TAP Vol 2 Issue 2 by Harborside Press LLC

Bevacizumab in breast ca 3

Emerging therapies for ovarian ca 20

VOLUME 2, ISSUE 2

Quality indicators and psychosocial care 24

JANUARY 15, 2011 ASCOPost.com

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

52nd ASH Annual Meeting

Intensified R-ACVBP More Toxic but Improves Survival vs R‑CHOP in B-cell Lymphoma

Prostate Cancer, Pediatrics, and Priorities

By Alice Goodman

ntensified chemoimChemoimmunotherapy for Diffuse Large munotherapy with B-cell Lymphoma R-ACVBP (rituximab [Rituxan] plus doxorubi■■ R-ACVBP, an intensified treatment regimen, improved survival cin, cyclophosphamide, vs standard R‑CHOP in younger patients with diffuse large B-cell vindesine, bleomycin, and lymphoma (DLBCL). prednisone) significantly ■■ R-ACVBP produced greater hematologic toxicity than R-CHOP. improved event-free sur■■ It is not clear that this regimen is best for all younger patients with vival, progression-free DLBCL, perhaps just for those with at least one clinical factor included survival, disease-free surin the age-adjusted International Prognostic Index. vival, and overall survival ■■ Vindesine (a component of the R-ACVBP regimen) is currently not compared with R-CHOP approved for use by the FDA. (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in younger patients with LNH03-2B trial conducted by the GELA (Groupe diffuse large B-cell lymphoma (DLBCL), as reported d’Etude Des Lymphomes De l’Adulte).1 However, continued on page 11 in the multicenter, phase III, open-label, randomized Health-care Policy

Clinical Trial Activation Has Slowed to Critical Point: ‘All Systems Go’ on Reform NCI, Cooperative Groups implement operational efficiency recommendations By Margot Fromer

merica has the best health care that money can buy, but there is not enough money. Is it reasonable to have our nation pay for sipuleucel-T (Provenge), a $10,000/month medication that will prolong the life of a Medicare patient with widespread metastatic prostate cancer by maybe 4 months and yet not have the money to immunize children? For example, availability of a vaccine (palivizumab [Synagis]) to prevent respiratory syncytial virus in children is severely restricted, although it is proven to prevent a potentially life-threatening pulmonary infection. The estimated cost is $10,000 per child for 5 months of the cold season. Is it reasonable to have a national policy that any medication approved by the FDA is also paid for with public funds? Perhaps, but there are consequences. Sipuleucel-T is not only a new treatment; it has become an example of advancement of science without regard to the economics of medicine. It is a metaphor for possible misappropriation of limited resources and priorities. continued on page 28

nefficiencies in the NCI-funded cancer clinical trials endeavor prompted the NCI Clinical Trials and Translational Research Advisory Committee (CTAC) to establish the Operational Efficiency Working Group (OEWG). This body was charged with identi-

fying barriers to speed and efficiency in protocol development and approval—and devising ways to eliminate them. NCI approved the first phase of OEWG’s work in March, and it went into effect this January. The 14 recommendations (see sidebar, OEWG Recommendations 830 for Trial Activation on page 8) contain enforceable timelines for protocol development and 550 implementation, including a “drop dead” date, at which Current median time time it will be terminated. to activation 300 Draconian? Not really, said 210 200 OEWG target James H. Doroshow, MD, 90 Director, NCI Division of Cancer Therapy Evaluation Cooperative group Cancer center CTEP early drug Program (CTEP) and Chair phase III trials investigator– initiated development phase II of the 63-member working trials trials (cooperative group. “The report was unanigroup and N01) mously endorsed, and everyFig. 1: Median number of days to trial activation. Current median time includes IRB approval, industry negotiations, and FDA approval. CTEP = Clinical Therapy Evaluation Program; IRB = internal one agreed on the timelines.” review board; OEWG = Operational Efficiency Working Group. Courtesy of James H. Doroshow, MD.

By Richard J. Boxer, MD

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

MORE IN THIS ISSUE Oncology Meetings Coverage

52nd ASH Annual Meeting �� 1, 11, 22 33rd Annual San Antonio Breast Cancer Symposium ��6, 18 Direct from ASCO �� 12 Responsible Spending in Cancer Care �� 29

continued on page 7

A Harborside Press Publication

The ASCO Post | JANUARY 15, 2011

PAGE 2

Editorial

From the Deputy Editor By Elizabeth Reed, MD

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

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

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

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

s we enter a new year, the time is ripe to remember the goals of The ASCO Post (TAP) and consider how we’ve been doing so far. The ASCO Post was launched last June as a newspaper for the oncology community, covering broad areas of multidisciplinary cancer care with thoughtful opinion pieces from leaders in the field. The publication quickly found its niche in the busy field of oncology “tabloids” with a balance of news reports, features, and editorials. Each issue offers important information on clinical research, health-care policy issues, and technologic advances, as well as personal perspectives on the day-to-day practice of oncology. I readily agreed to assist in editing The ASCO Post because I thought it would be a good way to help stay current about cancers that I do not treat, which is everything but breast cancer. My expectations have been met and in many ways exceeded. We are curious about your expectations, too, and how The ASCO Post can best serve your needs. We encourage you to write to us at Editor@ASCOPost.com to let us know what issues and topics you would like to see covered in this publication.

Inside The ASCO Post I have found the bullet point summaries in each story to offer useful reinforcement of key issues, and the Expert Point of View sidebars to provide good complementary perspectives on the news reports. Likewise, the Pro/Con, or “TAP Caucus” editorials have contained enlightening debates, and I look forward to more of these discussions by our colleagues in surgery, radiation therapy, radiology, and pathology. “TAP on Technology” is a feature designed to provide reviews of new technology and scientific research. Although I have certainly discussed the option of robotic prostatectomy with patients and house staff at the University of Nebraska Medical Center, I have a much clearer understanding of the procedure after reading the article, “Robot-assisted Laparoscopic Radical See page 31 Prostatectomy: Risks

and Benefits,” in the November 2010 issue (see 2D barcode). What other areas of new technology and clinical research would you like to read about?

Our Responsibilities in the Oncology Community I was not surprised that reading The ASCO Post has broadened my clinical and scientific knowledge. I did not, however, expect the burgeoning realization about the problems oncology is facing and the seriousness of these issues such as the “Doc Fix” and new endpoints for evaluating expensive biologic agents. All of us in the oncology community have a responsibility to be better informed, to be part of a constructive dialogue, and to shoulder some responsibility for ensuring the future of quality cancer care. Engaging in dialogue with our peers in a public forum developed specifically for the oncology community, such as The ASCO Post, is one such means to this end. The ASCO Post can and should serve as a forum to foster active discussion on the multidisciplinary treatment of cancer patients and care plans that deliver the best treatment without duplication of effort or increase in expense. Oncologic medicine works best when it is collaborative, and we must understand the views and needs of scientists, physicians, payers, and all the other participants in our complex health-care system. Dialogue is more difficult, with its invitation to disagreement. It takes time and access to a forum; certainly, however, The ASCO Post can be one such forum.

■

Dr. Reed is Professor, Internal Medicine, Division of Hematology and Oncology, at the University of Nebraska Medical Center, Omaha.

We encourage reader feedback in the form of e-mails or Letters to the Editor (write to Editor@ASCOPost.com). All inquiries will be acknowledged, and selected correspondence will be published. Let us know how The ASCO Post can best serve you.

ASCOPost.com | JANUARY 15, 2011

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News Health-care Policy

FDA Recommends Removal of Bevacizumab’s Breast Cancer Indication By Caroline Helwick

n a move that came as little surprise, on December 16 the U.S. Food and Drug Administration (FDA) recommended removing the first-line metastatic breast cancer indication from the label for bevacizumab (Avastin). Ironically, on the same day, the European Medicines Agency (EMA) affirmed the use of bevacizumab when paired with paclitaxel in this setting. The FDA made its recommendation after reviewing four clinical trials and concluding bevacizumab does not prolong survival or provide “sufficient benefit” in slowing disease progression “to outweigh the significant risk to patients.” The FDA news release cited the potential for hypertension, bleeding and hemorrhage, perforations (in the nose, stomach, and intestines), heart attacks, and heart failure.1 “Subsequent studies failed to confirm the benefit observed in the original trial [E2100, which paired bevacizumab with paclitaxel]… The limited effects of [bevacizumab] combined with the significant risks led us to this difficult decision. The results of these studies are disappointing,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research. “We encourage [Genentech, the drug’s manufacturer] to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”

Genentech Not Backing Down Genentech did not agree to “remove the breast cancer indication voluntarily,”

the FDA’s news release noted. Instead, Genentech requested a hearing to maintain bevacizumab as a treatment option for HER2-negative metastatic breast cancer, in combination with paclitaxel. In a statement, Genentech noted an intention to demonstrate “there are genuine and substantial issues of material fact that require a hearing,” and to explain “our view as to why a hearing is particularly warranted given the 2 years of clinician and patient reliance on this important indication, along with the contrary views that the European Medicines Agency reached on the same data supporting the use of [bevacizumab] with paclitaxel in [metastatic breast cancer].”3 Genentech noted in its request that the magnitude of benefit for bevacizumab paired with paclitaxel supports its indication, “these benefits are underscored by clinical experience,” and bevacizumab’s “importance continues to be recognized in consensus treatment guidelines.” In addition, the company maintained the safety profile is “well-characterized, with no new safety signals observed in the recent clinical trials.” The removal of the indication will be a process, and the FDA’s December 16 recommendation was the first step. Genentech is submitting its request for a hearing in January. If the FDA grants a hearing, there is no set date for when this would occur. The current action has no immediate impact on the drug’s use in breast cancer, and until the proceedings are concluded oncologists can continue to prescribe it in combination with paclitaxel.

Which Patients Benefit?

he FDA’s recent decision on bevacizumab (Avastin) was not surprising given the vote by the Oncology Drugs Advisory Committee last July. Although the data did not support a survival benefit from bevacizumab, they clearly show that the drug does have activity in breast cancer. Response rates and progression-free survival are improved with the addition of bevacizumab. The critical point is that we have yet to determine which specific patients benefit from this drug. Many studies have been done in an attempt to find a marker for activity in breast cancer tumors, but they have not given a solid result. The one group that appears to benefit from the addition of bevacizumab is women with HER2-positive disease. These patients have a higher VEGF level and have been shown in Pegram’s study of the combination of bevacizumab and trastuzumab (Herceptin) to have a very high response rate, even in heavily pretreated patients. The other group that possibly could benefit comprises patients with triple-negative disease. We should have more answers regarding this last point soon, as a large adjuvant trial in triple-negative disease was recently completed. Research should continue to maximize the benefit we can get for our patients by improving survival, which is our ultimate goal. —Sandra M. Swain, MD Medical Director, Washington Cancer Institute, Washington, DC

■

A Disappointing Decision

am disappointed by the FDA’s decision. A much better decision would have been to leave the current indication intact and probably add the capecitabine-plus-bevacizumab indication to it, with the proviso that the sponsor has X amount of time to develop a set of biomarkers that allow users to enrich patient groups that are more or less likely to benefit from the drug. I hope the FDA takes this opportunity to consult with the breast cancer Gabriel Hortobagyi, MD community to define what are reasonable trial endpoints, and adopts a more transparent and predictable set of guidelines for industry to develop new drugs. As it stands now, industry is expected to read the mind of FDA, both qualitatively and quantitatively. Such an approach doesn’t protect patients and just places obstacles in the path of rational drug development. — Gabriel Hortobagyi, MD Chairman, Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center, Houston

■

EMA Still Recommends Bevacizumab Taking the opposite stance, the EMA and its Committee for Medicinal Products for Human Use (CHMP) maintained that “the available data have convincingly shown [bevacizumab] to prolong progression-free survival of breast cancer patients without a negative effect on the overall survival.” Therefore, the combination of bevacizumab with paclitaxel should remain “a valuable treatment option,” according to the Agency.2 The EMA and CHMP also concluded that bevacizumab should not be used in combination with docetaxel or capecitabine. A European Commission decision on this recommendation will be forthcoming.

NCCN Recommendation Stands Bevacizumab plus paclitaxel is among the recommended treatments in the NCCN guidelines for metastatic breast cancer, and this has not changed with the FDA announcement. The recommendation for bevacizumab plus paclitaxel carries an evidence designation of 2A (based on lower-level evidence and uniform agreement of the panel). “The Breast Cancer Treatment Panel reviewed the same studies that the FDA reviewed, and we reaffirmed our recommendation that paclitaxel and bevacizumab be a treatment option for women with metastatic breast cancer,” Panel Chair Robert Carlson, MD, of Stanford University, told The ASCO Post. “This was a unanimous vote,” he added. “The Breast Panel has met either

Robert Carlson, MD

in person or by teleconference on three occasions with bevacizumab as an agenda item. The issue has been looked at multiple times, and I am convinced that unless additional results become available from the trials, the recommendation will stand—at least until the Panel’s next meeting in the summer.”

■

References 1. U.S. Food and Drug Administration: FDA begins process to remove breast cancer indication from Avastin label. Available at www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm237172.htm? Accessed January 3, 2011. 2. European Medicines Agency: European Medicines Agency completes its review of Avastin used in breast cancer. Available at www. ema.europa.eu/ema/index.jsp?curl=pages/ new s_and_events/new s/2010/12/ news_detail_001166.jsp&murl=menus/ news_and_events/news_and_events. jsp&mid=WC0b01ac058004d5c1. Accessed January 3, 2011. 3. Rohrer MH: Request for hearing (letter). Available at www.gene.com/gene/news/ news-events/avastin/documents/avastin_ use.pdf. Accessed January 3, 2011.

The ASCO Post | JANUARY 15, 2011

PAGE 4

Expert’s Corner Leadership

A Conversation with 2011–2012 ASCO President-Elect Sandra M. Swain, MD By Caroline Helwick

Sandra M. Swain, MD

andra M. Swain, MD, will take office as President-Elect of ASCO at its 47th Annual Meeting. Dr. Swain is the Medical Director of the Washington Cancer Institute, Washington, DC, and Professor of Medicine at Georgetown University. She previously served as the Deputy Director of the Medicine Branch and Chief of the Cancer Therapeutics Branch at the National Cancer Institute. As an internationally recognized breast cancer specialist, she had led more than 20 clinical trials. She recently shared with The ASCO Post how she envisions her term as ASCO President.

