gramont reported. Six patients (7.6%) had stable disease and only nine (11.4%) showed disease progression while on treatment (three patients were not evaluable). For the full analysis set, the response rate was 80.6%. Complete responses on endoscopic ultrasound were observed in 40% of patients. The median progression-free survival was 13.8 months, after a median follow-up time of 19.4 months. More than half the population was alive at the time of analysis. Overall survival, postsurgical outcomes, and quality-oflife data are currently being analyzed. The regimen was fairly well tolerated. The major grade 3/4 toxicities seen with chemoradiotherapy and cetuximab were neutropenia (28%), dysphagia (12%), and rash (11%). One toxic death (1.3%) related to esophagitis with gastrointestinal bleeding oc-

Expert Point of View Cetuximab in Esophageal Cancer Still an Open Question

espite the fact that the ERaFOX trial—one of the largest studies of cetuximab in esophageal cancer—met its objective, much remains to be determined about the future utility and safety of cetuximab in this tumor site, according to Peter Enzinger, MD, Clinical Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, Boston. As the invited discussant of the ERaFOX investigation at the 2011 Gastrointestinal Cancers Symposium, Dr. Enzinger commented, “Overall, the regimen seems to have a very good clinical response rate and to be well tolerated. However, I would argue that the FOLFOX backbone has not been proven in this venue. We must wait for results of the ongoing randomized phase III ACCORD trial [FRE-FNCLCC-ACCORD-17/0707], in which 266 patients are receiving a modified FOLFOX regimen or the more traditional cisplatin and infusional 5-FU regimen.”

‘Hints of Activity’ It is premature to state with certainty that there is a “signal” for cetuximab to target in esophageal cancer, Dr. Enzinger maintained, “although there have been tantalizing hints of activity.” The Cancer and Leukemia Group B (CALGB) 80403 trial demonstrated a 15% improvement in response rates and a prolongation of survival, compared to historical controls, he noted.1 In addition, several small randomized phase II studies have suggested there may be a small benefit in patients with squamous cell carcinoma. Toxicity also warrants a closer look, he added. The ongoing Radiation Therapy Oncology Group (RTOG) 0436 study of cetuximab with paclitaxel and cisplatin has been plagued by significant toxicity. “At least in the United States, the toxicity has raised concerns about using cetuximab with radiation therapy in this arena,” he said. “Certainly, there will be patients who develop serious rash.”

Other Ongoing Trials “Ultimately, we must wait for two large randomized studies to indicate if cetuximab [or other inhibitors of the epidermal growth factor receptor] has efficacy in esophageal cancer,” he concluded. The REAL 3 trial is evaluating the addition of panitumumab (Vectibix) to EOX (epirubicin, oxaliplatin, capecitabine [Xeloda]), while the EXPAND study is evaluating capecitabine plus cisplatin, with or without cetuximab. He concluded, “I would argue there is no clear signal as yet from the available data, and the RTOG study raises a flag of caution. I say we proceed with cetuximab if the ongoing phase III studies are positive or encouraging, but as yet we don’t have these results.”

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Reference 1. Enzinger PC, Burtness B, Hollis D, et al: CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC< FOLFOX) and cetuximab in metastatic esophageal and GE junction cancer. 2010 ASCO Annual Meeting. Abstract 4006. Presented June 7, 2010.

Cetuximab in Esophageal Cancer ■■ In the French ERaFOX trial, patients with locally advanced esophageal cancer who received cetuximab along with FOLFOX and radiotherapy had a response rate of 77%.

■■ Progression-free survival was almost 14 months. ■■ Phase III studies are needed to determine the full value of this approach.

curred after chemoradiotherapy. “We believe this strategy should be evaluated in a phase III trial,” Dr. de Gramont said.

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Reference 1. Lledo G, Michel P, Dahan L, et al:

Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX). 2011 Gastrointestinal Cancers Symposium. Abstract 8. Presented by Aimery de Gramont, MD, January 20, 2011.

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33rd Annual San Antonio Breast Cancer Symposium Triple-negative Breast Cancer continued from page 1

expression patterns and gene ontologies,” Dr. Lehmann reported. The investigators identified two basal-like subtypes characterized by cell cycle and DNA damage response genes; two mesenchymal-like subtypes enriched in cell differentiation, epithelial-mesenchymal transition, and growth factor pathways; an immunomodulatory subgroup defined by immune cell surface antigens, receptors, and signal transduction genes; and a luminal subgroup driven by androgen-receptor signaling. “Using tumor gene-expression signatures, we identified representative cell lines to model each of the subgroups and also pharmacologically targeted prominent signaling pathways,” he said. Through the treatment of xenografts of these triple-negative breast cancer tumor subtypes, they found that basal-like triple-negative disease is sensitive to cisplatin, mesenchymal-like triple-negative breast cancers may preferentially respond to Src and PI3K/mTOR inhibitors, and the luminal subtype is sensitive to the androgen-receptor antagonist bi-

calutamide and to HSP90 inhibitors. “The data generated in this study have significant value for target selection in drug discovery, clinical trial design, and selection of biomarkers that will enable the alignment of patients with triple-negative breast cancer to the appropriate targeted therapy,” Dr. Lehmann said.

Subtypes with Good Prognosis Similarly, German investigators evaluated 28 breast cancer datasets and identified a dozen molecular phenotypes upon 579 triple-negative breast cancer samples.2 This is the largest analysis of all available gene-expression data on triple-negative breast cancer, according to Achim Rody, MD, of Goethe University, Frankfurt, Germany. “Triple-negative breast cancers represent molecularly and clinically distinct subtypes,” Dr. Rody said. The analysis showed 73% to be basal-like tumors. The rest were classified into phenotypes according to gene function, ie, immune activity, angiogenesis, proliferation, apocrine activity, inflammation, and others. Clinical prognosis was associated

Molecular Refinement of Triple-negative Breast Cancer ■■ Triple-negative breast cancer is a heterogeneous disease characterized by several distinct genetic subtypes.

■■ The molecular subtypes are variously associated with functions such

as angiogenesis, inflammation, and proliferation, and some subtypes carry a more favorable prognosis.

■■ Finding and targeting the most relevant pathways for each subtype may be therapeutically advantageous.

Maximizing Quality of Life continued from page 1

and the development of care plans to be communicated with survivors and their other health-care providers. However, the 12 million U.S. cancer survivors need not and should not wait for these future advances to receive quality survivorship care in 2011. There is much we can do to implement a set of services no matter where a patient is being followed, whether it’s in a private practice group, community hospital, or cancer center. It’s possible to make posttreatment follow-up a formal period of care today, including a set of streamlined yet comprehensive services.

Key Follow-up Elements In addition to the traditional surveillance for recurrence that we’re all familiar with as the mainstay of post-treatment

care, it’s important that the follow-up visit include a number of other key elements that address both medical and psychosocial issues. First, just as we routinely assess patients for symptoms of toxicity during active treatment, we should consider a focused assessment for the persistence of long-term toxicities and new onset of late affects just as important. This can even be done with a simple checklist that is filled out in the waiting room prior to the visit, to elicit information that serves as a guide during the exam and discussion. Second, either through written materials or in discussion, recommendations for healthy living can be provided, including advice about diet, exercise, and smoking cessation. Pamphlets and flyers for local community and hospital programs can serve as referral materials and extend the services of the oncol-

with genetic subtype. There were no outcome differences between basallike tumors and non–basal-like tumors. However, high B-cell (immune system) and low IL-8 (inflammation) metagene expression identified a subset of patients (32% of all tumors) with a favorable prognosis and a 5-year event-free survival of 84%. “In the multivariate analysis, only the metagene ratio and lymph node status were significant predictors of triplenegative breast cancer in our cohort,” he noted, adding that inhibition of the related pathways might provide new therapeutic approaches.

High MYC Signature, Worse Outcomes Focusing on a single oncogene transcription factor—MYC—investigators from the University of California, San Francisco, demonstrated that triple-negative breast tumors with high expression of MYC had worse clinical outcomes.3 MYC is known to be associated with poorly differentiated aggressive tumors, and the genomic locus is amplified in 20% to 50% of all breast tumors. From gene-expression arrays on 149 patients in the I-SPY trial, MYC was found to be abundant in triple-negative breast cancers. Patients with tumors that had high MYC signatures had worse outcomes in the trial. Disease-free survival at 5 years was approximately 95% for patients with low MYC, compared with 80% in the setting of intermediate expression and 55% with high MYC expression, reported Andrei Goga, MD, PhD. MYC pathway activation is another ogy practice without adding overhead or personnel. Third, advising survivors of the need to continue or begin screening for other cancers—for example, through mammography and colonoscopy—can make a tremendous difference in compliance with these important interventions. Research has shown tremendous variation in routine preventive care among cancer survivors, and this reminder by the oncologist can be very effective in improving adherence, reinforcing the advice of the primary care physician. Fourth, finding ways of communicating with the patient’s other health-care providers is a much discussed and debated strategy, as the use of a Treatment Summary and Care Plan is often thought to be an onerous undertaking in busy clinical practices. However, there are products available and in development

predictor of poor outcome beyond triple-negative status. In a multivariate analysis considering receptor status and MYC pathway activation as a continuous variable, triple-negative status carried a hazard ratio of 1.5, but the hazard ratio for MYC pathway activation is 16.7, he said. The MYC pathway can be targeted via inhibition of cyclin-dependent kinase (CDK1), which upregulates the proapoptotic Bcl2 family member BIM. Exploiting the synthetic lethal interaction between MYC overexpression and CDK1 inhibition induces cell death in triple-negative breast cancer cells and regression of tumor xenografts. The CDK1 inhibitor SCH-727965, currently in phase II trials, has shrunk tumors in mouse models of triple-negative breast cancer.

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References 1. Lehmann BD, Bauer JA, Chen X, et al: Transcriptome analysis of triple negative breast cancers identifies six distinct biological subgroups and reveals therapeutic strategies. 33rd Annual San Antonio Breast Cancer Symposium. Abstract PD01-07. Presented December 9, 2010. 2. Rody A, Karn T, Liedtke C, et al: Identification of a clinically relevant gene signature in triple negative and basal-like breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S5-5. Presented December 11, 2010. 3. Goga A, Horiuchi D, Kusdra L, et al: Synthetic-lethality of triple-negative breast cancers via the MYC oncogene pathway. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S5-4. Presented December 11, 2010.

that are well worth reviewing to see how best to include this approach in practice. And, finally, depending on the patient population, there may be specific assessments and services that will be uniquely valuable to offer directly or as a referral—for example, for young patients, referrals to a reproductive endocrinologist, and for elderly patients at risk for depression, a simple screen that can be used for further assessment during the visit.

