A Harborside Press Publication

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

VOLUME 2, ISSUE 2

JANUARY 15, 2011

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MORE IN THIS ISSUE

Oncology Meetings Coverage52nd ASH Annual Meeting ....... 1, 11, 2233rd Annual San Antonio Breast Cancer Symposium ..................6, 18

Direct from ASCO ......................................12Responsible Spending in Cancer Care ........29

America has the best health care that money can buy, but there is not enough money. Is

it reasonable to have our nation pay for sipuleu-cel-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 severe-ly restricted, although it is proven to prevent a potentially life-threatening pulmonary infec-tion. 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.

52nd ASH Annual Meeting

Health-care Policy

Prostate Cancer, Pediatrics, and

Priorities

Inefficiencies in the NCI-funded cancer clinical tri-als 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-

Clinical Trial Activation Has Slowed to Critical Point: ‘All Systems Go’ on ReformNCI, Cooperative Groups implement operational efficiency recommendationsBy Margot Fromer

continued on page 28

Bevacizumab in breast ca 3 | Emerging therapies for ovarian ca 20 | Quality indicators and psychosocial care 24

Intensified chemoim-munotherapy with

R-ACVBP (rituximab [Rituxan] plus doxorubi-cin, cyclophosphamide, vindesine, bleomycin, and prednisone) significantly improved event-free sur-vival, progression-free survival, disease-free sur-vival, and overall survival compared with R-CHOP (rituximab plus cyclophos-phamide, doxorubicin, vincristine, and prednisone) in younger patients with diffuse large B-cell lymphoma (DLBCL), as reported in the multicenter, phase III, open-label, randomized

LNH03-2B trial conducted by the GELA (Groupe d’Etude Des Lymphomes De l’Adulte).1 However,

Intensified R-ACVBP More Toxic but Improves Survival vs R-CHOP in B-cell LymphomaBy Alice Goodman

By Richard J. Boxer, MD

fying barriers to speed and efficiency in protocol de-velopment and approval—and devising ways to elimi-nate them.

NCI approved the first phase of OEWG’s work in March, and it went into effect this January. The 14 rec-

ommendations (see sidebar, OEWG Recommendations for Trial Activation on page 8) contain enforceable timelines for protocol development and implementation, including a “drop dead” date, at which time it will be terminated.

Draconian? Not really, said James H. Doroshow, MD, Director, NCI Division of Cancer Therapy Evaluation Program (CTEP) and Chair of the 63-member working group. “The report was unani-mously endorsed, and every-one agreed on the timelines.”

Dr. Boxer is Professor of Clinical Urology at the Uni-versity of Miami, and Clinical Professor at the Univer-sity of Wisconsin, Madison, and the Medical College of Wisconsin.

■ R-ACVBP, an intensified treatment regimen, improved survival vs standard R-CHOP in younger patients with diffuse large B-cell lymphoma (DLBCL).

■ R-ACVBP produced greater hematologic toxicity than R-CHOP.

■ It is not clear that this regimen is best for all younger patients with DLBCL, perhaps just for those with at least one clinical factor included in the age-adjusted International Prognostic Index.

■ Vindesine (a component of the R-ACVBP regimen) is currently not approved for use by the FDA.

Chemoimmunotherapy for Diffuse Large B-cell Lymphoma

830

300

200

90

550

210

Current median timeto activation

OEWG target

Cooperative groupphase III trials

Cancer centerinvestigator– initiated

trials

CTEP early drugdevelopment phase II

trials (cooperativegroup and N01)

Fig. 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 review board; OEWG = Operational Efficiency Working Group. Courtesy of James H. Doroshow, MD.

PAGE 2 The ASCO Post | JANUARY 15, 2011

Editorial

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 EDITORSClement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria

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

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

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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

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

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

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

Conor Lynch, Executive Editor Conor@harborsidepress.com

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Michael Buckley, Graphic Designer Michael@harborsidepress.com

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Editorial Board

Harborside Press Publishing Staff

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.

As 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 can-cer 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 is-sues, 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 ev-erything but breast cancer. My expecta-tions have been met and in many ways exceeded.

We are curious about your expecta-tions, 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 publica-tion.

Inside The ASCO PostI have found the bullet point sum-

maries in each story to offer useful rein-forcement 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 col-leagues in surgery, radiation therapy, ra-diology, and pathology.

“TAP on Technology” is a feature designed to provide reviews of new tech-nology 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 Lap-aroscopic Radical Prostatectomy: Risks

and Benefits,” in the November 2010 is-sue (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, how-ever, 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 commu-nity have a responsibility to be better informed, to be part of a constructive dialogue, and to shoulder some respon-sibility for ensuring the future of quality cancer care. Engaging in dialogue with our peers in a public forum developed specifically for the oncology commu-nity, 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 ef-fort or increase in expense.

Oncologic medicine works best when it is collaborative, and we must understand the views and needs of scien-tists, 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, Divi-sion of Hematology and Oncology, at the Uni-versity of Nebraska Medical Center, Omaha.

From the Deputy EditorBy Elizabeth Reed, MD

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

See page 31

ASCOPost.com | JANUARY 15, 2011 PAGE 3

News

In 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 beva-cizumab (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 con-cluding bevacizumab does not prolong sur-vival or provide “sufficient benefit” in slow-ing 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 at-tacks, and heart failure.1

“Subsequent studies failed to con-firm the benefit observed in the original trial [E2100, which paired bevacizumab with paclitaxel]… The limited effects of [bevacizumab] combined with the signifi-cant risks led us to this difficult decision. The results of these studies are disappoint-ing,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research. “We encourage [Genentech, the drug’s manufacturer] to conduct addi-tional 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, Ge-nentech requested a hearing to maintain bevacizumab as a treatment option for HER2-negative metastatic breast cancer, in combination with paclitaxel. In a state-ment, Genentech noted an intention to demonstrate “there are genuine and sub-stantial 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 Medi-cines 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 indica-tion, “these benefits are underscored by clinical experience,” and bevacizumab’s “im-portance continues to be recognized in con-sensus 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 rec-ommendation was the first step. Genen-tech is submitting its request for a hearing in January. If the FDA grants a hearing, there is no set date for when this would oc-cur. 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.

