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ASCO 2011 3, 6, 10, 13, 14

FDA update 18, 19, 26, 27

Suicide risk in patients with cancer 31

AUGUST 15, 2011 ASCOPost.com

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

Expert’s Corner

VOLUME 2, ISSUE 12

Acting on Fear

A Landmark Lung Screening Trial: What Does It Mean for Clinicians and Their Patients? By Ronald Piana

he NCI-funded NaNational Lung Screening Trial tional Lung Screening Trial (NLST), pub■■ The NLST reported 20% fewer lung cancer deaths in those screened with lished recently in The New low-dose helical CT compared with chest x-rays. England Journal of Medi1 ■ ■ NLST participants included 53,454 individuals between 55 and 74 years at cine, was heralded as a randomization with a history of at least 30 pack-years of cigarette smoking; landmark study in lung if former smokers, participants had quit within the previous 15 years. cancer detection. This ■■ All-cause mortality (deaths due to any factor, including lung cancer) in study is the first comprethe NLST was 7% lower in those screened with low-dose helical CT. hensive clinical trial to find that screening highCT in lung cancer screening has been vigorously chalrisk individuals with lowlenged. What was your general sense of the issue going dose CT reduces lung cancer deaths by 20% cominto the trial? pared with chest x-ray. One of the trial’s co-leaders, My history with this study dates back to the Christine Berg, MD, spoke with The ASCO Post fall of 1998, when I learned of the discussion at about how the data answer critics the Varese Conference for lung cancer screening of the study. addressing the potential of low-dose helical CT Early Thoughts on Lung for early detection. The preliminary information Cancer Screening indicated that low-dose helical CT screening had SEE PAGE 45 The value of low-dose helical continued on page 4 Perspective

Rising Costs of Cancer Care: It’s More Than Drugs By Ronald Piana

ll parties—the government, payers, and consumers—agree that, left unchecked, rising health-care costs will eventually hamstring vital portions of our delivery system. For example, Medicare, which covers more than 50% of the nation’s patients with cancer, is marching headlong toward insolvency. Largely due to sticker-shock prices of some newer therapeutics, oncology is in the spotlight of the health-care spending debate. In an occasional series of articles, The ASCO Post will look at oncology costs and how to reduce spending without hampering the quality of care.

Costs and Value Put simply, health-care spending is calculated as units of care multiplied by their respective costs. While numerous studies indicate that more services do not necessarily result in better outcomes, determining the true clinical value of health services—especially in a complex disease like cancer—is where much of today’s debate begins and ends. While it is true that oncology costs are rising

at an unsustainable rate, it is important to weigh costs against outcomes. For instance, a study led by Aman Buzdar, MD, FACP, Professor of Breast Medical Oncology, The University of Texas MD Anderson Cancer Aman Buzdar, MD, FACP Center, Houston, looked at survival data for nearly 57,000 patients with breast cancer from 1944 to 2004 and calculated 10-year survival rates. Dramatic improvements were seen in local, regional, and metastatic disease. Among women with regional disease from 1944 to 1954, only 16.2% of women were still alive 10 years later, compared with 74% in the most recent decade analyzed, from 1995 to 2004. Naturally, improvements over the past decades in breast cancer survival are due to a number of factors,

By Deb Stewart, BSN, RN, CBCN, BPNC-IC As told to Jo Cavallo

hen I was first diagnosed with breast cancer in 1979 there was no global movement to raise awareness of the disease, there were no pink ribbon pins to show support, and there was no Internet with which to search for information. My doctor gave me the news on a Friday night, and the following Monday I had a mastectomy on my left breast. Everything was urgent. I had this cancer and it had to be treated right away. I was just 25 and I didn’t understand a lot of what was going on, even though I was a nurse. I didn’t have anything about my diagnosis in writing, and I couldn’t find anyone my age to talk to about having breast cancer. I just acted on fear. continued on page 2

Ms. Stewart is a nurse and breast health educator at the Johns Hopkins Avon Foundation Breast Center in Baltimore.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 ASCO Annual Meeting Breast Cancer �� 3 Multiple Myeloma �� 6 Ovarian Cancer �� 10 Prostate Cancer �� 13 Hepatocellular Carcinoma �� 14 Direct from ASCO �� 20 Psychosocial Oncology �� 31 Integrative Oncology �� 39 TAP Caucus �� 42

continued on page 28

A Harborside Press® Publication

The ASCO Post | AUGUST 15, 2011

PAGE 2

Patient’s Corner Survivorship

Acting on Fear continued from page 1

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

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

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 Louis B. Harrison, MD Continuum Cancer Centers of New York 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

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 William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of 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, 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, Jo Cavallo, Margot J. Fromer, Alice Goodman,

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Twenty years later, I had a second breast cancer diagnosis, but this time I was able to gather information. I took my time, I got a second opinion, and I weighed my options. I decided to have a mastectomy instead of a lumpectomy because I felt that having had cancer before and having it now, I would likely have it again. I took control. What has been such a privilege for me as a patient navigator is to be able to interact with patients on a daily basis, to listen to their fears and assess their stress level. I can also relate to their emotional pain. I remember a patient saying to me, ‘You have no idea of what I’m going through.’ I explained that even though everyone’s experience with cancer is different, I, too, am a breast cancer survivor and I understand what fear feels like. I understand what grief feels like and what it feels like to lose a breast and miss it. We were able to connect through our shared experiences of grief and loss.

Developing a Survivors’ Care Plan In my professional experience the biggest fear that breast cancer survivors have is of recurrence, followed by uncertainty and death. They also have ongoing health concerns about the long-term side effects of treatment. Body image and sexual dysfunction are another two big issues for breast cancer survivors, yet doctors rarely raise these problems with their patients, and many women are often reluctant to bring them up themselves. Encouraging women to be more open about their concerns and to ask questions would go a long way in alleviating some of the challenges associated with a cancer diagnosis. Having a universally adopted survivors’ care plan following cancer treatment would also greatly improve both the emotional and physical lives

After Cancer Treatment:

What’s Next?

Once their treatment is over, cancer survivors should receive direction about specific followup plans, detailing how often they need to be seen by a physician; for how long; and by whom. Questions for discussion include:

■■ Should they continue to see

their oncologist or should their primary care physician look after them?

■■ What long-term treatment

after effects should they expect, and what health screenings should they have and when?

■■ If survivors are still having

emotional difficulty coping with their cancer diagnosis, should they be referred to a support group and/or to a mental health professional for treatment?

of cancer survivors. After cancer treatment is completed, survivors should be given explicit information about their follow-up care (see box).

Loss and Change When I was recovering from my first bout with breast cancer, I couldn’t stop thinking about what I went through, and then one day I woke up and I didn’t think about breast cancer until lunchtime and I thought, “This is a good day.” In addition to fear, feelings of loss are always present in breast cancer survivors. It is not just the sense of loss over a missing breast, however, it’s a lot of things. It’s losing your self-identity and thinking you are no longer who you were. As medical professionals, we have to acknowledge the losses and changes patients face and guide them in their transition through the stages of treatment and beyond.

■

Erratum Marvin J. Stone, MD, is Director of Oncology Medical Education, Quality & Safety, and Associate Director of the Baylor Charles A. Sammons Cancer Center, Dallas. In the July 1, 2011, issue of The ASCO Post, the affiliation published with Dr. Stone’s byline was incorrect. We apologize for this error. To view the full commentary by Dr. Stone, “On William Osler: the Old Art and the New Science,” visit http://www.ascopost.com/articles/july-1-2011/onwilliam-osler-the-old-art-and-the-new-science/.

ASCOPost.com | AUGUST 15, 2011

PAGE 3

2011 ASCO Annual Meeting Patients with Early Breast Cancer Benefit from Regional Nodal Irradiation Local and distant recurrences were significantly reduced. By Caroline Helwick

indings from a Canadian study presented at the 2011 ASCO Annual Meeting may expand the pool of patients with lymph node–positive breast cancer offered extended-field irradiation.1

Timothy Whelan, MD

“Results from MA.20 suggest that all women with node-positive disease following breast-conserving surgery be offered regional node irradiation provided they are made aware of the associated toxicities,” said Timothy Whelan, MD, of McMaster University and the Juravinski Cancer Centre in Hamilton, Ontario.

Study Rationale American Society for Radiation Oncology (ASTRO) and ASCO guidelines recommend locoregional radiation following mastectomy for women with tumors > 5 cm or more than three positive axillary lymph nodes. The benefit in women with one to three positive nodes and in those treated with breast-conserving surgery has been unclear. Following breast-conserving surgery, women normally receive whole breast irradiation, which may involve radiation to the lower axilla and some of the internal mammary nodes. Regional nodal irradiation to the internal mammary, supraclavicular, and high axillary lymph nodes may provide added benefits to whole breast irradiation, but can be more toxic. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.20 trial evaluated the benefit of regional nodal irradiation in addition to whole breast irradiation after breast-conserving sur-

Expert Point of View

homas Buchholz, MD, of the University of Texas MD Anderson Cancer Center, Houston, commented that the “well conducted and analyzed” MA.20 study addressed a “simple clinically relevant question,” and the findings “add to the conclusive evidence that radiation eradication of local-regional microscopic disease reduces subsequent distant metastases and can improve survival.” He said the locoregional results are not surprising, as outcomes were consistent with expectations. “A 5.5% locoregional recurrence rate at 5 years is expected, and the 2.3% absolute improvement is reasonable,” he noted. “By itself, the locoregional Thomas Buchholz, MD benefit and risks are equal.” But he found the 4.3% absolute reduction (from 12.7% to 8.4%) in distant metastases “surprising,” and suggested that based on these data, “the benefits now clearly outweigh the risks.” While surprising, there are a number of possible reasons why protection from distant metastases was greater than for locoregional recurrences, but what seems certain is that lymph node risk is heterogeneous within the subset of patients with one to three positive nodes, Dr. Buchholz offered. “I agree with the investigators’ conclusions,” he said. “We should offer regional nodal irradiation for higher-risk patients with one to three positive lymph nodes, but we should await additional data for low-risk patients with one to three positive nodes.”

■

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

Regional Irradiation in Early Breast Cancer ■■ In the NCIC-CTG MA.20 trial, regional nodal irradiation, added to whole breast irradiation following breast-conserving surgery, improved disease-free survival, with a trend toward improved overall survival.

■■ Locoregional recurrences were reduced by a relative 42%, and distant recurrences, by 36%.

■■ The additional radiation was associated with more lymphedema, pneumonitis, and radiation dermatitis.

gery for women with node-positive and high-risk node-negative breast cancer. The latter group included women with tumors ≥ 5 cm, and those with tumors ≥ 2 cm and fewer than 10 axillary nodes removed who were estrogen receptor–negative, had histologic grade 3 tumors, or had lymphovascular invasion. The study accrued patients from March 2000 to March 2007. After the March 2011 interim analysis, the Data Safety and Monitoring Committee recommended that the results be released. The study randomly assigned 1,832 patients to receive whole breast irradiation (50 Gy in 25 fractions, with boost irradiation of 10 Gy in 5 fractions permitted) or whole breast plus regional nodal irradiation (45 Gy in 25 fractions).

Nearly a 6% Absolute Difference in Events At a median follow-up of 62 months, the addition of regional nodal irradiation to whole breast irradiation significantly improved disease-free survival, preventing both locoregional and distant recurrences. There was also a trend toward improved overall survival, but this was not statistically significant, Dr. Whelan reported. The 5-year disease-free survival rate was 84.0% in the whole breast irradiation arm and 89.7% in the whole breast/regional nodal irradiation arm, based on 144 and 102 events (recurrence, contralateral breast cancer, or breast cancer death), respectively. This represented a 33% reduction in events that was highly significant (P = .003).

Locoregional disease-free survival was 94.5% with whole breast irradiation and 96.8% with whole breast/ regional nodal irradiation, for a 42% SEE PAGE 45 reduction in risk (P = .02). Two-thirds of regional recurrences were in the axillae. More unexpected was the protection achieved against distant recurrences, with the distant disease-free survival rate being 87.0% with whole breast irradiation and 92.4% with whole breast/regional nodal irradiation, a 36% reduction in risk (P = .002), he reported. Five-year overall survival rates were 90.7% and 92.3%, respectively, based on 96 deaths in the whole breast irradiation arm and 74 in the whole breast/ regional nodal irradiation arm—a 23% reduction in mortality (P = .07). The trade-off for this disease-free survival improvement was more radiation dermatitis with the regional nodal irradiation addition (50% vs 40%; P < .001), pneumonitis (1.3% vs 0.2%; P = .01), and lymphedema (7% vs 4%; P = .004). While cosmetic outcomes were similar at 3 years, more of the regional nodal irradiation group considered the outcome “fair or poor” at 5 years (36% vs 29%; P = .047).

■

Disclosure: Dr. Whelan reported no potential conflicts of interest.

Reference 1. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. 2011 ASCO Annual Meeting. Abstract LBA1003. Presented June 6, 2011.

The ASCO Post | AUGUST 15, 2011

PAGE 4

Expert’s Corner Cancer Screening

National Lung Screening Trial continued from page 1

if the results had proved no benefit for low-dose helical CT, it still would have been an important outcome because we would have had to go back to the drawing board and examine why this promising screening approach did not work. That’s how scientific discovery works.

promise in terms of detecting more lung cancers than chest x-ray. Then Dr. Claudia Henschke’s major 1999 paper in The Lancet received positive interest,2 and its report of earlier-stage lung cancers detected with low-dose helical CT helped launch a Design and Data vigorous debate as to next steps. What gave this trial solid answers? At the time, much of the debate The NCI-funded study was decentered on three opinions: One signed and conducted by the Nationgroup thought that evidence for al Lung Screening Trial Research low-dose helical CT screening was Team, a joint effort of my group, the so powerful that we didn’t need a Lung Screening Study, under contrial and we should move forward tract from the Division of Cancer with lung cancer screening. AnPrevention, and a group other opinion was that from the American Colalthough the prelimilege of Radiology Imagnary information looked ing Network (ACRIN), good, we have had many a Cooperative Group, situations in oncology in funded by the Division which the first informaof Cancer Treatment and tion was promising but Diagnosis. We enrolled a randomized, well-pow53,454 individuals who ered trial ends up showwere at high risk but ing no benefit. Then Christine Berg, MD healthy enough to unthere were the true skepdergo surgery if needed. tics who thought this So it was a very large sample of the complex, aggressive disease could high-risk population. If it had been not be detected early enough to afa smaller study with a few thousand fect its dismal natural history. They participants it would not have been reasoned that the positive benefits statistically robust. NLST provided would not be offset by the complia valid scientific answer to the quescations of surgery, radiation, and tion we asked: Does screening with other interventions with risk. low-dose helical CT confer a signifiThe scientific community could cant reduction in lung cancer mornot reach a consensus on this istality compared with chest x-ray? sue. However, the gold standard in answering clinical questions of this Have you looked at harms in relaimportance has been the randomtion to benefits data? ized controlled trial. So despite the Yes. In our primary manuscript, many critics, conducting the NLST we produced data delineating and was the right decision. In fact, even

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.

A Clinician Weighs In on the National Lung Screening Trial By Ramaswamy Govindan, MD

Ramaswamy Govindan, MD

he results of the National Lung Screening Trial (NLST) will have important implications for practicing oncologists if low-dose helical CT screening is used routinely in the clinic. First, we will begin to find many more small tumors than we do now. This will pose new sets of questions for research: What should be the optimal strategy to manage these tumors? Should we be considering lesser resection for very small tumors instead of the conventional lobectomy? Will stereotactic radiotherapy be a preferable option to

surgery for these tumors? Second, are these small tumors detected through the CT screening process in asymptomatic individuals biologically different from the tumors we currently see when patients present with symptoms?

Fodder for Future Research NLST is just the beginning. There are 1 billion smokers (current and former) in the world today. It is simply unrealistic to screen all smokers for lung cancer. The cost issues and logistics are not trivial. The important fact to keep in mind is that 1 in 10 smokers die of lung cancer. Is there a way to identify the population predisposed to developing lung cancer so that CT screening can focus on the really enriched population at risk? Recent advances in genomics give us hope that one day a simple and inexpensive molecular screening assay will identify the at-risk population for yearly CT screening. Like all good studies, NLST data not only advance the practice but also provide fodder for future research. Disclosure: Dr. Govindan reported no potential conflicts of interest.