Formal Focus on Survivorship Making survivorship a formal focus in oncology care will occur incrementally and require attention to evidence, value, quality, professional collaboration, and patient satisfaction. It’s a wonderful challenge facing the field of oncology— working to maximize quality of life for cancer survivors and their families.

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Direct from ASCO

ASCO Launches Mobile Tool for Patients, Caregivers

iPhone/iPad/iPod Users Can Now Obtain Info, Log Symptoms, Store Questions for Next Doctor Visit

ncologists already tell their patients about Cancer.Net—the ASCO website that offers reliable information about more than 120 types of cancer, plus helpful guides for aspects such as caregiving, survivorship, and coping. Now patients and survivors—and their families and caregivers—can have valuable resources from Cancer.Net at their fingertips, no matter where they are. ASCO has created an application specifically for iPhones, iPads, and iPods—the market leaders among smartphones, tablet computers, and portable media players that use apps. ASCO research found that mobile phone apps related specifically to cancer are few and far between. “We wanted to create a mobile app that is robust and easy to use—a tool that will be the go-to cancer resource, having the credibility of ASCO behind it,” says Diane Blum, MSW, Cancer.Net Editor-in-Chief. With this objective, ASCO developed the new Cancer.Net iPhone app being launched this month.

What’s Special about the New App? The Cancer.Net iPhone app has five main functional areas. “Al-

though it draws on Cancer.Net for updated information, it’s not just a portable version of Cancer.Net,” according to Ms. Blum. “The best apps are organized around a clear, simple purpose and have features to accomplish specific tasks,” she explains. These are the app’s five main groups of functions: Info—Users can select information about specific cancer types, including medical illustrations and terminology, sections from Cancer. Net for newly diagnosed patients, and sections on topics such as coping and survivorship. Also available

are feature articles delivered every Monday on a range of topic areas, including screening and prevention, quality of life, and family and friends. Questions—This interactive utility lets users store questions to ask the doctor. They can type in their own questions or browse through a list of suggested questions. They also can record the answers using audio. Medicines—With this photobased tool, patients can store details they want to remember about their medicine, such as dosages, and even store pictures of their medicine. A template makes it easy to add drug information, and users can e-mail themselves photos or other information to include. Symptoms—Patients can record symptoms and their severity as they occur, rather than having to remember to jot them down after they get home. The incorporated clock and calendar helps in tracking symptoms for easy reference at the next doctor’s visit. Multimedia—This feature allows the patient to use the iPhone’s builtin media controls to play videos and podcasts available regularly from Cancer.Net. The app automatically checks for new content and alerts

the user when items are available— a function similar to a notification of new e-mail.

Spread the Word ASCO urges oncologists, nurses, and patient advocates to become familiar with the new iPhone app themselves and let patients and caregivers know about it. “The new app has the same important features as Cancer.Net—it is oncologist-approved, comprehensive, and patient-centered,” Ms. Blum points out. ASCO is launching this new tool at an ideal time, as people are increasingly using mobile platforms for personal health information. Just as the number of visits to the Cancer. Net website has grown significantly—nearly 20% from 2009–2010 alone—the number of users of this application is likely to grow considerably as people learn that ASCO is behind the new app. “ASCO is a key leader in cancer patient education,” Ms. Blum comments. “With this new app, our goal is make authoritative cancer information available wherever patients are.”

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Focus Under Forty™: What You Might Not Know about Patients with Cancer Aged 15 to 39 ASCO Launches Free Online Education Program

new ASCO University® program, Focus Under Forty, addresses the challenges of treating adolescent and young adult (AYA) patients with cancer. In contrast to the progress in cancer survival rates overall, the survival rates for patients aged 15 through 39 years who have cancer have not improved in more than 30 years. Acute lymphoblastic leukemia (ALL) is a case in point. The survival rate of young adults is nearly half that of patients younger than 15. “Data from Europe and the United States show that the way pediatric oncolo-

gists treat ALL is different from the way adult oncologists do,” explains ASCO member Brandon HayesLattin, MD, an Associate Professor at Knight Cancer Institute of Oregon Health & Science University and a member of the task force that planned the Focus Under Forty curriculum. He adds, “Patients in the ‘inbetween’ age group of 15 to 20 years could be treated for ALL in either the pediatric or adult world, but studies show that patients who received adult treatment fared much worse.” Focus Under Forty addresses such disparities, focusing on the specific

challenges of diagnosing and treating AYA patients with cancer. ASCO and its philanthropic arm, the Conquer Cancer Foundation (formerly known as The ASCO Cancer Foundation), teamed with LIVESTRONG® to develop the program.

Why Do Survival Rates for This Age Group Lag Behind? A number of interrelated factors have contributed to the lack of progress in cancer care in AYAs—delayed diagnosis, limitations in access to care, widely varying referral patterns, and inconsistency in treatment and

follow-up care. “These patients are getting lost,” says Joyce Reineke, JD, a cancer and fertility advisor to LIVESTRONG who also serves on the joint Focus Under Forty planning task force. Delayed diagnosis is common because AYAs typically see themselves as invulnerable, ignoring symptoms or delaying going to a doctor. In addition, providers often miss the cancer diagnosis initially because they do not suspect cancer in this population. To address delays in diagnosis, Focus Under Forty has educational content designed specifically by and for pri-

ASCOPost.com | FEBRUARY 15, 2011

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mary care providers. Lack of research also contributes to the challenges in treating AYAs. An exceedingly low rate of participation in clinical trials and the high mobility of this population have hampered research. “The basic biology of cancers in this group differs from that in older patients, but we have a poor understanding of what distinguishes cancers in this population,” Dr. Hayes-Lattin notes.

Fertility Preservation Is a Significant Issue Ms. Reinecke was 29 years old when she was diagnosed with leiomyosarcoma. “I wasn’t told right away, after my diagnosis, that my planned treatment could put me at risk for infertility. But when I met with several oncologists after surgery to talk about my future treatment, one of the oncology fellows brought

this up.” Ms. Reinecke and her husband then “scrambled to find an IVF facility” in order to create and then store embryos. They subsequently had twin daughters using a surrogate. Ms. Reinecke says that breakdowns in communication about fertility preservation for women can often result in a loss of critical few weeks between diagnosis and implementation of chemotherapy or other treatments. “For example, the surgical oncologist might not include fertility preservation in patient discussions because it is not a direct risk of surgery,” she points out. “However, by the time the patient gets to the medical oncologist, she probably won’t have time to undertake something like egg banking before treatment.” Focus Under Forty includes two case-based modules that specifically address fertility preservation.

Psychosocial and Practical Concerns Different for this Group Awareness of the significant psychosocial, financial, and practical concerns of this age group is also important. Both Ms. Reinecke and Dr. Hayes-Lattin, who had testicular cancer at age 28, point out that more oncologists need to understand the specific challenges faced by AYAs, whose concerns differ from those of either the child or the older adult with cancer. For example, after a cancer diagnosis, AYAs may be concerned about fertility preservation options. In addition, many of these patients have concerns about issues such as body image and relationships. “You are there in the waiting room and everyone is a generation away from you,” Ms. Reinecke comments. “It’s very scary and isolating to be facing these issues—issues like mortal-

ity—and not to have peers there. You are out of sync with your own peers.”

New Collaboration This is the first time ASCO and LIVESTRONG have partnered on education. “It’s exciting to see this collaboration address these critical issues and realize the impact this education can have on patients’ lives,” comments Dr. Hayes-Lattin, who is a senior medical advisor for LIVESTRONG. “The goal of Focus Under Forty is to have everyone who interacts with these patients understand what the differences are for this age group and know that the approach to care should be different.” To access Focus Under Forty, hosted on ASCO University, visit http:// university.asco.org/focusunder40.

■

How Does Your Practice Measure Up?

More than 650 Practices Registered in QOPI®—The Quality Oncology Practice Initiative

OPI is a free quality assessment and improvement program, developed by ASCO, which allows an oncology practice to compare the performance of its providers in more than 90 areas to the performance in other practices across the country.

What Is Measured? QOPI collects data on measures adapted from evidence-based guidelines such as those of the National Initiative on Cancer Care Quality. All practices report on 25 core measures, such as those related to pain assessment and control, smoking cessation, and psychosocial support. In addition, each practice chooses at least two other

categories of data to report. These categories relate to management of disease areas (breast cancer, colorectal cancer, etc.), end-of-life care, or symptoms and toxicity management. Up to twice a year, participating practices submit data from a sample of charts of patients seen in the office in the previous six months. The number of charts abstracted depends on the number of full-time-equivalent medical oncologist/hematologists at the practice. Practices that have multiple locations may abstract charts from selected sites or from across the practice as a whole. Practice personnel enter the data through a secure web portal that prompts the chart abstractor for data to

QOPI® Site Registration Number of Sites 0 1-5 6 -9 10 - 29 30 - 49 50+

input for each measure. Within 30 days of the close of the collection round, each participating practice can view its own confidential performance report online. QOPI reports the practice’s score for each measure (eg, the percentage of times the practice documented cigarette smoking status by the second office visit) and the national mean, minimum, and maximum scores, including detail on number of charts and practices reporting. Practices can customize reports in a number of ways. For example, they can compare their scores to those of practices of a similar type, such as academic center or private/independent practices.