EMA Still Recommends Bevacizumab

Taking the opposite stance, the EMA and its Committee for Medicinal Prod-ucts for Human Use (CHMP) maintained that “the available data have convincingly shown [bevacizumab] to prolong progres-sion-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 recommenda-tion for bevacizumab plus paclitaxel carries an evidence designation of 2A (based on lower-level evidence and uniform agree-ment of the panel).

“The Breast Cancer Treatment Panel reviewed the same studies that the FDA re-viewed, and we reaffirmed our recommen-dation that paclitaxel and bevacizumab be a treatment option for women with meta-static 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

in person or by teleconference on three occasions with bevacizumab as an agen-da item. The issue has been looked at multiple times, and I am convinced that unless additional results become avail-able 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 can-cer indication from Avastin label. Available at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm237172.htm? Ac-cessed 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/n e w s _ a n d _ e v e n t s / n e w s / 2 0 1 0 / 1 2 /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 (let-ter). Available at www.gene.com/gene/news/news-events/avastin/documents/avastin_use.pdf. Accessed January 3, 2011.

A Disappointing Decision

I 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 like-ly to benefit from the drug. I hope the FDA takes this opportunity to consult with the breast cancer community to define what are reasonable trial end-points, and adopts a more transparent and predict-

able 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 quanti-tatively. 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

Which Patients Benefit?

The 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 beva-cizumab. 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 heav-ily 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 re-cently 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

Gabriel Hortobagyi, MD

Robert Carlson, MD

FDA Recommends Removal of Bevacizumab’s Breast Cancer IndicationBy Caroline Helwick

Health-care Policy

PAGE 4 The ASCO Post | JANUARY 15, 2011

Expert’s Corner

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; Institu-tional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

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.

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Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards.

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

Sandra M. Swain, MD, will take of-fice as President-Elect of ASCO at

its 47th Annual Meeting. Dr. Swain is the Medical Director of the Washing-ton Cancer Institute, Washington, DC, and Professor of Medicine at George-town University. She previously served as the Deputy Director of the Medi-cine 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 PresidentDr. Swain, you have had an impressive

career, but did you ever imagine you would become president of a major oncology or-ganization?

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 in-credible 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 opportuni-ties 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 through-out 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 in-cluded on that list. I will rely heavily on the collective experiences from both my personal career and ASCO participa-tion to guide me through my tenure as president.

To be elected by an organization of 30,000 members must indeed be hum-bling. What other thoughts do you have about your new role?

Dr. Swain: Throughout my career I have maintained a keen interest in men-toring. 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 op-portunity.

Addressing ChallengesWhat do you see as the challenges fac-

ing ASCO, and how can you help to ad-dress them?

Dr. Swain: As our name implies, we are the premier organization for oncol-

ogy in the United States. In fact, we set the standard for the advancement of on-cology worldwide. We have a very dedi-cated and active international member-ship. 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 devel-op a more comprehensive international perspective, especially on issues of edu-cation 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 An-nual Meeting is our seminal event each year, not only for the tremendous train-ing, but for the obvious networking op-portunities. Unfortunately, for varying reasons, some individuals cannot travel to it and others want a condensed ver-sion, so I think bringing further strength to this endeavor will prove highly ben-eficial to ASCO in the long run.

We also need to incorporate a more comprehensive multidisciplinary ap-proach to all aspects of ASCO activ-ity—not just at the Annual Meeting but throughout the year. Our member-ship primarily consists of medical on-cologists, but oncology in our everyday practice encompasses surgeons, radio-therapists, 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 ad-dressing their concerns?

Dr. Swain: I believe that the primary concerns of the community-based on-cologist are, in fact, the same as for any-one 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 over-arching 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 TasksHow will you balance these future en-

deavors 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 profes-sionals to work with at the Washington Cancer Institute, but to also have the unwavering support of the executive staff of the Washington Hospital Cen-ter and MedStar Health. On the ASCO side of the equation, the professional-ism 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 hav-ing a wonderful experience. ■

Sandra M. Swain, MD

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

Leadership

PAGE 6 The ASCO Post | JANUARY 15, 2011

33rd Annual San Antonio Breast Cancer Symposium

In the first ever head-to-head com-parative trial of a drug against anas-

trozole, 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,” re-ported Study Chair Paul E. Goss, MD, PhD, of Massachusetts General Hospi-tal, 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 TherapiesDr. Goss believes the trial was posi-

tive 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 op-tion for 5 years of upfront adjuvant ther-apy. On the face of things, these may ap-pear to be slightly ‘ho hum’ results. The aromatase inhibitors are coming off pat-ent, and there is not much excitement over such results,” he told The ASCO

Post. “But remember these constitute the single most important class of anti-cancer 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 steroi-dal aromatase inhibitor. The nonsteroi-dal agent anastrozole is approved for monotherapy in the adjuvant setting, whereas the steroidal inhibitor exemes-tane 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 be-cause it is “irreversible and more potent, does not induce intratumoral aroma-tase, and through its mild androgenic activity may exert a second antitumor effect and a more favorable bone and lipid metabolism profile.”

Excellent Disease-free Survival in Each Arm

MA.27 randomly assigned 7,576 patients to 5 years of treatment with an-astrozole (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 an-nounced.

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 exemes-tane arm and in 9.1% of the anastrozole arm (P = .85). About 4% per arm expe-rienced distant metastases. All subset analyses were similar as well. The low event rates probably reflect “the low-risk population and improvements in breast cancer care,” he said.

Dr. Goss prefers not to view the findings as “negative,” he said. He not-ed 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. Car-diovascular effects were similar and infrequent. Hypertriglyceridemia and hypercholesterolemia occurred less with exemestane, as did new diagnoses of osteoporosis, though clinical frac-ture rates were similar. By 3 years, ap-proximately 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 con-tinued.

Dr. Goss offered exemestane as perhaps the better choice for women with baseline osteoporosis, osteope-nia, or lipid abnormalities, in whom breast cancer treatment may trigger the need for yet another pill to coun-teract the side effects.