■

Dr. Govindan is Professor of Medicine, and Co-Director, Section of Medical Oncology, Washington University School of Medicine, St Louis.

categorizing the severity of the adverse events. The Data and Safety Monitoring Board was regularly reviewing the data, and when we looked at the overall benefit for lung cancer mortality it included screen-

ing-associated harms. The overall assessment was a net benefit.

Where Do We Go From Here? Although NCI does not offer advice continued on page 7

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.

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PAGE 6

2011 ASCO Annual Meeting Hematology

Second Primary Malignancies Explored in Multiple Myeloma By Alice Goodman

hree randomized controlled trials presented at the 2010 Annual Meeting of the American Society of Hematology (ASH) suggested that treating multiple myeloma with lenalidomide (Revlimid) increased the risk of second primary malignancies; of particular concern is transformation to acute myeloid leukemia or myelodysplastic syndromes.1-3 At the ASCO Annual Meeting in June, additional studies that explored this issue suggested that the risk of second primary malignancies in this setting is low and the benefits of lenalidomide seem to outweigh the risks, but a number of questions remain unresolved. “Currently, we lack clear answers as to which patients will develop second primary malignancies after myeloma,” said Ola Landgren, MD, PhD, Chief of the Multiple Myeloma Section at NCI and formal discussant of the three papers at the ASCO meeting. “We lack SEE PAGE 45 clear answers due to small numbers of patients in these studies and limitations of the study designs. We have to discuss benefits vs risks with patients, but there are no clear data to guide us at this time. A concerted effort is needed to characterize the molecular features of patients who develop second primary malignancies after myeloma.”

MM-015 Study MM-015 was one of the three studies at ASH raising concern about second primary malignancies.3 At ASCO, an updated analysis related to second

primary malignancies was presented. MM-015 enrolled 459 newly diagnosed, transplant-ineligible patients with a median age of about 71 years at 82 centers in Europe, Australia, and Israel.4 Patients with newly diagnosed multiple myeloma were randomly assigned to (1) melphalan/prednisone/ lenalidomide followed by lenalidomide maintenance, or (2) melphalan/ prednisone/lenalidomide, or (3) melphalan/prednisone and treated until disease progression, at which point they all received lenalidomide plus dexamethasone.

Antonio Palumbo, MD

The continuous lenalidomide arm (arm 1) achieved a significant and “unprecedented” improvement in progression-free survival (median = 31 vs 13 months, respectively; 60% reduced risk of progression; P < .001). Progression-free survival was even more impressive in patients aged 65 to 75 years (69% reduced risk of progression; P < .001). However, no difference in 5-year survival was seen among the three arms. Presenting author of this paper, Antonio Palumbo, MD, University of Torino, Italy, said that with longer follow-up, a survival difference may emerge.

Lenalidomide in Multiple Myeloma ■■ Based on small numbers, an increase in second malignancies has been observed in the lenalidomide arm of randomized trials of multiple myeloma patients treated with maintenance lenalidomide; the evidence for causation is inconclusive.

■■ Lenalidomide achieves statistically significantly longer progression-

free survival, and one study has found a statistically significant overall survival benefit.

■■ The benefits of treatment should be balanced against the risk of second primary malignancies and leukemic transformation.

■■ Physicians need to discuss the risks with their patients, although the data are currently not clear.

■■ More research is needed to characterize the molecular features of

myeloma patients who develop second primary malignancies after treatment with lenalidomide.

Expert Point of View

ormal discussant Ola Landgren, MD, PhD, Chief of the Multiple Myeloma Section at NCI, had some additional comments about the 2011 ASCO presentations on second primary malignancies in lenalidomide-treated patients.1 He said that the reporting of second primaries has several limitations that patients and doctors need to be aware of. For example, these randomized studies were designed to evaluate responses and survival rates between the study arms. Thus, the sample sizes are Ola Landgren, MD, PhD too small to allow a careful characterization of the risk—and underlying mechanisms—of second primary malignancies. An alternative strategy to increase the sample size could be to pool several clinical studies and then do a retrospective collection of second primary malignancies. However, analysis-based retrospective data will inherently underestimate their true incidence. On a general note, when interpreting data on second primary malignancies, and when comparing results from different studies, one has to be cautious. For example, differences in study design, including follow-up time, sample size, controls, and quality of data, will always influence the results. Also, variations in survival differences between study arms play a role. Most likely, several factors play a role in the development of second primary malignancies, including host-related, treatment-related, myeloma-related, and behavioral factors. An important future research focus should be to determine the relative roles of each of these factors to elucidate the mechanisms involved, as well as to characterize the molecular features of patients who develop second malignancies following myeloma.

■

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

Reference 1. Landgren O: Secondary malignancies following multiple myeloma. 2011 ASCO Annual Meeting. Presented June 8, 2011.

At a median follow-up of 30 months, the number of invasive second primary malignancies was 12 (7 hematologic malignancies, 5 solid tumors) in the lenalidomide maintenance arm of the trial, 9 (5 hematologic malignancies, 4 solid tumors) in the melphalan/prednisone/lenalidomide arm, and 4 (1 hematologic malignancy, 3 solid tumors) in the melphalan/ prednisone arm. Dr. Palumbo emphasized that the risk of second primary malignancies, although increased by the concomitant use of lenalidomide and melphalan, is low and that the benefit-risk profile strongly favors the use of continuous lenalidomide for newly diagnosed patients.

BiRD Study The BiRD study also explored this issue.5 BiRD was a small phase II trial involving 72 patients, median age 63 years, with newly diagnosed mul-

tiple myeloma. Patients were treated with lenalidomide, clarithromycin, and dexamethasone until progressive disease, stem cell transplantation, or unacceptable toxicity. At baseline, 8 patients had prior solid tumors, 2 had skin cancers, and 1 had lymphoma. At a median follow-up of 6 years, median progression-free survival was 70.8 months and median 4-year overall survival was 82.2%; median 5-year overall survival had not yet been reached. Follow-up at 5 years revealed five new primary solid tumors and no new hematologic malignancies. Progression-free survival remains encouraging; frequency of second primary malignancies was low and similar to that reported in the Surveillance, Epidemiology, and End Results (SEER) database for people of similar age, said presenting author Adriana Rossi, MD, Weill-Cornell Medical College, New York. “Routine screening and prevention measures should

ASCOPost.com | AUGUST 15, 2011

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2011 ASCO Annual Meeting continue as medically indicated for each patient, including examination for skin cancer,” Dr. Rossi noted.

MM990/010 Study MM990/010 was a pooled analysis of two phase III studies with a total of 704 patients with relapsed/refractory multiple myeloma treated with lenalidomide plus dexamethasone or placebo plus dexamethasone until disease progression.6 During the active treatment phase, 8 invasive second primary malignancies developed in the lenalidomide arm vs 2 in the placebo arm; 11 noninvasive and 2 noninvasive second primaries developed in the two arms, respectively. Moreover, 3 of the 8 invasive malignancies occurred within the first 13 months of treatment. “No clear pattern of invasive second primaries was seen. Nonmelanoma skin cancers developed in 11 patients on lenalidomide plus dexamethasone and

2 patients on placebo,” said presenting author Ruben Niesvizky, MD, WeillCornell Medical College, New York. The incidence of second primary malignancies was low and similar to the background incidence of similarly aged persons in the general population. However, overall survival was significantly longer in the group treated with lenalidomide plus dexamethasone, and improvement persisted with long-term follow-up.

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Disclosure: Dr. Palumbo has served as a consultant for and received honoraria from Celgene and Janssen-Cilag, and has also received honoraria from Ortho Biotech. Dr. Rossi reported no potential conflicts of interest. Dr. Niesvizky has served as an advisor or consultant for Celgene, Millenium, and Onyx, has received honoraria from Celgene and Millenium, has received research funding from Proteolix, Seattle Genetics, Onyx, Millenium, and Celgene, has served on a data monitoring committee for Proteolix, and on an advisory committee/board of directors for Millenium and Celgene.

National Lung Screening Trial

Our colleagues in ACRIN are looking at costs related to the ento clinicians, shouldn’t this trial inititire screening process, in terms of ate a serious discussion about how we issues such as follow-up examinaproceed with lung cancer screening? tions to evaluate findings suspiThe discuscious for lung sion has already cancers and othIt is vital that we do begun. The NCI er illnesses, surresults are clearly gery done to bieverything we can of importance to opsy abnormal to help individuals the population lesions, treatthat we studied. ments delivered, in the United States What we are doetc. If lung canand worldwide ing to further cer screening is the discussion is to be used, we quit smoking or working with the need to underusing other tobacco Cancer Intervenstand not only tion and Surveilthe potential products. lance Modeling benefits but also Network (CISthe costs. All inNET), which conducts modeling of terested parties should weigh in on screening benefits for a variety of this important issue. cancers. The modelers will validate that their models replicate our 20% Any last thoughts on lung cancer mortality reduction from low-dose and its prevention? helical CT screening of a high-risk It is vital that we do everything group as studied in the NLST. Then we can to help individuals in the these modelers will introduce differUnited States and worldwide quit ent parameters conferring lower risks smoking or using other tobacco of lung cancer, such as a younger age products. More important, it is up to or lower pack-years of smoking, to us to intensify our efforts so that our determine a potential benefit-to-risk youth never start smoking. Disclosure: Dr. Berg reported no potential ratio. This information is important conflict of interest in dissemination of screening to a broader population. Additionally, References CISNET will model the potential 1. The National Lung Screening Trial benefit of more rounds of screening Research Team: Reduced lung-cancer or different frequencies. continued from page 4

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References 1. Attal M, Laywers VC, Marit G, et al: Maintenance treatment with lenalidomide after transplantation for MYELOMA: Final analysis of the IFM 2005-02. 52nd ASH Annual Meeting. Abstract 310. Presented December 6, 2010. 2. McCarthy PL, Owzar K, Anderson KC, et al: Phase III Intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplant for multiple myeloma: CALGB 100104. 52nd ASH Annual Meeting. Abstract 37. Presented December 5, 2010. 3. Palumbo AP, Delforge M, Catalano J, et al: A phase 3 study evaluating the efficacy and safety of lenalidomide combining melphalan and prednisone in patients ≥ 65 year with newly diagnosed multiple myeloma (NDMM): Continuous use of lenalidomide vs fixedduration regimens. 52nd ASH Annual Meeting. Abstract 622. Presented December 6, 2010.

4. Palumbo AP, Delforge M, Catalano J, et al: The incidence of second primary malignancies (SPM) in melphalanprednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) aged 65 or older. 2011 ASCO Annual Meeting. Abstract 8007. Presented June 5, 2011. 5. Rossi AC, Mark TM, Jayabalan D, et al: Incidence of second primary malignancies (SPM) after 6-years follow-up of continuous lenalidomide in first-line treatment of multiple myeloma (MM). 2011 ASCO Annual Meeting. Abstract 8008. Presented June 5, 2011. 6. Dimoupoulos MA, Orlowski RZ, Niesvizky R, et al: Lenalidomide and dexamethasone (LEN plus DEX) treatment in relapsed refractory myeloma (RRMM) patients and risk of second primary malignancy (SPM): Analysis of MM-009/010. 2011 ASCO Annual Meeting. Abstract 8009. Presented June 5, 2011.

American Lung Association Reflects on the National Lung Screening Trial

he American Lung Association is optimistic about the promising results of NCI’s National Lung Screening Trial, which indicate low-dose CT scans can have significant impact on lung cancer mortality. This study is the first comprehensive clinical trial to find that screening high-risk individuals with low-dose CT reduces lung cancer deaths by 20% compared with chest x-ray. “Although the National Lung Screening Trial results are an important step forward in the fight against lung cancer, the single most important thing any smoker can do to reduce their chances of developing or dying Low-dose CT scans from lung cancer is to quit smoking,” can have significant said Albert Rizzo, MD, American Lung Association Board Chair-Elect, impact on lung cancer and a pulmonary and critical care mortality. physician. “The Surgeon General’s 30th Report released in December confirmed that there is no safe level of exposure to tobacco smoke, and the sooner someone quits smoking, the less likely he or she is to develop tobacco-related diseases.” The American Lung Association is also convening an expert panel to review the National Lung Screening Trial study and to make policy recommendations. This panel will be lead by Jonathan M. Samet, MD, MS, a lung health expert and a member of the American Lung Association’s Scientific Advisory Committee. “If current or former smokers have questions regarding whether or not they should receive screening, the Lung Association recommends they speak with their health-care provider about the benefits and risks associated with screening,” said Dr. Rizzo.

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mortality with low-dose computed tomographic screening. N Engl J Med 365:395-409, 2011. 2. Henschke CI, McCauley DI, Yan-

kelevitz DF, et al: Early Lung Cancer Action Project: Overall design and findings from baseline screening. Lancet 354:99-105, 1999.

Indication HalavenTM is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia • Monitor complete blood counts prior to each dose, and

increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new

or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation • In an uncontrolled ECG study in 26 patients, QT

prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (ChildPugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Please see accompanying brief summary of Halaven full Prescribing Information. References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed February 2, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923. HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA /May 2011 ERI 81

Scan this code to visit www.halaven.com

Included in the NCCN Guidelines1

DISCOVER

OVERALL SURVIVAL

Halaven: The FIRST and ONLY third-line, single-agent therapy proven to significantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10 The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events had been observed, median OS with Halaven vs Control Arm (Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2,11 UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2 Halaven (n=508)

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

1.0 0.9

PROPORTION OF PATIENTS ALIVE

0.8 0.7 0.6

Halaven

0.5

Control Arm

0.4 0.3 0.2 0.1 0.0

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2 Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracycline, 10% other chemotherapy) and 3% hormonal therapy.2, 11

CI=confidence interval; HR=hazard ratio.

*EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2 Halaven: Safety profile • Studied in the Phase III EMBRACE trial2 Most Common Adverse Reactions • Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

ADVANCING SURVIVAL

The ASCO Post | AUGUST 15, 2011

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2011 ASCO Annual Meeting Gynecologic Cancer

Bevacizumab Makes Inroads against Ovarian Cancer By Alice Goodman

evacizumab (Avastin) administered with chemotherapy and continued after chemotherapy improves outcomes in ovarian cancer, according to two multicenter, random-

ized, double-blind phase III investigations presented at the 2011 ASCO Annual Meeting. The first study, ICON7, incorporated bevacizumab as part of first-line treatment with standard

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information. 2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose. Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm3 – Grade 3 or 4 non-hematological toxicities • The Day 8 dose may be delayed for a maximum of 1 week. – If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose. – If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later. Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. • Do not re-escalate HALAVEN dose after it has been reduced. Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count. Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. 5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3. 5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less. 5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. 5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome. 6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/ fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%). Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%). The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group. Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 HALAVEN (n=503) Control Group (n=247) MedDRA ver 10.0 All Grades ≥ Grade 3 All Grades ≥ Grade 3 a Blood and Lymphatic System Disorders Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders Peripheral neuropathyb 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1%

chemotherapy,1 and the second study, OCEANS, used the monoclonal antibody to treat platinum-sensitive, recurrent ovarian, primary peritoneal, or fallopian tube cancer.2

Table 2 (cont’d) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders Alopecia 45% NAc 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia). Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colonystimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy. Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose. Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption. 8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established. 8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). 8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min). 10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay. The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination. • Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

ICON7 Trial Earlier results of ICON7 presented at the 2010 European Society for Medical Oncology (ESMO) meeting showed that combining bevacizumab with a platinum-containing doublet improved progression-free survival. Gunnar Kristensen, MD, a lead investigator of the study and Senior Consultant in the Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo, presented an updated progression-free survival analysis and an interim analysis of overall survival at the ASCO meeting. Mature overall survival results will be presented in 2013, he said.

Gunnar Kristensen, MD

The phase III study randomly assigned 1,528 women with high-risk early-stage and advanced-stage ovarian cancer to 6 cycles of carboplatin plus paclitaxel every 3 weeks vs the same chemotherapy with bevacizumab at 7.5 mg/kg every 3 weeks continued for an additional 12 cycles. At baseline, median age was 57 years, and 69% had serous histology. The updated analysis showed a prolongation of progression-free survival for the addition of bevacizumab, with a net gain of 2.4 months. Median progression-free survival was 17.4 in the control arm vs 19.8 in the bevacizumabcontaining arm (P = .039). At a median follow-up of 28 months, a trend toward prolonged overall survival with bevacizumab was observed in the interim analysis, with median overall survival not yet reached (hazard ratio = 0.85; 95% confidence interval = 0.69–1.04). Further analysis of overall survival showed that patients with a high risk of recurrence (ie, stage III suboptimally debulked with > 1 cm tumor after surgery or stage IV after surgery) derived greater benefit from bevacizumab than other patients. At a median follow-up of 28 months, 47% of high-risk controls were dead vs 34% of high-risk women treated with bevacizumab (P = .002).