Required: A Culture of Self-Examination and Improvement Why have hundreds of oncology practices voluntarily chosen to participate in ASCO’s quality measurement program? Sharon M. Ondreyco, MD, of Palo Verde Hematology Oncology in Phoenix, AZ, gave three reasons right off the bat: ■■ We wanted to make sure our group was practicing the best hematology/oncology care possible. ■■ In anticipation of the possibility

Next Data Collection Period: Spring 2011 March 24–April 28

that CMS [Centers for Medicare & Medicaid Services] or insurance companies will require a performance program. ■■ It’s an excellent way to benchmark our community practice’s performance compared to others, including major academic centers. Lynn Ratzlaff, CHSM, the practice administrator with Dr. Ondreyco’s group, adds, “QOPI provides an excellent tool for evaluating new physicians’ documentation and practice standards. The return in knowledge gained is worth the time spent abstracting charts.” Many QOPI participants point to the fact that the process “shines a light” on areas needing attention, prompting the clarification of protocols or initiation of new patient information programs, for example. “Our doctors are now better at documenting what they are doing, especially in areas such as staging and pain assessment and treatment,” Dr. Ondreyco notes. continued on page 16

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ASCO Recommends Steps to Improve Advanced Cancer Care Planning

SCO is calling upon the oncology community to help improve the quality of life of patients with advanced cancer. In a policy statement issued last month, ASCO outlined four priorities for advanced cancer care planning as well as steps to ensure care is individualized to address patients’ needs and preferences throughout the course of treatment. ASCO’s policy statement lays out four key priorities for advanced cancer care planning: ■■ Assess whether the cancer can be treated: Evidence suggests that patients with advanced cancer often

receive overly optimistic assessments of prognosis, which may lead them to receive unnecessary treatment. ■■ Make quality of life an explicit priority throughout the treatment continuum: Patients should understand all potential treatment options; in cases where curative treatment is unlikely to extended survival, palliative therapies should be discussed as an alternative. ■■ Initiate candid discussions about options soon after diagnosis: Candid conversations about advanced cancer care occur less than 40% of

the time. However, multiple studies have shown that palliative treatment options improve patient and caregiver quality of life, and can even extend life. ■■ Increase participation in clinical trials: Very few patients with advanced cancer participate in trials due to strict eligibility criteria, and few trials address quality of life issues. Increasing opportunities for patients to potentially benefit from trials should be a high priority. Significant barriers currently prevent patients with advanced cancer from openly discussing care options. These range from limited educational and training resources for oncologists to a lack of insurance reimbursement for palliative care discussions.

To address these barriers ASCO recommends: ■■ emphasizing advanced cancer care planning in physician training and education ■■ providing insurance coverage for advanced care planning discussions ■■ increasing educational resources for patients with advanced cancer ■■ increasing opportunities for patients with advanced cancer to participate in clinical research To help oncologists overcome the barriers related to advanced cancer care planning, ASCO will issue guidance on the integration of palliative care service into oncology practice.

■

New Name, Enduring Mission

ASCO’s philanthropic arm renamed Conquer Cancer Foundation Critical Support for a Broad Range of Programs

uring its 11-year existence, The ASCO Cancer Foundation has been vital to ASCO programs, providing support that would not be possible through member dues only— more than $10 million in 2009 alone. During that time, the Foundation has continued to evolve from the charitable arm of its parent society, ASCO, to an increasingly high-profile philanthropic foundation. Beginning in 2011, the Foundation will be known by a new name that reflects that evolution: the Conquer Cancer Foundation of the American Society of Clinical Oncology. The name Conquer Cancer Foundation inspires confidence and makes its mission instantly comprehensible to the general public and donors. Along with the name change, the Foundation has updated its mission and vision statements. Its mission: to conquer cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. Its vision: a

world free from the fear of cancer. “Conquer Cancer Foundation is more than a name. It reinforces our individual and collective consecration to our mission. It creates our invitation to all who will partner with us as we seek to fulfill our Foundation’s new name and our abiding mission…the mission to conquer cancer.” —Martin Murphy, Jr, PhD, DMedSc, Chair, Conquer Cancer Foundation Although ASCO is well known among oncology professionals, the public at large is not necessarily familiar with the Society or with clinical oncology. While ASCO continues to provide resources to its members, the Conquer Cancer Foundation reaches beyond the membership, to individuals and organizations of all types, for support. The new name distinguishes the Foundation as a separate organization and establishes a differentiated mission that audiences will find relevant and care about, while remaining closely tied to ASCO.

“ASCO has the expertise and competency to deliver a tremendous array of programs to both our members and the public. What transforms these ideas into reality is financial support, and that must come from sources beyond ASCO membership dues.” —Allen S. Lichter, MD, ASCO CEO The Foundation seeks support for programs including Annual Meeting educational tracks, enduring materials, thematic symposia, Virtual Meetings, and online Abstracts. It helps support ASCO’s award-winning patient education website, Cancer.Net, which provides timely, oncologist-

approved information to patients and their families. Its reach extends from the grassroots level, through support of the State Affiliate Program, to across international borders, through the Advanced Cancer Courses and the Long-term International Fellowship program. Much of the Foundation’s fundraising has focused on its Grants and Awards Program. Established by ASCO in 1983, the Grants Program awarded its first Young Investigator Award in 1984. In 1992, the program was expanded to include the Career Development Award, and now, the Grants program offers funding to every level of physician-scientist, both

The 2011 Conquer Cancer Foundation Board of Directors Martin J. Murphy, Jr, PhD, DMedSc, Chair Allen S. Lichter, MD, Chief Executive Officer Richard L. Schilsky, MD, Secretary

Lawrence H. Einhorn, MD John H. Glick, MD Gabriel N. Hortobagyi, MD, FACP Thomas Marsland, MD Robert J. Mayer, MD

W. Charles Penley, MD, Treasurer

Sandra M. Swain, MD

Nora A. Janjan, MD, MPSA, MBA, Member-At-Large

Nancy R. Daly, MS, MPH, Executive Director

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in the United States and throughout the world. To date, more than $66 million in research grants have been awarded to more than 800 investigators. Along with research grants, the Foundation administers a robust Awards Program designed to recognize and promote the career development of high-quality clinicians and researchers. More than $1 million has been awarded to researchers through the International Development and Education Award (IDEA), Clinical Trials Participation Award (CTPA), and Merit Award. Established in 2009, the ASCO Diversity in Oncology Initiative, funded by Susan G. Komen for the Cure®, has provided support for three additional award programs: the Loan Repayment Program, Medical Student Rotation Program, and Resident Travel Award.

Collaborating for Success Given that treating cancer requires a collaborative relationship among a multidisciplinary team of caregivers, funding cancer research and education programs also benefits from a collaborative approach. To this end, the Foundation has broken new ground in developing relationships with like-minded organizations. A first-of-its-kind collaboration with Susan G. Komen for the Cure was formed in 2008, when the Foundation received $10 million from Komen for the Cure to develop programs focused on access to, quality of, and delivery of cancer care. Through this relationship, ASCO and the Foundation have created several important initiatives, among them the Diversity in Oncology Initiative, designed to facilitate the recruitment and retention of individuals from populations underrepresented in medicine to cancer careers, and the Improving Cancer Care Grant, the largest-ever grant offered by the Foundation, at $1.35 million. “The collaborative relationship with Komen was new territory for the Foundation. Now, more than 2 years later, both organizations are thrilled with how productive and fruitful it has been. Not only do we look forward to continuing our association with Komen, we look forward to building similar relationships with other organizations, all with the objective of benefitting people living with cancer.” — Nancy R. Daly,

MS, MPH, Executive Director, Conquer Cancer Foundation

Building Personal and Public Support Recognizing the need to both increase efforts and ensure its longev-

ity, the Foundation in 2008 established its Mission Endowment. The Endowment represents an opportunity for corporations and individuals to invest in the Foundation’s critical mission areas: research, professional education, patient and family sup-

port, international outreach, and access to care. The Mission Endowment is an investment in the future of the practice of oncology, for the benefit of patients. The Foundation continues to seek continued on page 16

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New Foundation Name continued from page 15

innovative ways to spread its message and bring notice to the work it does. In 2010, the Foundation launched a new Annual Giving Campaign, Leadership to Legacy, which supports the Foundation’s Research Grants Program. This campaign is an opportunity for ASCO members and other oncology professionals to support the next generation of researchers. Leadership of ASCO and the Foundation, and ASCO members and nonmembers alike, have risen to this challenge, and thus far, Leadership to Legacy has raised sufficient funds to support a Young Investigator Award. The Conquer Cancer Foundation moves into its second decade with not just a new name, but also a

Vol 28, No 34

December 1, 2010

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

JCO.org

www.jco.org

■

Journal of Oncology Practice

American Society of Clinical Oncology

THE AUTHORITATIVE RESOURCE

VOLUME 6

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

The Dandelion Effect: Treat the Whole Lawn or Weed Selectively? Minesh Mehta 29(2): 121

Taming Glioblastoma by Targeting Angiogenesis: 3 Years Later Eric T. Wong 29(2): 124 Amifostine in the Treatment of Head and Neck Cancer: Intravenous Administration, Subcutaneous Administration, or None of the Above Avraham Eisbruch 29(2): 119

Obesity and Breast Cancer Prognosis: Weight of the Evidence Frank A. Sinicrope 29(1): 4

Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08 Carmen J. Allegra, et al 29(1): 11

Insulin Breast Cancer Connection: Confirmatory Data Set the Stage for Better Care Andrea DeCensi 29(1): 7 Multicenter Phase III Randomized Trial Comparing Docetaxel and Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens Vicente Valero, et al 29(2): 149 Adjuvant Whole-Brain Radiotherapy Versus Observation After Radiosurgery or Surgical Resection of One to Three Cerebral Metastases: Results of the EORTC 22952-26001 Study Martin Kocher, et al 29(2): 134

10. The Swinging Pendulum of the Anemia of Cancer: Erythropoietin Trumps Hepcidin Stanley Zucker 29(2): e42

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

What’s Hot in

JOP Online jop.ascopubs.org

Medication Safety of Five Oral Chemotherapies: A Proactive Risk Assessment Saul N. Weingart, et al 7(1): 2

Safe Handling of Oral Chemotherapeutic Agents in Clinical Practice: Recommendations From an International Pharmacy Panel Susan Goodin, et al 7(1): 7

Chemotherapy Dosing in Obese Patients With Cancer—The Need for Evidence-Based Clinical Practice Guidelines Gary H. Lyman 7(1): 17

Multidisciplinary Health Care Professionals’ Perceptions of the Use and Utility of a Symptom Assessment System for Oncology Patients Daryl Bainbridge, et al 7(1): 19

Encouraging Clinicians to Incorporate Longitudinal Patient-Reported Symptoms in Routine Clinical Practice Ethan Basch, et al 7(1): 23

What’s Hot in

1. Lessons From the Adjuvant Bevacizumab Trial on Colon Cancer: What Next? Eric Van Cutsem 29(1): 1 2.

renewed sense of direction and purpose. Through comprehensive marketing and communications plans and its new consumer-friendly brand, the Foundation hopes to reach new audiences outside the traditional cancer community, acquiring new friends while renewing the support of existing donors. Through this outreach, the Foundation will be able to expand its portfolio of programs benefitting people living with cancer and the people who care for and about them. Visit ConquerCancerFoundation. org to learn about the programs we support, apply for grants and awards, or make a gift.