MA.27 is a huge repository of data, and findings will continue to emanate from the study, he added. Addition-ally, Dr. Goss is heading up the NCIC

CTG placebo-con-trolled MAP.3 trial that is evaluating exemestane for pre-vention in women with moderate breast cancer risk.

“This will be a vehicle for determining if aromatase inhibitors are as power-ful 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 post-menopausal women with hormone re-ceptor positive primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 9, 2010.

Expert Point of View

Aman 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 an-astrozole.

“All the commercially available aromatase in-hibitors are very similar, whether used for first-line or second-line metastatic disease, and now in the adjuvant setting,” he said. “There may be slight dif-

ferences 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 can-cer. 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.” ■

Exemestane and Anastrozole Comparable in MA.27 Final AnalysisBy Caroline Helwick

Aman Buzdar, MD

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.

Aromatase Inhibitors in Early Breast Cancer

See page 31

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

Visit The ASCO Post online at www.ASCOPost.com

Coming in the February 15, 2011 issue of

ASCOPost.com | JANUARY 15, 2011 PAGE 7

News

How did inefficiencies in the clinical trial system evolve? Gabriel Horto-bagyi, MD, Professor of Medicine and Chair, Department of Breast Medical Oncology, MD Anderson Cancer Cen-ter, and Co-Chair of OEWG, said there are several major reasons.

First are the overwhelming regu-lations. “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 ap-proval, 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 propos-al, and filling out more forms.”

And that’s only when a single insti-tution is doing the study. When it’s a multisite affair, such as with a coopera-tive group, the time, expense, bureau-cratic intervention, and aggravation are multiplied exponentially.

Dr. Doroshow agrees. “The minu-

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 con-sent form was a page or so. Now each

file is inches thick,” he said.“The boilerplate is excessive, con-

sent forms are so long and involved that a lawyer can barely understand them, let alone a patient,” he continued. “Ev-erything has more steps, involves more people, takes more time, and costs more money. There are too many rules and regulations.”

Clinical Trial Activationcontinued from page 1

continued on page 8

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 ex-ception.

Despite challenges, the federally

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

Adjuvant Breast and Bowel Project, As-sociate 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 ques-tions as well. We’ve had considerable success, and so have many other insti-tutions and cooperative groups.”

Time to Trial Activation and Accrual

Before improvements were made to the system, some trials took so long to get started that investigators lost inter-est 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 tri-als (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

James H. Doroshow, MD Gabriel Hortobagyi, MD Lawrence Wickerham, MD

Health-care Policy

MULTIDISCIPLINARY ASSESSMENT IN

ADVANCED RENAL CELL CARCINOMA:TRANSLATING EVIDENCE INTO PRACTICE

This activity is supported by independent educational grants from Genentech BioOncology, and Prometheus Laboratories, Inc.

Jointly sponsored by:

A Free CME-Certified Satellite Dinner Symposium to be Held During the American Society of Clinical Oncology (ASCO)Genitourinary Cancer Symposium

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

FaculTy

Physician conTinuing educaTionThis 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.

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

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

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

Robert A. Figlin, MD, FACPCedars-Sinai Medical Center; SamuelOschin Comprehensive Cancer Institute; David Geffen School of Medicine at UCLA

THURSDAY, FEBRUARY 17, 2011 • 6:30 PM – 9:00 PMORLANDO WORLD CENTER MARRIOTT

8701 WORLD CENTER DRIVE • ORLANDO, FL 32821PRE-REGISTRATION IS SUGGESTED, AS SPACE IS LIMITED.

634 asco gu ad_STD_v4:Layout 1 12/17/10 4:54 PM Page 1

PAGE 8 The ASCO Post | JANUARY 15, 2011

News

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 pa-tients 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 ac-crual, and only 1 of 4 colorectal stud-ies 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 en-rolling any patient in a trial that will not be completed,” he said.

Other trial groups have equally posi-tive 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 RemediesIn addition to OEWG’s 14 initia-

tives, the committee established tar-gets for trial activation: 300 days for phase  III, 210 days for phase  II, and 90 days for investigator-initiated tri-als. 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, ret-roactive to January 2011.

Cancer centers that conduct NCI-funded grants can improve internal management to increase efficiency (see sidebar, Recommendations to Increase Efficiency at NCI-funded Cancer Cen-ters), but some are reluctant to partici-pate in multisite trials because collabo-ration in such efforts is not recognized as a legitimate academic activity, nor

■ 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.

Recommendations to Increase Efficiency at NCI-funded Cancer Centers

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

timeline.

■ 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 agreed-

upon 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.

is it seen as an important service. As a remedy, OEWG recommended the fol-lowing 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, es-tablish consistency in protocol develop-ment, and resolve issues of trial objec-tives and design.

Collaborative EffortsThe OEWG initiatives will be “tak-

en 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 ef-ficient, 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 gov-ernment agencies, private industry members, politicians, and advocacy groups for it to work even reasonably smoothly. “It takes 800 steps to per-form 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 pro-posals, 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 especial-ly helpful. During the course of getting a trial up and running, innumerable ques-tions 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 confer-ence 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, ex-plained 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. ■

Health-care Policy

Clinical Trial Activationcontinued from page 7

Concerned about CYP2D6 in breast cancer?Fareston® may be the answer.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010

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

Fareston helps reduce the guess work

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

ALREADY ACTIVEParent compound binds to and blocks estrogen receptors

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

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

Please see full prescribing information on the following page.

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

Important safety information:

FARESTON® (toremifene citrate) tablets

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

and the molecular formula is C26

H28

CINO • C6H

8O

7. The molecular weight of toremifene citrate is

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1E Rev. 12/2004

OCH2CH2NCH3

CH3

CH2

CH2COOH

CH2COOHCH2Cl

C CC COOHHO

ASCOPost.com | JANUARY 15, 2011 PAGE 11

News

Expert Point of ViewAt the presentation of results for the LNH03-

2B study at the 52nd ASH Annual Meeting, Andrew Zelenetz, MD, PhD, of Memorial Sloan-Kettering 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 best treatment for younger patients,” Dr. Zelenetz commented. Dr. Recher conceded that the inten-

sified regimen might be best for younger patients with at least one clinical factor described by the age-adjusted International Prognostic Index, where-as R-CHOP could be reserved for very low-risk patients (age-adjusted In-dex = 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 con-ducted in patients aged 18 to 59 years with precisely one risk factor accord-ing 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 popu-lations,” 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. ■

the more intensified ACVBP regimen did incur greater hematologic toxicity.