ASCOPost.com | AUGUST 15, 2011

PAGE 11

2011 ASCO Annual Meeting Gynecologic Cancer

“This represents a median gain in survival of about 8 months and a 36% reduction of risk of dying among highrisk patients,” Dr. Kristensen stated. Given the high cost of using bevacizumab and the fact that the high-risk group derived preferential benefit from frontline bevacizumab, Dr. Kristensen said that for now, he restricts the use of bevacizumab to high-risk patients. “We need the final survival analysis,” he added.

OCEANS Trial OCEANS was a positive study showing that bevacizumab added to carboplatin/gemcitabine followed by bevacizumab maintenance therapy provided a clinically meaningful benefit in recurrent ovarian cancer, achieving a 52% reduction in risk of progression and a median increase of 4 months in progression-free survival compared with SEE PAGE 45 carboplatin/gemcitabine alone. According to the investigators, safety data were reassuring and consistent with the known side-effect profile of bevacizumab. “Bevacizumab plus carboplatin/ gemcitabine followed by bevacizumab maintenance should be considered a new option for recurrent, platinum-sensitive ovarian cancer,” said

Carol Aghajanian, MD, of Memorial Sloan-Kettering Cancer Center in New York, who presented results at the Annual Meeting. OCEANS randomly assigned 484 patients in a 1:1 ratio to receive either four cycles of carboplatin/gemcitabine plus placebo or the same regimen of carboplatin/gemcitabine plus bevacizumab at 15 mg/kg every 3 weeks continued until disease progression. The primary endpoint of progression-free survival was met. At a median followup of 24 months, median progressionfree survival was 8.4 months with standard carboplatin/gemcitabine vs 12.4 months for the bevacizumab-containing arm (P < .0001). Moreover, 79% of women who received bevacizumab had significant tumor shrinkage vs 57% in the carboplatin/gemcitabine–alone group. The curves separated between the two arms at 2 months and remained separate at 2.5 years of follow-up. Dr. Aghajanian said that the next step is to evaluate the role of bevacizumab plus chemotherapy in platinum-resistant ovarian cancer and to combine it with other emerging novel therapies.

Added Perspective Andrew Seidman, MD, Memorial Sloan-Kettering Cancer Center, who moderated a press conference

Expert Point of View

ormal discussant, Anil Sood, MD, The University of Texas MD Anderson Cancer Center, Houston, said that both studies presented important information, but several issues should be considered, including the best combination with bevacizumab, whether the benefits accrue from bevacizumab alone or chemotherapy plus bevacizumab, the optimal dose of bevacizumab, how long to continue treatment, and the true role of bevaciAnil Sood, MD zumab in platinum-sensitive disease. “The gains in progression-free survival [with bevacizumab] are relatively modest. This raises questions about the best chemotherapy partners and the bevacizumab dose. When you stop giving bevacizumab, there is a falling off of benefit. We don’t know how long to continue treatment. Also cost is a factor…. Bevacizumab costs about $100,000 per year,” Dr. Sood said. “We are not necessarily curing patients [with bevacizumab]. They may develop adaptive-evasive responses. Much more work needs to be done to identify and develop more effective therapies,” he commented.

■

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

where these data were released, noted that ICON7 and OCEANS show the benefit of antiangiogenic maintenance therapy at two different doses of bevacizumab (7.5 and 15 mg). No head-tohead studies comparing the two doses have been performed.

High-risk and Recurrent Ovarian Cancer ■■ The ICON7 trial showed that front-line bevacizumab added to platinumcontaining chemotherapy and continued as maintenance therapy extended progression-free survival in high-risk early-stage or advanced ovarian cancer by a median of 2.4 months.

■■ The OCEANS trial showed that platinum-based chemotherapy plus

bevacizumab, with bevacizumab continued until disease progression, improved median progression-free survival by about 4 months in women with recurrent ovarian cancer.

■■ These trials raise questions about optimal timing and dose of

bevacizumab, best chemotherapy combinations, and which patients to treat in the absence of biomarkers, given the high cost of the drug and modest improvements in progression-free survival.

Andrew Seidman, MD

“The data support a potential role for bevacizumab as the first biologic agent in ovarian cancer,” he stated. Regarding the OCEANS results, he said: “A 52% improvement in progression-free survival with time away from cytotoxic chemotherapy

lets women live longer and have more active lives. It is reassuring that there were no new safety signals [with bevacizumab] in this trial.”

■

Disclosure: Dr. Kristensen has been a consultant for Roche. Dr. Aghajanian has been a consultant for and has received research funding from Genentech. Dr. Seidman reported no potential conflicts of interest.

References 1. Kristensen G, Perren T, Qian W, et al: Result of interim analysis of overall survival in the GCIG ICON7 phase III randomised trial of bevacizumab in women with newly diagnosed ovarian cancer. 2011 ASCO Annual Meeting. Abstract LBA5006. Presented June 4, 2011. 2. Aghajanian C, Finkler NJ, Rutherford T, et al: OCEANS: A randomized, double-blinded, placebo-contolled, phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. 2011 ASCO Annual Meeting. Abstract LBA5007. Presented June 4, 2011.

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ASCOPost.com | AUGUST 15, 2011

PAGE 13

2011 ASCO Annual Meeting Genitourinary Cancer

Intermittent or Continuous Androgen Suppression Produces Comparable Survival after Radical Therapy in Prostate Cancer By Larry J. Rosenberg, PhD

en with prostate cancer who receive intermittent courses of androgen-suppressing therapy can live as long as those who are treated with continuous therapy, according to results of a recently concluded study. Until now, standard treatment has consisted of continuous therapy, but this is expected to change as a result of these findings. Juanita Crook, MD, FRCPC,

Juanita Crook, MD, FRCPC

of the University of British Columbia, presented the results of the phase IIII randomized trial conducted by the �� National Cancer Institute of Canada�� Clinical Trials Group (NCIC CTG PR.7/ SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013), at the 2011 ASCO Annual Meeting.1 Conventional radiation therapy for localized prostate cancer is associated with a >30% incidence of prostatespecific antigen (PSA) failure, which is typically treated with hormonal therapy. Intermittent androgen suppression for PSA recurrence following surgical or radiation treatment for prostate cancer can delay hormone resistance and improve quality of life, but it was not known if this approach could prolong survival. This open-label, noninfeSEE PAGE 45 riority randomized trial compared intermittent androgen suppression and continuous androgen deprivation to evaluate effects on survival and quality of life.

Study Design Patients eligible for enrollment had rising PSA levels > 3.0 ng/mL more

than 1 year post-radiotherapy and may have had up to 1 year of neoadjuvant or adjuvant androgen-deprivation therapy for localized prostate cancer. Stratification factors consisted of time since radiotherapy (> 1–3 vs > 3 years), initial PSA (< 15 vs > 15 ng/mL), and prior radical prostatectomy or androgen-deprivation therapy. Intermittent androgen suppression cycles consisted of 8 months of treatment with PSAdetermined off-treatment periods. The primary endpoint was overall survival; secondary endpoints were hormone resistance, cholesterol/HDL/LDL, length of nontreatment periods, testosterone level, quality of life, and potency recovery. Men who enrolled in this clinical trial had initially undergone definitive radiotherapy for their prostate cancer, either as primary treatment or as salvage for recurrence after radical prostatectomy, but subsequently developed elevated levels of PSA, indicating relapse. Nearly 1,400 men par-

for extended “drug holidays” lasting several months to years. Patients were monitored for PSA levels every 2 months. When PSA levels rose to > 10 ng/mL while off treatment, LHRH blocker therapy was resumed for another 8-month cycle.

Major Results The trial follow-up period was stopped early (median follow-up, 6.9 years) because a planned interim analysis, reviewed by an independent data and safety monitoring committee, unequivocally demonstrated no difference in survival outcome between the two treatment groups. Median overall survival was 8.8 years on intermittent androgen suppression vs 9.1 years on continuous androgen deprivation (HR = 1.02; 95% CI = 0.86–1.21; P = .009 for noninferiority [HR ≥ 1.25 for intermittent androgen suppression vs continuous androgen deprivation]). Patients on the intermittent androgen suppression arm had more disease-

Intermittent vs Continuous Androgen Suppression for Prostate Cancer ■■ In men with PSA recurrence following definitive radiotherapy for

prostate cancer, intermittent androgen-suppressing therapy produces survival equivalent to continuous therapy.

■■ Intermittent androgen suppression was associated with improved quality of life compared with continuous androgen deprivation.

■■ The results suggest intermittent therapy should be the standard of

care for most patients who experience PSA recurrence after definitive radiotherapy and are initiating androgen-deprivation therapy.

ticipated in the trial, which recruited patients from 1999 until 2005. Most enrolled patients were from Canada, but others were from the United States and United Kingdom. Patients randomly assigned to the control group (n = 696)�� received �� continuous injections of a slow-release l�� uteinizing hormone–releasing hormone (LHRH) blocker, usually at 3-month intervals. Those in the experimental group (n = 690) received the same drug but in 8-month treatment cycles, which were interrupted

related deaths (122 vs 97) and fewer disease-unrelated deaths (134 vs 146). Patients receiving intermittent androgen suppression therapy had a reduced incidence of hot flashes, but rates of other adverse events, including myocardial events and osteoporotic fractures, were similar between the two groups. Full testosterone recovery was noted in 35% of men on the intermittent androgen suppression arm. Those receiving intermittent courses of the testosterone-suppressing drug reported better quality of life because

of fewer or less intense side effects. �� Using a 10-point change from baseline score as a clinically meaningful criterion for quality-of-life change, intermittent androgen suppression patients had significant improvements in physical function, fatigue, urinary problems, hot flashes, desire for sexual activity, and erectile function compared with men on the continuous androgen deprivation arm (all P ≤ .01).

Other Implications “These important findings also have significant economic and quality-oflife implications,” noted Dr. Crook. Patients on the intermittent therapy used only one-third the amount of drug as compared with continuous therapy, reducing both cost and toxicity. Adverse effects associated with androgen-suppressing therapy include hot flashes, sexual impotence, growth of breast tissue, insomnia, weight gain, worsening of diabetes, loss of muscle mass, and osteoporosis. According to Dr. Crook, “For PSA recurrence after definitive radiation therapy, intermittent androgen suppression given as per the PR.7 algorithm is not inferior to continuous androgen deprivation with respect to overall survival. “Intermittent androgen suppression should be the standard of care for most men with PSA recurrence after definitive radiotherapy—either primary or salvage post–radical prostatectomy—who are initiating androgen-deprivation therapy,” she concluded.

■

Disclosure: Dr. Crook has received honoraria and research funding from Abbott, AstraZeneca, and sanofi-aventis.

Reference 1. Crook JM, O’Callaghan CJ, Ding K, et al: A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013). 2011 ASCO Annual Meeting. Abstract 4514. Presented June 6, 2011.

The ASCO Post | AUGUST 15, 2011

PAGE 14

2011 ASCO Annual Meeting Gastrointestinal Cancer

Sorafenib Acceptable in Child-Pugh B Patients with Hepatocellular Carcinoma But should not be routinely prescribed, yet By Caroline Helwick

atients with hepatocellular carcinoma and moderate liver dysfunction can derive benefit from, and be treated safely with, sorafenib (Nexavar), according to the second interim analysis of the GIDEON trial,

Expert Point of View

presented at the 2011 ASCO Annual Meeting by Jorge A. Marrero, MD, of the University of Michigan in Ann Arbor.1

Real-life Practice Settings GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of Its Treatment

with Sorafenib) is an ongoing, global, prospective study of sorafenib in reallife practice. It is evaluating the drug in diverse settings and patient subgroups

For Locally or Regionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)...

Select ERBITUX + RT Bert H. O’Neil, MD

he GIDEON trial “can provide us with important information on safety and single-arm efficacy in the Child-Pugh B population,” said Bert H. O’Neil, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill. “The results suggest that safety is similar between Child-Pugh A and Child-Pugh B patients; however, the duration of therapy for the Child-Pugh B population was exceedingly short, 8.5 weeks. This suggests that equivalent numbers of adverse events occur in a shorter period of time,” Dr. O’Neill said. “The low number of dose reductions in the Child-Pugh B population is also interesting, but is also affected by the short treatment duration.” Taken together, these findings suggest that sorafenib can be started at full doses in future studies of the ChildPugh B population, he said. Dr. O’Neil cautioned against extrapolating these results to current clinical practice at this time, concluding that sorafenib should remain investigational in Child-Pugh B patients, for whom the “the standard of care remains best supportive care.” Sorafenib should probably not be used at all in the Child-Pugh C cirrhotic population, he added.

■

Disclosure: Dr. O’Neil reported having a consultant or advisory role for Amgen and Bayer-Onyx and receiving honoraria from Amgen.

ERBITUX Indications ■ 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 ■ 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

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

Please see brief summary of Full Prescribing Information and 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).

ASCOPost.com | AUGUST 15, 2011

PAGE 15

2011 ASCO Annual Meeting Child-Pugh Score

he Child-Pugh score, a prognostic measure used in patients with chronic liver disease, is determined by five clinical measures, including total bilirubin level; serum albumin level; prothrombin time expressed by international normalized ratio (INR), presence of ascites (none, mild, severe);

and presence of hepatic encephalopathy (none; grade I-II; grade III-IV). Each clinical measure is assigned 1 to 3 points ranging from least severe (1 point) to most severe (3 points). A total score based on the five clinical measures is used to determine Child-Pugh class of disease (A, B, or C).

■

for Increased OVERALL SURVIVAL ERBITUX Is the Only Anti-EGFR MAb With Increased Overall Survival in Combination With RT Survival in Combination With RT*1,2 ERBITUX + RT (n=211)

RT alone (n=213)

Median overall survival 49.0 months

29.3 months

45%

19.7

month improvement

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

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; 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 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. 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 ■ 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 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 acneiform 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%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ 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 were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

where data are limited, such as for patients with Child-Pugh B disease, who are generally excluded from liver cancer trials. Approximately half of the 3,322 patients enrolled were eligible for the second interim safety analysis, 957 of whom were classified Child-Pugh continued on page 16

The ASCO Post | AUGUST 15, 2011

PAGE 16

2011 ASCO Annual Meeting Hepatocellular Carcinoma continued from page 15

A, 367 were Child-Pugh B, and 35 were Child-Pugh C patients. Adverse events were similar among the arms but serious events occurred in 56% of Child-Pugh B and 63% of ChildPugh C patients, vs 29% of ChildPugh A patients. Drug-related serious

adverse events were seen in 15%, 6%, and 8%, respectively, and events resulting in permanent discontinuation of sorafenib were observed in 38% of Child-Pugh B, 51% of Child-Pugh C, and 24% of Child-Pugh A patients. “Compared with Child-Pugh A patients, Child-Pugh B patients did not have a higher incidence of drug-re-

lated adverse events but had a higher incidence of liver-associated events. Also, as liver function worsened, there was a significant increase in the death rate,” he added, noting that most deaths were due to tumor progression or underlying liver disorders. “Our preliminary interim analysis of results indicates that the sorafenib

safety profile is generally similar in the Child-Pugh B and Child-Pugh A patients,” Dr. Marrero concluded.

Survival Data While median overall survival reached 10.3 months for Child-Pugh A patients, it was 4.8 months for Child-Pugh B and just 2.0 months for

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. In three patients with prior history of coronary artery disease, 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 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 acneiform 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. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneiform rash occurred in 1-17% of patients — Acneiform 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 | AUGUST 15, 2011

PAGE 17

2011 ASCO Annual Meeting Child-Pugh C patients. However, time to progression was similar for ChildPugh B and Child-Pugh A: 3.6 and 4.2 months, respectively, vs 2.1 months for Child-Pugh C. “The shorter median overall survival in the Child-Pugh B patients most likely reflects the poorer prognosis and natural history of liver disease in

this population,” he suggested. “Consistent with previously reported studies, these preliminary data indicate that Child-Pugh status appears to be a useful prognostic factor for overall survival.” Mean daily dose was 630 mg, which was similar among the groups, and, somewhat surprisingly, dose in-

terruptions and modifications were also comparable. Median duration of treatment, however, was significantly shorter for Child-Pugh B: 9 weeks vs 12 weeks for Child-Pugh A, and only 4 weeks for Child-Pugh C.

■

Disclosure: Dr. Marrero reported receiving honoraria from Bayer and Onyx and research funding from Bayer.