Becoming President Dr. Swain, you have had an impressive career, but did you ever imagine you would become president of a major oncology organization? Dr. Swain: When my participation on various ASCO committees began several years back, I never envisioned that it would culminate in the honor of serving as the 48th president of this incredible organization. Very early in my medical career I knew that I wanted to focus my efforts on clinical research. To

achieve that goal, I pursued opportunities that allowed me to interact and train with some of the finest researchers and opinion leaders in our profession. That experience has served me well throughout my career. My experience serving on the various ASCO committees has also afforded me the opportunity to work with extremely dedicated ASCO members. When I look at the names of the individuals who have preceded me in this position, it is humbling to be included on that list. I will rely heavily on the collective experiences from both my personal career and ASCO participation to guide me through my tenure as president. To be elected by an organization of 30,000 members must indeed be humbling. What other thoughts do you have about your new role? Dr. Swain: Throughout my career I have maintained a keen interest in mentoring. I have always taken particular pride in seeing my former fellows move on to establish highly successful careers in the oncology profession. I see my role as ASCO president as the ultimate mentoring program. Only now, instead of focusing my attention on maximizing the success of a few I will be dedicating my efforts to the success of our entire profession. This is truly an exciting opportunity.

Addressing Challenges What do you see as the challenges facing ASCO, and how can you help to address them? Dr. Swain: As our name implies, we are the premier organization for oncol-

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.

ogy in the United States. In fact, we set the standard for the advancement of oncology worldwide. We have a very dedicated and active international membership. The international representation at ASCO’s Annual Meeting proves this point. I would like to see us make better use of this inherent strength and develop a more comprehensive international perspective, especially on issues of education and global health concerns. We have already brought ASCO ideas and research to other countries through the Best of ASCO meetings, which will be held in 19 countries in 2011. The Annual Meeting is our seminal event each year, not only for the tremendous training, but for the obvious networking opportunities. Unfortunately, for varying reasons, some individuals cannot travel to it and others want a condensed version, so I think bringing further strength to this endeavor will prove highly beneficial to ASCO in the long run. We also need to incorporate a more comprehensive multidisciplinary approach to all aspects of ASCO activity—not just at the Annual Meeting but throughout the year. Our membership primarily consists of medical oncologists, but oncology in our everyday practice encompasses surgeons, radiotherapists, oncologic gynecologists, and others. We have approached this reality by electing these other specialists as board members and organizing the specialty ASCO meetings. We need to continue to engage these specialties. Community oncologists today face many challenges. How will ASCO be addressing their concerns?

Dr. Swain: I believe that the primary concerns of the community-based oncologist are, in fact, the same as for anyone in our profession. The true impact of health-care reform, reimbursement, clinical trials access and participation, and the ongoing implementation of electronic medical records are affecting all of us to one degree or another. While there may be competing subset issues in each of these areas, there are key overarching issues that resonate with all of us. I think it is imperative that we clearly identify these overarching issues and establish an ASCO “core position” for each. Once established, we will be in a stronger position to advance our cause to those who are in a position to affect the desired outcome.

Balancing Tasks How will you balance these future endeavors and your “day job”? Dr. Swain: As any successful leader will tell you, success is contingent upon the quality of the people with whom you surround yourself. In my case, I have been extremely fortunate to have not only built a great team of professionals to work with at the Washington Cancer Institute, but to also have the unwavering support of the executive staff of the Washington Hospital Center and MedStar Health. On the ASCO side of the equation, the professionalism and commitment of the permanent staff at ASCO Headquarters is already widely known and respected. With the continued support of both of these great teams, I have every expectation of having a wonderful experience.

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

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

The ASCO Post | JANUARY 15, 2011

PAGE 6

33rd Annual San Antonio Breast Cancer Symposium Breast Cancer

Exemestane and Anastrozole Comparable in MA.27 Final Analysis By Caroline Helwick

Post. “But remember these constitute the single most important class of anticancer drugs in breast cancer, and they form the backbone for novel therapies,” he added. “Exemestane is the third pony in the race because it started later, not because it is not a good runner. It’s just as fast as the lead horse.” MA.27 is the first trial in hormone receptor–positive early breast cancer to compare a nonsteroidal and steroidal aromatase inhibitor. The nonsteroidal agent anastrozole is approved for monotherapy in the adjuvant setting, whereas the steroidal inhibitor exemestane is indicated only in sequence after an initial 2 to 3 years of tamoxifen. According to Dr. Goss, the study investigators believed that exemestane might have greater efficacy and better end-organ safety than anastrozole because it is “irreversible and more potent, does not induce intratumoral aromatase, and through its mild androgenic activity may exert a second antitumor effect and a more favorable bone and lipid metabolism profile.”

n the first ever head-to-head comparative trial of a drug against anastrozole, the most common treatment for breast cancer, exemestane was not superior to anastrozole but comparable in its anticancer effects and likely better in terms of its side-effect profile,” reported Study Chair Paul E. Goss, MD, PhD, of Massachusetts General Hospital, Boston. Dr. Goss presented the final analysis of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.27 at the 33rd Annual San Antonio Breast Cancer Symposium.1

Backbone for Novel Therapies Dr. Goss believes the trial was positive in terms of a superior side-effect profile, particularly on bone density, something that he hopes further reports in 2011 will prove. “We see this as providing a new option for 5 years of upfront adjuvant therapy. On the face of things, these may appear to be slightly ‘ho hum’ results. The aromatase inhibitors are coming off patent, and there is not much excitement over such results,” he told The ASCO

Expert Point of View

man Buzdar, MD, of The University of Texas MD Anderson Cancer Center, Houston, the physician who led the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial of anastrozole, commented that he was not surprised MA.27 failed to show a difference between exemestane and anastrozole. “All the commercially available aromatase inhibitors are very similar, whether used for first-line Aman Buzdar, MD or second-line metastatic disease, and now in the adjuvant setting,” he said. “There may be slight differences in the safety profile, but we won’t know this unless we do a blinded randomized, controlled trial. A European study is also evaluating letrozole vs anastrozole, and I will be surprised if we see differences between those agents. The main thing is that beyond a shadow of a doubt, aromatase inhibitors as a group are better than tamoxifen in the treatment of patients with breast cancer. If you give an aromatase inhibitor vs tamoxifen, you keep at least one out of five additional women alive and free of cancer, and with longer analyses we see a survival trend emerging as well.”

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Coming in the February 15, 2011 issue of

Aromatase Inhibitors in Early Breast Cancer ■■ The first head-to-head comparison between anastrozole and

exemestane in postmenopausal women with hormone receptor– positive breast cancer revealed comparable anticancer effects for the two agents (disease-free survival rate of 91% in both arms).

■■ Exemestane produced a superior side-effect profile, particularly on bone density.

■■ Further results are anticipated from the trial’s huge data repository.

Excellent Disease-free Survival in Each Arm MA.27 randomly assigned 7,576 patients to 5 years of treatment with anastrozole (1 mg/d) or exemestane (25 mg/d). No differences were observed between arms. “Exemestane was not superior to anastrozole, which was the primary objective of the trial. The event-free survival curves were superimposable at 4.1 years of follow-up,” Dr. Goss announced. The disease-free survival rate was 91% in both arms of MA.27. Events (recurrence, new breast cancer, death) were observed in 9.2% of the exemestane arm and in 9.1% of the anastrozole arm (P = .85). About 4% per arm experienced distant metastases. All subset analyses were similar as well. The low event rates probably reflect “the lowrisk population and improvements in breast cancer care,” he said. Dr. Goss prefers not to view the findings as “negative,” he said. He noted that differences were observed in the end-organ effects for the two aromatase inhibitors, and these may be clinically important. Menopause-like symptoms occurred equally between the arms, although vaginal bleeding was slightly less common with exemestane. Cardiovascular effects were similar and infrequent. Hypertriglyceridemia and hypercholesterolemia occurred less with exemestane, as did new diagnoses of osteoporosis, though clinical fracture rates were similar. By 3 years, approximately one-fourth of patients had discontinued treatment on both arms.

Differing Side-effect Profiles “Because the side-effect profiles are somewhat different, if patients have symptoms on one drug they can try another one without doing harm. We now know that exemestane will not impair cancer outcomes,” he continued. Dr. Goss offered exemestane as perhaps the better choice for women with baseline osteoporosis, osteopenia, or lipid abnormalities, in whom breast cancer treatment may trigger the need for yet another pill to counteract the side effects. MA.27 is a huge repository of data, and findings will continue to emanate from the study, he added. Additionally, Dr. Goss is heading up the NCIC CTG placebo-controlled MAP.3 trial that is evaluating exemestane for prevention in women with moderate See page 31 breast cancer risk. “This will be a vehicle for determining if aromatase inhibitors are as powerful in preventing breast cancer as we think they are.”

■

Reference 1. Goss PE, Ingle JN, Chapman J-AW, et al: Final analysis of NCIC CTG MA.27: A randomized phase III trial of exemestane versus anastrozole in postmenopausal women with hormone receptor positive primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 9, 2010.

Continuing coverage of 33rd Annual San Antonio Breast Cancer Symposium 52nd American Society of Hematology Annual Meeting and much more

Visit The ASCO Post online at www.ASCOPost.com

ASCOPost.com | JANUARY 15, 2011

PAGE 7

News Health-care Policy

Clinical Trial Activation continued from page 1

How did inefficiencies in the clinical trial system evolve? Gabriel Hortobagyi, MD, Professor of Medicine and Chair, Department of Breast Medical Oncology, MD Anderson Cancer Center, and Co-Chair of OEWG, said there are several major reasons. First are the overwhelming regulations. “Thirty years ago, it took less than a month to get a trial going, from an investigator’s idea to accrual of the first patient, and that included writing the protocol, IRB submission and approval, and calling a pharmaceutical company for sponsorship. Now all that takes a year or more—not including all the bureaucratic rigmarole of reporting adverse events, modifying the proposal, and filling out more forms.” And that’s only when a single institution is doing the study. When it’s a multisite affair, such as with a cooperative group, the time, expense, bureaucratic intervention, and aggravation are multiplied exponentially. Doroshow agrees. “The4:54 minu634 asco gu Dr. ad_STD_v4:Layout 1 12/17/10 PM

tiae of bureaucracy eat up so much time and so many resources that it has become impossible to control. When I first came to work at NCI in 1975, a protocol was 5 or 10 pages long. A consent form was a page or so. Now each

Second is the health-care economy in general. There are many well-known reasons why everything costs more each year, and clinical trials are no exception. Despite challenges, the federally

Adjuvant Breast and Bowel Project, Associate Professor of Human Oncology, Drexel University College of Medicine, Pittsburgh, and OEWG member, told The ASCO Post. “We at NSABP design trials that not only can meet accrual goals but can answer the scientific questions as well. We’ve had considerable success, and so have many other institutions and cooperative groups.”

Time to Trial Activation and Accrual

James H. Doroshow, MD

Gabriel Hortobagyi, MD

file is inches thick,” he said. “The boilerplate is excessive, consent forms are so long and involved that a lawyer can barely understand them, let alone a patient,” he continued. “Everything has more steps, involves more people, takes more time, and costs more money. There are too many rules and Page 1 regulations.”

MULTIDISCIPLINARY ASSESSMENT IN ADVANCED RENAL CELL CARCINOMA: TRANSLATING EVIDENCE INTO PRACTICE

Lawrence Wickerham, MD

funded clincal trials system has led to countless breakthroughs that have transformed cancer care. Removing bureaucratic impediments to trial activation will unleash the potential of the system to move quickly to investigate the latest ideas for new treatment options, Lawrence Wickerham, MD, Associate Chairman, National Surgical

Before improvements were made to the system, some trials took so long to get started that investigators lost interest before the first patient was recruited. Cooperative group phase III trials have a current median time to activation of 830 days—more than 2 years. It is 550 days for phase II trials and 200 days for investigator-initiated cancer center trials (see Fig. 1 on page 1). Many trials accrue only a small percentage of the required subjects, and some accrue none. In fact, the longer the process takes, the less likely continued on page 8

THURSDAY, FEBRUARY 17, 2011 • 6:30 PM – 9:00 PM ORLANDO WORLD CENTER MARRIOTT 8701 WORLD CENTER DRIVE • ORLANDO, FL 32821 PRE-REGISTRATION IS SUGGESTED, AS SPACE IS LIMITED. A Free CME-Certified Satellite Dinner Symposium to be Held During the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium

TargeT audience

This activity is intended for medical oncologists, surgical oncologists, urologists, radiation oncologists, pathologists, and other healthcare professionals involved in the treatment of patients with renal cell carcinoma (RCC).

FaculTy

Brian I. Rini, MD (Chairperson) Cleveland Clinic Taussig Cancer Institute

Axel Bex, MD, PhD The Netherlands Cancer Institute; Amsterdam, The Netherlands

Michael B. Atkins, MD Beth Israel Deaconess Medical Center; Harvard Medical School; Dana-Farber/Harvard Cancer Center

Robert A. Figlin, MD, FACP Cedars-Sinai Medical Center; Samuel Oschin Comprehensive Cancer Institute; David Geffen School of Medicine at UCLA

Physician conTinuing educaTion

This activity has been approved for AMA PRA Category 1 Credit™.

To register please go to www.IMERonline.com/ASCO-GU-2011 This activity is not part of the official 2011 ASCO-GU symposium. Jointly sponsored by: This activity is supported by independent educational grants from Genentech BioOncology, and Prometheus Laboratories, Inc.

The ASCO Post | JANUARY 15, 2011

PAGE 8

News Health-care Policy

Clinical Trial Activation continued from page 7

full accrual will be reached. A recent study sponsored by CTEP found that only 18.5% of all trials achieved their minimum accrual goals, and 54.2% of 2,685 trials at 14 NCI comprehensive cancer centers did not accrue any patients at all. Only 26.6% accrued more than two patients. The situation is not all that dire, however, said Dr. Wickerham. “Of 10 NSABP breast cancer trials activated between 2000 and 2007, only 1 was stopped because of inadequate accrual, and only 1 of 4 colorectal studies failed to meet its goal. Of the more than 34,000 patients in these trials, only 0.5% entered a study that was closed due to low accrual. We try to avoid enrolling any patient in a trial that will not be completed,” he said. Other trial groups have equally positive numbers; nevertheless, the clinical trial community must develop better

ways to choose trials, get them going with minimal delay, accrue patients— and stop them when it is pointless to continue.

The Remedies In addition to OEWG’s 14 initiatives, the committee established targets for trial activation: 300 days for phase III, 210 days for phase II, and 90 days for investigator-initiated trials. Protocols that have been in the review pipeline for more than 24 months (for phase III) or 18 months (for phase II) will be terminated, retroactive to January 2011. Cancer centers that conduct NCIfunded grants can improve internal management to increase efficiency (see sidebar, Recommendations to Increase Efficiency at NCI-funded Cancer Centers), but some are reluctant to participate in multisite trials because collaboration in such efforts is not recognized as a legitimate academic activity, nor

OEWG Recommendations for Trial Activation Cooperative group phase III trials

■■ Cooperative groups will develop an action plan to achieve an agreed-upon timeline.