Despite a high rate of febrile neu-tropenia (seen in almost 40% of pa-tients) and greater need for transfusion in the R-ACVBP arm, the toxicity was manageable, said lead author Chris-tian Recher, MD, PhD, CHU Tou-louse, France, who presented results of the trial at the 52nd Annual Meeting of the American Society of Hematol-ogy (ASH), held December 4–7 in Orlando.

Study DataThe 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 in-tensified 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, cy-clophosphamide 1,200 mg/m2 on day 1, vindesine 2 mg/m2 on days 1 and 5, bleomycin 10 mg on days 1 and 5, pred-nisone 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. Pa-

tients then received several cycles of an intensive consolida-tion therapy. Stan-dard R-CHOP was given every 3 weeks

for eight cycles along with intrathecal methotrexate on day 1 of the first four cycles. No radiotherapy was given in ei-ther arm.

The primary endpoint was event-free 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 involve-ment.

ResultsAt 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 event-free survival rate (the primary end-point) was 81% (95% CI = 74%–86%) vs 67% (95% CI = 59%–73%), which was significantly superior for the ex-perimental arm (P = .0035). Progres-sion-free, disease-free, and overall sur-vival 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 im-

provement in overall survival in patients with DLBCL in the rituximab era.

Toxicity and Other ConcernsSerious adverse events occurred

more frequently in the R-ACVBP arm (42% vs 15%). Grade 3 or 4 hemato-logic toxicity was increased in that arm, as was grade 3 mucositis. A higher percentage in the R-ACVBP arm ex-perienced febrile neutropenia (39% vs 9%), and a higher percentage of pa-tients in that arm required red blood cell (51% vs 7%) or platelet (13% vs 1%) transfusions. Five toxic deaths oc-curred 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 evalu-ate quality of life, but it is clear that R-ACVBP could not be safely deliv-

ered to patients over 60 years old. He suspected that quality of life would be worse on the experimental treat-ment, given the side effects, but only in the first 2 months of treatment, be-cause 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 compar-ing 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.

Intensified Therapycontinued from page 1

Andrew Zelenetz, MD, PhD

Christian Recher, MD, PhD

Hematologic Disease

See page 31

Visit The ASCO Post website at: ASCOPost.com

PAGE 12 The ASCO Post | JANUARY 15, 2011

Direct from ASCO

A funny thing about being a pro-gram 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 hema-tology-oncology training program at Dartmouth-Hitchcock Medi-cal Center since 1997. “Program directors are reading journals and reports of clinical trials every day, but there is very little in the medi-cal literature about the day-to-day stuff we do in training.” Dr. Davis comments.

Enter the ASCO Oncology Training Program Directors’ Re-treat, a 1-day meeting that com-bines educational sessions with that most important antidote for isolation—networking. Seventy-seven 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 hematol-ogy, oncology, and combined hem-onc fellowship training programs.

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.”

Thomas H. Davis, MD

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

New ACGME Duty-Hour Rules Discussed

Sparking a lot of interest and discussion at the recent retreat was a presentation about the respon-sibilities of the Residency Review Committee (RRC) and the review processes used to accredit train-ing programs. RRC member Sara J. Grethlein, MD, Professor of Hema-tology and Oncology at the State University of New York Update Medical University, presented the session.

Attendees at the retreat particu-larly 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, not-ing that the biggest change is limit-ing first-year residents to 16-hour shifts.

“It was useful to hear her perspec-tive 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 lon-ger 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 tak-ing 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, implica-tions of national health-care reform for training programs, and employ-ment law as it applies to graduate medical education, other parts dealt with nuts-and-bolts issues in direct-ing a training program.

For example, Frances Collichio, MD, the Associate Program Direc-tor at the University of North Caro-lina, shared her program’s teaching methods, educational materials, and documentation process for teach-ing and verifying competency in the

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

Learning from OthersMeeting with other program

directors is a side benefit of the re-treat, but in truth it may be the most important aspect. “Everyone comes with something they do very well, and in the question-and-answer ses-sions you pick up ideas from others,”

Dr. Davis points out. “It’s also help-ful to hear about the trials and tribu-lations 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. ■© 2011. American Society of Clinical Oncology. All rights reserved.

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

Many people—including those with cancer—see the begin-

ning of a new year as an opportunity for a fresh start, establishing resolu-tions 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 out-lines seven steps for a healthier new year. They will also find a section

on cancer risk factors and preven-tion (www.cancer.net/prevention) that includes topics such as cancer screening, diet and nutrition, physi-cal activity, and more. ■© 2011. American Society of Clinical On-cology. All Rights Reserved.

Training Directors Get RechargedAnnual Retreat Offers Education, Networking

The retreat is a rare and wonderful opportunity to touch base with people doing the same thing you do.

ASCOPost.com | JANUARY 15, 2011 PAGE 13

Direct from ASCODirect from ASCO

ASCO’s Journal of Oncology Practice Announces Innovative Podcast Program

ASCO’s Journal of Oncology Practice (JOP) now offers free podcasts

to the general public on its website (http://jop.ascopubs.org/site/pod-casts/index.xhtml), as well as to those who subscribe to the podcasts on iTunes. These insightful and informa-tive 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 Cen-ter at Johns Hopkins, now directs the conceptualization and creation of each JOP podcast. The articles to be high-lighted 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 con-venient 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 inter-viewing 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 produc-tion myself on my 4-year-old MacBook Pro.…We conduct the conversation over Skype.”

Podcast HighlightsOne recent article Dr. Miller pre-

sented 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 pres-sures that could not be overcome.” Dr. Keech not only highlights the various aspects and advantages of private prac-tice care; his comments are emotionally compelling and heartfelt. “I was appre-ciative 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 Prac-tice 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 oncol-ogy 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 analy-sis 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 pro-gram, Dr. Miller says, “My goal is to in-crease readership and attention to JOP and its content. We may experiment with more of a news summary format in addition to the interview format.” Lis-teners are encouraged to provide their comments and suggestions, which can be made directly on the iTunes site or e-mailed to jopeditorsdesk@asco.org. ■© 2011. American Society of Clinical Oncology. All Rights Reserved.