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 acneiform 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 (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) 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 Company; March 2011. 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 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).

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, 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.

693US11AB05808

5/11

Reference 1. Marrero JA, Lencloni R, Kudo M, et al: Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of Its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients: Clinical findings in patients with liver dysfunction. 2011 ASCO Annual Meeting. Abstract 4001. Presented June 7, 2011.

The ASCO Post | AUGUST 15, 2011

PAGE 18

FDA Update

FDA Issues Guidance for Diagnostic Tests Used with Targeted Therapies

he FDA issued a new draft guidance to facilitate the development and review of “companion diagnostics”—tests used to help health-care professionals determine whether a patient with a particular disease or condition should receive

a particular drug therapy or how much of the drug to give. The draft document is intended to provide companies with guidance on the agency’s policy for reviewing a companion

diagnostic and the corresponding therapy. One common type of companion diagnostic looks for whether a patient has a specific gene amplification or protein overex-

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 acneiform 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. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneiform rash occurred in 1–17% of patients. Acneiform 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.

pression that could predict whether a drug might benefit the patient or lead to harm. For example, trastuzumab (Herceptin) was approved with a companion test, and testing is routinely performed on women diagnosed with breast cancer to

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 Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 0 9 1 Dyspepsia 14 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 Alanine Transaminase, high 43 2 21 1 3 38 1 24 1 Aspartate Transaminase, high 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages 87 17 10 1 Acneiform 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. Acneiform 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.

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FDA Update

help determine whether the patient should receive the drug. “These proposed guidelines support the development of innovative new targeted medicines and their corresponding diagnostic tests and are intended to provide manufacturers with greater predictability,” said Jeffrey Shuren, MD, Direc-

tor of the FDA’s Center for Devices and Radiological Health. “It is the agency’s goal to help stimulate early collaborations between drug and device makers so they can develop the best medical products for treating patients.” The draft guidance also clarifies the FDA’s definition of a compan-

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 2 Preferred Term Grades 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 8 10 18 Mouth Dryness 11 0 4 0 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 acneiform 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 acneiform 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.

ion diagnostic, recommends early engagement between the FDA and manufacturers, highlights the FDA’s intention to conduct simultaneous reviews of a drug or biologic therapy and its corresponding companion diagnostic, and identifies instances where the FDA may approve a targeted medicine in the absence

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, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. 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-03-11

Rev March 2011

of a cleared or approved companion diagnostic. The FDA is seeking public input on the draft guidance. Comments can be submitted onlin e or in writing to: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852.

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ODAC Recommends Accelerated Approval for Brentuximab

eattle Genetics, Inc, announced that the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 10-0 to recommend that the agency grant accelerated approval of brentuximab vedotin (ADCETRIS) for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant (ASCT). In addition, ODAC voted 10-0 to recommend that the FDA grant accelerated approval of brentuximab for the treatment of patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). The FDA is expected to act on the two Biologics License Applications (BLAs) for brentuximab by August 30, 2011, under the Prescription Drug User Fee Act. Brentuximab is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of Hodgkin lymphoma and ALCL. The ADCETRIS BLAs were based primarily on data from a pivotal trial in relapsed or refractory Hodgkin lymphoma that was conducted under a Special Protocol Assessment with the FDA and from a phase II trial in relapsed or refractory systemic ALCL.

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Send Us Your News Send your news of new appointments, awards, or significant events to The ASCO Post. Write to editor@ ASCOPost.com. All submissions will be

considered for publication.

The ASCO Post | AUGUST 15, 2011

PAGE 20

Direct from ASCO

ASCO’s International Cancer Corps Launches Initiatives in Ethiopia and Vietnam Volunteers sought to help build cancer care infrastructure.

because Honduras has fewer than 20 over 3 to 4 times a year, said Quyen training to surgeons, radiotherapy oncologists to serve a population of D. Chu, MD, HVO Program Direcspecialists, nurses, pathologists, and 8 million, and just one public hospitor for Vietnam. Dr. Chu is Albert other health-care professionals who tal where cancer care is available. The Sklar Endowed Proprovide cancer Honduras HVO/ICC program focusfessor of Surgery and es on three hospitals in the capital city Director of the Periof Tegucigalpa, with special attention toneal Surface Magiven to the surgical oncology residenlignancies Program cy program there, which has just two at the Feist-Weiller residents at any one time. Cancer Center at Linus Chuang, MD, volunteered Louisiana State in Honduras in May and November University Health 2010. What impressed him most Sciences Center in about the HVO/ICC program was Shreveport. its focus on capacity building. Dr. Through the Chuang, Associate Professor of the new HVO/ICC Division of Gynecologic Oncology partnership with and Co-Director of the Minimally Vietnam’s UniverInvasive Surgery Department of Obsity of Hue, volEthiopia: (left to right) Kenneth D. Miller, MD stetrics, Gynecology, and Reproducunteers will help , and Bogale Solomon Desalegne , MD, MSc, Head of the Radiotherapy Center tive Science at Mount Sinai School of develop curricula, at Addis Ababa Unive rsity and Director of the Cancer Center at Tik ur An be ssa Hospital in October 201 Medicine, said that other humanitarlead workshops 0. ian efforts he’s been involved with foin treatment arcused primarily on caring for patients eas that have the in immediate need. In contrast, this greatest need, and provide side-bycare at Black Lion. Volunprogram’s value is in sharing clinical side clinical instruction. “The point is teers will also help develop a national knowledge and skills with internato assist with building infrastructure, cancer plan and education in cancer tional colleagues, helping residents, enhancing what they already have prevention measures. Assignments fellows, and doctors already on the and helping them keep abreast of will range from 2 to 4 weeks. ground enhance the way they manage the latest technology,” said Dr. Chu, The HVO Program Director for cancer patients. who conducted a needs assessment Ethiopia is Kenneth D. Miller, MD, Director of the Adult Cancer Sur“These young doctors will go and in Vietnam for the new ICC program Priorities Targeted to Each vivorship Program at Dana-Farber work in little villages, and in their and volunteered there in 2010. Country’s Needs Cancer Institute. lifetimes they will help countless paBecause the lack of a national In the coming months, ASCO tients—not just the screening program in Vietnam conmember volunteers will begin pack20 people I could tributes to a significant number of ing up and heading to the two new help during my short patients presenting only after their sites, singly or in teams, staying for time there,” said Dr. disease is advanced, developing a 1 to 4 weeks, with other health proChuang, adding that more robust palliative care program fessionals going his volunteer work is a priority there. through HVO/ICC In Ethiopia, the HVO/ was one of the most ICC’s major objective will edifying things he’s be addressing the shortage ever done. of oncologists. Volunteers For additional inwill help establish a 3-year formation about the residency program in cliniInternational Cancer cal oncology at Tikur AnCorps program with bessa (Black Lion) HosHVO and to learn how pital in Addis Ababa, the Honduras: (left to right) Linus T. Chua ng, MD, Jose Ange l to volunteer in Honduonly hospital in Ethiopia Sanchez, MD, the on-site coordinator for the volunteer oncology program (adult cancers), ras, Ethiopia, or Vietthat sees cancer patients. and Frederic V. Price, MD, FACS, in May 2010. nam, send an email to In addition, HVO/ICC ASCO at internationvolunteers will provide al@asco.org or to HVO training to residents enHonduras Focus Has Been on at d.stonehirsch@hvousa.org. rolled in the hospital’s Training Providers internal medicine trainASCO and HVO chose Honduras © 2011. American Society of Clinical ing program, and more mastectomy at a ing rm rfo Oncology. All rights reserved. pe , as their first location for collaboration, specialized oncologic right : Quyen Chu, MD, tnam.

magine just four oncologists attempting to provide care for a population of 82 million people living in a country covering twice the territory of Texas. That’s the state of cancer care in Ethiopia. And imagine a country of more than 90 million people—more than twice the population of California— where the lion’s share of people with cancer don’t know they have cancer and thus don’t seek medical attention until their disease is advanced. This is Vietnam. Epidemiologists estimate that a majority of the world’s new cases of cancer are in low- and middleincome countries like Ethiopia and Vietnam. The situation is dire. That’s why the International Cancer Corps (ICC)—which ASCO launched with the international medical education organization Health Volunteers Overseas (HVO) in Honduras in 2010—has just expanded to Ethiopia and Vietnam. The purpose: to help bring care to underserved populations by assisting with the training of oncologists and others involved with the treatment of cancer patients.

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Vietnam macy in Vie edicine and Phar Hue College of M

ASCOPost.com | AUGUST 15, 2011

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Direct from ASCO

Oncology Community Briefs Members of Congress and Calls for Action

SCO and seven other oncology organizations held a Capitol Hill briefing in July and explained to nearly 200 members of Congress and their staffs how widespread cancer drug shortages are creating “a crisis in care.” According to the University of Utah Drug Information Service, the number of drug shortages has tripled between January 2006 and December 2010. Last year there were over 211 medications in short supply affecting numerous classes, including chemotherapy drugs, antibiotics, and anesthetic drugs.

Dire Consequences At the briefing, ASCO President Michael P. Link MD, explained how 2011 could be the worst year since the problem has been tracked. “Through the middle of June, there are already 156 new drug shortages. If this trend holds through the rest of the year we must brace ourselves for more than 300 new cases.” Dr. Link outlined the many consequences shortages have on cancer patients and oncology practices including treatment delays, less effective or no workaround therapies, patient anxiety, the time and expense practices waste on finding supply, the adverse effect on ongoing clinical trials, and a price markup that increases the cost of care.

Congressional Bills Many in the oncology community, including ASCO, are backing two Congressional bills introduced this year for provisions that are important first steps in addressing this complex issue. The Preserving Access to LifeSaving Medications Act, introduced in February by Senators Amy Klobuchar (D-Minn) and Robert Casey (D-Pa), contains some of the recommendations from the November 2010 Drug Shortages Summit co-convened by ASCO. In June, Representatives Tom Rooney (R-Fla) and Diana DeGette (D-Colo) introduced HR 2245, which provides the FDA with enhanced authority to require notification from manufacturers expecting a disruption in their usual supply of drugs.

Briefing participants included ASCO, Association of Community Cancer Centers, Association of Oncology Social Work, American Society of

Health System Pharmacists, Community Oncology Alliance, Leukemia & Lymphoma Society, Oncology Nursing Society, Children’s Cause for Can-

cer Advocacy, and US Oncology.

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Direct from ASCO

ASCO’s Oncology Slide Library Functions as a Share‑and‑Exchange Forum More then two-thirds of those asked shared their slides at the Annual Meeting.

SCO’s Oncology Slide Library—which allows ASCO meeting attendees to upload and share their ASCO meeting presentation slides with slide-library subscribers—may only be a year old, but participation is already very high. This year’s Annual Meeting in June marked the first time ASCO gave each speaker the opportunity to have his or her presentation slides included in the library, and just over two-thirds said yes.

Medicine and Director of Thoracic Medical Oncology at Beth Israel Hospital. “This includes preclinical data, such as the discovery of a new molecular pathway, as well as the clinical trials involving new drugs that target these pathways. Recognizing this complexity, there exists a need to simplify, explain, and share the groundswell of information that we are faced with every day as physicians. I think the ASCO slide library will help achieve this goal and meet the needs of ASCO members, who for a long time have been asking for a service like this.”

What’s in the Slide Library?

Benjamin Levy, MD

Benjamin Levy, MD, Head of the ASCO Integrated Media and Technology Committee (IMTC) planning group for the slide library, is excited about this, saying that the nascent library is a truly collaborative way for all ASCO members to stay up to date on fast-moving research. “Oncology has become an extremely complicated field as new data emerges in different tumor types,” said Dr. Levy, Assistant Professor at Albert Einstein College of

Currently in the Oncology Slide Library are 2,371 slide or poster presentations uploaded by ASCO meeting presenters and 899 individual slides or presentations owned by ASCO. Most were uploaded during ASCO’s Annual Meeting this summer, but some are from the 2011 Gastrointestinal Cancers Symposium and the 2011 Genitourinary Cancers Symposium. The highest areas of use thus far have been in breast cancer and gastrointestinal cancers. All presenters at all meetings associated with ASCO will now be asked whether they’d like to add their slides to the library, which is hosted on the ASCO University website. A large influx of slides is ex-

Help Your Patients Manage the Cost of Cancer Care

ecause the cost of cancer care can be high, it is important for your patients to understand what to expect before starting treatment so that they can manage the financial effect of cancer in the most effective way possible. To that end, Cancer.Net, ASCO’s patient information website, offers a guide designed to help patients talk with the health-care team about these issues (www.cancer.net/managing-

costofcare). It outlines what costs to expect, types of insurance, how insurance rules are changing under the 2010 health reform law, financial resources, tips to organize financial paperwork, and more. Free printed copies are available through ASCO’s bookstore (www.cancer.net/eStore).

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pected after the Breast Cancer Symposium in September. To make sure nothing inaccurate winds up in the library, Dr. Levy said IMTC members closely oversee the content as it comes in. They also watch closely for material uploaded by individuals who don’t hold the copyright to it.

How Can the Slides Be Used? Anyone who has an ASCO account can subscribe and download content from the slide library for educational purposes. The cost is $50 per year. Nonsubscribers can browse the slides but not download them. User-uploaded slides are marked as hailing from an external source and are downloadable as

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

PowerPoint files. The ASCO slides, marked as copyrighted by ASCO, can also be downloaded. Neither can be altered once uploaded. In addition, users can create and save personalized slide sets right on the website. Stephanie Williams, MD, President of Hematology-Oncology Associates of Illinois and Professor of Clinical Medicine at Northwestern Feinberg School of Medicine, used the slide library just after ASCO’s Annual Meeting this summer, when she was asked to deliver an update on the lymphoma abstracts presented at the meeting to fellow physicians back home in the Chicago area. Dr. Williams said she loved the library’s ease of use, and that it

What’s Hot in

JCO

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

JCO.org 1. Impact of KRAS and BRAF Gene Mutations on Targeted Therapies in Colorectal Cancer Adam Bass 29(19): 2728 2. Breast Cancer Tumor Size, Nodal Status, and Prognosis: Biology Trumps Anatomy Elizabeth A. Comen, et al 29(19): 2610 3. Palliative Care and the Quality of Life Diane E. Meier, et al 29(20): 2750 4. Anti–Vascular Endothelial Growth Factor Therapy for Breast Cancer: Can We Pick the Winners? Bryan P. Schneider, et al 29(18): 2444 5. The Paradox of Positive Thinking Eliezer M. Van Allen 29(19): 2730

6. New Initiatives at Journal of Clinical Oncology Stephen A. Cannistra 29(19): 2609 7. Rectal Cancer Trials: No Movement Martin R. Weiser 29(20): 2746 8. Expanding Our Therapeutic Options: Beta Blockers for Breast Cancer? Patricia A. Ganz, et al 29(19): 2612 9. Stat5: From Breast Development to Cancer Prognosis, Prediction, and Progression David Tweardy, et al 29(18): 2443 10. Newly Diagnosed Acute Promyelocytic Leukemia: Arsenic Moves Front and Center Elihu H. Estey 29(20): 2743

ASCOPost.com | AUGUST 15, 2011

PAGE 23

Direct from ASCO

allowed her to quickly pull together slides from various presentations, which would have taken her much longer if she had to contact each of the presenters to obtain their slides and their permission. Plus, she said, having such easy access to presentation slides can help oncologists stay boned up on what they learned at recent meetings.

been a very exciting time, but also very complex. The only way physicians will get a handle on all of it is through a sharing and exchange of information like this. The hope is to

level the playing field as more of us oncologists are exposed to all of the information out there. And patients are the ultimate winners.” ASCO’s Oncology Slide Library

What’s Hot in

can be found here: www.university. asco.org/slides.