■■ CTEP will develop an action plan for a timeline. ■■ CTEP and cooperative groups will collaborate on revising concepts and protocols that meet agreed-upon timelines.

■■ NCI and cooperative groups will collaborate in rewarding timeline achievement.

CTEP phase II early drug development trials

■■ CTEP will develop an action plan to achieve an agreed-upon t imeline.

■■ CTEP will collaborate with trial sites to revise letters of intent and protocols that meet the agreed-upon timeline.

NCI-designated cancer center investigator–initiated trials

■■ Each cancer center will develop an action plan to achieve an agreedupon timeline.

■■ NCI and cancer centers will develop and implement initiatives to

streamline university contracting and financial review processes.

All categories of trials

■■ Cooperative groups and cancer centers will standardize protocol elements and development tools.

■■ NCI will enhance funding capabilities for biomarkers in trials. ■■ Cancer centers will perform rigorous review of each proposed trial concept before protocol development.

NCI trial programs not directly related to activation time

■■ NCI and academic institutions will provide incentives for cancer

center participation in cooperative group and other multisite trials.

■■ Cancer centers will develop periodic strategic review of clinical trial programs.

■■ NCI will enhance research and mentoring programs.

Recommendations to Increase Efficiency at NCI-funded Cancer Centers ■■ Evaluate the best use of existing resources, and do periodic strategic review.

■■ Be realistic about the feasibility of new protocols. ■■ Determine the adequacy of the pool of potential subjects and establish reasonable eligibility requirements.

■■ Determine if the necessary tools to do the research (imaging, laboratory, specimen-processing, etc) exist.

■■ Establish internal deadlines for various aspects of the protocol (accrual rates and methods, for example), thus ensuring overall timeliness.

■■ Perform various tasks (preparing budgets, drawing up contracts, and the like) simultaneously.

■■ Set aside dedicated contracting staff from an institution’s own legal

department to work only on clinical trial matters, and have them devise master agreements that can be adapted to all trials.

■■ Use computerized tracking systems to determine the course of progress and prevent protocol overlap.

■■ Share best practices and successful strategies with other institutions. is it seen as an important service. As a remedy, OEWG recommended the following measures: ■■ Including trial leadership, as well as accrual of patients in trials led by others, as a criterion for academic tenure and promotion ■■ Encouraging deans and department chairs to honor trial participation ■■ Enhancing training and mentorship for junior investigators as incentives to remain in academic medicine and clinical research (NCI will create new training programs to further this goal) OEWG also recommended that CTEP and cooperative groups work with FDA, industry, and NCI to define standards about registration studies, establish consistency in protocol development, and resolve issues of trial objectives and design.

Collaborative Efforts The OEWG initiatives will be “taken seriously by everyone involved,” said Dr. Wickerham, “and I’m sure that people will put forth their best effort to make them work.” Yes, everyone agrees that clinical trials need to be faster and more efficient, said Dr. Hortobagyi. And if it were up to only those conducting them, it wouldn’t be such a problem. But the system is enormous, unwieldy, and fractured. There are too many government agencies, private industry members, politicians, and advocacy groups for it to work even reasonably smoothly. “It takes 800 steps to perform one trial, so we must change the systemic problems.”

It’s Starting to Work Between April 1 and December 1, 2010, CTEP received 13 phase III proposals, 45 unsolicited phase I, I/II, or II proposals from cooperative groups, and a number of intramural ones. Of those approved, all are on schedule. “People respond well to targets,” said Dr. Doroshow. “This new system will get clinical trials moving again, increase transparency, and improve accrual.” NCI has instituted initiatives to help achieve OEWG goals. Two are especially helpful. During the course of getting a trial up and running, innumerable questions and problems arise. They have traditionally been resolved by sending e-mails, twiddling thumbs while they languish in in-boxes, waiting for replies, and then asking someone else the same or related questions. This takes weeks. A much better way is to conduct a conference call and hash things out in a matter of minutes. “These calls save enormous amounts of time and frustration,” said Dr. Doroshow. The other initiative is establishment of a website to track timelines. Steve Friedman, MHSA, Chief, Clinical Trials Operations and Informatics Branch, explained that the website provides access to NCI employees and investigators who need to follow a protocol’s progress. All steps are listed in a timeline (how much time each took, how much time is left, etc), which can be compared to those of other protocols. “It works like the FedEx tracking system: You know where your package is, when it’s on the truck, and when the driver is going to ring your doorbell,” he said.

■

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

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

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Parent compound binds to and blocks estrogen receptors

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

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

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

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

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

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

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

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

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

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

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

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

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

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

ASCOPost.com | JANUARY 15, 2011

PAGE 11

News Hematologic Disease

Intensified Therapy continued from page 1

the more intensified ACVBP regimen did incur greater hematologic toxicity.

Christian Recher, MD, PhD

Despite a high rate of febrile neutropenia (seen in almost 40% of patients) and greater need for transfusion in the R-ACVBP arm, the toxicity was manageable, said lead author Christian Recher, MD, PhD, CHU Toulouse, France, who presented results of the trial at the 52nd Annual Meeting of the American Society of Hematology (ASH), held December 4–7 in Orlando.

Study Data The study enrolled 380 patients at 73 different centers in France with DLBCL and International Prognostic Index score of 1 from December 2003 through December 2008. Patients were randomly assigned to receive either intensified chemotherapy with R-ACVBP or R-CHOP. R-ACVBP was given in four induction courses given every 2 weeks; rituximab 375 mg/m2) on day 1, doxorubicin 75 mg/m2 on day 1, cyclophosphamide 1,200 mg/m2 on day 1, vindesine 2 mg/m2 on days 1 and 5, bleomycin 10 mg on days 1 and 5, prednisone 60 mg/m2 from day 1 to day 5, intrathecal methotrexate 15 mg on day 2, and G-CSF from day 6 to day 13. Patients then received several cycles of an intensive consolidation therapy. Standard R-CHOP was See page 31 given every 3 weeks

for eight cycles along with intrathecal methotrexate on day 1 of the first four cycles. No radiotherapy was given in either arm. The primary endpoint was eventfree survival, with secondary endpoints of response rate at end of treatment, and progression-free, disease-free, and overall survival. Mean follow-up was 44 months. At baseline, both groups were well balanced for age, stage, and disease characteristics. Approximately 59% were male; 55% had stage III or IV disease; 44% had elevated LDH; 22% had a tumor mass greater than 10 cm; 28% had B symptoms; 26% had more than one extranodal disease site, and 13% had bone marrow involvement.

Results At a mean follow-up of 44 months, no difference was observed between treatment arms for response. Overall response rate was 92% for R-ACVBP and 88% for R-CHOP. Complete remission and complete remission– unconfirmed rates were 82.7% and 80.3%, respectively. The 3-year eventfree survival rate (the primary endpoint) was 81% (95% CI = 74%–86%) vs 67% (95% CI = 59%–73%), which was significantly superior for the experimental arm (P = .0035). Progression-free, disease-free, and overall survival were also significantly better for the R-ACVBP arm: ■■ The 3-year progression-free survival rate was 87% (95% CI = 81%–91%) vs 73% (95% CI = 66%–79%) (P = .0015) ■■ The 3-year disease-free survival rate was 91% (95% CI = 85%–95%) vs 80% (95% CI = 73%–86%) (P = .0019) ■■ The 3-year median overall survival rate was 92% (95% CI = 87%–95%) vs 84% (95% CI = 77%–89%), respectively (P = .0071) This is the first study to show an improvement in overall survival in patients with DLBCL in the rituximab era.

Visit The ASCO Post website at:

Expert Point of View

t the presentation of results for the LNH032B study at the 52nd ASH Annual Meeting, Andrew Zelenetz, MD, PhD, of Memorial SloanKettering Cancer Center, New York, questioned Dr. Recher’s conclusions. “This study had strict inclusion criteria, but your broad conclusion is that R-ACVBP is the Andrew Zelenetz, MD, PhD best treatment for younger patients,” Dr. Zelenetz commented. Dr. Recher conceded that the intensified regimen might be best for younger patients with at least one clinical factor described by the age-adjusted International Prognostic Index, whereas R-CHOP could be reserved for very low-risk patients (age-adjusted Index = 0 and no bulky disease). Dr. Zelenetz pointed out that LNH03-2B is part of a larger strategy for managing patients with DLBCL. The study presented was specifically conducted in patients aged 18 to 59 years with precisely one risk factor according to the age-adjusted International Prognostic Index. Although the results may be generalizable to patients in all risk groups, that possibility was not addressed in the current study. “Care needs to be taken in extrapolating [results] to other patient populations,” he emphasized. LNH03-3B is exploring the role of R-ACVBP in combination with high-dose therapy and autologous stem-cell rescue for a higher-risk group—patients aged 18 to 59 years with two to three risk factors. “The standard of care in the United States for patients with high-risk DLBCL remains R-CHOP-21. However, other strategies are being explored for these patients, as the results with R-CHOP-21 remain suboptimal,” Dr. Zelenetz stated.

■

Toxicity and Other Concerns Serious adverse events occurred more frequently in the R-ACVBP arm (42% vs 15%). Grade 3 or 4 hematologic toxicity was increased in that arm, as was grade 3 mucositis. A higher percentage in the R-ACVBP arm experienced febrile neutropenia (39% vs 9%), and a higher percentage of patients in that arm required red blood cell (51% vs 7%) or platelet (13% vs 1%) transfusions. Five toxic deaths occurred in the R-ACVBP arm (2.6%) and three occurred in the R-CHOP arm (1.6%). In response to a question from the audience, Dr. Recher said that the GELA investigators did not evaluate quality of life, but it is clear that R-ACVBP could not be safely deliv-

ASCOPost.com

ered to patients over 60 years old. He suspected that quality of life would be worse on the experimental treatment, given the side effects, but only in the first 2 months of treatment, because consolidation with high-dose methotrexate, followed by rituximab/ ifosfamide and etoposide, is very well tolerated.

■

Reference 1. Recher C, Coiffier B, Haioun C, et al: A prospective, randomized study comparing dose intensive immunochemotherapy with R-ACVBP vs. standard R-CHOP in younger patients with diffuse large B-cell lymphoma (DLBCL). Groupe d’Etude Des Lymphomes De l’Adulte (GELA) study LNH03-2B. 52nd ASH Annual Meeting. Abstract 109. Presented December 5, 2010.

The ASCO Post | JANUARY 15, 2011

PAGE 12

Direct from ASCO

Training Directors Get Recharged Annual Retreat Offers Education, Networking

funny thing about being a program director is that you feel isolated,” says Thomas H. Davis, MD, Chair of ASCO’s Oncology Training Programs Subcommittee. Dr. Davis ought to know. While the average program director tenure is 5 years, he has directed the hematology-oncology training program at Dartmouth-Hitchcock Medical Center since 1997. “Program directors are reading journals and reports of clinical trials every day, but there is very little in the medical literature about the day-to-day stuff we do in training.” Dr. Davis comments.

Thomas H. Davis, MD

Enter the ASCO Oncology Training Program Directors’ Retreat, a 1-day meeting that combines educational sessions with that most important antidote for isolation—networking. Seventyseven individuals participated in the October 2010 retreat, held at ASCO headquarters in Alexandria, Virginia. The subcommittee plans the retreat, designed for directors and associate directors of hematology, oncology, and combined hemonc fellowship training programs.

The retreat is a rare and wonderful opportunity to touch base with people doing the same thing you do. Dr. Davis says that if he had to describe the purpose of the retreat in one line, it would be to “recharge your program director battery.”

New ACGME Duty-Hour Rules Discussed Sparking a lot of interest and discussion at the recent retreat was a presentation about the responsibilities of the Residency Review Committee (RRC) and the review processes used to accredit training programs. RRC member Sara J. Grethlein, MD, Professor of Hematology and Oncology at the State University of New York Update Medical University, presented the session. Attendees at the retreat particularly appreciated her discussion of the new work-hour requirements that the Accreditation Committee for Graduate Medical Education (ACGME) is putting into effect July 1, according to Dr. Davis, noting that the biggest change is limiting first-year residents to 16-hour shifts. “It was useful to hear her perspective on the process the ACGME used in adopting the new hour rules,” Dr. Davis comments. “The rules put tighter protections on the trainees who are most vulnerable to being abused and the least able to handle fatigue and performance challenges. We were also comforted to learn that the rules for work hours will no longer be ‘one size fits all.’ There will be more laxity for senior trainees—we won’t have to boot them out [when their shift ends] in the middle of taking care of a sick patient.”

Best Practices: Chemotherapy Competency Protocol Shared While part of the retreat agenda addressed big-picture issues such as the ACGME requirements, implications of national health-care reform for training programs, and employment law as it applies to graduate medical education, other parts dealt with nuts-and-bolts issues in directing a training program. For example, Frances Collichio, MD, the Associate Program Director at the University of North Carolina, shared her program’s teaching methods, educational materials, and documentation process for teaching and verifying competency in the

ASCO Services and Products for Training Programs and Fellows ■■ Free membership for residents and fellows ■■ In-training examination for medical oncology: Registration now open! Go to http://www.asco.org/medoncite.

■■ Program directors’ breakfast and special session at the Annual Meeting

■■ Quality Oncology Practice Initiative (QOPI) for fellows ■■ Education products such as the Education Essentials Package for Oncology Fellows, the Oncology Slide Library, and ASCO-SEP®

■■ Ongoing monitoring and reporting on ACGME accreditation issues

■■ Support for match participation ■■ LISTSERV for program directors ■■ Cosponsorship of Clinical Methods in Cancer Research Workshop ■■ 2011 Training Program Directors’ Retreat—tentative date: October 28

administration of chemotherapy. “Chemotherapy administration is a specific skill that needs a lot a safeguards, and Dr. Collicihio’s program has organized this particularly well,” Dr. Davis notes.

Learning from Others Meeting with other program directors is a side benefit of the retreat, but in truth it may be the most important aspect. “Everyone comes with something they do very well, and in the question-and-answer sessions you pick up ideas from others,”

Dr. Davis points out. “It’s also helpful to hear about the trials and tribulations of others who have the same responsibilities you do. It’s a great opportunity for program directors to learn about new best practices.” The Oncology Training Programs Subcommittee also plans two other networking and learning events for directors—a breakfast meeting and a special session offered annually at the ASCO Annual Meeting.

■

Help Your Patients Get Off to a Healthy Start in the New Year

any people—including those with cancer—see the beginning of a new year as an opportunity for a fresh start, establishing resolutions to improve health and wellness. To help your patients set and achieve their goals, point them to Cancer.Net (www.cancer.net), ASCO’s patient

website, where they will find an article that outlines seven steps for a healthier new year. They will also find a section on cancer risk factors and prevention (www.cancer.net/prevention) that includes topics such as cancer screening, diet and nutrition, physical activity, and more.