Vol 28, No 34 December 1, 2010

OURNAL OFLINICALNCOLOGY

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

JCO

JCO

Impact of Androgen-Deprivation Therapy on Cognitive Function in Men WithNonmetastatic Prostate Cancer. S.M.H. Alibhai et al

Impact of Androgen-Deprivation Therapy on Physical Function and QOL inMen With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al

Optimizing Collection of Adverse Event Data in Cancer Clinical TrialsSupporting Supplemental Indications. L.D. Kaiser et alEditorial: D.J. Sargent et al

Availability of Experimental Therapy Outside of Randomized Clinical Trials inOncology. E.P. Hamilton et al

Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-ExistingAutoimmune Disease. O. Landgren et al

Prospective Analysis of Hepatitis B Virus Reactivation in Patients With DiffuseLarge B-Cell Lymphoma After Rituximab Combination ChemotherapyN. Niitsu et al

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by ContinuousTreatment With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: ARandomized Controlled Trial. A. Palumbo et al

Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab inPatients With Metastatic Breast Cancer Pretreated With TrastuzumabF. Andre et al

Review Article: Strategies for Prolonged Therapy in Patients With AdvancedNon–Small-Cell Lung Cancer. P. Fidias et al

Art of Oncology: Stand and Wait. G.F. Blackall

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

JCO.org

1. Denosumab: Second Chapter in Controlling Bone Metastases or a New Book?Monica N. Fornier 28(35): 5127

2. Stand and WaitGeorge F. Blackall 28(34): 5124

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

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

5. Denosumab Compared With Zole-dronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Ran-domized, Double-Blind StudyAlison T. Stopeck, et al 28(35): 5132

6. Clinical Implications of the Cancer GenomeLaura E. MacConaill, et al 28(35): 5219

7. Clinical Trials Data Collection: When Less Is MoreDaniel J. Sargent 28(34): 5019

8. Neoadjuvant Chemotherapy Compared With Surgery Alone for Locally Advanced Cancer of the Stomach and Cardia: European

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 CancerCarl D. Atkins 28(35): e746

10. Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin Plus Eto-poside for Patients With Relapsed Primary Mediastinal Nonsemino-matous Germ Cell Tumors: Benefit From Chemotherapy, Surgery, or Both? Lawrence H. Einhorn 28(35): e739

Save the Date2011 ASCO Annual

Meeting

June 3-7, 2011McCormick PlaceChicago, Illinois

PAGE 14 The ASCO Post | JANUARY 15, 2011

Direct from ASCO

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

Last month, Congress voted to de-lay a potentially devastating 25%

Medicare physician pay cut through

2011. ASCO is advocating that Con-gress use the 12-month reprieve to re-peal 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 pa-tients should the SGR cut be imple-mented. ASCO has already reached out to incumbents and new members of Congress to ensure that Medicare reim-bursement remains a priority for 2011.

Congress Passes Legislation Exempting Physicians from FTC ‘Red Flags Rule’

Congress has passed a bill exempt-ing 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 addi-tional 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 In-stitute 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 imple-mentation 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 coopera-tive groups, public and private payors, the FDA, industry, community and aca-demic investigators, patient advocates, and cancer centers. ■

PHASE III TRIAL CURRENTLY RECRUITING

ASCOPost.com | JANUARY 15, 2011 PAGE 15

52nd ASH Annual MeetingDirect from ASCO

The prognosis for patients with classical Hodgkin lymphoma

treated today is significantly bet-ter 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 aban-doned, radiotherapy fields and doses have been lowered, very toxic chemo-therapy 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 Washing-ton University, St. Louis.

“But despite the overall excellent prognosis in most patients, the op-timal treatment for both early and advanced disease remains contro-versial,” she added. “Successful treat-ment must balance the highest cure rate with primary therapy with the fewest treatment-related complica-tions.”

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 in-terim PET/CT after the first few cycles of chemotherapy to assess re-sponse can potentially help. “If cur-rent 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 educa-tional session at the 52nd American Society of Hematology (ASH) An-nual Meeting, held December 4–7 in Orlando, Florida.

Targeted TherapiesGreater understanding of the bi-

ology of Hodgkin lymphoma and recognition of prognostic biomark-ers has led to the development of targeted therapies that address the multiple pathways thought to be dys-regulated or altered in Hodgkin lym-phoma. These targeted agents will be expensive, and clinicians will want to use them upfront (at diagnosis), in combinations, and possibly as main-tenance therapy.

The pathways in question include NF-ĸB, PI3/AKT, mTOR, surface receptor signaling through CD30, CD40, and RANK, and immuno-

logic defects through alterations in the tumor microenvironment. The future of Hodgkin disease therapeu-tics, 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 poor-prognosis Hodgkin lymphoma. At this time, most of the focus is on ritux-imab (Rituxan), brentuximab vedotin (SGN-35), lenalidomide (Revlimid), and panobinostat in the front-line set-ting or as maintenance therapy after

autologous stem cell transplantation. While several of these agents

have significant single-agent activ-ity in relapsed disease, combinations are likely to be more effective. Pre-clinical studies to determine which agents are synergistic with chemo-therapies or other targeted agents are underway.

“These novel therapies should also eventually be incorporated into front-line regimens or used as maintenance therapy, with the aim of reducing toxicity in patients with very favor-able disease and improving outcomes in those at high risk for relapse,” Dr. Blum said. ■

New Ways of Predicting the Course of Hodgkin Lymphoma

Existing models for predicting outcome in patients with Hodgkin lym-phoma, including the International Prognostic Score (IPS), may be los-

ing their accuracy and robustness, in light of recent improvements in treat-ment, 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 fac-tors, 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 BiomarkersOne biomarker is emerging as quite promising, according to Dr. Blum.