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JOP

Top 5 most-accessed articles recently published in Journal of Oncology Practice Volume 7, Issue 3

May 2011

Journal of oncology Practice Stephanie Williams, MD

“It’s a very good resource to have so you can go back over what you heard in the sessions,” said Dr. Williams, who added that she would continue to use the slide library to enhance and inform future talks she gives to residents, fellows, and other physicians. Dr. Levy said the timing of the library couldn’t be better. “The last 5 years in cancer research have

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

jop.ascopubs.org

1. Genomic Testing and Therapies for Breast Cancer in Clinical Practice Jennifer S. Haas, et al 7(3S): e1s 2. Health Technology Assessment and Private Payers’ Coverage of Personalized Medicine Julia R. Trosman, et al 7(3S): 18s 3. Characterizing Medical Care by Disease Phase in Metastatic Colorectal Cancer Xue Song, et al 7(3S): 25s 4. Advancing Performance Measurement in Oncology: Quality Oncology Practice Initiative Participation and Quality Outcomes Francis X. Campion, et al 7(3S): 31s 5. Effect of the Pay-for-Performance Program for Breast Cancer Care in Taiwan Raymond N.C. Kuo, et al 7(3S): e8s

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%). Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages. ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004T

For more information: Please visit www.istodax.com or call 1-888-423-5436

The ASCO Post | AUGUST 15, 2011

PAGE 26

FDA Update

New Safety Information Reported for 5-alpha Reductase Inhibitors

he FDA announced that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor class of drugs has been revised to include new safety information about the increased risk of being

diagnosed with high-grade prostate cancer. This risk appears to be low, but health-care professionals should be aware of this safety information, and weigh the known benefits against the potential risks when prescribing these

drugs, ie, finasteride (Propecia, Proscar) and dutasteride (Avodart, and in combination with tamsulosin, Jalyn). The new safety information is based on FDA’s review of two large, randomized controlled trials that demon-

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

strated an overall reduction in prostate cancer diagnoses with finasteride and dutasteride treatment. However, this reduction was due to a decreased incidence of lower-risk forms of prostate cancer.

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5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS 6.1 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. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months). Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

ASCOPost.com | AUGUST 15, 2011

PAGE 27

FDA Update

FDA Outlines Oversight of Mobile Medical Applications

he FDA is seeking input on its proposed oversight approach for mobile medical applications (“apps”) designed for use on smartphones and other mobile computing devices. This approach encourages

the development of new apps, focuses only on a select group of applications, and will not regulate the sale or general consumer use of smartphones or tablets.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

The agency’s draft guidance defines a small subset of mobile medical apps, including those that are used as an accessory to medical devices already regulated by the FDA, or that

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

transform a mobile communications device into a regulated medical device by using attachments, sensors, or other devices. The FDA will update the guidance based on feedback received.

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The ASCO Post | AUGUST 15, 2011

PAGE 28

Perspective

Rising Costs of Cancer Care continued from page 1

including earlier diagnosis and better surgical techniques. However, increased use of expensive chemotherapies and biologics in the adjuvant and metastatic setting also play a role in increased survival rates. Much lay press coverage on this subject gives particular attention

to high-priced agents, which obscures the discussion over rising costs. Policymakers intent on reducing cancer care spending need a more nuanced appreciation of the clinical value of oncology treatments, from diagnosis to death.

The Gray Area of Costs The ASCO Post asked health-care pol-

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus. In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study. 8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area. Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

icy expert, Peter B. Bach, MD, MAPP, Director of the Center for Health Policy and Outcomes at Memorial SloanKettering, whether overutilization of services is a main driver of rising costs. “For obvious reasons, cancer spending gets singled out because the unit-of-care prices are so transparent. The challenge with aggregate data on the macro level is

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area. 16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)]. • Patients should be instructed to read the patient insert carefully. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

that it is difficult to figure out which services are actually needed, which services are unnecessary, and which services we could pay less for,” said Dr. Bach. He said that overutilization is one hypothesis for the upward spending trend. “But the cost issue is grayer than that. Of course we overuse services. The classic example is third- and fourth-line cancer agents in clinical scenarios where cure or even prolonging life is not viable,” said Dr. Bach. “But the unit pricing of our health care is also a factor. For example, we pay much more per unit of care, such as hospital days, than Western European countries, and in some regard with no better outcomes,” he added.

Shifting Incentives Dr. Bach stressed that constraining oncology spending is a huge challenge, one that requires a multipronged approach. “Among other things, we need to shift our payment incentives toward cost containment and increase our focus on evidence-based medicine. Doing that will decrease incentives to overtreat,” said Dr. Bach. According to Dr. Bach, a partial solution is to shift the incentives created by our current fee-for-service system, which reimburses each separate element of care, to an episode-based model that combines the collective costs of care into a single payment. Although Medicare has used episode-based payment models in a limited fashion, and the concept has been explored in certain chronic diseases such as diabetes, the complexity of cancer presents difficult challenges.

We need to shift our payment incentives toward cost containment and increase our focus on evidence-based medicine. Doing that will decrease incentives to overtreat. –Peter B. Bach, MD, MAPP

ASCOPost.com | AUGUST 15, 2011

PAGE 29

Perspective

In a recent paper published in Health Affairs,1 Dr. Bach and colleagues proposed an episode-based pilot for Medicare using metastatic lung cancer as their model, proffering that oncology is compatible with episode-based payments because it is evidence-based and employs updated guidelines in codifying standard care, providing opportunities for both savings and quality control. According to the proposal by Dr. Bach and coauthors, participating oncologists would receive an episode-based payment for drugs and administration costs and would agree to use regimens accepted by the Centers for Medicare & Medicaid Services. The pilot would be divided into a traditional fee-for-service model followed by an episode-based phase. “Physicians would submit information from both phases. The first phase would document individual services; the second, a new claim code, would define the episode,” explained Dr. Bach. Phase 1 fee-for-service claims would be used to determine the average cost of the episode of care, and Medicare would then shift to providing a single payment based on that average. A central feature of episode-based payment in this clinical scenario is the creation of incentives for oncologists to select lower-priced therapies from the choices judged equally appropriate. Dr. Bach pointed out that along with the obvious savings associated with using lower-cost regimens, adoption of an episode-based payment model could have the added fiscal benefit of pressuring drug manufacturers to reduce their prices, lowering costs within providers’ budgets. “We believe that our proposal has strong potential to serve as a stepping-off point toward comprehensive payment reform in oncology,” said Dr. Bach.

Burgeoning Cancer Population Researchers at RTI International, Emory University in Atlanta, and the Centers for Disease Control and Prevention found that although over the past 2 decades medical costs for treating cancer have nearly doubled, the main driver for the increased costs is the growing number of cancer cases, not treatment.2 “The number of cancer cases has increased proportionately more than medical expenditures, indicating that the increase in the cost of treating cancer has been driven mainly by the increase in the number of cases and not by the cost per treated cancer case,” coauthor Justin Trogdon, PhD, told The ASCO Post. He added that early detection and enhanced prevention

along with longer survival rates is going to play a large role in cancer trends and their related costs,” said Dr. Yabroff. Using linked SEER-Medicare data, Dr. Yabroff and colleagues have looked at cancer costs across three periods: the initial phase, defined as the first 12 months after diagnosis; last-year-of-life phase, defined as the final 12 months of life; and continuing phase, defined as all months between the initial and last-year-of-life phases of care. Allowing for survival variations in certain cancers, the NCI researchers found that the costliest phases of care were the initial and last year of life. Dr. Yabroff commented that parsing the exact drivers of costs is difficult. However, her studies have shown that costs of hospitalizations and greater use of surgery and adjuvant therapy among the elderly

The cost of treating cancer has been driven mainly by the increase in the number of cases and not by the cost per treated cancer case. —Justin Trogdon, PhD

are sound strategies for addressing the upcoming cancer population problem. In an interview with The ASCO Post, Robin Yabroff, PhD, MBA, an epidemiologist in the Health Services and Economics Branch of NCI, concurred that our population was a major driver of cancer care spending. “The U.S. population is aging and growing, which has a major influence on the rising costs of cancer care. A higher absolute number of newly diagnosed patients with cancer

are also contributors. “The larger number of patients with cancer is a trend that we can comfortably predict as continuing and a future driver of cancer care costs. There’s more uncertainty about how treatment trends will impact the costs of care in the future,” said Dr. Yabroff.

Conclusions It is projected that in 2011, healthcare spending in the United States will cost approximately $2.7 trillion, ac-

Visit The ASCO Post website at:

counting for almost 18% of our gross domestic product (GDP). We spend more per person and a greater proportion of GDP on health care than any other country. Cancer care costs are about 5% of our total health-care spending, and although we have seen major advances in treatments and survival rates over the past several decades, if the escalating growth in oncology spending remains unchecked, it will contribute to the greater ills and insolvency facing vital parts of our delivery system. Finding value within the multiple layers of our cancer care delivery system is an enormous challenge that requires honest examination of which therapeutic strategies provide the best, most costeffective outcomes. Studies have shown that although the quantity and costs of services and drugs have increased at disquieting rates, it is the sheer number of new cases and longer survival rates of patients with cancer that are the main drivers of burgeoning spending. Expenditures will be of even greater concern as the baby boomer population begins swelling the already financially stressed Medicare program in 2011. Identifying and understanding the drivers of costs help policymakers and health-care experts wrestle with possible solutions.

■

Disclosure: Dr. Bach has received speaking fees from Genentech. Drs. Buzdar and Trogdon reported no potential conflicts of interest.

References 1. Bach PB, Mirkin JN, Luke JJ: Episode-based payment for cancer care: A proposed pilot for Medicare. Health Affairs 30:500-509, 2011. 2. Tangka FK, Trogdon JG, Richardson LC, et al: Cancer treatment cost in the United States: Has the burden shifted over time? Cancer 116:3477–3484, 2010.

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PAGE 31

Psychosocial Oncology

Evaluating Risk for Suicide in People Diagnosed or Living with Cancer By Andrew J. Roth, MD

he challenges of life-threatening physical illness can sometimes lead to suicide. In fact, given the critical stressors that a person with cancer faces, we might expect suicide to be a more common reaction. Patients with cancer are at increased risk of completed suicide, though the prevalence

Andrew J. Roth, MD

cers.3 Older adults have the highest rate of suicide compared with any other age group. Given the increasing numbers of older people being diagnosed with cancer, we are likely to see an upturn in those at risk for suicide. Several studies have shown that suicide among older patients with cancer is higher than in patients with other medical illnesses, after controlling for psychiatric illness and risk of dying within a year.4‑7 The presence of a physical condition is a risk factor for suicidal behavior even in the absence of mental disorder or when controlling for depressive illness and alcohol use.8,9 The risk is increased with the number of physical ailments.

Suicidal Ideation of suicidal ideation among these individuals is equivalent to that seen in the general population.1 A review of Surveillance, Epidemiology, and End Results (SEER) data found 0.2% of patients diagnosed with cancer committed suicide, most within the first year after diagnosis. Suicidal risk appears to peak in the first month after diagnosis2 and may remain high for a few months thereafter. Suicide is significantly increased in male patients with respiratory can-

Suicidal ideation is frightening and upsetting for the patient, the family, and the oncology team members. Often suicidal thoughts may be considered a potentially treatable coping response, but one that needs to be identified and addressed in a timely manner. Though suicidal ideation may be prevalent among patients with cancer,10 it is not usually a sign of imminent harm. Understanding the identifiable risk factors and interventions to prevent bad outcomes are impor-

Table 1: Questions for Assessing Suicide Risk in Patients with Cancer Acknowledgement

Open with the following statement (which does not enhance risk):

■■ Most patients with cancer have passing

thoughts about suicide, such as “I might do something if it gets bad enough.”

■■ Have you ever had thoughts like that? ■■ Have you had any thoughts of not wanting to

live or that it would be easier if you were to die?

Seriousness

■■ Do you have thoughts of suicide? ■■ Have you planned for it? ■■ Have you thought about how you would do it?

Prior history

■■ Have you ever been depressed or made a suicide attempt?

■■ Have you ever been treated for other psychiatric problems?

■■ Have you been psychiatrically hospitalized before being diagnosed with cancer?

Substance use

■■ Have you ever had a problem with alcohol or

Bereavement

■■ Have you lost anyone close to you recently

drugs?

(family, friends, or fellow patients)

Adapted from Roth AJ, Holland JC: Psychological Aspects of Hematologic Malignancies, in Wiernik PH, Goldman JM, Dutch JP, et al (eds): Neoplastic Diseases of the Blood, 4th edition, pp 1161. New York, Cambridge University Press, 2003.

tant for oncologists, oncology nurses, consultants, and ancillary services participating in oncology treatment, including social workers, physical and occupational therapists, and nutritionists.11 Some propose screening specifically for suicidal ideation, as distinct from general depressive symptoms. Passive thoughts of wanting to die may occur quite frequently, particularly in the setting of advanced physical disease, and may serve as a mechanism of control over fears of an uncertain future of suffering based on worst case scenarios that come to mind when people think of cancer-related deaths. It is not unusual for people to think in a conditional manner, especially when they are not very debilitated, “If the pain gets bad enough, I will end my life,” or “If I start to lose my faculties I would want to die.” Suicidal statements may reflect an offhand comment resulting from frustration or disgust with a treatment course: “If I have to have one more MRI this year, I’ll kill myself.” However, an indication of significant despair may also be heard: “I can no longer bear what this disease is doing to all of us; I feel like such a burden. I think everyone would be better off without me.” Exploring the seriousness of the thoughts is imperative. Table 1 lists questions for assessing suicidal ideation in patients with cancer. It is important to ask if the patient has made a definite plan. Is the patient stockpiling medication? Does he or she own or have access to a weapon?

Risk Factors There are several important predictors of suicide risk (Table 2), including psychological and medical variables: history of a psychiatric disorder, particularly depression or substance abuse; recent bereavement; few social supports; poorly controlled pain; advance stage of disease with debilitation; mild delirium with poor impulse control; and hopelessness or helplessness in the context of depression. Addressing the medical and psychiatric variables with commitment to therapy may reduce suicidal ideation and risk. If the patient is actively suicidal, a 24hour companion should monitor the patient’s behavior. Bolund12 reports that fully half of all Swedish cancer suicides had previ-

Table 2: Factors That May Identify a Higher Risk for Suicide Medical History

■■ Poorly controlled pain ■■ Advanced stage of disease ■■ Mild delirium/mental status changes with poor impulse control

Personal History

■■ Prior psychiatric history/prior suicide attempts

■■ Substance abuse ■■ Recent bereavement ■■ Few social supports ■■ Hopelessness ■■ Family history of suicide ously conveyed suicidal thoughts or plans to their relatives. In addition, many of the completed cancer suicides had been preceded by an attempted suicide. This is consistent with the statistics for suicide in general, which show that a previous suicide attempt greatly increases the risk of completed suicide.13-15 A family history of suicide is of increasing relevance in assessing suicide risk. Patients with advanced illness are at highest risk, perhaps because they are most likely to have such complications as pain, major depression, delirium, and deficit symptoms. Suicidal ideation has also been reported as an uncomfortable activating, disinhibiting, or depressive side effect of medications that may be prescribed for patients with cancer, including antidepressants,16 steroids, opioids, benzodiazepines, asthma medications, interferon, and hypnotics. This does not mean we should limit the use of these medications, but we should provide appropriate information and follow up. Psychiatric disorders are frequently present in hospitalized patients who are suicidal.17,18 Farberow and colleagues19 reported that 86% of suicides occurred in the preterminal or terminal stages of illness, despite greatly reduced physical capacity. Poor prognosis and advanced illness usually go hand-in-hand. It is thus not surprising that in Sweden, those who were expected to die within a matter of months were the most likely to commit suicide. Uncontrolled pain in patients with cancer is a dramatically important continued on page 34

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

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

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

The ASCO Post | AUGUST 15, 2011

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Psychosocial Oncology

Suicide Risk in Patients with Cancer continued from page 31

risk factor for suicide. In several studies, the vast majority of cancer-related suicides were committed by patients with severe pain, which was often inadequately controlled and poorly tolerated.12,20

Depression Depression is a factor in 50% of all suicides. Approximately 25% of all patients with cancer experience severe depressive symptoms, including major depression.21,22 Among those with advanced illness and progressively impaired physical function, symptoms of severe depression rise to 77%.23 Depression also appears to be important in terms of patient preferences for life-sustaining medical therapy. Ganzini et al24 reported that among elderly depressed patients, an increase in the desire for life-sustaining medical therapies followed treatment of depression in subjects

Jimmie Holland, MD, Guest Editor

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

who had been initially more severely depressed, more hopeless, and more likely to overestimate the risks and to underestimate the benefits of treatment. They found that patients with mild to moderate depression are unlikely to alter their decisions regarding life-sustaining medical treatment (despite treatment for their depression). However, they concluded that severely depressed patients—particularly those who are hopeless—should be encouraged to defer advance treatment directives until after treatment of their depression.