■

ASCOPost.com | JANUARY 15, 2011

PAGE 13

Direct from ASCO

ASCO’s Journal of Oncology Practice Announces Innovative Podcast Program

SCO’s Journal of Oncology Practice (JOP) now offers free podcasts to the general public on its website (http://jop.ascopubs.org/site/podcasts/index.xhtml), as well as to those who subscribe to the podcasts on iTunes. These insightful and informative podcasts focus on a wide variety of topics by highlighting chosen articles in each issue of JOP. Robert S. Miller, MD, a member of the JOP Editorial Board and practitioner at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, now directs the conceptualization and creation of each JOP podcast. The articles to be highlighted are selected by Dr. Miller; John V. Cox, DO, MBA, FACP, Editor in Chief of JOP; and JOP staff. Each new issue of JOP is accompanied by at least one podcast. These podcasts are a convenient and helpful resource for any busy clinician or reader interested in

learning more about a featured article in JOP. “I envision the podcasts as a way of enhancing the content that is in the Journal,” notes Dr. Miller. “I focus on articles…and to date have been interviewing the authors. [This allows them] to expand on their ideas for their article and fill in background information that readers might find interesting, in a more conversational, informal manner.” He uses a hands-on approach to producing each podcast. “I do all of the production myself on my 4-year-old MacBook Pro.…We conduct the conversation over Skype.”

Podcast Highlights One recent article Dr. Miller presented is by John A. Keech, MD, “The Dinosaur Is Extinct: The Demise of Solo Medical Oncology Practice in the United States,” published in the Septem-

ber issue of JOP. Dr. Miller explains that the interview with Dr. Keech features the author’s “personal story of how he was forced to close his solo practice in California after many years of success and hard work, due to business pressures that could not be overcome.” Dr. Keech not only highlights the various aspects and advantages of private practice care; his comments are emotionally compelling and heartfelt. “I was appreciative of his openness and willingness to share,” Dr. Miller said. Another recent podcast features an article that also ran in the September issue of JOP, entitled “National Practice Benchmark: 2010 Report on 2009 Data,” by Thomas R. Barr and Elaine Towle. Dr. Miller interviewed the two authors about a national survey they conducted, in which community oncology practices were asked to provide data for use in managing today’s financially

challenging practice environment. “It was interesting to hear the background on their rationale for the questions on the benchmark survey and their analysis of the data,” Dr. Miller said. “They made some great comments about [their interpretation of the results] in the context of the current landscape of oncology practice in the United States and the challenges faced.” As for the future of the podcast program, Dr. Miller says, “My goal is to increase readership and attention to JOP and its content. We may experiment with more of a news summary format in addition to the interview format.” Listeners are encouraged to provide their comments and suggestions, which can be made directly on the iTunes site or emailed to jopeditorsdesk@asco.org.

■

What’s Hot in JCO Online

Top 10 most-accessed articles recently published in Journal of Clinical Oncology Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al

1. Denosumab: Second Chapter in Controlling Bone Metastases or a New Book? Monica N. Fornier 28(35): 5127 2. Stand and Wait George F. Blackall 28(34): 5124

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

JCO.org

3. Another Step Toward the Cure of Metastatic Renal Cell Carcinoma? Nicholas J. Vogelzang 28(34): 5017

www.jco.org

4. Strategies for Prolonged Therapy in Patients With Advanced Non– Small-Cell Lung Cancer Panos Fidias, et al 28(34): 5116

5. Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study Alison T. Stopeck, et al 28(35): 5132 6. Clinical Implications of the Cancer Genome Laura E. MacConaill, et al 28(35): 5219 7. Clinical Trials Data Collection: When Less Is More Daniel J. Sargent 28(34): 5019 8. Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European

Save the Date 2011 ASCO Annual Meeting

Organisation for Research and Treatment of Cancer Randomized Trial 40954 Christoph Schuhmacher, et al 28(35): 5210 9. Predictive Value of Defective Mismatch Repair in Adjuvant Colon Cancer Carl D. Atkins 28(35): e746 10. Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin Plus Etoposide for Patients With Relapsed Primary Mediastinal Nonseminomatous Germ Cell Tumors: Benefit From Chemotherapy, Surgery, or Both? Lawrence H. Einhorn 28(35): e739

June 3-7, 2011 McCormick Place Chicago, Illinois

The ASCO Post | JANUARY 15, 2011

PAGE 14

Direct from ASCO

ASCO in Action Updates ASCO to Continue to Advocate for Permanent Repeal of SGR in 2011

ast month, Congress voted to delay a potentially devastating 25% Medicare physician pay cut through

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2011. ASCO is advocating that Congress use the 12-month reprieve to repeal the flawed sustainable growth rate (SGR) formula for a new system that pays physicians fairly for their services. An ASCO poll revealed that nearly one-third of members would consider closing their practice to Medicare patients should the SGR cut be implemented. ASCO has already reached out to incumbents and new members of Congress to ensure that Medicare reimbursement remains a priority for 2011.

Congress Passes Legislation Exempting Physicians from FTC ‘Red Flags Rule’ Congress has passed a bill exempting physicians from the Federal Trade Commission’s “Red Flags Rule.” The rule would have required physicians to be treated as creditors and mandated they implement identity theft and monitoring programs, creating additional bureaucracies for practices. This past summer, ASCO along with 24 other medical societies filed a motion to be added as plaintiffs to the federal lawsuit filed by the American Medical Association, the American Osteopathic Association, and the Medical Society for the District of Columbia, contesting the application of the Red Flags Rule to physicians.

IOM & ASCO to Host Implementation Workshops on Cooperative Group Report ASCO is partnering with the Institute of Medicine (IOM) to host implementation workshops related to the IOM consensus report, A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. The initial workshop is scheduled for March. The goal of the workshops is to identify and examine ways to implement the report’s recommendations and establish implementation expectations for the coming year. Subsequent workshops will be held in 2012 to discuss progress and identify additional action steps. Invited stakeholders include representatives from the NCI, clinical trials cooperative groups, public and private payors, the FDA, industry, community and academic investigators, patient advocates, and cancer centers.

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ASCOPost.com | JANUARY 15, 2011

PAGE 15

52nd ASH Annual Meeting Hematologic Disease

Novel Treatments to Watch for in Hodgkin Lymphoma By Caroline Helwick

he prognosis for patients with classical Hodgkin lymphoma treated today is significantly better than it would have been 15 years ago. More than 90% of patients with early-stage disease and 80% with advanced-stage disease will be cured. Several factors may be responsible for this: Splenectomy has been abandoned, radiotherapy fields and doses have been lowered, very toxic chemotherapy drugs have been eliminated from first-line therapy, and patients with relapsed disease now benefit from stem cell transplantation. “While this evidence is indirect, population-based findings provide credence to the idea that reducing the intensity of first-line therapy has not resulted in worse overall outcomes for patients with classical Hodgkin lymphoma, and supports increasing efforts to minimize therapy further,” said Nancy L. Bartlett, MD, of the Siteman Cancer Center at Washington University, St. Louis. “But despite the overall excellent prognosis in most patients, the optimal treatment for both early and advanced disease remains controversial,” she added. “Successful treatment must balance the highest cure rate with primary therapy with the fewest treatment-related complications.” Historically, overtreatment with both chemotherapy and radiothera-

py has been the rule in most patients, but some investigators believe that toxicity can be reduced and good outcomes maintained. Applying interim PET/CT after the first few cycles of chemotherapy to assess response can potentially help. “If current trials confirm the usefulness of midtreatment PET/CT assessments, perhaps we can resolve the debate regarding ‘too much’ or ‘too little’ therapy,” she said. Dr. Bartlett and Kristie Blum, MD, described the state of the art in Hodgkin lymphoma at an educational session at the 52nd American Society of Hematology (ASH) Annual Meeting, held December 4–7 in Orlando, Florida.

Targeted Therapies Greater understanding of the biology of Hodgkin lymphoma and recognition of prognostic biomarkers has led to the development of targeted therapies that address the multiple pathways thought to be dysregulated or altered in Hodgkin lymphoma. These targeted agents will be expensive, and clinicians will want to use them upfront (at diagnosis), in combinations, and possibly as maintenance therapy. The pathways in question include NF-ĸB, PI3/AKT, mTOR, surface receptor signaling through CD30, CD40, and RANK, and immuno-

Table 1: Agents in Clinical Development for Treatment of Hodgkin Lymphoma Target

Potential Therapeutic Agents

CD30

SGN-30, MDX-060, SGN-35, XmAb2513

CD20

Rituximab

CD80

Galiximab

Histone deacetylase

MGCD0103, vorinostat, panobinostat

mTOR

Everolimus

NK-ĸB

Bortezomib, carfilzomib, NPI-0052, MLN9708

Immunomodulatory

Lenalidomide

AKT-B-cell receptor signaling

CAL101, MK2206, PCI-32765

Bcl-2

Obatoclax, ABT-263

EBV

LMP2-specific cytotoxic T lymphocytes

Heat shock protein 90

17AAG, 17DMAG

New Ways of Predicting the Course of Hodgkin Lymphoma

xisting models for predicting outcome in patients with Hodgkin lymphoma, including the International Prognostic Score (IPS), may be losing their accuracy and robustness, in light of recent improvements in treatment, increasing dose intensity, early recognition of toxicity, and enhanced supportive care for these patients, according to Kristie A. Blum, MD, of Ohio State University, Columbus. The addition of biologic markers to recognized clinical prognostic factors, including the IPS, may improve risk stratification of these patients and guide therapy in the future. However, it has been difficult to fully establish these markers due to the lack of large confirmatory prospective trials and the inadequacy of the assays, she added.

Promising Biomarkers One biomarker is emerging as quite promising, according to Dr. Blum. CD68 is present on tumor-infiltrating macrophages and detectable by immunohistochemical staining, and is significantly associated with shortened progression-free and disease-specific survival both at diagnosis and at relapse. In addition, the presence of less than 5% CD68-positive cells correlates with a 100% disease-specific survival in patients with early-stage Hodgkin lymphoma. In a multivariate analysis, CD68 expression was superior to the IPS in predicting disease-free survival. “CD68 represents just one of the many prognostic markers that could eventually be used to risk-stratify therapy and may also serve as therapeutic targets in Hodgkin lymphoma,” she said. CD20 expression may be another biomarker. An increased number of tumor-infiltrating CD20-positive small B cells was associated with both prolonged progression-free and disease-free survival, although not all studies have validated this. Recent data suggest that an increased number of CD20positive infiltrating B cells coupled with low CD68 expression on tumorinfiltrating macrophages may identify patients with very favorable Hodgkin lymphoma. A variety of other prognostic markers have been described in the disease, although their value so far is not as strong. There is no current consensus on how best to use these markers along with current clinical prognostic risk factors or how to use them to alter treatment. This information will only become clear when they are incorporated into clinical trials.

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logic defects through alterations in the tumor microenvironment. The future of Hodgkin disease therapeutics, therefore, may involve targeting multiple pathways simultaneously, according to Dr. Blum. Table 1 shows some of the agents in clinical development that are selective for these pathways that may one day become accepted therapeutic options for patients with relapsed or poorprognosis Hodgkin lymphoma. At this time, most of the focus is on rituximab (Rituxan), brentuximab vedotin (SGN-35), lenalidomide (Revlimid), and panobinostat in the front-line setting or as maintenance therapy after

autologous stem cell transplantation. While several of these agents have significant single-agent activity in relapsed disease, combinations are likely to be more effective. Preclinical studies to determine which agents are synergistic with chemotherapies or other targeted agents are underway. “These novel therapies should also eventually be incorporated into frontline regimens or used as maintenance therapy, with the aim of reducing toxicity in patients with very favorable disease and improving outcomes in those at high risk for relapse,” Dr. Blum said.

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EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

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

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

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33rd Annual San Antonio Breast Cancer Symposium High Response Rates Achieved with ‘Complete Blockade’ for Neoadjuvant Treatment of HER2-positive Breast Cancer By Caroline Helwick

he concept of complete HER2 blockade with biologic agents gained steam at the 33rd Annual San Antonio Breast Cancer Symposium upon the results of several phase III studies in the neoadjuvant setting. High rates of pathologic complete responses (pCR) were observed with various regimens of trastuzumab (Herceptin), lapatinib (Tykerb), and the investigational agent pertuzumab (Omnitarg), leading one scientist in the field to predict that chemotherapy might be eliminated altogether for some patients. Neil Spector, MD, Director of Translational Oncology Research at the Duke Cancer Institute in North Carolina, delivered a plenary lecture on anti-HER2 therapies at the San Antonio meeting, which was held December 8–12, 2010. He commented at a press briefing, “I have always believed total HER2 blockade is optimal. Since we have three targeted therapies, each acting differently but aimed at the same target, I can envision future trials of these agents in combination, perhaps moving away from chemotherapy in a subset of patients.” He added, “This is a very exciting area. We have gone from HER2-overexpressing disease being the most lethal type of breast cancer to a subtype that we are talking about curing.” But Eric Winer, MD, Director of the Breast Oncology Center at DanaFarber Cancer Institute, Boston, tempered the enthusiasm with a note of caution as the invited discussant of the studies. Although pCR is consistently associated with excellent clinical out-

comes, he said improvements in pCR have not always been associated with statistically significant improvements in disease-free and overall survival. Therefore, he maintained, pCR (regardless of the agent used) should not yet be used as an “endpoint for drug approval or practice change.”

NeoALLTO and GeparQuinto Lapatinib came up short in two phase III studies that examined its effect. NeoALTTO, conducted by the Breast International group (BIG), compared lapatinib, trastuzumab, and lapatinib/trastuzumab combination therapy, all with paclitaxel, in 455 patients.1 Patients received 6 weeks of the biologic(s), with weekly paclitaxel added to the regimen for 12 more weeks, yielding a total of 18 weeks of neoadjuvant treatment. Jose Baselga, MD, Associate Director of the Massachusetts General Hospital Cancer Center, Boston, reported that the pCR rate by National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines (absence of invasive cancer cells in the breast at surgery or only noninvasive in situ cancer in the breast) was 51.3% with lapatinib/trastuzumab vs 24.7% for lapatinib and 29.5% for trastuzumab (P = .0001). Pathologic CR rates in the breast and lymph nodes were 47% with lapatinib/trastuzumab, 20% with lapatinib, and 28% with trastuzumab, Dr. Baselga reported. Thus, with regard to the primary objective of the NeoALLTO trial (pCR), the combination proved superior, and the investigators concluded that dual blockade of the

Anti-HER2 Regimens Studied NeoALLTO (n = 450): Six cycles of trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly; lapatinib 1,500 mg/d; or lapatinib 1,000 mg/d plus trastuzumab. Targeted therapy was continued with the addition of weekly paclitaxel 80 mg/m2 for 12 more weeks. GeparQuinto (n = 600): Four cycles of epirubicin/cyclophosphamide 90/600 mg/m2 followed by four cycles of docetaxel 100 mg/m2 in combination with either trastuzumab 8 mg/kg loading dose followed by 6/mg/kg or lapatinib 1,000–1,250 mg/d throughout all cycles. NeoSphere (n = 400): Four cycles of docetaxel 75 mg/m2 (escalate to 100 mg/m2) plus either trastuzumab 8 mg/kg loading dose and 6 mg/kg maintenance, pertuzumab 840 mg loading dose and 420 mg maintenance, or trastuzumab plus pertuzumab; or trastzumab/pertuzumab alone.