CD68 is present on tumor-infiltrating macrophages and detectable by im-munohistochemical staining, and is significantly associated with shortened progression-free and disease-specific survival both at diagnosis and at re-lapse. In addition, the presence of less than 5% CD68-positive cells corre-lates with a 100% disease-specific survival in patients with early-stage Hodg-kin 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 tu-mor-infiltrating CD20-positive small B cells was associated with both pro-longed progression-free and disease-free survival, although not all studies have validated this. Recent data suggest that an increased number of CD20-positive infiltrating B  cells coupled with low CD68 expression on tumor-infiltrating 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. ■

Novel Treatments to Watch for in Hodgkin LymphomaBy Caroline Helwick

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

Hematologic Disease

PHASE III TRIAL CURRENTLY RECRUITING

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

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.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

© 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

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.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

© 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

PAGE 18 The ASCO Post | JANUARY 15, 2011

33rd Annual San Antonio Breast Cancer Symposium

The 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 re-sponses (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 De-cember 8–12, 2010. He commented at a press briefing, “I have always be-lieved 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, per-haps moving away from chemotherapy in a subset of patients.”

He added, “This is a very exciting area. We have gone from HER2-over-expressing disease being the most le-thal type of breast cancer to a subtype that we are talking about curing.”

But Eric Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, tem-pered 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 (re-gardless of the agent used) should not yet be used as an “endpoint for drug approval or practice change.”

NeoALLTO and GeparQuintoLapatinib came up short in two

phase III studies that examined its ef-fect. NeoALTTO, conducted by the Breast International group (BIG), compared lapatinib, trastuzumab, and lapatinib/trastuzumab combination therapy, all with paclitaxel, in 455 pa-tients.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 Di-rector of the Massachusetts General Hospital Cancer Center, Boston, re-ported 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 Neo-ALLTO trial (pCR), the combination proved superior, and the investigators concluded that dual blockade of the

HER2 pathway is a valid concept.Overall clinical responses at 6

weeks (before paclitaxel was given) were highest in both arms with lapa-tinib (67.1% with lapatinib/trastu-zumab 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 trastu-zumab.

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 trastu-zumab, respectively [P = .03]).

In the 85-center GeparQuinto study, 620 patients were randomly assigned to receive epirubicin/cyclo-phosphamide for four cycles followed by docetaxel for four cycles plus trastu-zumab or lapatinib initiated with che-motherapy.2 After surgery, trastuzumab was given for 6 more months in the trastuzumab arm and for 12 months to patients initially receiving lapatinib.

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

Putting 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 transla-tional questions,” but they do not, he added, es-tablish pathologic complete response (pCR) as a surrogate for disease-free and overall survival.

“We need to wait for ALTTO and other tri-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 prema-ture 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 South-ern 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 vali-date the long-standing theory that cancer cells have an “oncogene addiction”—a hypothesis he once doubted, based on the clinical contradic-tion that patients inevitably develop resistance to 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.” ■Anti-HER2 Regimens Studied

NeoALLTO (n = 450): Six cycles of trastuzumab 4 mg/kg loading dose fol-lowed 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 combina-tion 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.

High Response Rates Achieved with ‘Complete Blockade’ for Neoadjuvant Treatment of HER2-positive Breast Cancer By Caroline Helwick

Eric P. Winer, MD

Debu Tripathy, MD

ASCOPost.com | JANUARY 15, 2011 PAGE 19

33rd Annual San Antonio Breast Cancer Symposium

The trastuzumab arm achieved a significantly higher pCR rate accord-ing to the NSABP definition—50.4% and 35.2%, respectively (P  < .05)—and also by the investigators’ more stringent definition of pCR (no mi-croscopic 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 Multidisci-plinary Breast Cancer at the Helios Clinic, Berlin.

In another component of the Ge-parQuinto trial reported at the meet-ing, bevacizumab (Avastin) added no benefit to neoadjuvant treatment with epirubicin/cyclophosphamide fol-lowed by docetaxel.3

Impressive Outcomes with Pertuzumab/Trastuzumab

In the four-arm NeoSphere trial of 417 women, triple therapy with per-tuzumab, trastuzumab, and docetax-el produced 50% more pCRs than were achieved with trastuzumab and docetaxel, reported Luca Gianni, MD, Director of Medical Oncology at the Fondazione IRCCS Istituto Tu-mori in Milan.4

“In addition, this combination without chemotherapy was capable of eradicating the tumor in a remark-able number of cases (17%), therefore avoiding the toxicities seen with che-motherapy,” Dr. Gianni noted.

The pCR rate (by NSABP defini-tion) 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-

trast to 45% to 57% for the docetaxel-containing arms. There was no mean-ingful increase in cardiac risk with the addition of pertuzumab over the short four-cycle course of neoadjuvant treat-ment.

“Pertuzumab has the ability to en-hance the activity of trastuzumab. The combination has good tolerability and remarkable antitumor activity in meta-static breast cancer that has progressed after trastuzumab,” Dr. Gianni com-mented. “The combination has a very favorable therapeutic ratio that justi-fies its continued use as adjuvant treat-ment after the end of chemotherapy.”

Interesting Responses by Hormonal Status

Unexpectedly in NeoALLTO and GeparQuinto, pCR rates were higher in estrogen receptor (ER)-negative pa-tients than in those with ER-positive disease.

“In NeoALLTO, both hormone subgroups benefited from the lapa-tinib/trastuzumab combination, al-though it is worth noting that the ER-

negative group did better,” Dr. Baselga commented.

Patients with ER-negative tumors had a pCR rate of 61.3% with lapa-tinib plus trastuzumab, compared with 36.5% for the trastuzumab group and

33.8% for the lapatinib group (P  = .005). Rates in the in ER-positive pa-tients, 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 pa-tients.

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-pos-itive, 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 HER2-positive patients.” Failure to achieve a pCR appears to be less predictive of poor out-come 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 GeparQuin-to, approximately 35% of patients on the lapatinib arms were unable to receive the full planned doses of this agent. In Neo-ALLTO, 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 re-ported.

In GeparQuinto, the investigators observed 10% more treatment discon-tinuations with lapatinib than with trastu-zumab (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 lapa-tinib 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 stud-ies within these phase III trials. For Neo-ALLTO, 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 iden-tify predictive markers of sensitivity and resistance. We will also perform PET-CT and assess circulating tumor cells in a sub-set,” Dr. Baselga said.