Help Your Patients Understand Cancer Care for Older Adults

irect your patients to Cancer. Net (www.cancer.net/olderadults), ASCO’s patient website, to learn about the unique needs and concerns of older adults with cancer and their families. They will find practical tips for managing their can-

Practice Measures continued from page 13

Additional QOPI Benefits Recertifying oncologists can use QOPI data in the self-directed Performance Improvement Module for Maintenance of Certification requirements of the American Board of Internal Medicine (ABIM). ABIM awards 20 points for completing an improvement plan based on QOPI data. Physician participants can also use QOPI data to earn up to 20 continuing medical education credits. Nonphysican QOPI participants can receive a certificate of participation from ASCO to obtain continuing education units from their respective

cer care, as well as information about health assessments, treatment options, coexisting conditions, clinical trials, questions to ask, and patient resources. To order free copies of the Cancer in Older Adults booklet, visit ASCO’s bookstore (www.cancer. net/ordermaterials). © 2011. American Society of Clinical Oncology. All Rights Reserved.

certification bodies. Many health insurance programs recognize QOPI participation by actions such as giving practices special designation in their physician directories, providing financial support for chart abstraction, or waiving prior authorization requirements. “I recommend QOPI to all groups,” Dr. Ondreyco stresses. “With insurance companies looking over our shoulders so much, this is another way we can prove quality and standardization.” For more information, visit qopi. asco.org.

■

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

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

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

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

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

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

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

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

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

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

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

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

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

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

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

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

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

ASCOPost.com | FEBRUARY 15, 2011

PAGE 19

52nd ASH Annual Meeting Hematology

Escalated BEACOPP Superior to Standard Treatment of Early Unfavorable Hodgkin Lymphoma but More Toxic By Alice Goodman

n aggressive strategy combining an escalated BEACOPP regimen plus ABVD and radiotherapy improved tumor control compared with standard treatment (ie, ABVD plus radiation) in patients with early unfavorable Hodgkin lymphoma in the German Hodgkin Study Group HD14 trial. Lead author Andreas Engert, MD, University Hospital Cologne in Cologne, Germany, presented final results of the trial at the 52nd American Society of Hematology (ASH) Annual Meeting.1 Although tumor control, measured by the rate of freedom from treatment failure, was superior with the more aggressive strategy, overall survival was not improved. This study was also published in the Journal of Clinical Oncology.2 “We achieved overall better tumor control with more aggressive treatment, and this treatment is now our standard of care for continuing studies. Hematologic toxicity was slightly higher with the escalated BEACOPP regimen, but this did not result in more treatment-related deaths,” Dr. Engert said. He added that with short follow-up of 5 years, no overall survival difference was seen.

Study Details Standard treatment for early unfavorable Hodgkin lymphoma consists of four cycles of ABVD chemotherapy and involved-field radiotherapy. The previous HD8 study by the same group of investigators showed that standard therapy achieved a 5-year overall survival rate of 91% and freedom from treatment failure rate of 83%. In the present study, the escalated BEACOPP regimen improved the 5-year freedom from treatment failure rate by approximately 6% to 7%. In the HD14 trial, patients in the

experimental arm received two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, and cyclophosphamide, plus vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by involved-field radiotherapy of 30 Gy. The control arm received four cycles of ABVD followed by the same radiotherapy. The primary endpoint was freedom from treatment failure. The study enrolled 1,655 patients aged 16 to 60 years with early unfavorable Hodgkin lymphoma. Stage I–IIA patients (two-thirds of the study population) were required to have at least one of the following risk factors: large mediastinal mass, extranodal disease, erythrocyte sedimentation rate ≥ 50 mm/h or ≥ 30 mm/h and B symptoms, or at least three nodal areas. Stage IIB patients had a sedimentation rate ≥ 50 mm/h or ≥ 30 mm/h and B symptoms or at least three nodal areas. In the final intention-to-treat analysis of 1,528 patients, at 5 years 87.6% of patients receiving standard treatment were free from treatment failure (relapses and deaths) vs 94.3% receiving escalated BEACOPP (P < .0001). “This absolute difference of about 7% was highly significant and met predefined criteria for stopping the trial in July of 2008,” Dr. Engert stated. “We now consider the escalated BEACOPP regimen a new standard of care.”

Results The more aggressive regimen achieved superior results on other measures as well, including progressive disease, early relapse, and late relapse. With standard treatment vs escalated

Aggressive Therapy for Hodgkin Lymphoma ■■ The phase III German HD14 trial showed that an escalated BEACOPP regimen plus ABVD and radiotherapy improved tumor control compared with standard treatment (ABVD plus radiation) in patients with early unfavorable Hodgkin lymphoma.

■■ Freedom from treatment failure rates were 94.3% for patients given escalated

Expert Point of View

inna G. Laport, MD, Associate Professor of Medicine at Stanford University Medical Center, said she currently reserves the standard BEACOPP regimen for Hodgkin lymphoma patients with more advanced disease or high-risk features. “I can’t say I would change practice based on this study, though the results are titillating,” she commented. “This is a very large and well conducted trial, and although the toxicity is concerning, there was no Ginna G. Laport, MD difference in treatment-related mortality. It would be reasonable for physicians to switch to this regimen, but the higher toxicities must be carefully considered, especially since the overall survival was not significantly different between the two treatment arms.” However, when Dr. Laport was questioned about why this new regimen would not enjoy widespread use in the United States, she indicated that choice of regimen for unfavorable Hodgkin lymphoma patients depends on national/regional preference. For example, Stanford has developed its own regimen (Stanford V) using lower doses and shorter delivery schedules of chemotherapy agents, whereas many other U.S. centers consider ABVD standard of care because it has acceptable toxicity, produces comparable response rates compared with Stanford V, and is associated with a less complex schedule of administration, Dr. Laport commented.

■

BEACOPP, respectively, disease progression was observed in 3.0% vs 0.8% of patients, respectively; early relapse occurred in 3.0% vs 0.9%, respectively; and late relapse occurred in 2.4% vs 0.8%, respectively. “These were stunning differences in tumor control,” he commented. Response rates were similar with the two regimens: about 95%. Twenty patients in each arm died; treatmentrelated deaths occurred in five control patients and four patients in the experimental arm. Secondary neoplasias were observed in 19 patients after standard therapy and in 16 patients with escalated BEACOPP. Grade 3/4 acute toxicities occurred in 51% of the ABVD-alone arm vs 87% of those in the escalated BEACOPP arm. Grade 3/4 hematologic toxicity was observed in about 30% of the control arm compared with 70% receiving escalated BEACOPP. The more aggressive regimen had higher rates of hematologic tox-

BEACOPP vs 87.6% for standard treatment (P < .0001).

■■ Overall survival did not differ between the two groups. ■■ The grade 3/4 acute toxicity rate was considerably higher in the escalated

BEACOPP arm (87% vs 51%). Grade 3/4 hematologic toxicity was about 70% vs 30%, respectively.

■■ U.S. oncologists may not widely adopt this treatment approach, given regional preferences.

Use your smartphone to view abstract 765 from the 52nd ASH Annual Meeting SEE PAGE 38 and the JCO paper referenced in this article.

icities: 24% for controls and 80% for escalated BEACOPP, and of leukopenia with infections: 1.2 % and 9.8%, respectively. More acute myeloid leukemia occurred with the escalated BEACOPP regimen: 0 for controls and 3 cases, respectively; whereas more cases of non-Hodgkin lymphoma were reported in the control arm: 10 vs 5 cases, respectively. Despite these positive results from a large phase III trial, some hematologists consider escalated BEACOPP too toxic and are concerned about treatment-induced secondary malignancies and fertility.

■

References 1. Engert A, Borchmann P, Pluetschow A, et al: Dose-escalation with BEACOPP escalated is superior to ABVD in the combined-modality treatment of early unfavorable Hodgkin lymphoma: Final analysis of the German Hodgkin Study Group (GHSG) HD14 trial. 52nd ASH Annual Meeting. Abstract 765. Presented December 6, 2010. 2. Eich HT, Diehl V, Gorgen H, et al: Intensified chemotherapy and dosereduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: Final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol 28:4199-4206, 2010.

In advanced RCC:

Change to Afinitor after initial VEGFR-TKI* failure (sunitinib or sorafenib)â&#x20AC; mTOR Inhibition

OD VESSEL CEL L BLO

TUMOR CELL

mTOR

Reduced cell growth and proliferation

mTOR

Reduced cell metabolism

Reduced angiogenesis

A different target from VEGFR-TKIs: mTOR is an intracellular regulator downstream of VEGF1,2 mTOR regulates both angiogenic and proliferative tumor progression pathways1-4 Afinitor targets both tumor and blood vessel cells1,3,5 Adverse events are frequently class related and different from those seen with VEGFR-TKIs2,6,7 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitor. â&#x20AC; Inhibition of mTOR by Afinitor has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 2. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 3. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82: 381-388. 4. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471-484. 5. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926-1945. 6. Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. In press. 7. Creel PA. Management of mTOR inhibitor side effects. Clin J Oncol Nurs. 2009;13(suppl):19-23.

2.5mg 5mg 10mg

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936

Printed in U.S.A.

08/10

C-AFI-100068

AFINITOR (everolimus) tablets for oral administration

Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. • Infections [see Warnings and Precautions (5.2)]. 6.1 Clinical Studies 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. The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 14 4 Pneumonitisc

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

Hematologya Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

Grade 3 %

Grade 4 %

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

The ASCO Post | FEBRUARY 15, 2011

PAGE 24

Health-care Policy Legislation

The 112th Congress: What’s in Store for Cancer Care in 2011? By Ronald Piana

he 111th Congress is gone but not forgotten, having passed into law the landmark Affordable Care Act of 2010. Although this legislation has several interesting appropriations for cancer research, a core principle of the bill is finding ways to reduce health-care spending, which gives the oncology community an uneasy sense of déjà vu: The Medicare Modernization Act of 2003 hammered oncology with deep cuts in reimbursement for Part B drugs, leaving many community infusion centers underwater. Oncology practices, especially smaller one- to three-person groups, have to wonder how much more change they can take. Despite the 1-year “patch,” the sustainable growth rate (SGR) is still the elephant in the room, a problem no one wants to tackle head-on. But Ted Okon, Executive Director of the Community Oncology Alliance (COA), explained that the problem runs deeper than the outdated SGR formula. “Studies have shown that the United States has the best cancer care

Another SGR ‘Patch’

he 111th Congress approved a 1-year postponement to the 23% SGR-driven Medicare cuts in physician fees. David Eagle, MD, President of the Community Oncology Alliance, responded, “Until Congress eliminates the SGR, we can expect a recurring problem that becomes more difficult to fix. Oncology practices are actively failing, secondary to the current insufficient payments from Medicare and others. Cancer patients can only be served well when payers recognize the true level of resources required to provide high-quality care. “

■

David Eagle, MD

delivery system in the world, meaningfully higher survival than Canada or Western Europe. But without attention from this Congress, we’re at risk of having that system dismantled,” said Mr. Okon.

munity Cancer Centers (ACCC), told The ASCO Post, “ACCC has been part of a coalition advocating on the Hill for removal of the prompt pay discount. But there’s a lot of work to do, especially with the newer mem-

cerned that comparative effectiveness research might narrow their treatment options. Steven Pearson, MD, MSc, Founder of the Institute for Clinical and Economic Review, remarked, “Ultimately, comparative effectiveness research information will be available to patients, doctors, and payers to be used in ways to improve outcomes and reduce costs, not through the blind rationing and up-down decision-making that some spend too much time worrying about.”