Helplessness A sense of helplessness in the face of illness is an important factor in suicide vulnerability.25 Helplessness and a loss of control may be induced by symptoms or deficits due to the illness or its treatments, as well as the excessive need on the part of some patients to be in control of all aspects of living or dying. Being left to face illness alone may create a sense of isolation and abandonment that also leads to the development of hopelessness. It is not uncommon for illnessrelated events to induce a great sense of helplessness even in those who are not typically controlling individuals. Impairments or deficits induced by the patient’s illness or its treatments often include loss of mobility, paraplegia, loss of bowel and bladder function, amputation, aphonia, sensory loss, and inability to eat or swallow. Most distressing to patients is the sense that they are losing control of their minds, especially when they are confused or sedated by medications. The risk of suicide is increased in patients with such physical impairments, especially when accompanied by psychological distress and disturbed interpersonal relationships due to these deficits.20

Management The management of a patient with cancer who is suicidal is based on the following goals: developing and maintaining a supportive relationship and trustworthy communication; assessing the risk and status of suicidal ideation,

intent, and plan to hurt oneself; and offering the patient a sense of control by helping him or her to focus on that which can be controlled. Moreover, it is essential to convey the attitude that much can be done to improve the quality, if not the quantity, of life. Thus, it is important to actively treat the symptoms of pain, nausea, insomnia, anxiety or restlessness, depression, confusion, and fatigue.

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Disclosure: Dr. Roth reported no potential conflicts of interest.

References 1. Robson A, Scrutton F, Wilkinson L, et al: The risk of suicide in cancer patients: A review of the literature. Psychooncology 19:1250-1258, 2010. 2. Johnson TV, Garlow SJ, Brawley OW, et al: Peak window of suicides occurs within the first month of diagnosis: Implications for clinical oncology. Psychooncology. January 24, 2011 (early release online). 3. Hem E, Loge J, Haldorsen T, et al: Suicide risk in cancer patients from 1960 to 1999. J Clin Oncol 22:4209-4216, 2004. 4. Chochinov HMC, Wilson KG, Enns M, et al: Desire for death in the terminally ill. Am J Psychiatry 152:1185-1191, 1995. 5. Breitbart W, Rosenfeld B, Pessin H, et al: Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA 284:29072911, 2000. 6. Rosenfeld B, Breitbart W, Stein K, et al: Measuring desire for death among patients with HIV/AIDS: The schedule of attitudes toward hastened death. Am J Psychiatry 156:94-100, 1999. 7. Rosenfeld B, Breitbart W, Galietta M, et al: The schedule of attitudes toward hastened death: Measuring desire for hastened death in terminally ill cancer patients. Cancer 88:2868-2875, 2000. 8. Scott KM, Hwang I, Chiu WT, et al: Chronic physical conditions and their association with first onset of suicidal behavior in the world mental health surveys. Psychosom Med 72:712-719, 2010. 9. Druss B, Pincus H: Suicidal ideation and suicide attempts in general medical illnesses. Arch Intern Med 160:1522-1526, 2000. 10. Walker J, Waters RA, Murray G, et al: Better off dead: Suicidal thoughts in cancer patients. J Clin Oncol 26:47254730, 2008. 11. Valente SM: Oncology nurses’

knowledge of suicide evaluation and prevention. Cancer Nurs 33:290-295, 2010. 12. Bolund C: Suicide and cancer: II. Medical and care factors in suicide by cancer patients in Sweden. �� 1973-1976. J Psychosoc Onc 3:17-30, 1985. 13. Zweig R, Hinrichsen G: Factors associated with suicide attempts by depressed older adults: A prospective study. Am J Psychiatry 150:1687-1692, 1993. 14. Dubovsky SL: Averting suicide in terminally ill patients. Psychosomatics 19:113-115, 1978. 15. Murphy GE: Suicide and attempted suicide. Hosp Pract 12:78-81, 1977. 16. Nishida T, Wada M, Wada M, et al: Activation syndrome caused by paroxetine in a cancer patient. Palliat Support Care 6:183-185, 2008. 17. Breitbart W: Cancer pain and suicide, in Foley K, Bonica JJ, Ventafridda V (eds): Advances in Pain Research and Therapy, vol 16, pp 399-412. New York, Raven Press, 1990. 18. Breitbart W: Suicide in cancer patients. Oncology 1(2):49-55, 1987. 19. Farberow NL, Schneidman ES, Leonard CV: Suicide among general medical and surgical hospital patients with malignant neoplasms. Medical Bulletin 9; Washington, DC; U.S. Veterans Administration; 1963. 20. Farberow NL, Ganzler S, Cuter F, et al: An eight year survey of hospital suicides. Suicide Life Threat Behav 1:184201, 1971. 21. Chochinov HMC, Wilson K, Enns M, et al: Prevalence of depression in the terminally ill: effects of diagnostic criteria and symptom threshold judgments. Am J Psychiatry 151:537-540, 1994. 22. Massie MJ, Holland JC, Straker N: Psychotherapeutic interventions, in: Holland JC, Rowland JH (eds): Handbook of Psychooncology: Psychological Care of the Patient with Cancer, pp 455-469. New York, Oxford University Press. 1989. 23. Breitbart W, Jaramillo JR, Chochinov HM: Palliative and terminal care, in Holland JC, Breitbart W, Jacobsen PB, et al (eds): Psycho-oncology, pp 437449. New York, Oxford University Press. 1998. 24. Ganzini L, Lec MA, Heintz RT, et al: The effect of depression treatment on elderly patients’ preferences for lifesustaining medical therapy. Am J Psych 151:1613-1616, 1994. 25. Chochinov HM, Wilson KG, Enns M, et al: Depression, hopelessness, and suicidal ideation in the terminally ill. Psychosomatics 39:366-370, 1998.

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JCO Spotlight Hematology

Combined Therapy Produces Good Outcomes in Primary Testicular Diffuse Large B-cell Lymphoma By Charlotte Bath

systemic control of the disease with no contralateral testis relapses and a low incidence of central nervous system relapse. They added that the accept-

B:8.625 in

able toxicity profile of treatment seen in T:7.625 in their trial was remarkable considering S:6.75 in that, as usual for this disease, half the patients were over age 65.

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Reference 1. Vitolo U, et al: J Clin Oncol 29:27662772, 2011.

C M

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Cosmos Communications 718.482.1800 1 Q1 LS 06.21.11 133 M8

inal results of an international phase II trial of first-line treatment for primary testicular diffuse large B-cell lymphoma show that using a combined treatment strategy including chemotherapy and central nervous system and testicular prophlaxis “was associated with a good outcome.” The results were reported in the Journal of Clinical Oncology.1 Radiotherapy prevented contralateral testis relapses, but central nervous system prophylaxis JOB#: 10157 PROOF#: 1 “deserves further investigation,” the inCLIENT: Exelixis vestigators stated. DESC: Advertorial Color: 4C Conducted by AD: TBrancaccio TRAFFIC: EAnonuevo International the OPERATOR: md Extranodal LymGALLEY#: 1 DATE: 2011/06/21 phoma- 16:50 Study Group CREATED: 6/20/11 - 10:14 AM and the FONTS:(IELSG) Neo Sans Pro Medium, Neo SEE PAGE 45 Sans Pro Bold, Neo Sans Pro Regular, Italian Lymphoma Helvetica Neue LT Std 77 Bold Condensed, Neue LT Std 47 Foundation, the trialHelvetica (IELSG-10) inLight Condensed, Helvetica Neue LT Std volved 53 patients, aged 22 to 79, with 47 Light Condensed Oblique 10157_ untreated stageIMAGES: I orExelixis_KO.eps, II primary testicuJA_twk.tif C=24lymphoma. M=0 Y=98 K=8, lar diffuse largeCOLORS: B-cell The M=7 Y=80 K=0, Paper treatment plan C=0 consisted of six to eight NOTES: DOC PATH: EXL_XLX_Q10157:EXL_ courses of R-CHOP (rituximab [RituxXLX_Q10157_JA_D01.indd an] added to cyclophosphamide, doxoDOC SIZE: 10” X 13” PRINT SCALE: 100% rubicin, vincristine, and prednisone) every 21 days (R-CHOP21), CNS prophylaxis with four doses of intrathecal methotrexate, and radiotherapy to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease. Y K

Patient Outcomes

One patient experienced progressive disease at nodal and extranodal sites during treatment and died. All the others achieved a complete response. At a median follow-up of 65 months, the 5-year progression-free survival rate was 74% and overall survival rate was 85%. Nine patients relapsed; five of those patients died of lymphoma and the other four had salvage therapy. The 5-year cumulative incidence of central nervous system relapse was 6%, and no contralateral testis relapses occurred. A total of 10 patients died, none from toxicities, which were mild during the R-CHOP21 treatment. Grade 3/4 toxicities included hematologic effects (28%), neurologic effects (13%), and infections (2%). The investigators concluded that combined treatment with R-CHOP21 plus central nervous system and testicular prophylaxis is a promising approach for primary testicular diffuse large Bcell lymphoma, achieving an effective

Despite advances in targeted cancer therapy,

an important escape pathway remains: MET Although advanced antitumor therapies have become available, many tumor types continue to evade treatment.1 Research has identified the MET pathway as one of the most critical escape pathways utilized by tumors. In most normal tissues, MET and its only known ligand, hepatocyte growth factor (HGF), are found in low levels. But in a range of malignancies—including thyroid, prostate, ovarian, lung, and breast cancers—MET is upregulated and drives more invasive and aggressive behavior of tumor cells, resulting in metastasis.2-7 Recent evidence also shows that inhibition of angiogenesis creates hypoxic conditions in the tumor that may further upregulate MET and ultimately promote disease progression.5,7 Exelixis is fully devoted to shutting down MET-driven escape in cancer. Therefore, we are investigating the dual targeting of the MET and VEGF pathways to simultaneously inhibit metastasis and angiogenesis in several cancers.

Visit www.METinhibition.com to learn more about the role of MET in tumor escape. References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. http://seer.cancer.gov/csr/1975_2008/. Accessed May 10, 2011. 2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth [draft manuscript]. 2011. Data on file, Exelixis, Inc. 3. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 4. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109:863-867. 5. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347-361. 6. Capdevila J, Argiles G, Rodriguez-Frexinos V, Nuñez I, Tabernero J. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med. 2010;9:153-162. 7. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207-2214.

The ASCO Post | AUGUST 15, 2011

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In the News Genitourinary Cancer

Optimizing Treatment for Advanced Prostate Cancer Requires Shifting Focus from Individual Drugs to Integrated Therapies By Charlotte Bath

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

ewer drugs, including sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone (Zytiga), can extend survival modestly and ease symptoms for men with advanced prostate cancer. Maximizing the benefit to patients will require shifting the focus from developing individual drugs to developing integrated therapies, according to Christopher J. Logothetis, MD, Chair of the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “There are multiple new drugs available to patients with advanced prostate cancer. While each drug works individually, we believe developing optimal combinations and sequences with these drugs is the key to further improving therapy,” Dr. Logothetis said. “By developing a manual on how to use prostate cancer drugs in optimal combinations and sequences, we will be able to design therapies that are greater than the sum of the individual drugs,” Dr. Logothetis explained in an interview with The ASCO Post.

Unique Opportunity “When you look at other cancer types, the greatest clinical benefit has come from using drugs at the right time during the course of the disease and in the right combinations. What is unique about prostate cancer, however, is that the disease is relatively slower-growing and less threatening in the immediate term than other cancer types. This creates an opportunity for clinical research with drug combinations that will actually help the patient being treated in the study and not just create knowledge for the next generation of patients. If drug development is moving quickly enough and the disease is growing slowly enough, the patient can choose to participate in research for both altruistic and pragmatic reasons. In essence, we are prescribing research to help him.”

Developing a manual for using prostate cancer drugs “is both straightforward and difficult,” Dr. Logothetis said. “The task is straightforward in the sense that different individual drug companies appreciate it is in their best interests to collaborate and design trials that optimize the most effective drug combinations. It is clear a shared clinical research platform needs to develop very quickly.” More complex and difficult may be the job of designing trials in which data collected from one trial are interpreted not only in the context of that trial,

but also integrated with data sets from other trials. “What we are advocating is the creation of a new set of trial designs that allow us to look at the consequences of one therapy and how it impacts another,” Dr. Logothetis said. He also advocates “creating a new set of biomarkers that are specific to both the disease and the drug and integrate them to see if they change over time.”

Empiricism and Beyond Choosing which drug to administer to a patient with prostate cancer is cur-

rently based on “empirically derived general rules that have not always been critically tested,” Dr. Logothetis said. “For example, one general rule is that patients who have disease with symptoms or the impending likelihood of symptoms should receive chemotherapy, while patients with less symptomatic, lower-volume disease should initially receive less toxic therapies like immunotherapies.” While this seems logical, there is little evidence to back it up, he said. With sipuleucel-T, an immunothercontinued on page 38

Expect Questions from Your Patients

rugs for the treatment of prostate cancer have been in the news because of recent approvals by the FDA, the costs connected with their use, and associated improvements in survival.1 More recently reported was the decision to allow Medicare coverage of sipuleucelT treatment for men who met the FDA approval criteria. The following information may be helpful for physicians fielding questions from patients who have read or heard about these new drugs and want to know if the drugs are right for them. What is the FDA-approved use for sipuleucel-T? Sipuleucel-T (Provenge) was approved in April 2010 for the treatment of v or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer. A cellular immunotherapy, sipuleucel-T consists of autologous peripheral blood mononuclear cells activated with a recombinant human protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor (PAP–GM-CSF). Common adverse reactions reported in safety evaluations were chills, fatigue, fever, back pain, nausea, joint ache, and headache. What is the FDA-approved use for cabazitaxel? Cabazitaxel (Jevtana), a taxane, was approved in June 2010 for use in combination with prednisone to treat metastatic, hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. In clinical trials, the most common grade 3/4 adverse

reactions were neutropenia, leukopenia, anemia, diarrhea, fatigue, and asthenia. What is the FDA-approved use for abiraterone? Abiraterone (Zytiga) was approved in May 2011 for the treatment of men with metastatic, castrate-resistant prostate cancer who are no longer responding to docetaxel. According to the NCI, “abiraterone is the first in an approaching wave of new agents for prostate cancer that, directly or indirectly, target testosterone.”2 Abiraterone “can also be considered in patients who have symptomatic disease who are not good candidates for chemotherapy” and might be used before chemotherapy, noted Christopher J. Logothetis, MD, of The University of Texas MD Anderson Cancer Center. “The study of abiraterone in patients who have not yet received docetaxel-based chemotherapy has completed accrual, and the results will hopefully be available this year. The results from that study will provide insights into optimizing the sequence of abiraterone and chemotherapy.” What other new drugs are being used for patients with prostate cancer? Denosumab (Xgeva) is a monoclonal antibody that was approved in June 2010 for the prevention of skeletal-related events in patients with metastases from solid tumors, including prostate cancer. Denosumab can be used for “the relief and delay of bone symptoms” and “should be considered a supportive agent,” Dr. Logothetis said, but “does not impact survival.”

Christopher J. Logothetis, MD

Cabozantinib (XL184) has not received FDA approval but has been shown in a phase I clinical trial to shrink prostate tumors or stop their growth and shrink bone metastases in most patients with prostate cancer. The FDA granted orphan drug designation to the agent in January 2011. Dr. Logothetis called cabozantinib a “very exciting drug” and said that this targeted therapy “may be particularly relevant because it blocks c-Met and VEGF, two pathways that are known to integrate with androgen signaling.” Cabozantinib has potential toxicities, however, as evidenced by the deaths of six participants in the randomized discontinuation trial of cabozantinib, reported at the 2011 ASCO Annual Meeting. Studies are presently underway to identify the safest, most effective dose of this drug in patients with advanced prostate cancer.

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References 1. Pollack A: New drugs fight prostate cancer, but a high cost. New York Times, June 27, 2011. 2. FDA approves abiraterone for advanced prostate cancer. NCI Cancer Bulletin 8:9, May 3, 2011.