The companion adjuvant ALLTO trial, which will randomly assign 8,400 patients to various adjuvant regimens us-ing 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/pertu-zumab combination. One of the main messages from this study is that the neo-adjuvant approach allows for rapid test-ing and ranking of new therapies.” ■References

1. Baselga J, Bradbury I, Eidtmann H, et al: First results of the NeoALTTO trial (BIG 01-06 / EGF 106903): A phase III, random-ized, open label, neoadjuvant study of lapa-tinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. 33rd Annual San Anto-nio Breast Cancer Symposium. Abstract S3-3. Presented December 10, 2010.

2. Untch M, Loibl S, Bischoff J, et al: Lapa-tinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based che-motherapy: Primary efficacy endpoint analy-sis of the GEPARQUINTO study (GBG 44). 33rd Annual San Antonio Breast Cancer Sym-posium. 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 end-point 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.

■ 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 trastuzumab-containing 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.

Neoadjuvant HER2 Blockade in Breast Cancer

See page 31

Neil Spector, MD Jose Baselga, MD Luca Gianni, MD

PAGE 20 The ASCO Post | JANUARY 15, 2011

News

The pivotal cascade of molecular events that culminate in ovar-

ian cancer has not been fully eluci-dated, 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 recom-bination, 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 ef-fectively fight the tumor.

The PARP inhibitor olaparib, ac-tive 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% re-sponse rate to single-agent olaparib 400 mg twice daily on a continuous basis in 4-week cycles. Those with-out the mutation had a 23% response rate. Median progression-free sur-vival was 219 days, considered espe-cially striking for heavily pretreated patients with advanced disease, ac-cording to principal investigator Karen Gelmon, MD, of the BC Can-cer 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-mu-tated ovarian cancer… Serous ovar-ian 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 in-teresting class of agents,” he said.

The data appeared so encour-aging that a listener at the session

commented, “Patients are dying be-cause 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 impor-tance in identifying somatic muta-tions for response.

Also showing promise in both sporadic and BRCA-deficient tu-mors is the oral PARP inhibitor MK-4827.2 Among 19 patients treated, the clinical benefit rate (stable dis-ease 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 che-motherapy and had responded for al-most 1 year. BSI-121 is a third PARP inhibitor being evaluated in ovarian cancer. Seven others are being stud-ied in breast cancer and melanoma.

Monoclonal Antibody TherapyTreatment 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 com-bined with standard therapy in a phase II clinical trial including 44 patients with ovarian cancer in first relapse. Total clinical benefit ex-ceeded 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 platinum-free 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.

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

farletuzumab monotherapy could proceed onto the combination che-motherapy while continuing far-letuzumab. Combination therapy was associated with a median pro-gression-free survival of 10 months.

Expert Point of View

Among 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 ben-efits 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), carbo-platin, 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 in-teresting, 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 recombi-nation pathway. Homologous recombination is a type of genetic recombi-nation 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 recombi-nation pathway is not properly functioning. PARP inhibitors may work in many of these instances.

Encouraging StrategiesFarletuzumab is another encouraging compound that is based on a

new target in ovarian cancer, folate receptor-alpha, which is highly over-expressed 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. Beva-cizumab has significant single-agent activity when given alone for the treat-ment 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 progres-sion-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

Ovarian Cancer: Hopes Pinned on Emerging TherapiesBy Caroline Helwick

Gynecologic Cancer

James H. Doroshow, MD

ASCOPost.com | JANUARY 15, 2011 PAGE 21

News

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

Antiangiogenesis AgentsAgents that block angiogenesis

may also enter the armamentarium in ovarian cancer, based on encour-aging results seen with bevacizumab in a study that earned a coveted ple-nary session spot at the 2010 ASCO Annual Meeting.4 Bevacizumab (Avastin) added to carboplatin/pa-clitaxel, followed by bevacizumab maintenance, extended progression-free survival by nearly 4 months (14.1 vs 10.3 months; P < .0001), in the Gynecologic Oncology Group 0218 study (see the July 2010 is-sue of The ASCO Post). AMG 386, a first-in-class peptibody that inhib-its angiopoietin-1 and -2, has also shown early activity in combination with paclitaxel.5

Other ApproachesAs a single agent, NKTR-102, a

topoisomerase I inhibitor-polymer conjugate, showed strong activ-ity in a phase II study of 68 patients with platinum-resistant disease.6 Response rates were 24% to 41% (depending on criteria), and me-dian progression-free survival was 18 weeks. Based on these results, in patients whose median platinum-free interval was only 1 month, lead author Ignace Vergote, MD, of the Catholic University, Leuven, Bel-gium, maintained that NKTR-102 has “great therapeutic potential.” ■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-nega-tive breast cancer. 2010 ASCO Annual Meeting. Abstract 3002. Presented June 5, 2010.

2. Sandhu SK, Wenham RM, Wild-ing 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-defi-cient and sporadic ovarian cancers. 2010 ASCO Annual Meeting. Abstract 3001. Presented June 5, 2010.

3. White AJ, Coleman RL, Arm-strong DK, et al: Efficacy and safety of farletuzumab, a humanized monoclo-

nal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a mul-ticenter phase II study. 2010 ASCO An-nual 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 peri-toneal 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, placebo-controlled 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/refrac-tory ovarian cancer. 2010 ASCO Annual Meeting. Abstract 5013. Presented June 7, 2010.

Copyright © 2010 US Oncology, Inc. All rights reserved.

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

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PAGE 22 The ASCO Post | JANUARY 15, 2011

52nd ASH Annual Meeting

Biologic agents and novel chemo-therapies in various stages of clinical

development hold promise for the treat-ment of hematologic malignancies, but as past experience shows, results of prelimi-nary 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 promis-ing drugs for chronic myelogenous leuke-mia, lymphoma, and multiple myeloma based on presentations at the 52nd An-nual 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 thera-py for chronic myelogenous leukemia (CML), and both dasatinib (Sprycel) and nilotinib (Tasigna) were recently approved by the FDA as first-line thera-pies 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 bo-sutinib 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 Gam-bacorti-Passerini, MD, Professor at the University of Milano Bicocca, Monza, Italy, bosutinib’s effect on treatment fail-ure 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 empha-sized that it will be important to deter-mine which patients with CML would benefit from bosutinib compared with other agents used in this setting. He and his colleagues are currently doing ge-nomic sequencing studies on leukemic cells to try to identify characteristics of those patients.