Incentive for Less Care Matthew Farber, MA

Steven Pearson, MD, MSc

Policymakers on the Hill tend to focus on expensive chemotherapies, but Mr. Okon referenced the COA Components of Care Study, which looked at oncology practice expenses as they relate to Medicare. “Looking at 2009 data, we found that if you take the drugs out of the equation, Medicare reimburses only 57% of the costs for administering chemotherapy. It gives a picture of how low Medicare payment is for oncology services, and it’s getting worse on the drug side as well.”

Unfinished Business Considering Medicare pay cuts, community practices that rely too heavily on the agency for their revenue cannot survive. Consequently, private payers have become the lifeblood of community oncology. However, customary prompt pay discounts (financing terms between manufacturers and distributors that artificially lower Medicare Part B drug reimbursement) have placed many community practices in jeopardy. Companion bipartisan bills—S. 1221 and H.R. 1392—that eliminate prompt pay discounts from the calculation of the average sales price (which is the basis for Medicare reimbursement rates for community clinics), were introduced but came up short in last year’s Congressional battle over a health-care bill. Major cancer groups are gearing up their lobbying efforts for 2011’s legislative calendar. Matthew Farber, MA, Director of Provider Economics and Public Policy at the Association of Com-

Alan M. Garber, MD, PhD

bers of Congress.” He cautioned that given last year’s bloody reform battle, stand-alone health-care bills have an uphill battle. “Attaching prompt pay to another vehicle, perhaps a spending bill, will be our best shot at getting the prompt pay bills passed,” added Mr. Farber.

Comparative Effectiveness Research Gaining Ground Another initiative getting careful scrutiny from the oncology community is the comparative effectiveness research (CER) program, authorized by the Affordable Care Act, and funded and managed by the new Patient-Centered Outcomes Research Institute. In short, comparative effectiveness research uses pragmatic trials to determine which treatment works best, for whom, and under what circumstances.

Are High-priced Cancer Drugs in Line for CER Scrutiny? The FDA does not require comparative effectiveness data to approve a new drug, although some foreign regulatory authorities do. Given the high cost of newer biologics, some in the oncology community are con-

Another cost-saving proposal in the new health-care reform bill is the Medicare Shared Savings Program, designated to encourage the formation of accountable care organizations (ACOs). The Centers for Medicare & Medicaid Services defines ACOs as organizations of health-care providers accountable for the quality, cost, and overall care of its beneficiaries. Although enhancing quality is the purported underpinning of these organizations, the real driver behind this initiative is reducing medical costs. Accountable care organizations lower costs, in part, by setting a cost benchmark and sharing profits when the amount is below the benchmark. How ACOs play out in the complex world of oncology, without limiting care, remains to be seen. Alan M. Garber, MD, PhD, Henry J. Kaiser Jr. Professor of Economics at Stanford University, threw the ball back into the comparative effectiveness research court. “For ACOs to deliver better outcomes at lower costs, they really need to know what works. I see comparative effectiveness research as a method to provide the information that all the participants in an accountable care organizations need. One can institute changes in payment, as pro-

Average Wholesale Price vs Average Sales Price ■■ Average wholesale price, or AWP, is the average price specified by its

manufacturer. Generally, the AWP is the cost of a drug with a standard 20% markup.

■■ Average sales price, or ASP, is based on manufacturers’ quarterly sales data as reported to the Centers for Medicare & Medicaid Services.

■■ What do the terms mean for oncology: Medicare Part B payments for infusion drugs are based on the ASP. The ASP is usually less than the AWP because it reflects all drug sales, including volume discounts.

ASCOPost.com | FEBRUARY 15, 2011

PAGE 25

Health-care Policy

posed in ACOs. However, without an instrument like comparative effectiveness research, you can reduce costs, but I would feel uncomfortable about the possibility that patients would be deprived of essential services.” The oncology landscape was impacted in 2003 with the passage of the Medicare Modernization Act. Switching Medicare Part B reimbursement from average wholesale price to average sales price + 6% reduced drug payments to untenable levels. Moreover, rising costs of running infusion centers have largely gone uncompen-

sated, due, in part, to a lack of knowledge of practice expenses. As a result, community oncology practices are trending toward consolidation as they seek alternative business models to survive. The question oncology needs to ask moving forward is will community practices be able to survive in this new era of change.

■

Two Bills Passed by the 111th Congress ■■ The Cures Acceleration Network Act empowers the NIH Director with $500 million the first year to support bench-to-bedside discoveries.

■■ The Family Smoking Prevention and Tobacco Control Act gives the FDA unprecedented authority to regulate tobacco products.

ERBITUX Increased Overall Survival in Both:

FDA Update

FDA Approves Rituximab as Maintenance Tx for Follicular Lymphoma

Squamous Cell Carcinoma of the Head and Neck (SCCHN) in Combination With RT in Locoregionally Advanced Disease

EGFR-Expressing Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure as a Single Agent

ituximab (Rituxan) received FDA approval as a maintenance therapy for advanced follicular lymphoma in patients who responded to induction therapy with rituximab plus chemotherapy, according to a press release issued by Genentech. Approval of rituximab as maintenance therapy was based on results of the PRIMA study (Primary Rituxan and Maintenance), sponsored by the Groupe d’Etude des Lymphomes de l’Adulte (GELA).1 Results of this study showed continuing rituximab administration every 2 months for 2 years in patients who responded to initial treatment with rituximab plus chemotherapy nearly doubled the progression-free survival rate (PFS) compared to those who stopped treatment (based on a hazard ratio of 0.54, 95% CI, 0.42 to 0.70; P ≤ .0001). PRIMA is an international, multicenter, randomized, phase III clinical study that enrolled 1,217 patients with previously untreated advanced follicular lymphoma. The study evaluated the efficacy and safety profile of maintenance rituximab.

■

Reference 1. Salles G, Seymour JF, Offner F: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 377(9759):42-51, 2011. Epub 2010 Dec 20.

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

SOLUTION FOR INTRAVENOUS INFUSION

The ASCO Post | FEBRUARY 15, 2011

PAGE 26

Patient Advocacy

Cancer Legal Resource Center Aids Patients with Financial and Legal Issues By Caroline Helwick

s a matter of course, patients with cancer receive treatment for their tumor and palliation for side effects, but one aspect of cancer care is frequently missing: solutions to the financial and even legal challenges that

can accompany a cancer diagnosis. A national organization based in Los Angeles can help to fill this gap: the Cancer Legal Resource Center (CLRC), a joint program of the Disability Rights Legal Center and Loyola

Law School Los Angeles. Besides the full-time staff, a professional panel of volunteer attorneys, insurance agents, and accountants are on call to help patients navigate this maze. “We know that financial and legal is-

sues cause patients a lot of unnecessary worry, confusion, and stress, and these can be overwhelming. When these issues are not addressed, patients may get through treatment but end up losing their home, job, or health insurance,” said

ERBITUX Significantly Increased SCCHN

in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

RT alone (n=213)

29.3 months

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7

month improvement

P=0.05 RT=radiation therapy; HR=hazard ratio; CI=confidence interval.

* A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration

of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

ASCOPost.com | FEBRUARY 15, 2011

PAGE 27

Patient Advocacy

Joanna Morales, Esq, CLRC Director. The CLRC provides free and confidential information on cancer-related financial and legal issues to cancer survivors, families, employers, health-care professionals, and others dealing with cancer. These issues range from insurance coverage and claims denials to workplace discrimination and estate planning. Staff

can answer questions about laws relevant to the patient’s situation (which can vary state by state) and can direct individuals to the appropriate resources.

‘A Drop in the Bucket’ The CLRC recently fielded its 35,000th telephone call (1-866-THECLRC), according to Ms. Morales.

“Unfortunately, there is a big need for our services,” she said. “And we think this number is just a drop in the bucket.” Interested persons can also obtain detailed written information. But the CLRC is not just a resource for patients, she emphasized. “Ultimately, our goal is to train health-care professionals to identify cancer-related legal issues and legal

Overall Survival in Both: EGFR-Expressing mCRC

after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

34%

4.57 months BSC alone (n=285)

improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. † NCIC CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome

measure of the trial was overall survival.1

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

SOLUTION FOR INTRAVENOUS INFUSION

barriers to health care. We can give them resources to help their patients navigate through these issues, which we believe will improve their quality of life,” she said. For the oncology team, webinars are held on a variety of topics, and a resource manual can be downloaded through a grant from LIVESTRONG. The CLRC continued on page 28

The ASCO Post | FEBRUARY 15, 2011

PAGE 28

Patient Advocacy

Cancer Legal Resource Center continued from page 27

also hosts national Cancer Rights Conferences. In 2011, the Conferences will be held in Chicago and Washington, DC. These events are especially targeted to patients and caregivers, as well as nurses, social workers, marriage and family therapists, and attorneys.