‘Scorecard’ on Anti-HER2 Combinations in the Neoadjuvant Setting

utting the three anti-HER2 neoadjuvant studies in perspective was Eric P. Winer, MD, Chief of the Division of Women’s Cancer at Dana-Farber Cancer Institute, Boston. He noted that neoadjuvant trials such as these “have great potential to answer critical clinical and translational questions,” but they do not, he added, establish pathologic complete response (pCR) as a surrogate for disease-free and overall survival. “We need to wait for ALTTO and other triEric P. Winer, MD als,” he said. Additional studies, such as CALGB 40601, will also evaluate neoadjuvant responses to trastuzumab, lapatinib, and the combination plus paclitaxel. Ranking the studies’ regimens in terms of their promise, Dr. Winer gave a thumbs up to trastuzumab plus pertuzumab with docetaxel, which he said “is ready for an adjuvant trial, and the non–chemotherapy-containing doublet of trastuzumab plus pertuzumab could be evaluated in a group of low-risk patients.” He also was impressed with trastuzumab plus lapatinib and paclitaxel, but said its neoadjuvant or adjuvant use would be premature before the ALTTO results are known. Similarly, “the jury is still out on single-agent lapatinib plus chemotherapy, which “appears a little less active and more toxic.” He gave a gentle thumbs down to single-agent pertuzumab plus chemotherapy. “This one is hard to get excited about.” Debu Tripathy, MD, Professor of Medicine at the University of Southern California, Los Angeles, said the neoadjuvant HER2 blockade studies were the most exciting data to emerge at the San Antonio Breast Cancer Symposium. Not only do the findings of high pCR rates suggest there are better clinical outcomes with combination HER2 blockade, but they validate the long-standing theory that cancer cells have an “oncogene addiction”—a hypothesis he once doubted, based on the clinical contradiction that patients inevitably develop resistance to Debu Tripathy, MD trastuzumab, he told The ASCO Post. “Hitting a pathway at multiple levels appears to be important,” he said. “The molecular features driving a tumor will always be dependent on this pathway, and you will get greater clinical impact by creating a linear blockade that involves multiple sites.”

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HER2 pathway is a valid concept. Overall clinical responses at 6 weeks (before paclitaxel was given) were highest in both arms with lapatinib (67.1% with lapatinib/trastuzumab and 52.6% with lapatinib), but at the time of surgery response rates were fairly similar among the arms: 80.3% with the combination, 74.0% with lapatinib, and 70.5% with trastuzumab. Rates of breast-conserving surgery were similar among the three arms (around 40%), and in the node-neg-

ative subsets, rates were highest with lapatinib/trastuzumab (69% vs 48% with lapatinib and 56.6% with trastuzumab, respectively [P = .03]). In the 85-center GeparQuinto study, 620 patients were randomly assigned to receive epirubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles plus trastuzumab or lapatinib initiated with chemotherapy.2 After surgery, trastuzumab was given for 6 more months in the trastuzumab arm and for 12 months to patients initially receiving lapatinib.

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33rd Annual San Antonio Breast Cancer Symposium The trastuzumab arm achieved a significantly higher pCR rate according to the NSABP definition—50.4% and 35.2%, respectively (P < .05)— and also by the investigators’ more stringent definition of pCR (no microscopic evidence of residual tumor cells, invasive or noninvasive, in the breast or nodes): 31.3% vs 21.7% with lapatinib (P < .05), reported Michael Untch, MD, head of the Multidisciplinary Breast Cancer at the Helios Clinic, Berlin. In another component of the GeparQuinto trial reported at the meeting, bevacizumab (Avastin) added no benefit to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel.3

Impressive Outcomes with Pertuzumab/Trastuzumab In the four-arm NeoSphere trial of 417 women, triple therapy with pertuzumab, trastuzumab, and docetaxel produced 50% more pCRs than were achieved with trastuzumab and docetaxel, reported Luca Gianni, MD, Director of Medical Oncology at the Fondazione IRCCS Istituto Tumori in Milan.4 “In addition, this combination without chemotherapy was capable of eradicating the tumor in a remarkable number of cases (17%), therefore avoiding the toxicities seen with chemotherapy,” Dr. Gianni noted. The pCR rate (by NSABP definition) was 45.8% with trastuzumab/ pertuzumab/docetaxel, compared with 24.0% with pertuzumab/ docetaxel (P = .003), 29.0% with trastuzumab/docetaxel, and 16.8% with trastuzumab/pertuzumab (P = .0198). The triplet was well tolerated, with

no significant differences in grade 3/4 adverse events over the other arms. Strikingly low toxicity was noted for trastuzumab/pertuzumab, which was associated with grade 3/4 toxicity in less than 3% of patients, in sharp con-

Neil Spector, MD

Jose Baselga, MD

trast to 45% to 57% for the docetaxelcontaining arms. There was no meaningful increase in cardiac risk with the addition of pertuzumab over the short four-cycle course of neoadjuvant treatment. “Pertuzumab has the ability to enhance the activity of trastuzumab. The combination has good tolerability and remarkable antitumor activity in metastatic breast cancer that has progressed after trastuzumab,” Dr. Gianni commented. “The combination has a very favorable therapeutic ratio that justifies its continued use as adjuvant treatment after the end of chemotherapy.”

Interesting Responses by Hormonal Status Unexpectedly in NeoALLTO and GeparQuinto, pCR rates were higher in estrogen receptor (ER)-negative patients than in those with ER-positive disease. “In NeoALLTO, both hormone subgroups benefited from the lapatinib/trastuzumab combination, although it is worth noting that the ER-

Neoadjuvant HER2 Blockade in Breast Cancer ■■ Several phase III trials presented at the 2010 San Antonio Breast Cancer

Symposium showed high response rates for complete HER2 blockade as a neoadjuvant strategy in HER2-positive breast cancer.

■■ Pathologic complete response (pCR) rates in the NeoALLTO trial were 51.3% with lapatinib/trastuzumab vs 24.7% for lapatinib alone and 29.5% for trastuzumab alone (P = .0001).

■■ The GeparQuinto study showed pCR rates of 50.4% for a trastuzumabcontaining regimen vs 35.2% for a lapatinib-based combination.

■■ In the NeoSphere trial, pCR rates were 45.8% with trastuzumab/

pertuzumab/docetaxel, compared with 24.0% with pertuzumab/ docetaxel (P = .003), 29.0% with trastuzumab/docetaxel, and 16.8% with trastuzumab/pertuzumab (P = .0198).

■■ In NeoALLTO and GeparQuinto, toxicity was considerable with lapatinib, frequently leading to treatment discontinuation.

negative group did better,” Dr. Baselga commented. Patients with ER-negative tumors had a pCR rate of 61.3% with lapatinib plus trastuzumab, compared with 36.5% for the trastuzumab group and

Luca Gianni, MD

33.8% for the lapatinib group (P = .005). Rates in the in ER-positive patients, respectively, were 41.6% vs 22.7% and 16.2% (P = .03). In NeoSphere, the triplet yielded a 63% pCR rate in ER-negative women, compared with 26% in ER-positive patients. Dr. Winer said the higher pathologic CR rates for ER-negative tumors needs to be “reconciled with” the generally better disease-free survival seen for HER2-positive, ER-positive patients in the adjuvant setting. “The implication is that tumor kinetics vary by ER status,” he suggested, “and that ER remains important in HER2positive patients.” Failure to achieve a pCR appears to be less predictive of poor outcome in patients with ER-positive tumors than those with ER-negative tumors, he added.

More Adverse Events with Lapatinib Dr. Baselga and Dr. Untch both noted the greater toxicity of lapatinib in their studies. In NeoALLTO and GeparQuinto, approximately 35% of patients on the lapatinib arms were unable to receive the full planned doses of this agent. In NeoALLTO, grade 3 diarrhea was observed in more than 20% of patients on lapatinib compared with 2% with single-agent trastuzumab. Additionally, elevated liver enzymes were observed in 22% on both lapatinib-containing arms compared with 1% receiving trastuzumab, Dr. Baselga reported. In GeparQuinto, the investigators observed 10% more treatment discontinuations with lapatinib than with trastuzumab (23% vs 13%), largely due to side effects, and that may have affected the efficacy seen in this arm, Dr. Untch said. “Compliance of patients receiving lapatinib with epirubicin/cyclophosphamide and docetaxel was lower than with trastu-

zumab,” he noted. “We learned a lesson and lowered the dose of lapatinib. And we gave loperamide for the diarrhea.”

Translational Studies Forthcoming Refinement of these findings will come from a wealth of translational studies within these phase III trials. For NeoALLTO, 10 specimens are collected at each time point (at baseline, week 2, and surgery), which will yield 30 specimens per patient and a total of 11,091 samples. “Our future research is intended to identify predictive markers of sensitivity and resistance. We will also perform PET-CT and assess circulating tumor cells in a subset,” Dr. Baselga said. The companion adjuvant ALLTO trial, which will randomly assign 8,400 patients to various adjuvant regimens using these drugs, will be very informative, he added. Dr. Gianni similarly said, “We are exploring in our extensive tumor bank the ability to identify biomarkers of benefit from the trastuzumab/pertuzumab combination. One of the main messages from this study is that the neoadjuvant approach allows for rapid testing and ranking of See page 31 new therapies.”

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References 1. Baselga J, Bradbury I, Eidtmann H, et al: First results of the NeoALTTO trial (BIG 01-06 / EGF 106903): A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-3. Presented December 10, 2010. 2. Untch M, Loibl S, Bischoff J, et al: Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: Primary efficacy endpoint analysis of the GEPARQUINTO study (GBG 44). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-1. Presented December 10, 2010. 3. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy with or without bevacizumab: Primary efficacy endpoint analysis of the GEPARQUINTO study (GBG 44). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S4-6. Presented December 10, 2010. 4. Gianni L, Pienkowski T, Im Y-H, et al: Neoadjuvant pertuzumab (P) and trastuzumab (H): Antitumor and safety analysis of a randomized phase II study (‘NeoSphere’). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-2. Presented December 10, 2010.

The ASCO Post | JANUARY 15, 2011

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News Gynecologic Cancer

Ovarian Cancer: Hopes Pinned on Emerging Therapies By Caroline Helwick

he pivotal cascade of molecular events that culminate in ovarian cancer has not been fully elucidated, and therefore, treatment of this tumor has lagged behind several others that now benefit significantly from targeted therapies. But as the underlying mechanisms for ovarian cancer slowly come to light, clinical research is paying off, and the poor prognosis for the average patient may be changing. The following are summaries of recent advances that are making news in ovarian cancer.

PARP Inhibition with Olaparib BRCA1/2 mutations, causing loss of homologous recombination– mediated DNA repair, is one of the few recognized oncogenic genetic changes in ovarian cancer. The base excision repair pathway, activated with the loss of homologous recombination, requires poly(ADP-ribose) polymerase (PARP). The targeting of this enzyme with the new class of PARP inhibitors may render a blow to this backup system and thereby effectively fight the tumor. The PARP inhibitor olaparib, active in some breast cancers, showed promise in ovarian cancer in a phase II Canadian study.1 Patients with advanced ovarian cancer associated with BRCA mutations had a 41% response rate to single-agent olaparib 400 mg twice daily on a continuous basis in 4-week cycles. Those without the mutation had a 23% response rate. Median progression-free survival was 219 days, considered especially striking for heavily pretreated patients with advanced disease, according to principal investigator Karen Gelmon, MD, of the BC Cancer Agency, Vancouver. Though small, this study was hailed as one of the most important at the 2010 ASCO Annual Meeting by James H. Doroshow, MD, of the National Cancer Institute. “This is the first clear demonstration of activity of PARP inhibition in non–BRCA-mutated ovarian cancer… Serous ovarian cancer may actually be a disease of inhibition of DNA repair…and this drug is likely to make an impact. I predict an exciting future for this interesting class of agents,” he said. The data appeared so encouraging that a listener at the session

Expert Point of View

A James H. Doroshow, MD

commented, “Patients are dying because of lack of access to good drugs. When can I get my hands on this as a physician in practice?” Ongoing resequencing efforts from this study are of major importance in identifying somatic mutations for response. Also showing promise in both sporadic and BRCA-deficient tumors is the oral PARP inhibitor MK4827.2 Among 19 patients treated, the clinical benefit rate (stable disease for 3 or more months) was 37%, and some patients had very prolonged responses (ie, 17, 22, and more than 44 weeks). One patient had received five prior lines of chemotherapy and had responded for almost 1 year. BSI-121 is a third PARP inhibitor being evaluated in ovarian cancer. Seven others are being studied in breast cancer and melanoma.

Monoclonal Antibody Therapy Treatment with farletuzumab, a humanized monoclonal antibody targeting folate receptor-alpha— which is overexpressed in more than 90% of ovarian cancers—led to a 70% response rate when combined with standard therapy in a phase II clinical trial including 44 patients with ovarian cancer in first relapse. Total clinical benefit exceeded 90%, and more than 20% of women had a second platinum-free interval that was longer than the first, according to Allan J. White, MD, of South Texas Oncology and Hematology at the START Center in San Antonio, Texas. 3 “Patients with a first platinumfree interval of less than 12 months responded as well as those with an interval of 12 months or greater,” Dr. White noted. The study included 54 women in first platinum-sensitive relapse after a first remission of 6 to 18 months.

mong the compounds emerging for the treatment of ovarian cancer, the PARP inhibitors are extremely exciting. This is a drug class with great potential in this disease, and there is evidence that they will have benefits in platinum-sensitive patients, which is most of our newly diagnosed patients. One hopes, therefore, are that we can move these agents up to the initial treatment setting. The Gynecologic Oncology Group, in fact, has a phase I dose-escalation trial in newly diagnosed patients combining the PARP inhibitor ABT-888 with paclitaxel (weekly or every 3 weeks), carboplatin, and bevacizumab (GOG 9923). We know that PARP inhibitors are active in tumors associated with BRCA mutations. But what has recently been reported, and is especially interesting, is that PARP inhibitors may work in non–BRCA-mutated tumors as well—those that result from other insults. At last year’s ASCO Annual Meeting, Karen Gelmon and colleagues reported a 23% response rate in heavily pretreated non–BRCA-mutated patients. Ovarian cancer appears to be a tumor that is characterized by a defect in the homologous recombination pathway. Homologous recombination is a type of genetic recombination that is used by cells to repair double-stranded DNA breaks, and in ovarian cancer it is critical to repairing damage induced by platinum drugs. A number of mutations in addition to BRCA are being defined in ovarian cancer, and there may be multiple reasons why the homologous recombination pathway is not properly functioning. PARP inhibitors may work in many of these instances.