The case for Vectibix® Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION: Vectibix® is indicated as a single agent for the treatment of occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus

epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical irinotecan-containing chemotherapy regimens. studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing pulmonary fibrosis and resulted in death. The second patient had symptoms of mCRC is based on progression-free survival. Currently, no data demonstrate an pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently improvement in disease-related symptoms or increased survival with Vectibix®. discontinue Vectibix® therapy in patients developing interstitial lung disease, Retrospective subset analyses of metastatic colorectal cancer trials have not shown pneumonitis, or lung infiltrates. a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in In a randomized, controlled clinical trial, median magnesium levels decreased by codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring cancer with these mutations. oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred Important Safety Information, including Boxed WARNINGS: 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and treatment (eg, oral or intravenous electrolyte repletion) as needed. were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months (5.1), and Adverse Reactions (6.1)]. after the last dose. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have patients. Fatal infusion reactions occurred in postmarketing experience. [See been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Interrupt or discontinue Vectibix® for acute or worsening keratitis. Reactions (6.1, 6.3)]. Adequate contraception in both males and females must be used while receiving In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to transmitted from the mother to the developing fetus and has the potential to cause the development of severe dermatologic toxicities, infectious complications, including fetal harm when administered to pregnant women. sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and Discontinue nursing or discontinue drug, taking into account the importance of the drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening drug to the mother. If nursing is interrupted, it should not be resumed earlier than dermatologic toxicity and monitor for inflammatory or infectious sequelae. 2 months following the last dose of Vectibix®. Terminate the infusion for severe infusion reactions. The most common adverse events of Vectibix® are skin rash with variable presentations, Vectibix® is not indicated for use in combination with chemotherapy. In an interim hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including analysis of a randomized clinical trial, the addition of Vectibix® to the combination of diarrhea resulting in dehydration. ® bevacizumab and chemotherapy resulted in decreased overall survival and increased The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion adverse reactions occurring at a higher rate in patients treated with Vectibix® included reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration Please see brief summary of Prescribing Information on next page. (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Reference: 1. Vectibix® (panitumumab) stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade prescribing information, Amgen. 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®. In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

The ASCO Post | AUGUST 15, 2011

PAGE 38

In the News

Prostate Cancer Treatment Shift continued from page 36

apy approved for patients with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer, Dr. Logothetis and his colleagues at MD Anderson “generally treat patients who have progressive disease but are relatively

well and whose cancers are not likely to threaten them within the next 6 months with sipuleucel-T,” he explained. “In contrast, patients with more advanced-stage disease who are more likely to develop symptoms receive chemotherapy.” Ideally, in order to prolong patient surTrim: 7.875” vival, the approach to administering prosLive: 7” tate cancer drugs should “move beyond

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. 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 panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in 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, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, 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 panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations]. Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v11, 3/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-E

and cytotoxic therapy so they enhance rather than inhibit each other has not been addressed in clinical trials, he said. “The current FDA-approved indications for both abiraterone and cabazitaxel specify that these agents should be given after docetaxel,” Dr. Logothetis continued, “but we are participating in clinical trials where these drugs are being used before docetaxel. If ever there was an anticipated interaction between agents that block pathways central to prostate cancer progression, it is with these drugs. We believe there is good reason to try these therapies in different sequences,” he explained. “I think the results from these trials are going to rapidly produce major therapy advances that will prolong survival in patients with advanced disease.”

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Disclosure: Dr. Logothetis has received research support and honoraria from Pfizer, Johnson & Johnson, and Bristol-Myers Squibb.

Timing of Prostate Cancer Drugs: Earlier But Not Too Early?

hile sipuleucel-T, abiraterone, and cabazitaxel have been approved for patients with advanced disease, they might also be used in patients with earlier-stage disease, according to Christopher J. Logothetis, MD, of MD Anderson Cancer Center. “I think it is fair to say that they will be used better and more efficiently in a select group of patients early in the disease. There are already trials using abiraterone in the preoperative setting before radical prostatectomy and they show promise in what appears to be an enhanced effect on the tumor,” he reported. “The unique problem with prostate cancer is that ‘earlier therapy’ can sometimes be too early,” Dr. Logothetis said. “If patients are only exposed to the drugs for 5 years, the side effects may be modest, but if patients live for an entire decade or more, continued exposure to therapy may be significantly more toxic. The goal is to offer therapies after the cancer has demonstrated its potential to get aggressive, but before the cancer is visibly causing problems. To do this, we need to develop better biomarkers that identify the transition to an aggressive cancer before it becomes obvious clinically,” he said

Trim: 10.75” Live: 10”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information]. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information]. DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

empiricism to a rational process based on understanding the underlying biology of the pathways these drugs target,” Dr. Logothetis stated. “For example, I think there is a real sense of urgency to better understand precisely how immunotherapies like sipuleucel-T interact with chemotherapy.” The critical question about how optimally to use immunotherapy

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Expert’s Corner Integrative Oncology

A Conversation with Barrie R. Cassileth, PhD

Separating quackery from legitimate integrative oncology care practices By Jo Cavallo

Barrie R. Cassileth, PhD

arrie R. Cassileth, PhD, Chief, Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, recently spoke with The ASCO Post about her quest to stamp out the illegitimate use of alternative medicine in cancer care and the results from her latest research. A researcher and educator about complementary practices for more than 30 years, Dr. Cassileth launched the Integrative Medicine Service at MSKCC 12 years ago to provide patients with integrative oncology care, to research the effectiveness of complementary therapies in improving patients’ specific symptoms, and to investigate the potential adjunctive antitumor effects of botanical agents.

Role of Integrative Oncology What is the role of integrative medicine in cancer care? Complementary interventions in oncology are adjunctive. They are not substitutes for conventional cancer treatment. Integrative medicine offers something that is much needed in oncology: a greater focus on controlling the serious physical and emotional symptoms that patients experience primarily as a consequence of today’s often effective cancer treatments. There is substantial evidence that a range of complementary modalities can, in fact, relieve many common symptoms, including pain, hot flashes, sexual dysfunction, urinary problems, fatigue, xerostomia, anxiety, depression, stress, osteoarthritis, shortness of breath, neuropathy, and lymphedema.

What types of integrative therapies are used in cancer care? We focus on six main categories of integrative care at MSKCC. These include acupuncture, massage therapies, and mind/body therapies, such as meditation and self-hypnosis. We also have a heavy emphasis on fitness and movement therapies because there is a survival advantage for many patients with cancer who engage in regular physical activity after diagnosis. Music therapy is profoundly helpful, particularly for those who are noncommunicative or terminally ill. Not only does it relax patients and reduce stress and pain, music therapy also reduces mood disturbance. We showed that in a randomized clinical trial. Nutrition and supplement counseling is the sixth main area of our clinical and research focus. We established the About Herbs website (mskcc.org/aboutherbs) because it was clear that this kind of information was sorely needed by both oncology professionals and patients. The site is free and now contains more than 250 continuously updated entries of evidence-based information. Judging by the number of hits and emails we receive, this award-winning website is clinically useful to oncology professionals from around the world. A second portal contains simplified information for patients. Anyone can enter either portal at no cost. We have also been studying botanicals, particularly medicinal mushrooms. We are exploring whether their immune-enhancing ability makes them potentially useful as adjuncts to mainstream cancer treatment. Many herbal compounds are used for medicinal purposes in areas of the world that rely on traditional medicines. In the developed world, they are often promoted and used inappropriately.

Acceptance of Integrative Medicine Are oncologists in the United States more receptive to the inclusion of integrative practices in traditional cancer therapies than oncologists in other parts of the world? There’s no question about it. Today, virtually every U.S. cancer program has an integrative medicine

Making Evidence-based Integrative Medicine Part of Mainstream Cancer Care

uring the 1960s and 1970s, the concept of a holistic approach to treating disease that took into account the body, mind, and spirit grew in patient popularity and morphed into two basic categories: alternative and complementary, which later became known by its acronym CAM (complementary and alternative medicine). However, because alternative therapy refers to unproven or disproven treatments that have no place in legitimate cancer care, integrative medicine experts, including Barrie R. Cassileth, PhD, Chief, Integrative Medicine Service at Memorial SloanKettering Cancer Center in New York, say the terminology is misleading and confusing and needs to be abandoned. Even the term “integrative medicine” can be misleading, said Dr. Cassileth, who instead uses a more accurate term to describe the practice of integrative oncology: evidencebased complementary medicine. “Evidence-based complementary medicine refers to interventions that are rational and that have been found useful as adjuncts for purposes of symptom control,” said Dr. Cassileth in an interview with The ASCO Post. “These therapies are not said to cure cancer. And they are not offered, promised, or sold as treatments to use instead of chemotherapy, radiation, or surgery. These therapies are meant to be used in combination with mainstream cancer treatment.”

Raising Awareness By making the term evidence-based complementary medicine more commonplace, Dr. Cassileth is hoping to educate both medical professionals and patients about the helpful, appropriate complementary therapies that are available, and distinguish them from the all-too-available questionable approaches. “If promoted techniques are found to be worthless or if they are patently absurd, such as homeopathy, they should be avoided. The medical world is in turmoil around these issues, and the public typically cannot tell the difference between viable interventions and quackery. I spend half my time studying whether complementary approaches relieve patients’ specific physical and emotional symptoms and the other half trying to get rid of quackery. It’s not an easy task,” said Dr. Cassileth.

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service of some kind. It may be as small as a massage therapist a halfday a week or a music therapy program once a month, but most major cancer programs in North America have more substantial sets of activities. They may not be as full-blown as ours in the sense that we cover every academic base: inpatient and outpatient care, research, education, and training. I see the United States as about a decade ahead of other countries in this regard, but the rest of the world is catching up. Our department at MSKCC was consciously developed as a prototype that others could learn from and use parts of in their own hospitals. We have had the heads of hospitals from the U.S. and many

other countries come to visit seeking advice about developing their own integrative medicine program, and they leave with a plan to develop an integrative medicine unit at their institutions.

Ongoing Research Talk about your research in botanicals and herbs, as well as in other integrative disciplines in cancer care. In general, I think the most important issue concerning medicinal herbs, other botanical agents, and most dietary supplements is that they should be avoided by people on active cancer treatment. Herb-drug interactions represent a serious concern. Herbal remedies can prolong continued on page 41

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Expert’s Corner

Barrie R. Cassileth, PhD continued from page 39

bleeding and create other problems. There are a number of really good reasons not to use dietary supplements during cancer treatment. Avoiding them is MSKCC policy. Our current research focuses on an extract from the maitake mushrooms, which has immuneenhancing potential. We have a study underway involving patients with myelodysplastic syndromes (MDS), to see whether the mushroom extract makes a difference clinically. We know, for example, that the extract increases neutrophil count and function in laboratory animals and in an early clinical study of patients with cancer. Our current phase II trial seeks to determine whether the extract enhances hematopoiesis in patients with MDS. Hopefully, we’ll find that neutrophil count and function are improved, and if that’s the case, we’ll move toward a larger study to look at survival and other responses. (For information about patient accrual, contact principal investigator Kathleen Wesa, MD, at 646-888-0845 or visit the Memorial Sloan-Kettering Cancer Center website at mskcc.org/mskcc/html/2270. cfm?IRBNO=09-094.) We are also doing a very important study with vitamin D. Our retrospective analysis of banked sera

from patients with colorectal cancer showed a strong relationship between length of survival and vitamin D levels. We’re now working on a similar study of data from patients with breast cancer and toward a prospective study to see whether replenishing patients’ vitamin D levels improves survival. We are also enthusiastic about our acupuncture research program, and we’re about to complete a study of acupuncture treatment for lymphedema. We first conducted a small pilot to make sure that acupuncture was safe. It was. The study had a stopping rule: achieving at least a 30% reduction in lymphedema in a minimum of 40% of patients. The study stopped very quickly. Now we are embarked on a larger pilot with a mechanism component.1 The regimen is two acupuncture treatments a week for 4 weeks and then monthly follow-up phone calls to make sure that no adverse late events occur. These are important areas of research for us.

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Disclosure: Dr. Cassileth reported no potential conflicts of interest.

Reference 1. Cassileth BR, Van Zee KJ, Chan Y, et al: A safety and efficacy pilot study of acupuncture for the treatment of chronic lymphoedema. Acupunct Med. June 18, 2011 (early release online).

The ASCO Post

Wants to Hear from You

First International Conference on Integrative Care

ast March, nearly 250 oncology professionals and representatives of patient organizations, insurance companies, and government agencies from 12 countries attended the First International Conference on Integrative Care for the Future held in Amsterdam. Barrie R. Cassileth, PhD, chaired the event. She explained that the goals of the conference were to raise awareness of evidence-based research in complementary therapies that effectively reduce troubling side effects associated with cancer and cancer treatment, and to distinguish the legitimate practice of integrative oncology from the big business of bogus alternative cancer cure claims. What was accomplished at the Conference on Integrative Care for the Future? Integrative medicine for cancer is in a peculiar position in the sense that it gets attacked from both ends of the cancer care spectrum. It is criticized at times by mainstream oncology—more so in Europe than in the United States—as being quackery, which adamantly it is not. The complementary therapies that are being used and studied today in major academic centers are rational, evidence-based interventions. At the other end of the spectrum, in Europe and in other parts of the world, purveyors of bogus “treatments” have taken over the term “integrative medicine.” In Europe especially, integrative medicine and integrative oncology have become synonymous with quackery. An important issue that emerged at this conference was the extent to which quackery is a huge problem throughout Europe and in other parts of the world. In the United States, where quackery has been prominent for many decades, it is a $40 billion-a-year business. And that hinders the use of legitimate integrative care if patients are confused about the meaning of integrative medicine? Absolutely. It also makes it very difficult for health-care professionals because they’re not always sure what the terms integrative medicine and integrative oncology imply. Words have meaning, and they can have a detrimental as well as clarifying impact. We fought very hard to get away from the term “alternative therapy” because there are no viable alternatives to mainstream cancer care. We have to clarify the terminology, and I am now referring to complementary therapies as “evidence-based complementary medicine.”

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

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TAP Caucus Hematology Point of View

Should Patients Over 70 Receive Aggressive Therapy for Acute Myeloid Leukemia? By Charles A. Schiffer, MD, and Farhad Ravandi, MD

he outcome of treatment of older adults with acute myeloid leukemia (AML) remains unsatisfactory, although certainly not a totally futile exercise. Patients satisfying the entry criteria for cooperative group clinical trials can be expected to have complete remission rates of 50% to 55%, with remission durations of about 9 months, albeit with long-term survival rates of only about 10%. We have seen relatively little Charles A. Schiffer, MD overall improvement in outcome for this population in recent decades. Nonetheless, these patients experience considerable benefit with complete remission, not the least of which is being at home for months with safe blood counts permitting normal activities. Even so, many oncologists, including those who readily treat patients with advanced solid tumors and compromised performance status, are reluctant to offer potentially remission-inducing chemotherapy to older patients with AML. One consideration of course, is the need for 3 to 4 weeks of hospitalization with the possibility that the patient may not survive or ever leave the hospital. However, advances in supportive care—most notably the development

The real dilemma concerns patients who are truly ‘elderly,’ regardless of their exact age, as evidenced by the presence of serious medical and/or cognitive comorbidities. of highly effective antiemetics and replacement of the debilitating and nephrotoxic amphotericin B with the more tolerable imidazoles—have permitted safer delivery of myelosuppressive chemotherapy, and the expected 30-day mortality is now approximately 10%.1

Inadequacy of Age Cutoffs

ver the past several decades, progress in the treatment of acute myeloid leukemia (AML) in the older population (generally considered to be older than 60 years) has been limited (Fig. 1). In particular, the outcome of patients over age 70 has been poor, with few long-term survivors. Although AML is predominantly a disease of older adults, until recently many of the trials had been conducted in the younger population, and much of the available Farhad Ravandi, MD data was inapplicable to the elderly. This was largely attributable to reluctance (by both patients and physicians) to expose older patients to the toxic effects of “standard” chemotherapy. Furthermore, the few trials conducted specifically in the older population generally excluded patients with poor performance status and comorbid medical conditions, again limiting their relevance to community practice. However, several studies have clearly demonstrated the benefit of treatment, showing an improved response rate and survival when older patients with AML receive leukemia-specific therapy, and this is not at the expense of a worsened quality of life.1,2 Using data from the Swedish Leukemia Registry, investigators have reported that the outcome of patients with AML was better in regions where they were more likely to be offered intensive induction chemotherapy.3 In another study, U.S. investigators using data from Medicare administrative claims linked to 11 Surveillance, Epidemiology, and End Results (SEER) registries showed that only about 30% of patients older than 65 were treated with chemotherapy, and the median survival of the entire population was only 2 months.1 Among patients over 70, fewer than 20% received chemotherapy. In a separate analysis, they compared the outcomes of matched patients

Several studies have clearly demonstrated the benefit of treatment, showing an improved response rate and survival when older patients with AML receive leukemia-specific therapy, and this is not at the expense of a worsened quality of life.