■

Avoiding Discrimination in the Workplace

oanna Morales, Esq, Director of the CLRC, said many cancer survivors worry about facing discrimination while looking for employment. “They wonder if they have to disclose

their cancer diagnosis in job interviews, and they need to know their legal rights,” she said. Under the Americans with Disabilities Act, cancer survivors do not

need to disclose their illness unless asking for a “reasonable accommodation” or medical leave. Additionally, an employer can make a job offer conditional on passing a medical exam

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

ASCOPost.com | FEBRUARY 15, 2011

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Patient Advocacy

only if this is required of all employees entering that position, and cannot rescind a job offer unless there are exam results that show the employee cannot perform the essential

Joanna Morales, Esq.

functions of the job, she said. “Often employers do ask on the application form whether the applicant has had cancer,” she added. “And I want to get that phone call from the cancer survivor. I

want to take that opportunity to educate both the employer and potential employee. Just because a law exists does not mean patients are not faced with these situations.” State fair employment laws vary, and the CLRC can decipher the legal

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages. Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US10AB08605

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SOLUTION FOR INTRAVENOUS INFUSION

milieu for the patient. Staff can also provide suggestions on how to rework a resume with regard to gaps in time off work. For additional information, visit: www.CancerandCareers.org and www. cancerlegalresourcecenter.org

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The ASCO Post | FEBRUARY 15, 2011

PAGE 30

Letters to the Editor

Let’s Not Subject Patients with Advanced Cancer to Autopilot Screening

s reported in the December issue of The ASCO Post,1 Sima et al used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to examine the rates of cancer and cholesterol screening among patients with advanced lung, colorectal,

breast, and gastrointestinal cancers.2 The study found that 8.9% of women had a mammogram and 5.8% had Pap testing; 15% of men had prostate cancer screening; and overall, 19.5% had cholesterol testing. The authors concluded that given the likely poor

overall prognosis among patients with advanced cancers, screening for other cancers and cholesterol represents unnecessary care that is also costly to Medicare, patients, and society. As general internists, we care for patients with and without cancer, much

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.] INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information]. CONTRAINDICATIONs None. WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.] Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.] Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

of our time is focused on disease prevention and health promotion, which includes screening for cancer and other conditions. While the U.S. Preventive Services Task Force provides guidelines about whom to screen in the general population, these guidelines are

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 16 0 5 0 Chills1 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 38 1 24 1 Aspartate Transaminase, high3 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction. Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

ASCOPost.com | FEBRUARY 15, 2011

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Letters to the Editor

not without controversy and uncertainty.3,4 Often, guidelines encourage us to engage patients, particularly the elderly and those with comorbidities, in discussions about screening and help them make decisions that are based on their understanding of the risks, benefits, and individual values. Unfortunately, for patients with a his-

tory of adult-onset cancer, especially advanced cancer, there are currently no evidence-based guidelines regarding screening for new cancers and/or other conditions. We agree with the authors’ conclusion that patients with advanced cancers may not benefit from screening and, in fact, may be at risk for suffering

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 Infusion Reactions3 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 11 0 4 0 Mouth Dryness Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls. Adverse events were graded using the NCI CTC, V 2.0. Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated. BSC = best supportive care 1 2 3

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%). Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

additional financial and nonfinancial costs of testing. We also agree with the hypothesis that clinicians are frequently not engaging patients with advanced cancer in discussions about stopping screening for cancer and/or other conditions. Such discussions, like those about stopping aggressive cancer treatment, associated with far greater finan-

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

ER-B0001A-09-10

Rev September 2010

Use your smartphone to view the original article, “Is ‘Autopilot’ Screening SEE PAGE 38 Subjecting Patients with Advanced Cancer to Meaningless Tests?” published in The ASCO Post, December 2010.

cial and nonfinancial costs, are critical in general medical and oncology settings.5 Rather than solely focusing on avoiding wasteful spending due to screening, we need to strive toward delivering quality care that is individualized and, to the extent possible, evidence-based. As the number of cancer survivors in the United States continues to grow,6 we need to define standards for cancer survivorship care and how to best deliver that care for patients across the spectrum of cancer diagnoses and stages. That includes ensuring that cancer survivors receive appropriate preventive care, surveillance, and screening, but also the necessary supportive and palliative care when the benefits of cancer screening clearly no longer apply. We are getting closer to developing standardized cancer survivorship care summaries for patients who have completed treatment and are transitioning from oncology to primary care. Likewise, for those patients with advanced cancer, we must encourage our oncology colleagues to prepare and share with primary care providers (and patients) a treatment plan that estimates the patients’ prognosis and outlines appropriate goals for both cancer and non-cancer–related care. Finally, we must train our health-care workforce to engage patients in difficult but informed discussions about the goals of care with confidence and skill. —Larissa Nekhlyudov, MD, MPH Harvard Medical School Linda Overholser, MD University of Colorado School of Medicine Kimberly S. Peairs, MD Johns Hopkins School of Medicine

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References 1. Bath C: Is ‘autopilot’ screening subjecting patients with advanced cancer to meaningless tests? The ASCO Post 1(12):68, 2010. 2. Sima CS, Panageas KS, Schrag D: Cancer screening among patients with advanced cancer. JAMA 304:1584-1591, 2010. continued on page 38

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33rd Annual San Antonio Breast Cancer Symposium Breast Cancer

ASCO President George Sledge Envisions the Future of Clinical Research By Caroline Helwick

eorge Sledge, MD, Professor of Medicine at Indiana University School of Medicine and current ASCO President, received the 2010 William L. McGuire Memorial Lecture Award at the San Antonio Breast Cancer Symposium, held December 8–12. In his presentation,1 Dr. Sledge reflected on the wisdom of the award’s namesake (see sidebar) and cast an eye to the future of breast cancer research. The scenario he envisioned would be exciting, were it not so worrisome. “The standard approach to breast cancer is to look at it as a biologic problem amenable to laboratory investigation, but increasingly it is becoming clear that breast cancer is a math problem,” Dr. Sledge maintained.

set of non–small cell lung cancers led to “stunning” results for a targeted agent, crizotinib. “More than half the patients receiving four or five prior lines of therapy responded,” he noted. “This is a triumph for targeted therapy. The good news is that crizotinib meets an important unmet medical need, has a straightforward and biologically based biomarker, and produces a high response rate in heavily pretreated patients. Thus, there is a low number needed to treat, and it’s also very safe,” he noted. “The bad news is that the gene is present in just 5% of patients. Therefore, we must screen 25 individuals to find 1 ALK-positive patient, and not all such patients are trial-eligible, nor would all give informed consent. So we are talking about screening 50 patients to enter 1 on a trial, and this screening requires specialty labs, time, money, certification, and so forth.”

Number Needed to Study Is Unfathomable George Sledge, MD

A decade ago, the human genome was deciphered at a cost of $3 billion. Today, society is at most 3 years away from “the thousand-dollar genome,” he said. “Data are becoming so cheap that some worry that our ability to generate genomic data may soon outpace our ability to store it.” In the near future, the patient with cancer will arrive at her oncologist’s office with a memory stick loaded with personal medical data. Every patient’s cancer will be informative for tumor biology. “This will be incredibly liberating, but things will also get very complicated,” he predicted. The complications will be seen on the individual level—because tumor complexity will become ever-more apparent—and the population level— because clinical trials cannot possibly evaluate the combinations of drugs that will be necessary to target multiple pathways within a given tumor.

EML4-ALK: Example of the Impossible Future “The recent triumph in the lung cancer world suggests this,” he said. The existence of the EML4-ALK fusion gene as the key driver for a sub-

Taking the drug into the breast cancer setting, he noted that the incidence of ALK gene rearrangement in breast cancer is 2.4%. When multiplied by 40,000 patients with metastatic breast cancer, this totals only 960 patients a year, and when further multiplied by the 3% who enter clinical trials, this results in just 28 patients available for drug development research. “It gets worse in a hurry,” he added. “Most tumors are not as ‘stupid’ as ALK-positive lung cancer tumors, which occur mainly in nonsmokers with low mutational loads.” Tumors such as gliomas, on the other hand, are “smart” in that they activate multiple kinases. Optimal cell kill requires that all are inhibited simultaneously. This type of tumor is “probably present more often than we would wish,” he pointed out. “My sense of cancer biology is that tumors are sorting themselves out based on the number of drivers of invasion and metastasis they employ,” Dr. Sledge said. “Smart” cancers will have multiple drivers that will require multiple inhibitors to derive sufficient clinical benefit. In breast cancer, the “smartest” may be the triple-negative tumor, which involves DNA damage and repair is-

The McGuire Rules

illiam L. McGuire, MD, was Professor of Medicine at The University of Texas Health Science Center in San Antonio and a founder of the San Antonio Breast Cancer Symposium. He was “a fierce competitor, inspiring leader, generous with praise, and a terrifying interrogator,” according to George Sledge, MD, who was mentored by Dr. McGuire and delivered the annual McGuire Lecture at the most recent Symposium. “Channeling his inner McGuire,” Dr. Sledge described the cancer research landscape according to what he fashioned as The McGuire Rules. “Bill McGuire’s lessons teach us how to conduct translational research in breast cancer,” he said, “and they are as important today as they were 20 years ago.” 1. Always save tissue: We can’t predict what new technology will become available. 2. Annotated tissue is key: Tumor biology only matters in the context of well-defined clinical populations. Therefore, obtaining demographics and long-term follow-up are as important as saving tissue. 3. Biology is destiny: Tumors respond to treatment according to their biologic identity. 4. Biomarkers demand care: Clinical trials must be appropriately powered to determine the value of biomarkers, which should be studied as rigorously as therapeutics. 5. The clinic is the final laboratory: Biology only matters if it is applied to clinical problems and in the context of clinical trials. Findings must be taken from bench to bedside and back again. 6. Respect the power of ‘normal’: Tumors should be compared to normal tissue and not just to other tumors. The paucity of normal tissues for comparison to tumor tissue is a flaw in breast cancer research. Host differences may affect therapeutic outcomes. 7. Surround yourself with excellence: Smart people make you smarter.

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sues and encourages an accumulation of mutations. Somatic rearrangements are common, as is message dysregulation, thus requiring that therapy target multiple points in the regulatory networks. In contrast, estrogen receptor– and progesterone receptor–positive, HER2-negative tumors have few inter- and intra-chromosomal rearrangements and might be less complicated to treat. “In the future, what will happen when the next 10 triple-negative patients you see require 8 different combination regimens based on their whole-genome analysis?” he asked. Sufficiently evaluating the variety of treatments for just one tumor type will be a daunting challenge, as the “number needed to study” will be unfeasible, according to Dr. Sledge. The number needed to study will be a critical concept when large numbers of genes are known to be driving invasion and metastases in a cancer type. At the same time, achieving this will be next to impossible, as calculations will be based on the fraction of patients

who are biomarker-positive, accounting for some degree of assay inaccuracy, exclusions for trial ineligibility, and patient refusal. Clinical evaluation of a two-kinase inhibitor combination could theoretically require an “impossible” number needed to study, Dr. Sledge has determined. This is a far more difficult venture than evaluating, for example, trastuzumab (Herceptin), for which investigators probably needed to screen an estimated 14 patients with metastatic breast cancer for every 1 patient entering the pivotal trial, according to Dr. Sledge’s calculations. “Who would screen 154 patients to enter 1 on a clinical trial? This ‘thought experiment’ suggests there are complications awaiting us in the era of cheap genomics,” Dr. Sledge commented. “We will be faced with large numbers needed to treat.” The concept of number needed to study has implications for clinical trials. Assays should be maximized for accuracy, preliminary pathologybased studies should be designed for continued on page 34

The ASCO Post | FEBRUARY 15, 2011

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33rd Annual San Antonio Breast Cancer Symposium Future of Clinical Research continued from page 33

Clinical Trial Implications of ‘Genomic Chaos’

“quick and dirty” characterization of tumors, exclusion criteria should be minimized, and trials should be made more user-friendly to enhance participation and regulatory approval, Dr. Sledge suggested.