Encouraging Strategies Farletuzumab is another encouraging compound that is based on a new target in ovarian cancer, folate receptor-alpha, which is highly overexpressed in ovarian cancers compared to normal ovarian tissue. A major benefit of farletuzumab is that it targets this receptor without depriving normal cells of folate. When we have used farletuzumab as a single agent, we have not seen striking activity, primarily responses based on CA-125 levels. Instead, it seems to make the chemotherapy with which it is paired work better, possibly by enhancing immune recognition of the cancer cells. It is now in phase III trials in both platinum-sensitive disease (given with paclitaxel and a platinum agent) and platinum-resistant disease (given with weekly paclitaxel). Antiangiogenesis agents attack ovarian cancer in yet another way. Bevacizumab has significant single-agent activity when given alone for the treatment of recurrent ovarian cancer. This is unique in ovarian cancer, and is not seen in other diseases. However, in a recently reported randomized trial combining bevacizumab with chemotherapy, treatment improved progression-free survival but not overall survival. Without a survival benefit, I am not an advocate of using this strategy in the upfront setting. AMG-386 also targets the vasculature but in a different way than bevacizumab. This new class of agents is also intriguing, but data are very preliminary. —Deborah K. Armstrong, MD Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center and Associate Professor of Gynecology and Obstetrics Johns Hopkins University School of Medicine, Baltimore

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Patients with asymptomatic relapse received single-agent farletuzumab, those with symptomatic relapse received carboplatin/taxane chemotherapy plus farletuzumab, and those with disease progression on

farletuzumab monotherapy could proceed onto the combination chemotherapy while continuing farletuzumab. Combination therapy was associated with a median progression-free survival of 10 months.

ASCOPost.com | JANUARY 15, 2011

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News

Several patients had impressive platinum-free intervals—41 months, 37 months, and 17 months, which were all at least double their first platinum-free interval. Robust responses in CA-125 levels were also observed, he reported.

Antiangiogenesis Agents Agents that block angiogenesis may also enter the armamentarium in ovarian cancer, based on encouraging results seen with bevacizumab in a study that earned a coveted plenary session spot at the 2010 ASCO Annual Meeting.4 Bevacizumab (Avastin) added to carboplatin/paclitaxel, followed by bevacizumab maintenance, extended progressionfree survival by nearly 4 months (14.1 vs 10.3 months; P < .0001), in the Gynecologic Oncology Group 0218 study (see the July 2010 issue of The ASCO Post). AMG 386, a first-in-class peptibody that inhibits angiopoietin-1 and -2, has also shown early activity in combination with paclitaxel.5

Other Approaches As a single agent, NKTR-102, a topoisomerase I inhibitor-polymer conjugate, showed strong activity in a phase II study of 68 patients with platinum-resistant disease.6 Response rates were 24% to 41% (depending on criteria), and median progression-free survival was 18 weeks. Based on these results, in patients whose median platinumfree interval was only 1 month, lead author Ignace Vergote, MD, of the Catholic University, Leuven, Belgium, maintained that NKTR-102 has “great therapeutic potential.”

nal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a multicenter phase II study. 2010 ASCO Annual Meeting. Abstract 5001. Presented June 7, 2010. 4. Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab in the primary treatment of advanced

epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer: A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010. 5. Karlan BY, Oza AM, Hansen VL, et al: Randomized double-blind, placebocontrolled phase II study of AMG 386 combined with weekly paclitaxel in pa-

tients with recurrent ovarian carcinoma. 2010 ASCO Annual Meeting. Abstract 5000. Presented June 7, 2010. 6. Vergote IB, Micha JP, Pippitt CH Jr, et al: Phase II study of NKTR-102 in women with platinum-resistant/refractory ovarian cancer. 2010 ASCO Annual Meeting. Abstract 5013. Presented June 7, 2010.

UNITED WE STAND

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References 1. Gelmon KA, Hirte HW, Robidoux A, et al: C we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. 2010 ASCO Annual Meeting. Abstract 3002. Presented June 5, 2010. 2. Sandhu SK, Wenham RM, Wilding G, et al: First-in-human trial of a poly(ADP-ribose) polymerase inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient and sporadic ovarian cancers. 2010 ASCO Annual Meeting. Abstract 3001. Presented June 5, 2010. 3. White AJ, Coleman RL, Armstrong DK, et al: Efficacy and safety of farletuzumab, a humanized monoclo-

Introducing the United Network of US Oncology. We are America’s largest network of community-based oncologists. We work together to advance the science of cancer care and realign reimbursement policies to reward quality care. And with our flexible options, there are more ways than ever to join us and stand strong together. To learn more about joining the United Network of US Oncology, visit usoncology.com/TAP

The ASCO Post | JANUARY 15, 2011

PAGE 22

52nd ASH Annual Meeting Novel Agents

Promising Data Reported on Hematology Drugs in the Pipeline By Alice Goodman

iologic agents and novel chemotherapies in various stages of clinical development hold promise for the treatment of hematologic malignancies, but as past experience shows, results of preliminary studies are not always confirmed in randomized controlled trials and many drugs with promising phase II data do not gain FDA approval. With that caveat, here are snapshots of some potentially promising drugs for chronic myelogenous leukemia, lymphoma, and multiple myeloma based on presentations at the 52nd Annual Meeting of the American Society of Hematology (ASH), held December 4–7 in Orlando, Florida.

Bosutinib for Chronic Myelogenous Leukemia Imatinib is standard first-line therapy for chronic myelogenous leukemia (CML), and both dasatinib (Sprycel) and nilotinib (Tasigna) were recently approved by the FDA as first-line therapies in CML. Bosutinib, a new tyrosine kinase inhibitor with a dual mechanism of action, may be another option for first-line therapy of CML if results of a phase III trial presented at ASH 2010 are confirmed.1 The randomized, phase III, open-label BELA study showed that bosutinib reduced the number of treatment failures compared with imatinib. At 1 year, treatment failure rates were 3% on the bosutinib arm vs 10% on the imatinib arm. According to lead author Carlo Gambacorti-Passerini, MD, Professor at the University of Milano Bicocca, Monza, Italy, bosutinib’s effect on treatment failure is the main message of this study. The overall net benefit of 7% would translate to about 500 patients newly diagnosed with CML in the United States each year, he said. Dr. Gambacorti-Passerini emphasized that it will be important to determine which patients with CML would benefit from bosutinib compared with other agents used in this setting. He and his colleagues are currently doing genomic sequencing studies on leukemic cells to try to identify characteristics of those patients. The study enrolled 502 newly diagnosed patients with CML. An intent-totreat analysis showed that at 1 year, the major molecular response rate was 39% with bosutinib vs See page 31 26% with imatinib

(P = .002). The study failed to meet its primary endpoint of superior complete cytogenetic response with bosutinib at 1 year: 70% for bosutinib vs 68% for imatinib, a difference that was not statistically significant. Bosutinib was associated with more diarrhea, nausea, vomiting, and rash compared with imatinib; the most frequent grade 3 and 4 adverse events were diarrhea (8%) and rash (2%). More muscle cramps, bone pain, and periorbital edema were associated with imatinib therapy. Treatment discontinuation rates were 25.4% with bosutinib and 13.5% with imatinib. Dr. Gambacorti-Passerini concluded that the higher discontinuation rate was mostly due to the lack of experience with bosutinib of most participating centers (bosutinib is not yet registered for any indication). Once it is reduced, the advantage of bosutinib will be even greater.

Ponatinib for Chronic Myelogenous Leukemia Despite the success of imatinib and its cousins dasatinib and nilotinib in treating CML, a proportion of patients with CML will experience treatment failure or develop resistance. Currently there are no effective drugs for resistance due to the T315I mutation, but ponatinib—a new tyrosine kinase inhibitor—appears to inhibit the entire spectrum of mutations responsible for resistance to tyrosine kinase inhibitors. A dose-escalation, phase I study of 74 patients with refractory hematologic malignancies (60 patients with CML), showed exciting results in a cohort of patients with chronic-phase CML.2 (Among the 60 patients with CML, 44 were in chronic phase, 7 were in accelerated phase, and 9 were in blast phase.) Among 38 evaluable patients with chronic-phase CML, 95% had a complete hematologic response, 66% a major cytogenetic response, and 53% a complete cytogenetic response. In nine evaluable patients from this group with chronic-phase CML and T315I mutations, 100% had a complete hematologic response, 100% had a major cytogenetic response, and 89% had a complete cytogenetic response. “These are very exciting responses in these patients,” said lead author Jorge Cortes, MD, of The University of Texas MD Anderson Cancer Center, Houston. If these preliminary results are confirmed in future trials, this drug may be able to

prevent the emergence of resistance due to mutations. Responses were less robust but still significant in patients with acceleratedand blast-phase CML, with no complete hematologic responses and major hematologic response observed in 35% of this group. Toxicity was acceptable. The most common adverse events (10% or greater) included thrombocytopenia, headache, nausea, arthralgia, fatigue, anemia, increased lipase, muscle spasms, rash, myalgia, and pancreatitis.

Pixantrone for Non-Hodgkin Lymphoma Pixantrone, a novel aza-anthracenedione structurally related to mitoxantrone and the anthracyclines, was superior to the investigator’s choice of therapy in the randomized, controlled, phase III EXTEND trial of relapsed aggressive non-Hodgkin lymphoma (NHL).3 In this pretreated, poor prognosis group of 140 patients previously treated with up to two lines of prior chemotherapy, pixantrone achieved superior rates of complete response/complete response unconfirmed, superior overall response rate, and superior progression-free survival compared with comparator agents. At 18 months of follow-up, the complete response/complete response unconfirmed rate was 20% for pixantrone vs 5.7% for comparators (ie, vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, gemcitabine, or rituximab [Rituxan]); overall response rate was 37.1% vs 14.3%, respectively; median progression-free survival at the end of the study was 5.3 vs 2.6 months, respectively (P = .005). Median overall survival was 10.2 months with pixantrone vs 7.6 months for the other agents, but this difference was not statistically significant. Ruth Pettengell, MD, of St. George’s Hospital in London, presented these trial results at a poster session.

Carfilzomib for Multiple Myeloma Although several effective therapies are available for multiple myeloma, patients treated with these therapies typically relapse and have limited treatment options. Carfilzomib, a novel highly selective next-generation proteosome inhibitor, achieved durable responses in a phase IIb study of 266 patients with relapsed/ refractory multiple myeloma previously treated with all available therapies. The

drug was generally well tolerated.4 Carfilzomib has the potential to offer substantial clinical benefit to patients who have relapsed or are refractory to other therapies, said lead author David Siegel, MD, PhD, of John Theurer Cancer Center, Hackensack, New Jersey. Patients enrolled in the phase IIb trial received at least two prior therapies, including bortezomib (Velcade) and either thalidomide (Thalomid) or lenalidomide (Revlimid), plus an alkylating agent. In 257 patients evaluable for response, overall response rate was 24.1% and median duration of response was 8.3 months. The clinical benefit rate (complete or partial plus minimal response rate) was 34.2%. The disease control rate, which includes stable disease, was 69%. Median overall survival was 15 months. The most common grade 3 or 4 toxicity was thrombocytopenia (27%), anemia (22%), lymphopenia (18%), and neutropenia (10%). Of particular note was the extremely low rate of peripheral neuropathy. Dr. Siegel said that these are good results in this group of heavily pretreated patients, with a median number of five previous lines of therapy, and multiple relapses and progressive disease at study entry. Onyx Pharmaceuticals plans to file a New Drug Application with FDA for carfilzomib in 2011.

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References 1. Gambacorti-Passerini C, Kim D-W, Kantarjian H, et al: An ongoing phase 3 study of bosutininb (SKI-606) versus imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia. 52nd ASH Annual Meeting. Abstract 208. Presented December 6, 2010. 2. Cortes J, Talpaz M, Bixby D, et al: A phase I trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: Emerging safety and clinical response findings. 52nd ASH Annual Meeting. Abstract 210. Presented December 6, 2010. 3. Pettengell R, Zinzani PL, Narayanan G, et al: Phase 3 trial of pixantrone dimaleate compared with other agents as third-line, single-agent treatment of relapsed aggressive non-Hodgkin lymphoma (EXTEND): End of study results. 52nd ASH Annual Meeting. Abstract 2833. Presented December 5, 2010. 4. Siegel D, Martin T, Wang M, et al: Results of PX-171-003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. 52nd ASH Annual Meeting.Abstract 985. Presented December 7, 2010.

Now

AvAilAble

www.halaven.com

The ASCO Post | JANUARY 15, 2011

PAGE 24

Psychosocial Oncology

Improving Psychosocial Care through the Use of Quality Indicators By Paul B. Jacobsen, PhD

Indicators of the Quality of Psychosocial Care Translating the IOM report’s recommendations into actions that will result in more patients receiving needed psychosocial services is no easy task. Clearly, more effort will be required than simply issuing reports and guidelines. One strategy used successfully in other contexts to change clinical practice is to give health-care providers feedback about the quality of care they provide.4 To address the lack of accepted indicators of the quality of psychosocial care, the American Psychosocial Oncology Society (APOS) formed a workgroup in 2007 that I chaired. Based on a review of relevant literature, including the IOM report1 and the National Comprehensive Cancer Network Guidelines for Distress Management,5 the workgroup developed indicators to measure two

Evaluating Psychosocial Quality Indicators The performance characteristics of these indicators were initially evaluated in a multicenter study that my colleagues and I conducted in outpatient medical oncology practices.6 Using the resources of the Florida Initiative for Quality Cancer Care (FIQCC),7 the psychosocial indicators were embedded in a larger set of quality indicators, and data were collected at 11 practice sites in Florida. Medical records of 1,660 patients with colorectal, breast, and non–small cell lung cancer first seen by a medical oncologist in 2006 were reviewed. Rates of assessment of emotional well-being within 1 month of a first visit with a medical oncologist ranged from 12% to 86% across sites (median = 47%). Among the 13% of patients identified as having a problem with

emotional well-being, rates of action taken (or explanation for no action) ranged from 13% to 100% (median = 57%). Direct comparison of mean performance rates indicated that pain was more likely to be assessed than emotional well-being (87% vs 52%, P < .0001). These findings show how use of these indicators permits identification of specific practice sites and processes of care that should be targeted for quality improvement efforts. The findings also demonstrate the extent to which routine assessment of emotional well-being lags behind routine assessment of pain in cancer patients.