The traditional breakpoint between younger and older (sometimes pejoratively termed “elderly”) patients,2 has been between 55 and 60 years of age, probably deriving from historical cutoffs for the application of allogeneic transplantation. Although it is true that the frequency of poor prognostic factors (such as higher-risk cytogenetics, overexpression of multidrug resistance proteins, and AML evolving from prior myelodysplasia) increases in older individuals, it is silly to assume that there are dichotomous differences in leukemia biology according to discrete boundaries in patient age. In addition, age alone is not a reliable surrogate for the ability to tolerate induction chemotherapy, and it is likely that subjective assessments of “performance” can be enhanced by the use of recently developed comorbidity indices. Thus, for patients with adequate baseline medical status and organ function, almost irrespective of age, the first instinct should be to consider standard induction therapy or a well-conceived clinical trial (remembering that many clinical “trials” do not address important questions or are not necessarily well conceived). Standard induction therapy should always be considered in the occasional older patient with “favorable” karyotypes (core binding factor AML, t(8;21) or abn16q22) or nucleophosmin1 (NPM1) mutations).3 The real dilemma concerns patients who are truly “elderly,” regard-

Several studies have shown that conventional induction chemotherapy using the traditional cytarabine-plus-anthracycline regimens is only beneficial in a subset of patients in this population. Although response rates as high as 50% and 60% have been reported in such trials, the inclusion criteria for participation in these studies are generally very stringent, limiting the applicability of conclusions to only the healthiest and fittest patients, typically in the 60- to 70-year-old group. A number of reports have examined the feasibility of intensive cytarabineand-anthracycline–based strategies in the older AML population and have identified risk factors that predict a low response rate, a high induction mortality, and a low likelihood of 1-year survival.4 Among them, age remains an important predictor, with the outcome worse in patients over 70 and 80 years of age. Using such risk scores, it may be possible to better select patients for

continued on page 43

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treated or not treated with chemotherapy and reported approximately a three times higher median and 1-year survival in treated patients.

Patient Selection

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TAP Caucus

Charles A. Schiffer, MD continued from page 42

less of their exact age, as evidenced by the presence of serious medical and/or cognitive comorbidities. Supportive approaches with transfusion and hydroxyurea are suitable for some of these patients. Many other older patients, however, who are otherwise reasonably well and functional, could benefit from therapies with the more modest aim of improvement in blood counts. The hypomethylating agents—azacitidine (Vidaza), decitabine (Dacogen), and, particularly in Europe,4,5 low-dose cytarabine—are now used frequently in the outpatient setting. These agents produce very low rates of complete remission and variable rates of “hematologic improvement,” albeit with the potential for significant cytopenias and hospitalization as well as the need for multiple courses of therapy. 5-8 No randomized trials have compared these putatively “gentler” approaches with standard anthracycline/cytarabine induction therapy.

Different AML Types When considering treatment in this population, it should be noted that AML in older patients can present in a couple of different “flavors”: ■■ “proliferative” AML with hypercellular marrows and rising levels of peripheral blasts ■■ “MDSy” AML (with or without a prior diagnosis of myelodysplastic syndrome) with more than 20% to 30% blasts but with slowly progressive cytopenias The former requires an almost immediate decision about the suitability of intensive induction therapy, while many of the latter patients may not require any treatment, other than perhaps red blood cell transfusion, for long periods of time. It is likely that patients with more slowly proliferative disease are overrepresented in the trials using hypomethylating agents and low-dose cytarabine, and one should be cautious in extrapolating even these modest outcomes to the more general population of older patients with AML.5-7

Limits of Benefit The treatment of less fit older patients has become an active area of clinical research. Portrayed as an “unmet medical need” and a potentially easy target because of the his-

torically poor results, multiple pharmaceutical companies have designed small, sometimes phase II trials in an attempt to get new drugs approved without directly challenging the standard of anthracycline and cytarabine in a phase III trial with survival as an endpoint. In addition to problems in defining a population of

patients who cannot tolerate induction chemotherapy, it has been difficult to prove that the side effects of such treatment are less than what would be expected with “7+3” chemotherapy. This was the major problem, as identified in an FDA review, with a phase II study of clofarabine (Clolar), a drug with considerable

single-agent activity, but with durations of marrow aplasia similar to what occurs after standard induction chemotherapy.8

Conclusion It seems likely that the limits of the benefit from chemotherapy have been continued on page 44

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defined, given the multiple mechanisms of resistance inherent in the stem cell origin of this group of leukemias. Real progress will be difficult but may depend on novel immunologic approaches and hopefully better understanding of stem cell biology. Until better science prevails, this complex decision in older patients is a reminder that there is still an “art” to medicine and that consultations with experienced leukemia centers are often advisable.

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Disclosure: Dr. Schiffer has served as a consultant for Genzyme, Celgene, Ambit, and Ariad. He has received research grants from Ambit, Ariad, and Celgene.

Farhad Ravandi, MD continued from page 42

receiving conventional induction chemotherapy (typically those younger than 65). Clearly, the rest of this population should be offered investigational, less intensive strategies in a clinical trial setting. With increased understanding of the biologic mechanisms of neoplastic transformation and with the identification of the molecular events that lead to leukemogenesis, several new drugs with potential activity in AML have been developed. In many cases, these drugs are targeted at molecular events occurring in specific subgroups of patients, allowing the possibility of a personalized approach with specific drugs used for patients whose leukemia expresses the relevant target. With further advances in the field, more and more such agents will be available, and their use, either as single agents or in combination with other similar drugs, may provide us with more effective, less toxic strategies for treating the older, less fit population.

Risk-Benefit Expectations Therefore, a decision regarding the best strategy should be based on ex-

References 1. Lowenberg B, Ossenkoppele GJ, van Putten W, et al: High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361:1235-1248, 2009. 2. Schiffer CA: “I am older, not elderly,” said the patient with acute myeloid leukemia. J Clin Oncol 28:521-523, 2010. 3. Becker H, Marcucci G, Maharry K, et al: Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: A Cancer and Leukemia Group B study. J Clin Oncol 28:596-604, 2010. 4. Burnett AK, Milligan D, Prentice AG, et al: A comparison of low-dose cytarabine

pected outcomes. Perhaps those with the expectation of a low 8-week mortality, high complete response rate, and reasonable 3-year survival should be treated using conventional regimens, whereas those with a high expectation of initial mortality and low long-term survival should be offered investigational agents. Arguments may be offered both for and against intensive chemotherapy for patients with riskbenefit expectations between these two groups. Clearly, conventional cytarabine/ anthracycline–based strategies are inadequate in the majority of older patients with AML, particularly in those over 70. For these patients, participation in clinical studies of new agents with novel mechanisms of action is highly recommended.

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Disclosure: Dr. Ravandi has received research funding from Sunesis, Bayer/Onyx, and Celgene. He has received honoraria from and served on the advisory board for Genzyme, Eisai, and Cephalon.

References 1. Menzin J, Lang K, Earle CC, et al: The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med 162:1597-1603, 2002. 2. Juliusson G, Billstrom R, Gruber A,

and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109:1114-1124, 2007. 5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10:223-232, 2009. 6. Blum W, Garzon R, Klisovic RB, et al: Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A 107:7473-7478, 2010. 7. Cashen AF, Schiller GJ, O’Donnell

1.0 Survival probability

Charles A. Schiffer, MD

Age ≥ 60 yr

MR, et al: Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556-561, 2009. 8. Kantarjian HM, Erba HP, Claxton D, et al: Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol 28:549-555, 2010. Dr. Schiffer is Professor of Oncology and Medicine, Head of the Multidisciplinary Leukemia/Lymphoma Team, Division of Hematology/Oncology, Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit.

Treatment Era Total Died Median 5-yr < 1970 1970-1979 1980-1989 1990-1999 2000-2009

0.8

40 170 276 572 921

0.6

40 169 274 541 70

0.9 mo 0% 1.6 mo 8% 3.7 mo 5% 5.5 mo 8% 7.4 mo 10%

P < .001

0.4 0.2 0.0 0

4 Years

Fig. 1: Limited progress in treatment of older patients with acute myeloid leukemia. Source: MD Anderson Cancer Center database.

et al: Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival. Leukemia 20:42-47, 2006. 3. Juliusson G, Antunovic P, Derolf A, et al: Age and acute myeloid leukemia: Real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113:4179-4187, 2009. 4. Kantarjian H, O’Brien S, Cortes J,

et al: Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106:1090-1098, 2006. Dr. Ravandi is Associate Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston.

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PAGE 45

In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Venous Thromboembolism More Frequent after Open Colorectal Surgery than Post-laparoscopy The risk of developing venous thromboembolism (VTE) may be nearly twice as high for patients undergoing open colorectal procedures as for those undergoing laparoscopic colorectal resections, according to a report in the Archives of Surgery. The authors also “identified malignancy, obesity, and congestive heart failure as statistically significant (P < .05) risk factors for VTE” in association with open and laparoscopic colorectal surgery. Researchers from the University of California–Irvine Medical Center, Orange, based their findings on National Inpatient Sample data for 149,304 patients who underwent laparoscopic or

open colorectal procedures from 2002 to 2006. Laparoscopic surgeries were performed in 7,848, or 5.3% of the total. While patients undergoing laparoscopic procedures generally had fewer comorbidities than those who underwent open procedures, the most com-

mon pathologic condition overall was cancer of any type, with an incidence of 42.4%, the authors reported.

Data Breakdown Overall, VTE was diagnosed in 2,102 patients (1.4%). The investiga-

tors found that the incidence of VTE was significantly lower in the laparoscopic group (65 patients) than in the open procedure group (2,036 patients)—0.8% vs 1.4%; P < .001. By pathologic condition, patients with continued on page 46

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PAGE 46

In the Literature

Emerging Clinical Data continued from page 45

inflammatory bowel disease had the highest incidence of VTE (1.4%), followed by cancer (1.3%) and diverticulitis (0.9%). By surgical resection site, rectal resection had the greatest incidence of VTE (2.8%), “which may be attributable to the extensive pelvic dissection required with resultant surrounding inflammatory involvement of the pelvic veins,” the authors stated. Factors associated with an increased risk of VTE were limited to congestive heart failure, obesity, and malignancy in the laparoscopic group, but in the open procedure group also included chronic pulmonary disease, pulmonary circulation disorders, and inflammatory bowel disease. “Our findings, therefore, call into question whether we should be using the same risk factors and stratification for [laparoscopic] procedures as we do for [open] procedures because certain risk factors for VTE in a patient undergoing open colorectal surgery do not seem to portend an increased risk of VTE in the same patient undergoing laparoscopic colorectal surgery,” the authors noted. “These study findings may be used by surgeons to more accurately assess a patient’s risk for perioperative VTE as well as to select appropriate thromboprophylaxis in patients undergoing laparoscopic colorectal surgery,” they concluded. Buchberg B, et al: Arch Surg 146:739743, 2011.

Endoscopic Excision May Be Viable Alternative to Surgical Resection of Large Colorectal Polyps A retrospective review of 104 consecutive patients with large colorectal lesions, including 39 with carcinoma, found that “endoscopic excision of large colorectal polyps is a viable alternative to surgical resection in a select group of patients and can be performed safely with a good success rate.” The patients all had lesions “deemed not amenable to endoscopic resection at initial colonoscopy,” most commonly performed for screening (51%) and positive fecal occult blood test results (24%), and had initially been referred for surgical resection. In 68% of the patients the polyps were located in the colon, and the other 32% had rectal polyps. The results of the review were published in the Archives of Surgery. Among the 104 patients brought to the endoscopy suite for endoscopic excision, 98 had excisions, which were performed by two interventional endoscopists. Most were complete excisions, although 20 patients had incomplete excision with residual disease. Six patients did not have excisions and were referred back for surgical evaluation. “We found that most patients (83%) could be successfully treated endoscopically, with only a small number of patients (14%) requiring operative resection to treat complications, incomplete excision after index intervention, or long-term residual disease that could not be eradicated endoscopically,” the

authors commented. Endoscopic reintervention was needed in 25 (27%) of 92 patients for reasons including residual disease in 12 patients and recurrence in 10 patients.

Reasons for Failure “Despite a high overall endoscopic success rate in our group of patients, a diagnosis of carcinoma in situ or invasive carcinoma was associated with a lower success rate,” the authors noted. “Most of the lesions in our study were sessile. Although endoscopic polypectomy may be a suitable option for many pedunculated malignant polyps, its role may be limited in sessile lesions. This may be owing to technical factors, such as inability to safely obtain a deep margin, or because of the limitation of endoscopy in addressing the lymphatic spread in case of invasion. In our experience, the reasons for failure of endoscopic management of some of the cases harboring carcinoma were incomplete excision, long-term residual disease, and concern about the suitability of endoscopic excision in the setting of poor histologic features, such as lymphovascular invasion, or poor differentiation.” The authors concluded that the involvement of surgeons is critical to determine which patients can benefit from endoscopic excision and which patients need surgical resection. “When counseling patients who may benefit from endoscopic excision, keep in mind that endoscopic reintervention or surgical resection is needed in approximately one-third of patients,” the authors cautioned. “Long-term surveillance is warranted for all lesions in view of the risk of recurrence, especially for lesions located in the rectum.” SEE PAGE 45

Kao KT, et al: Arch Surg 146:690-696, 2011.

BREAST CANCER Higher Risk of Recurrence for Triple-negative Breast Cancer after Modified Radical Mastectomy without Radiation

“The paucity of therapeutic options” for women with triple-negative breast cancer “emphasizes the urgent need to optimize the current locoregional management of patients with [triplenegative breast cancer] and reduce their risk of locoregional recurrence,”

noted the authors of a Canadian study reported in the Journal of Clinical Oncology. The study, which involved 768 patients treated at a single cancer center and identified from the Alberta Cancer Registry, found that women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without radiation had a significantly increased risk of locoregional recurrence compared to women treated with breast-conservation therapy, consisting of lumpectomy and adjuvant radiation therapy. The median age of the women was 56, although the study included a high percentage of younger women, with 40% of the women younger than 50 years at time of diagnosis. At a median follow-up of 7.2 years, 155 patients (20%) had disease progression, 77 patients (10%) experienced locoregional recurrence, 103 (13%) developed distant metastases, and 123 (54 with locoregional recurrence and 69 with distant metastases) died as a result of disease progression. Univariate analysis revealed that patients who had breast-conservation therapy (319, or 42%), had a 5-year locoregional recurrence–free survival rate of 94%, compared to 85% for patients who had modified radical mastectomy (287, or 37%), and 87% for patients who had modified radical mastectomy plus radiotherapy (162, or 21%).

Independent Prognostic Factor Multivariate analysis comparing modified radical mastectomy with breast-conservation therapy found that lymphovascular invasion and positive lymph nodes were associated with increased locoregional recurrence, and adjuvant chemotherapy was associated with decreased risk of locoregional recurrence. Modified radical mastectomy without radiotherapy was the only independent prognostic factor associated with increased risk of locoregional recurrence compared with breast-conservation therapy, the authors reported. The authors noted that their study requires further validation from prospective clinical trials addressing the issue of locoregional management and risk of locoregional recurrence specifically in triple-negative breast cancer, which may lead to tailoring of locoregional treatment based on risk of recurrence in this setting.

■

SEE PAGE 45

Abdulkarim BS, et al: J Clin Oncol. July 5, 2011 (early release online).

AVASTIN® (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).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion 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: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [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 healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. 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 The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor 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 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus 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 Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was 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 ≥ 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 of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

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‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2‑negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. 1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients 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 ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula 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 ≤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 ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 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 3−4 Adverse Events in Study 1 appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 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. IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (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 Body as a Whole 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 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. dipstick reading should undergo further assessment with a 24‑hour urine collection.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. NCI‑CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI‑CTC Grade 1‑4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole 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 Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN‑α 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 and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin 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 4–5 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 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under‑estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 ® hemorrhage, and traumatic hematoma). 1 DNA Way Avastin is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus South San Francisco, CA 94080‑4990 ©2011 Genentech, Inc. Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

In combination with IV 5-FU–containing chemotherapy in first- and second-line MCRC…

Think Avastin

Because overall survival matters The only FDA-approved biologic with significant overall survival (OS) benefits in first- and second-line MCRC1-4 4.7-month increase in median OS with Avastin plus IFL in pivotal first-line Study 21072,4

Percentage Surviving

100

First-line median OS:

20.3 vs 15.6 months

(HR=0.66 [95% CI, 0.54–0.81], P<0.001)

60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; IFL=5-FU/leucovorin (LV)/ irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indication 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

AVA0000402600

Printed in USA.

18 12 OS (Months)

OS in second-line Study E3200: 13.0 months with Avastin plus FOLFOX4 vs 10.8 months with FOLFOX4 alone (HR=0.75, [95% CI, 0.63–0.89] P=0.001)1,3 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 Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother 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%) 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 accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. February 2011. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544. 4. Data on file. Genentech, Inc.

(05/11)