“The real problem is not a science problem anymore. It’s that our current system is not designed to handle genomic chaos,” Dr. Sledge explained. The current clinical trial system emphasizes the development of one new

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drug at a time and virtually never employs multiple biomarker-driven studies. “Biomarker development and analysis are of secondary importance, and our regulatory apparatus is antithetical to biologic reality,” he said. “We have next-generation gene sequencing. We need a next-generation

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clinical trials system based on personal genomics, with real-time bioinformatics,” he emphasized. With the huge requirement for trial participants in the targeted combination scenarios, there is a need for an extensive national health information technology system linking drug developers and laboratory scientists, greater collaboration among companies, and more appropriate trial designs, all intended to facilitate the identification of novel combinations. The informed consent process and regulatory apparatus must also be overhauled. “None of this is easy, but I think all of it is necessary if we are to go down the path toward a cure for breast cancer,” he concluded.

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Reference 1. Sledge GW Jr: What would Bill do? Channeling your inner McGuire. 33rd Annual San Antonio Breast Cancer Symposium. William L. McGuire Memorial Lecture. Presented December 11, 2010. FDA Update

Breast Implants and Rare Lymphoma

he FDA announced a possible association between saline and silicone gel-filled breast implants and anaplastic large cell lymphoma (ALCL), a very rare type of cancer. Data reviewed by the agency suggest that patients with breast implants may have a very small but significant risk of ALCL in the scar capsule adjacent to the implant.1 The FDA is requesting that healthcare professionals report any confirmed cases of ALCL in women with breast implants. In an effort to ensure that patients receiving breast implants are informed of the possible risk, FDA will be working with breast implant manufacturers in the coming months to update their product labeling materials for patients and healthcare professionals. More information is available on the the FDA’s website (www.fda.gov). The agency plans to provide an update on its review in the spring of 2011.

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Reference 1. de Jong D, Vasmel WLE, de Boer JP: Anaplastic large-cell lymphoma in women with breast implants. JAMA 300(17):2030-2035, 2008.

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Health-care Policy Novel Technologies

Incorporating New Technologies into Routine Patient Care: A Focus on Evidence That Proves Value By Ronald Piana

eading off the Presidential Symposium at the 52nd ASTRO Annual Meeting, ASTRO President-Elect Michael L. Steinberg, MD, of David Geffen School of Medicine at UCLA, gave a presentation titled “How Do Technologies Emerge and How Are They Reimbursed?” Dr. Steinberg set the table for his lecture with a few facts about the U.S. health-care system. “It’s probably no surprise to this audience that the United States spends twice as much on health care as other developed countries, and our expenditures are quickly approaching 20% of our national gross domestic product. On top of that, the number of uninsured Americans continues to rise.” Dr. Steinberg ran down a list of “the usual suspects” in the blame game of rising health-care costs: bureaucratic inefficiencies, defensive medicine, perverse fee-for-service incentives, our aging population, and fraud and abuse. He pointed out that cost-control strategies and financing mechanisms such as Medicare’s sustainable growth rate (SGR) have not worked because they have not addressed a problem that is further upstream. “The real culprit in unsustainable costs is the rapid and uncontrolled demand for the introduction of new treatments before their effectiveness, cost, and comparative value are satisfactorily evaluated,” Dr. Steinberg commented. According to Dr. Steinberg, health economic studies have shown that technology is the major contributing factor in the health-care budget explosion, with 40% to 60% of rising costs attributable to the introduction of new technologies.

Reform and Comparative Effectiveness Research The Affordable Care Act of 2010 attempts, at least theoretically, to address the issue of rising costs from the evidence and value side. “The Obama Administration demanded reforms to make care more affordable for all U.S. citizens and demanded that we introduce methodologies to compare payment systems, delivery systems, and disease management approaches.

Enter a new era of comparative effectiveness research,” Dr. Steinberg explained.

in turn affect the practice of oncology? “Possibly, with this information an insurance company would cover brachytherapy, maybe allow IMRT with a copayment, and proton therapy might be noncovered or relegated to reference pricing, which relates to participation and trial,” Dr. Steinberg said.

The Political Reality Michael L. Steinberg, MD

Comparative effectiveness research is currently experiencing growing pains, due in part because it is a difficult-to-explain concept that opponents unfairly but effectively link to rationing of care. Nevertheless, the concept of evidence-based value is rooted into the policy of health care and will undoubtedly affect the way cancer care is delivered. Dr. Steinberg said that comparative effectiveness research utilizes systematic evidence review of prospective trials and observational data such as registries and then applies decision analysis and cost-effectiveness analysis to make its determinations.

Comparative Effectiveness Research and Coverage As an example of comparative effectiveness research in action, Dr. Steinberg used recent data from the Institute for Clinical and Economic Review (ICER), a Boston-based comparative effectiveness research facility. “Researchers at ICER take and consider net health and comparative value and then they evaluate the confidence in the information that they have to ensure that it’s valid. Using this methodology, researchers looked at proton-beam therapy vs brachytherapy in the treatment of prostate cancer,” Dr. Steinberg commented. ICER researchers found that although the clinical outcome was similar between both therapies, the cost was significantly higher in proton-beam therapy. So, what does this information mean in the crucial issue of how comparative effectiveness research can be used to address coverage questions, which

“A centerpiece of the Affordable Care Act (ACA) is the Patient-Centered Outcomes Research Institute (PCORI), which is basically a comparative effectiveness research institute. But interestingly, ACA prohibits the PCORI or HHS from mandating coverage based on its findings,” Dr. Steinberg said. After clarifying some of the other seemingly contradictory aspects of ACA’s cost-control proposals, Dr. Steinberg noted that the various comparative effectiveness research and evidence-based coverage determination vehicles are still theoretical pieces of the government’s reform initiative. Nevertheless, he said, major change is on the way, and oncology is in its crosshairs. Dr. Steinberg offered a succinct reason for oncology’s high profile in health-care reform. “Inflation-adjusted direct medical spending attributed

ment alone, for that single CPT code,” said Dr. Steinberg. According to Dr. Steinberg, the uncontrolled increase in IMRT services was fueled by high reimbursement rates as well as clinician, vendor, and patient enthusiasm about the possible benefits of IMRT over other prostate cancer therapies. “When insurance companies tried to curb the dramatic rise in utilization and cost, we made the ‘sharper knife’ argument, but it was not accepted because physical differences of dose distribution are not health outcomes,” he added. The bottom line: “There was little evidence developed to support the widespread use of IMRT—certainly not level 1 evidence,” Dr. Steinberg said. Then he paused and added, “Now, our elephant in the room is protonbeam therapy.”

Conclusion Dr. Steinberg defined the problem for radiation oncology moving forward: “The process of incorporating new technology into routine patient care, which is already complicated, will become even more challenging as increasing pressure for cost control mechanisms will demand higher levels of proof of cost-effectiveness.”

The real culprit in unsustainable costs is the rapid and uncontrolled demand for the introduction of new treatments before their effectiveness, cost, and comparative value are satisfactorily evaluated. to oncology has shown a 50% higher growth compared with the rest of health care over the past 20 years. If you feel you’re a target now, it is only going to get worse,” Dr. Steinberg stressed. But applying evidence and value to treatment and coverage decisions is not a zero-sum game. “The case in point for radiation oncology is intensity-modulated radiotherapy (IMRT), a salient example of rapid increase in utilization and cost to the system, spending more than $1 billion per year in Medicare reimburse-

He offered a proposal: “Coverage should be linked to data collection for new technologies and vendors, and payers and providers should participate in and support evidence development. We should build on the concept of ‘potential’ medical benefit—in other words, adequate initial evidence of benefit and value developed from appropriately designed early trials or prospective registries. And last, payors should cover promising, important, potentially high-value new treatments in the context of very careful investigation.”

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Opinion

Congress and the ‘Doctor Fix’: Looking Back, Looking Ahead By Nora Janjan, MD, MPSA, MBA, and John Goodman, PhD

ctions speak louder than words. After some complex political wrangling, Congress passed healthcare reform legislation, the Patient Protection and Affordable Care Act, which was signed into law on March 23, 2010. By passing a 1-year extension of current physician reimbursement rates, Congress did not show the same political will to address the sustainable growth rate (SGR) formula that has been a chronic problem for physician reimbursement with Medicare and TRICARE. If physician reimbursement took a back seat during the 2010 election cycle, what can be expected when it comes up again during the 2012 presidential election year, especially with the ongoing debates about the deficit and the health-care reform legislation?

History of SGR Reform Facing a 21.3% cut in physician reimbursement in January 2010, SGR reform first surfaced in the aptly numbered Senate Bill (S.B.) 1776, on October 21, 2009. The Senate fell 13 votes short of eliminating the SGR formula and freezing physician payments for 10 years (yea, 47; nay, 53). Although not indexed to future inflation, physicians were willing to trade a decade of uncertainty with inflation for the uncertainties in Congressional inaction about the SGR formula. Dr. Janjan is Senior Fellow and Dr. Goodman is President and CEO, National Center for Policy Analysis, a nonprofit conservative think tank headquartered in Dallas. We encourage readers of The ASCO Post to share your thoughts and/or comments about Medicare physician reimbursement, the Patient Protection and Affordable Care Act, and other issues relevant to health-care policy. Write to Editor@ASCOPost. com. Responses will be published in future issues of The ASCO Post.

What became known as the “Doc Fix,” S.B. 1776 failed to pass because the bill was not compliant with the previously passed Congressional “payas-you-go” provisions. Spending cuts were not included in S.B. 1776 to offset the cost of avoiding the 21.2% cuts in physician reimbursement. Unlike the party-line Senate passage of the Patient Protection and Affordable Care Act on December 24, 2009, 12 Democratic Senators voted against S.B. 1776. Apparently the old adage of “you get your votes before you count your votes” wasn’t sufficiently important in this case to ensure the bill’s passage. The House of Representatives passed the Medicare Physician Payment Reform Act of 2009 (H.R. 3961) on November 19, 2009. Busy with the health-care reform legislation, the Senate did not take up the bill. Instead, a 60-day extension of the 2009 conversion factor, expiring on March 1, 2010, was included in a Department of Defense appropriations bill that was passed at the end of December 2010.