Future Directions

The Quality Oncology Practice Initiative (QOPI) is ASCO’s voluntary practice-based quality improvement program.8 In 2008, QOPI added the two quality indicators for psychosocial care described above to its core set of measures completed by all participating practices. Practices participating in QOPI have the opportunity to submit chart audit information at 6-month intervals. Following submission of their data, each practice is provided with feedback about its own performance on each indicator as well as the average performance of all other participating practices on each indicator. With the permission of the QOPI steering committee, Pamela Kadlubek of ASCO and I were able to determine if performance on these indicators improved between Fall 2008 (when the indicators became part of the core measures) and Fall 2009.9 Our analysis was based on 166 practices that participated in both the Fall 2008 and Fall 2009 audits. These practices submitted data on approximately 15,000 patients at each time point.

Findings from QOPI suggest that providing feedback to practices resulted in an increase in assessment of patient emotional well-being. As would be expected, this increase corresponded to more patients being identified as having a problem with emotional wellbeing and more actions being taken to address these problems. Although an increase on process indicators of quality care is encouraging, additional research incorporating outcome measures is needed to determine if conducting more assessments results in actual improvements in patients’ emotional well-being. Moreover, while provision of feedback alone may yield improvements in the quality of psychosocial care, a more active approach could yield even greater results. Many practices would probably benefit from expert guidance about selecting and implementing appropriate psychosocial care models. This objective could be achieved by conducting rigorously designed demonstration projects that show how to successfully improve psychosocial care

100%

90%

80% 70% 60% 50%

Fall 2008 N = 15,012

As shown in Fig. 1, we found that the average rate per practice for performing an assessment of emotional well-being improved over time from 64% to 73% (P < .001). On the other hand, the average rate per practice for taking action if a problem with emotional well-being was identified increased only from 74% to 76% (P = .41; see Fig. 2). However, reflecting the increase from 13% to 17% in percentage of each practice’s patients identified as distressed (P < .001; see Fig. 3), the percentage of each practice’s patients for whom action was taken for a problem with emotional well-being increased from 9% to 13% (P < .001; see Fig. 4).

Changes over Time in the Quality of Psychosocial Care

Percent yes

2007 Institute of Medicine (IOM) report, titled “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs,” summarized the status of efforts to provide psychosocial care for people with cancer.1 The report concluded that despite evidence of the effectiveness of psychosocial services, many patients do not receive help for problems that would benefit from this type of care. The reasons for this failure are many and include the tendency of oncology care providers to underestimate distress in patients2 and to not link patients to services when needs are identified.3 To address these problems, the report recommended that provision of appropriate psychosocial services be adopted as a standard of quality cancer care. The report also identified a model for the effective delivery of psychosocial services that includes implementation of processes for identifying patients’ psychosocial needs and then implementing plans that link patients with needed psychosocial services.

Percent yes

Paul B. Jacobsen, PhD

components considered necessary for providing quality psychosocial care: a process for identifying distressed patients and a process for linking distressed patients with services. The first quality indicator stipulates there should be evidence in the medical record that the patient’s current emotional well-being was assessed within 1 month of the patient’s first visit with a medical oncologist. The second quality indicator stipulates that if a problem with emotional wellbeing was identified, there is evidence in the patient’s medical record that action was taken to address the problem or an explanation provided for why no action was taken. Measurement of these indicators is operationalized by formulating questions that can be answered yes or no based on the review of an individual patient’s medical record.

Fall 2009 N = 15,841

Fig. 1: Emotional well-being assessed (average practice rate).

80% 70% 60% 50%

Fall 2008 N = 1,616

Fall 2009 N = 2,461

Fig. 2: Action taken among patients with problem (average practice rate).

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PAGE 25

Psychosocial Oncology

in a variety of “real world” settings. In summary, there is growing awareness of the need to improve the psychosocial care of cancer patients. Tools are available that practices can use to evaluate the quality of psychosocial care their patients receive and identify the need for quality improvement efforts. The next step will be to develop strategies that can be disseminated readily to practices seeking guidance on how to improve the quality of psychosocial care they provide their patients.

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References 1. Adler NE, Page AEK (eds): Cancer care for the whole patient: Meeting psychosocial health needs. Washington, DC, National Academies Press, 2007. 2. Fallowfield L, Ratcliffe D, Jenkins V, et al: Psychiatric morbidity and its recognition by doctors in patients with cancer. Br J Cancer 84:1011-1015, 2001. 3. Institute of Medicine: Implementing cancer survivorship care planning. Washington, DC, National Academies Press, 2007. 4. Jacobson JO, Neuss MN, McNiff KK, et al: Improvement in oncology practice performance through voluntary participation in the Quality Oncology Practice Initiative. J Clin Oncol 26:1893-1898, 2008. 5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Distress management, version 1.2011. Available at http://www.

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 SloanKettering Cancer Center, New York.

nccn.org/professionals/physician_gls/ PDF/distress.pdf. 6. Jacobsen PB, Shibata D, Siegel EM, et al: Evaluating the quality of psychosocial care in outpatient medical oncology settings using performance indicators. Psycho-Oncol September 27, 2010 (epub ahead of print). 7. Malafa MP, Corman MM, Shibata

D, et al: The Florida Initiative for Quality Cancer Care: A regional project to measure and improve cancer care. Cancer Control 16:318-327, 2009. 8. Neuss MN, Desch CE, McNiff KK, et al: A process for measuring the quality of cancer care: The Quality Oncology Practice Initiative. J Clin Oncol 25:6233-6239, 2005. 9. Jacobsen PB, Kadlubek P: Chang-

es over time in quality of psychosocial care: Results from the Quality Oncology Practice Initiative (QOPI). J Clin Oncol 28(15S):Abstract 6000, 2010. Dr. Jacobsen is Chair of the Department of Health Outcomes and Behavior at the Moffitt Cancer Center and Professor of Psychology at the University of South Florida, Tampa.

The ASCO Post | JANUARY 15, 2011

PAGE 26

JOP Spotlight Drug Safety

Identifying Key Vulnerabilities of Oral Chemotherapy Leads to Recommendations for Remediation Strategies By Charlotte Bath

sing detailed failure mode and effects analyses (FMEAs), investigators at Dana-Farber Cancer Institute in Boston found that the medication-use processes associated with five oral chemotherapy agents were “surprisingly complex” and identified key vulnerabilities. These include “patient education about drug handling and adverse effects, prescription writing, patient self-administration and medication adherence, and failure to monitor and manage toxicities,” the investigators reported. Some of the failure modes revealed by the analyses were specific to just one agent, but many were found to be

were published in the Journal of Oncology Practice,1 and the lead author of that article, Saul N. Weingart, MD, PhD, offered additional insights in an interview with The ASCO Post. Dr. Weingart is Vice President for Quality Improvement and Patient Safety at Dana-Farber Cancer Institute. Saul N. Weingart, MD, PhD

common to all five oral chemotherapies studied, suggesting some common remediation strategies, such as improved patient education and using only electronic prescribing. Results of the study

High-risk Failure Modes Interdisciplinary teams conducted the failure mode and effects analyses for mercaptopurine (pediatric leukemia), temozolomide (brain cancer and melanoma), capecitabine (advanced colorectal and breast cancers), ima-

Table 1: Selected Recommendations to Address High-risk Failure Modes Affecting Five Oral Chemotherapies Recommendation

Source

Prescribing Create checklists to guide and remind clinicians about key elements required for patient education

Capecitabine/imatinib/temozolomide

Provide patients and families members with educational material about research protocol and call-in number for questions

Investigational agent

Provide patients and families with abbreviated protocol guide or roadmap

Investigational agent

Require study nurse to call patients and families shortly after starting protocol to review protocol and consent and ensure understanding

Investigational agent

Dedicate follow-up appointment specifically to medication education

Mercaptopurine

Dispensing Implement barcode scanning for dispensed medications

Capecitabine/imatinib/temozolomide

Provide patients with images of pills

Capecitabine/imatinib/temozolomide/investigational agent

Standardize clinician documentation of dose modifications to facilitate pharmacy verification

Capecitabine/imatinib/temozolomide/investigational agent

Standardize data entry in ambulatory pharmacy to avoid data entry errors

Mercaptopurine

Minimize number of dose forms and concentrations available in pharmacy

Mercaptopurine

Institute triple-check system for dispensing oral chemotherapies

Investigational agent/mercaptopurine

Administration, monitoring, and follow-up Provide patients with dosing calendars similar to those provided in clinical trials

Capecitabine/imatinib/temozolomide/mercaptopurine

Encourage use of automated reminder systems and prefilled pill boxes

Capecitabine/imatinib/temozolomide

Offer online educational and management tools for addressing adverse effects

Capecitabine/imatinib/temozolomide

Support safe home administration by reaching out to patients and families through nurse practitioner follow-up calls

Temozolomide

Encourage patients to bring in medication bottles to monitor adherence

Mercaptopurine

Identify specific clinic staff responsible for patient and family education about medications

Mercaptopurine

Provide oral chemotherapy travel kits to children whose parents are separated

Mercaptopurine

tinib (chronic myelogenous leukemia and GI stromal tumors [GIST]), and a phase II investigational agent used for treatment of GIST. “The analyses included an evaluation of electronic and paper-based prescription writing, preparation and dispensing of medications on site and at community-based pharmacies, administration (largely at home by the patient or caregiver), and follow-up and symptom monitoring,” the authors explained. The teams developed process maps for each medication, identified failure modes and high-risk failure modes (defined as “those with the highest severity and frequency scores and the lowest likelihood of detection) and suggested ways to mitigate the risks. The number of high-risk failure modes varied from 10 (for mercaptopurine) to 18 (for the investigational agent). Four high-risk failure modes were common in all five FMEAs. The authors list them as: ■■ Prescription writing errors resulting from shortcuts, miscalculations, or illegible handwriting ■■ Wrong tablets, liquid, dose, or number of tablets dispensed in the pharmacy ■■ Patient did not correctly adhere to regimen ■■ Patient failed to or incompletely reported adverse effects Some of the proposed remediation strategies were also common to all five study drugs. These include prohibiting handwritten and called-in prescriptions and using only electronic prescribing, and requiring written informed consent for all oral chemotherapy treatment. Table 1 lists a representative set of additional recommendations.

Targeted Improvement Efforts The failure mode analyses “turn out to be very resource-intensive, which is a limitation and one of the issues we raised in the paper,” Dr. Weingart told The ASCO Post. “If you are going to do a by-the-book FMEA, you have to really be prepared to spend a lot of time, including valuable clinicians’ time, doing this work. So we struggled a bit with how you might adapt it and make it more efficient and usable for a clinical environment.” That included using

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PAGE 27

JOP Spotlight

An Issue That Will Need Revisiting

ral chemotherapy in ambulatory oncology poses a new and emerging area of risk,” the Dana-Farber Cancer Institute investigators noted in the introduction to their report on medication safety analyses of oral chemotherapies. In an interview with The ASCO Post, Dr. Weingart said that continuing efforts are needed to make sure that risks are more fully understood. “Oral chemotherapy is supplementing infusion therapy as part of the armamentarium,” he said, but “we are just beginning to understand the way that these new therapies create hazards. As the drugs are more widely used and used in different ways in different populations, we are going to need to come back and repeat these kinds of proactive assessments, or even retrospective assessments, based on our experience with how oral chemotherapies are used. A lot of the identification of risk in this project was based on clinicians’ and other frontline staff ’s best judgment about what might pose problems.” But in a few years, he said, “we will actually have experience that we can look back on and learn from, and then try to make adjustments accordingly.”

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abbreviated FMEAs of two 2-hour meetings rather than the full four or five meetings and asking teams to verify and modify process maps based on previously conducted literature searches and interviews, rather than having to create the maps de novo.

The authors noted that the FMEA initiative “helped our organization to target improvement efforts.” These included enhancing the methods for writing prescription orders into the ambulatory electronic order entry system for oral chemotherapy and for

preparing the prescriptions, as well as developing specific informed consent documents for oral chemotherapy at the time of prescription. “The oral chemotherapy enhancements went into place about 6 months ago, and so we are anticipating getting data soon to see how they are being used,” Dr. Weingart said. The project for developing the consent documents has been approved and prioritized, and the documents are in the pipeline and are expected to be out in the next year, he added. Other improvements have been aimed at “trying to build in better double checks and provide more counseling to patients” in the onsite ambulatory pharmacy, he said, along with posting online updated patient education materials about oral chemotherapy.

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Reference 1. Weingart SN, Spencer J, Buia S, et al: Medication safety of five oral chemotherapies: A proactive risk assessment. J Oncol Pract. Dec. 8, 2010 (early release online).

Safety vs Privacy

ome of the failure mode and risk effect analyses and the proposed remediation strategies prompted “interesting” dialogue, Dr. Weingart said. “For example, a safety best practice is to include the diagnosis on a prescription. So if a patient takes the prescription to a community pharmacy, the pharmacist will know that the drug matches the diagnosis,” he explained. “But there was also a concern about patient privacy. We took this to our patient family advisory councils, who thought about it and came back to us and said that patients and providers should be able to suppress that information. But the default should be that the prescription includes the diagnosis, because that will ensure the highest level of safety. So we put that in place.”

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In the Literature

Emerging Clinical Data on Cancer Management LIVER CANCER Sorafenib plus Doxorubicin Adding sorafenib (Nexavar) to the doxorubicin regimen used to treat patients with advanced hepatocellular carcinoma (HCC) cancer resulted in greater overall and progression-free survival, compared to patients who received treatment with doxorubicin alone, according to a study in JAMA. A randomized, phase II study compared doxorubicin plus sorafenib to doxorubicin plus placebo in patients with advanced HCC (Eastern Cooperative Oncology Group performance status 0–2, Child-Pugh A status) and no prior systemic treatment. Patients were randomly assigned to receive 60 mg/m2 of doxorubicin intravenously every 21 days for a maximum on 360 mg/m2 plus either 400 mg of sorafenib or placebo orally twice a day. Following complete accrual of 96 patients (76% male; median age, 65 years), an unplanned early analysis for efficacy was performed by the independent data monitoring committee, and the trial was halted. The two patients remaining in the placebo group at that time were offered sorafenib.

Sorafenib/Doxorubicin Synergy? The median time to disease progres-

sion was 6.4 months for patients who received doxorubicin plus sorafenib vs 2.8 months for those who received doxorubicin plus placebo. During the course of the study, 63 patients died: 25 in the doxorubicin/sorafenib group and 38 in the doxorubicin/placebo group. Median overall survival was 13.7 months among patients treated with doxorubicin plus sorafenib vs 6.5 months among those who received doxorubicin plus placebo, with analysis of the two groups indicating a 51% reduction in the risk of death for patients in the doxorubicin/sorafenib group. The median progression-free survival was 6 months among patients treated with doxorubicin plus sorafenib vs 2.7 months among those who received doxorubicin plus placebo, with exploratory comparison of the two groups showing a 46% reduction in the risk of progression or death among patients in the doxorubicin/sorafenib group vs doxorubicin plus placebo. “Most toxicity events occurred at a rate expected with the individual agents alone,” the authors reported. The degree to which the improvement in median time to progression, overall survival, and progression-free survival “may represent synergism between sorafenib and doxorubicin remains to be defined,” the investigators stated. This tri-

al has served as the basis for an ongoing phase III trial of sorafenib/doxorubicin vs sorafenib alone, they added. Abou-Alfa GK, et al: JAMA 304:2154-2160, 2010.

BREAST CANCER Lasofoxifene in Chemoprevention Use of the investigational selective estrogen receptor modulator (SERM) lasofoxifene resulted in a statistically significant reduction of the overall risk of breast cancer, as well as estrogen receptor (ER)-positive invasive breast cancer in postmenopausal women with low bone density, according to a study published online in the Journal of the National Cancer Institute. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, 8,556 postmenopausal women between the ages of 59 and 80 with low bone density and normal mammograms were randomly assigned to either 0.25 or .0.50 mg/d of lasofoxifene or placebo. Breast cancer was confirmed in 49 women. Compared with placebo, the 0.5-mg dose of lasofoxifene statistically significantly reduced risk of total breast cancer by 79% and the risk of

ER-positive breast cancer by 83%. The authors noted that the risk reduction for breast cancer with lasofoxifene was similar to that reported for tamoxifen and raloxifene.

Attractive Option “The spectrum of activity for lasofoxifene, including the clinically and statistically significant reductions of nonvertebral fractures, stroke, and serious heart events, makes it an attractive option, particularly for use in postmenopausal women with osteoporosis or higher estradiol levels,” the authors wrote. They also pointed out some limitations of the study. “It is true that the PEARL trial was handicapped by a small number of both subjects and adverse events, yet the breast cancer risk reduction compared with placebo was dramatic at nearly 80%,” Victor G. Vogel, MD, of the Geisinger Medical Center in Danville, Pennsylvania, wrote in an accompanying editorial. “We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes, but the early data regarding its risks and benefits are encouraging,” he added. LaCroix AZ, et al: J Natl Cancer Inst 102:1706-1715, 2010. Vogel VG: J Natl Cancer Inst 102:1683-1685, 2010.

The ASCO Post | JANUARY 15, 2011

PAGE 28

Opinion

Health-care Priorities continued from page 1

Should we have an open discussion about the ramifications of balancing the budget on the back of health care? When members of Congress vote against suspending the sustainable growth rate (SGR) due to the cost, are they willing to say that

they are for prioritizing or rationing care? Some of the politicians who recently railed against “death panels”—something that was never proposed—are the same ones who have rallied crowds around the belief that the debt is unsustainable and that there must be control of the budget. For those politicians who want to eliminate the

SGR and thus not reduce money going to health care, are they willing to say that the $250 billion (and growing) cost of not implementing the SGR is not a concern to the economy? Is the national debt and voracious borrowing from China acceptable? The nation cannot have it both ways. The reason why there is such contention is

that these are very tough choices. The American way of solving the health-care crisis should be to prevent, diagnose early (using advanced biomarkers), and cure our way out of the problem.1 This would reduce costs, democratize health care by having cures (inherently much cheaper than prolonged treatments) available to all, and solve the fundamental issue—that the cause of the health-care crisis is the cost. It has been estimated that if medical science could push back the onset of Alzheimer’s disease by 5 years (not even prevent it), the Medicaid crisis would be resolved because Medicaid nursing homes would be emptied.

Where the Money Is When asked why he robbed banks, Willie Sutton reputedly said, “Because that’s where the money is!” Two other adages—“Show me the money,” from the movie Jerry McGuire, and “If they say it’s ‘not the money,’ you know it is the money”—are also instructive when it comes to the cost crisis in health care. There are only a few places in the U.S. economy that, if reduced, will make a real difference in the debt. Medicare and Medicaid make up 20% of the budget today. In 2050, they will consume 40%. If Americans are unwilling to solve the entitlement problem, the country will eventually be bankrupt, and even China will not be able to buy us out of it. There must be consistency in our thinking. Sipuleucel-T is a potentially valuable medication to a subpopulation of patients with metastatic prostate cancer refractory to hormones, for whom other chemotherapies have probably failed. These unfortunate individuals will gain an average of 4 months of life, although the quality of extended life might not be very satisfying. If budgets are ever to be balanced, this questionable benefit would likely result in others not being treated. So let us have a real debate about the cost of health care and the choices (including sacrifices) that need to be made to pay for it. Health-care economics must be viewed not in a vacuum, but rather, in a fiscal universe of choices and limitations. Let our priorities dictate that when there are limited funds, the children are first to receive the care they richly deserve. And finally, we should focus on applications and translational research that will bring prevention, early diagnosis, and cure to patients, thereby eliminating prolonged, costly, chronic treatments.

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Reference 1. Boxer RJ: American center for cures could ensure health-care reform leads to reform in health. The ASCO Post 1(2):3, 2010.

ASCOPost.com | JANUARY 15, 2011

PAGE 29

Opinion

Responsible Spending in Cancer Care: The Steps That Really Matter By J. Russell Hoverman, MD, PhD, Medical Director of Managed Care and Innovent Oncology, US Oncology, and Susan Russell, The Russell Mark Group

Direct medical costs, $93 billion

J. Russell Hoverman, MD, PhD

fter surgery and adjuvant therapy, a patient’s cancer recurs. A new drug is available, but its benefits are uncertain and its cost is $100,000. We all know the story; many of us have experienced it. But the cost equation is usually not as dramatic as these high-profile cases involving last-minute, high-stakes decisions. In fact, all physicians make decisions that affect the cost of care every day, in ways that may not be immediately obvious. Responsible spending in cancer care comes down to a series of continuous, step-by-step decisions throughout the months or years of treatment and follow-up, rather than the impressive, end-of-life gesture. Fortunately, quality care is not the same as expensive care. Many of the daily decisions that have been shown to lead to better outcomes for the patient—in health status, emotional well-being, and quality of life—are the ones that also help control costs.

Rising Costs for Society and Patients

Overall cancer costs (in billions)

There is no question that the costs associated with cancer treatment have risen rapidly and significantly. Between 1995 and 2004, the overall cost of treating cancer increased by 75%, according to the National

Susan Russell

Cancer Institute. In 2005, the United States spent $209 billion on overall costs for cancer care; by 2008, the figure was $228 billion (Fig. 1), including $93.2 billion in direct medical costs and the rest in lost productivity because of treatment or early death, according to the National Institutes of Health (Fig. 2). Although the rate of increase in cancer treatment spending has remained about the same as a percentage of overall health-care spending, as the population ages, this percentage is expected to increase as more cases are diagnosed and treatment becomes more expensive relative to other disease categories. Spending on cancer now accounts for about 5% of all medical treatment in the U.S. and about 10% of Medicare spending. However, over 40% of Medicare drug expenditures are for oncology/hematology drugs. The disproportionate cost of cancer drugs has been the topic of much discussion as a factor in the increasing cost of care. Cytotoxic and biologic agents are some of the most expensive drugs to develop, with no decrease in sight. According to a recent study, the cost of bringing a new cancer drug to market, including preclinical and clinical testing, is approximately $1 billion.1 $228

$230.0

$219

$220.0

$209

$210.0 $200.0 $190.0

$206

$190.0

Fig. 2: 2008 U.S. Cancer Costs ($228 billion), broken down by segment. Data courtesy of American Cancer Society and National Institutes of Health.

New imaging and radiation therapy techniques, while groundbreaking in their ability to diagnose, stage, and treat cancer, come with a big price tag as well: A single PET scan for cancer staging can be $5,000 to $10,000. In this instance, the important thing to consider is whether the patient is receiving benefit in proportion to the cost. Fortunately, as a result of these advancing technologies and new agents, survival rates have increased for patients facing cancer. This good news has its price, too. As patients live longer, the cost of their treatment increases with the length of survival. For example, treating a patient with breast cancer for a year vs that same treatment plus maintenance therapy for 8 years represents a sixfold increase in cost.2 Beyond the cost to society, the cost of cancer treatment for individuals is rising to a crippling level. Even when patients have insurance, they may still pay tens of thousands or even hundreds of thousands of dollars for treatment. Those without insurance may delay or forgo treatment, and they may not be able to afford the treatment their physicians would like to offer. (Not surprisingly, those at the low end of the socioeconomic ladder fare the worst—they have more advanced cancers at diagnosis, receive less aggressive treatment, and as a result, have shorter survival times.3)

Linking Positive Outcomes and Responsible Spending

$180.0 $170.0

Lost productivity, $135 billion

2004

2005

2006

2007

2008

Fig. 1: Overall U.S. Cancer Costs (in billions). Data courtesy of American Cancer Society and National Institutes of Health.

The cost repercussions of clinical decisions can be profound for patients and for society at large. In spite of the complexities of health-care

costs, physicians do have control over many of the aspects of how money is spent. Three pillars of responsible health-care spending have emerged from this picture as those that have the most effect on cost, with the best outcomes for patients and their families: evidence-based medicine, appropriate disease management, and compassionate end-of-life planning. Evidence-based Medicine. With evidence-based medicine, physicians can be sure they are working with the most clinically sound, up-to-date information available in the medical literature reviewed by their peers. Many studies have shown that reducing the variation in care improves its quality and diminishes errors. Although evidence-based medicine is relatively new in oncology, several organizations have made great strides in creating evidence-based pathways for cancer treatment, including ASCO, the National Comprehensive Cancer Network (NCCN), and the American Society of Hematology (ASH). By relying on the principles of evidence-based medicine, physicians can make clinical decisions about proven treatment regimens, resulting in better outcomes for their patients. Using proven pathways that address the majority of cancers decreases the variability in costs as well, and in several cases offers proof that a less expensive drug is shown to have the same benefit as one that is more expensive. In January 2010, the Journal of Oncology Practice published a study showing that evidence-based care for patients with non–small cell lung cancer results in an average cost savings of 35% over 12 months while demonstrating equivalent health outcomes. Disease Management. Comprehensive, timely disease management has demonstrated its effectiveness in improving health status, patient quality of life, and financial outcomes. Although previous emphasis has been on chronic diseases such as diabetes and congestive heart failure, cancer has now joined the list of disease states well suited to disease management. Implementing disease management as soon as a patient begins chemotherapy offers an opportunity to monitor drug reactions. If a patient is vomiting, he or she can report this continued on page 31

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PAGE 31

Opinion

Responsible Spending continued from page 29

(usually to a call-center nurse) and receive a prescription for antinausea medication. When patients are able to receive medical support and advice as needed, problems are caught earlier and fewer emergencies arise. Trips to the ER and hospital—expensive for both patients and health-care systems—are thus avoided, and the patient’s health benefits. End-of-life Planning. About 32% of total Medicare spending goes to care for patients in the last 2 years of their life, with much of it going toward costs associated with repeated hospitalizations. The 2008 Dartmouth Atlas of Health Care suggests that the care these patients get is not necessarily the care they want. Most patients with serious illness said they would prefer to die at home; yet many died in the hospital. “[P]atients often prefer a more conservative pattern of end-of-life care than they actually receive,” the report states.4 And although it is far from easy to determine how much end-of-life care is too much, such care must begin with frank end-of-life conversations. A recent study5 showed that despite physicians’ concerns that these discussions may cause psychological harm for their patients, in fact they are not associated with depression, sadness, terror, or worry. Instead, patients who had these discussions were more likely to forgo aggressive medical treatment, use hospice care, and experience improved quality of life. A compassionate end-of-life discussion is not a single event—it encompasses a series of conversations as the patient’s condition evolves. It has been estimated that when a patient first receives a cancer diagnosis, he or she recalls less than half of the conversation. Clearly the endof-life discussion should be initiated when the patient and family can focus on it, with enough time to make the arrangements that will honor the patient’s wishes.

More Is Not Better Although these pillars of responsible spending are not as dramatic as the brand-new, $100,000 drug with the short-term benefit or the legions of specialists at the bedside, when it comes to making good decisions on the cost of care, they are the ones that matter most. These steps are under the individual physician’s control, and

they are widely recommended to improve quality of care. Evidence-based pathways for cancer are now commonly available. More and more payers are offering access to disease management for cancer. A compassionate end-of-life conversation can begin as soon as the patient’s condition warrants it and the patient and family are ready to talk about it. “Incredible advances in technology and in medication treatment can save lives, but contribute to the rising costs of cancer care as well. Varying treatment approaches also add to the cost,” said Kirsten Anderson, MD, MPH, Chief of Staff to the Chief Medical Officer at Aetna. “We need to ensure that treatments, —especially new treatments, —are proven to improve the quality of life of patients. Evidence-based treatment, coupled with specialized patient support throughout treatment, can result in higher quality care at a more reasonable cost.” Every physician strives to give his or her patients the best advice. In this new world of expensive technology and drug therapies, that means helping make wise cost decisions as well as wise clinical decisions.

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References 1. Adams CP, Brantner VV: Estimating the cost of new drug development: Is it really 802 million dollars? Health Aff (Millwood) 25:420-428, 2006. 2. Brown ML, Riley GF, Schussler N, et al: Estimating health care costs related to cancer treatment from SEERMedicare data. Medical Care 40(8 suppl):IV-104-17, 2002. 3. Byers TE, Wolf HJ, Bauer KR, et al: The impact of socioeconomic status on survival after cancer in the United States. Cancer 113:582-591, 2008. 4. Wennberg JE, Fisher ES, Goodman DC, et al: Tracking the Care of Patients with Severe Chronic Illness: The Dartmouth Atlas of Health Care 2008. Lebanon, New Hampshire; Dartmouth Institute for Health Policy & Clinical Practice, 2008. 5. Wright AA, Zhang B, Ray A, et al: Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA 300:16651673, 2008. Dr. Hoverman is Vice President of Clinical Resource Management, Texas Oncology, and Medical Director of Managed Care and Innovent Oncology, US Oncology. Ms. Russell is Founder and CEO, The Russell Mark Group.

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Antibody-drug conjugates (ADCs):

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

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

Monoclonal antibody

Stable linker

Cytotoxic

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

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

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

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

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