Repeatedly Extended Deadlines In early February 2010, rumors were circulating that another shortterm patch was planned rather than pursuit of a long-term fix for the SGR issue. However, the deadline on March 1 to avert physician reimbursement cuts was missed again. In response, the Centers for Medicare and Medicaid Services (CMS) notified contractors, effective March 1, to hold Medicare physician claims for 10 business days. On the March 1 deadline, the House passed H.R. 4691, which extended a wide range of expiring programs in addition to postponing the SGR cuts until April 1, 2010. On March 2, 2010, the Senate passed H.R. 4691. In mid-March, with the clock ticking, H.R. 4851 was passed to extend the deadline for the Doc Fix to May 1, 2010. The Senate, however, was unable to pass this bill before adjourning for the spring recess. On April 1, 2010, the 21.3% Medicare physician pay cut was scheduled to go into effect. Once again, these pay cuts were delayed 10 business days by CMS. On April 15, 3 days after returning from spring recess, the Senate passed H.R. 4851, which retroactively reinstated physician payments for Medicare patients in April, postponing the 21.3% pay cut until

June 1, 2010. The Senate SGR proposal was then incorporated into H.R. 4213—the American Jobs and Closing Tax Loopholes Act of 2010—just before the Memorial Day holiday. Congress once again failed to act before the deadline. For the third time in 5 months, CMS held claims an additional 10 business days, until June 14, 2010, to allow Congress another opportunity to consider the SGR issue. Given that half of 2010 had already passed, physicians realized that the cuts scheduled for January 2011 would increase to 32%. On June 18, 2010, the Senate passed an amended version of H.R. 3962—the Preservation of Access to Care for Medicare Beneficiaries and Pension Relief Act of 2010—by unanimous consent. The legislation provided a 2.2% Medicare physician payment update from June 1 to November 30, a month after the impending midterm elections and right around the Thanksgiving holiday recess. Following House passage of the reconciliation bill, the Act was signed into law on June 25, 2010.

Program eligibility under the Patient Protection and Affordable Care Act; and (3) insurance subsidies provided through the exchanges under the Act. This expansion in the scope and cost of federal health-care programs was apparently not offset, as purported during the health-care reform debate, by a $500 billion reduction in Medicare benefits over the next decade. As expected, the prospects of repealing the SGR formula after the November 2010 midterm elections proved unlikely, given the precipitous upward projections of health-care costs by the Congressional Budget Office under the Patient Protection and Affordable Care Act. That Office’s recent health-care cost projections, which greatly exceeded the $900 billion estimate during the health-care debate, are particularly discouraging with the $500 billion reduction in Medicare benefits that underwrote over half of the estimated cost of the Act during the health-care debate. Cutting physician reimbursement approximately 30% under Medicare and TRICARE appeared to be an easy means of re-

The immediate message from this history is that physicians are not a priority. Health-care Spending Unsustainable Three months after the passage of the Patient Protection and Affordable Care Act, Douglas Elmendorf, Director of the Congressional Budget Office, reported to Congress on June 30, 2010, that federal spending on health care was unsustainable. Two factors—the aging population and the rapid growth of health-care costs per capita—accounted for the projected increases in federal health-care spending. Importantly, the healthcare reform legislation “will cause major changes in the components of federal spending on health care,” Mr. Elmendorf said. Federal spending for Medicare would roughly double as a share of gross domestic product over the next 25 years, from 5.5% to more than 10% in 2035, because of (1) the 7% growth of the retirement age segment from 13% to 20% of the population; (2) significant expansions in Medicaid and the Children’s Health Insurance

ducing the cost of health-care reform, but Congress delayed resolution of the SGR issue another year.

Other Concerns Also discouraging was the failure of the Patient Protection and Affordable Care Act to address tort reform, given that the Congressional Budget Office projected such measures could have saved $54 billion in health-care costs. According to Former Democratic National Committee Chair Dr. Howard Dean, the Congress that drafted the health-care reform legislation failed to include tort reform under the Act because of the fear of “taking on” the trial lawyers. Obviously, Congress doesn’t share the same concerns about physicians or Medicare recipients. More worrisome is the future reimbursement of physician services as the percentage of patients under federal programs continues to increase and physician demographics change. If reimbursement falls precipitously in a

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Opinion

year, many physicians may either retire or refuse to see Medicare patients, contributing to a shortage of physicians. Under the Patient Protection and Affordable Care Act, the government also assumed control of all student loan programs. Students can repay their government-backed student loans if, as new physicians, they take low-wage jobs in government facilities, thereby having their monthly payments capped at 10% of income instead of the current 15%. After 20 years, any debts that remain would be cancelled. Middle-aged physicians, who on average carry $200,000 of educational debt at the higher rate, will be particularly affected if physician reimbursement is allowed to decline significantly. The middle-aged physician typically also has additional pressures of a house mortgage and children and is financially incapable of retiring from medicine. The 111th Congress, which had unstoppable majorities in both the House and Senate, did not address the SGR issue within the more than 2,000 pages of the Patient Protection and Affordable Care Act. Yet again, a band-aid was placed on the pending reimbursement crisis for physicians who care for the elderly and military families under government programs. The immediate message from this history is that physicians are not a priority. The 1-year extension of physician

reimbursement rates may not be the last, as one more 1-year extension should be expected in 2012 (during the presidential election year). More concerning for the long term, however, is the transformation of the health-care system under the healthcare reform legislation that becomes fully implemented in 2013–2014. This

transformation may be so profound that the SGR and the current system of physician reimbursement become irrelevant. With looming federal deficits, the $500 billion cuts in Medicare, and health-care costs burgeoning from the new regulations, changes in physician reimbursement cannot be positive. Time will tell.

See pages 1, 24, and 35 for more on health-care policy in this issue of

The ASCO Post

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Letters to the Editor

Bevacizumab and the FDA

‘Autopilot’ Screening continued from page 31

3. Nelson HD, Tyne K, Naik A, et al: Screening for breast cancer: An update for the U.S. Preventive Services Task Force. Ann Intern Med 10:727-737, 2009. 4. U. S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 149:185-191, 2008.

5. Earle CC, Landrum MB, Souza JM, et al: Aggressiveness of cancer care near the end of life: Is it a quality-of-care issue? J Clin Oncol 26:3860-3866, 2008. 6. Institute of Medicine and National Research Council of the National Academies: From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC, National Academies Press, 2006.

Induction Therapy for Head and Neck Cancer: No Longer an ‘Experimental’ Option

read with particular interest the TAP Caucus article on induction chemotherapy for head and neck cancer (The ASCO Post 2[1]:25, 2011). As a practicing radiation oncologist with 25 years’ experience, I have personally observed the advantages that induction chemotherapy can have for patients with advanced head and neck cancers. First is the reduction in tumor volume for subsequent treatment planning, in the hope of ameliorating treatment complications. Second is the reduction in tumor activity on restaging PET scans, both for prognostic purposes and to allow for proper consolidative treatment options. Third is the rapid alleviation of often-significant patient symptoms, especially localized pain, radiating neuropathies, and necrotic byproducts. In the TAP Caucus discussion, Dr. Marshall Posner aptly describes appropriate patient selection for induction; his guidelines are similar to those I have used for more than a decade. Dr. William Lydiatt, however, expresses psychological concerns. In my experience, most patients achieving substantial tumor responses with the induction regimen are buoyed by their clinical improvement. They and their supporting caregivers become less disheartened by the diagnosis and actually express an increased interest in continuing aggressive management, ie, a subsequent course of combined chemoradiotherapy. I also believe one important point

e are writing in regard to a recent story published in The ASCO Post in which opinions were expressed by various oncology leaders on the FDA’s decision to begin the process to remove the breast cancer indication for bevacizumab (Avastin) (The ASCO Post 2[2]:3, 2011). We believe that the publication of such opinions in any oncology forum should be accompanied by conflict of interest statements from the respective individuals. Parenthetically, we have no conflict of interest in this matter. —H. Ian Robins, MD, PhD Professor of Medicine, Human Oncology and Neurology Noelle K. LoConte, MD Assistant Professor of Medicine Carbone Cancer Center University of Wisconsin Madison, Wisconsin

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was overlooked: Induction chemotherapy with cisplatin/fluorouracil (PF) results in a well-documented decreased incidence of metastatic (especially pulmonary) disease. The logic presented by Dr. Posner suggests that if TPF (docetaxel, cisplatin, fluorouracil) is superior to PF, then it might also reduce metastatic risks. Further randomized, controlled trials in this setting are problematic, with accrual goals becoming increasingly difficult as treating clinicians personally observe the advantages of induction. This is not an “unfortunate” outcome, as described by Dr. Lydiatt. Induction therapy has been studied for many years and could be for many more to come, but the endpoint should be local control, not survival. Too many patients with advanced head and neck cancer have far too many lifecompromising comorbidities to reasonably expect a statistically significant improvement in survival from a modality essentially designed to increase tumor responses. Therefore, I must agree with Dr. Posner that induction therapy is not “experimental” and should not be limited to formal trials. It should be considered another accepted option for clinically suitable, poorer-prognosis, nonsurgical, and otherwise treatable advanced head and neck cancers. — Theodore E. Yaeger, MD, FACRO, FRSM Associate Professor, Radiation Oncology Wake Forest University School of Medicine Winston-Salem, North Carolina

Editor’s note: We agree and regret this information was not included with the original story. Disclosure information is as follows: Gabriel Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center attended the ODAC meeting in July 2010 as a consultant to Genentech and made a presentation in support of preserving and expanding the indications for bevacizumab. Dr. Hortobagyi indicated that “For this meeting [ODAC, July 20, 2010], the company [Genentech] provided my travel and lodging expenses. I have otherwise no financial interest in the outcome of this meeting.” Sandra M. Swain, MD, of Washington Cancer Institute, Washington, DC, disclosed receipt of research funding from Genentech and participation on an Advisory Board for Genentech/Roche (uncompensated). Robert Carlson, MD, of Stanford University, has served as an advisor/ consultant to the Genentech/Roche (uncompensated). Stanford University received grant support from Genentech to support clinical trial participation for which Dr. Carlson was a principal investigator.

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

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

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).

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Use your smartphone to view the original article “Should Induction Chemotherapy Be Considered Standard of Care for Local-Regional Head and Neck Cancer?” published in The ASCO Post, January 1, 2011. © Drew Dernavich/The New Yorker Collection/www.cartoonbank.com

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

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

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

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

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

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

To reach beyond convention…

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

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

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