The study enrolled 502 newly diag-nosed patients with CML. An intent-to-

treat analysis showed that at 1 year, the major molecular re-sponse rate was 39% with bosutinib vs 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 ima-tinib, a difference that was not statistically significant.

Bosutinib was associated with more diarrhea, nausea, vomiting, and rash compared with imatinib; the most fre-quent grade 3 and 4 adverse events were diarrhea (8%) and rash (2%). More mus-cle 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 ad-vantage of bosutinib will be even greater.

Ponatinib for Chronic Myelogenous Leukemia

Despite the success of imatinib and its cousins dasatinib and nilotinib in treat-ing 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 ki-nase 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 acceler-ated phase, and 9 were in blast phase.)

Among 38 evaluable patients with chronic-phase CML, 95% had a com-plete hematologic response, 66% a ma-jor cytogenetic response, and 53% a complete cytogenetic response. In nine evaluable patients from this group with chronic-phase CML and T315I muta-tions, 100% had a complete hematologic response, 100% had a major cytogenetic response, and 89% had a complete cyto-genetic 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 accelerated- and blast-phase CML, with no complete hematologic responses and major hema-tologic 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, in-creased lipase, muscle spasms, rash, my-algia, and pancreatitis.

Pixantrone for Non-Hodgkin Lymphoma

Pixantrone, a novel aza-anthracenedi-one 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 sur-vival compared with comparator agents.

At 18 months of follow-up, the com-plete response/complete response un-confirmed rate was 20% for pixantrone vs 5.7% for comparators (ie, vinorelbine, oxaliplatin, ifosfamide, etoposide, mi-toxantrone, 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, respec-tively (P = .005). Median overall survival was 10.2 months with pixantrone vs 7.6 months for the other agents, but this dif-ference 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, pa-tients treated with these therapies typi-cally relapse and have limited treatment options. Carfilzomib, a novel highly selec-tive next-generation proteosome inhibi-tor, 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 of-fer substantial clinical benefit to patients who have relapsed or are refractory to other therapies, said lead author David Siegel, MD, PhD, of John Theurer Can-cer Center, Hackensack, New Jersey.

Patients enrolled in the phase IIb trial received at least two prior therapies, in-cluding bortezomib (Velcade) and either thalidomide (Thalomid) or lenalidomide (Revlimid), plus an alkylating agent. In 257 patients evaluable for response, over-all 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 tox-icity was thrombocytopenia (27%), ane-mia (22%), lymphopenia (18%), and neutropenia (10%). Of particular note was the extremely low rate of peripheral neuropathy.

Dr. Siegel said that these are good re-sults 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. ■References

1. Gambacorti-Passerini C, Kim D-W, Kan-tarjian H, et al: An ongoing phase 3 study of bo-sutininb (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. Pre-sented December 6, 2010.

3. Pettengell R, Zinzani PL, Narayanan G, et al: Phase 3 trial of pixantrone dimale-ate 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. Ab-stract 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 re-lapsed and refractory multiple myeloma. 52nd ASH Annual Meeting.Abstract 985. Presented December 7, 2010.

Promising Data Reported on Hematology Drugs in the PipelineBy Alice Goodman

Novel Agents

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PAGE 24 The ASCO Post | JANUARY 15, 2011

Psychosocial Oncology

A 2007 Institute of Medicine (IOM) report, titled “Cancer

Care for the Whole Patient: Meeting Psychosocial Health Needs,” summa-rized the status of efforts to provide psychosocial care for people with cancer.1 The report concluded that de-spite 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 oncol-ogy care providers to underestimate distress in patients2 and to not link pa-tients to services when needs are iden-tified.3 To address these problems, the report recommended that provision of appropriate psychosocial services be adopted as a standard of quality can-cer care. The report also identified a model for the effective delivery of psy-chosocial services that includes imple-mentation of processes for identifying patients’ psychosocial needs and then implementing plans that link patients with needed psychosocial services.

Indicators of the Quality of Psychosocial Care

Translating the IOM report’s rec-ommendations 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 suc-cessfully 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 qual-ity of psychosocial care, the Ameri-can 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 Comprehen-sive Cancer Network Guidelines for Distress Management,5 the workgroup developed indicators to measure two

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

components considered necessary for providing quality psychosocial care: a process for identifying distressed patients and a process for linking dis-tressed patients with services.

The first quality indicator stipulates there should be evidence in the medi-cal 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 well-being was identified, there is evidence in the patient’s medical record that ac-tion 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 an-swered yes or no based on the review of an individual patient’s medical re-cord.

Evaluating Psychosocial Quality Indicators

The performance characteristics of these indicators were initially evaluat-ed in a multicenter study that my col-leagues 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 embed-ded 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 (medi-an = 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 per-formance rates indicated that pain was more likely to be assessed than emo-tional well-being (87% vs 52%, P  < .0001). These findings show how use of these indicators permits identifica-tion of specific practice sites and pro-cesses of care that should be targeted for quality improvement efforts. The findings also demonstrate the extent to which routine assessment of emo-tional well-being lags behind routine assessment of pain in cancer patients.

Changes over Time in the Quality of Psychosocial Care

The Quality Oncology Practice Ini-tiative (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 participat-ing practices. Practices participating in QOPI have the opportunity to submit chart audit information at 6-month in-tervals. 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 par-ticipated in both the Fall 2008 and Fall 2009 audits. These practices submitted data on approximately 15,000 patients at each time point.

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 av-erage 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).

Future DirectionsFindings from QOPI suggest that

providing feedback to practices result-ed in an increase in assessment of pa-tient emotional well-being. As would be expected, this increase correspond-ed to more patients being identified as having a problem with emotional well-being and more actions being taken to address these problems. Although an increase on process indicators of quality care is encouraging, additional research incorporating outcome mea-sures is needed to determine if con-ducting more assessments results in actual improvements in patients’ emo-tional well-being.

Moreover, while provision of feed-back 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 ap-propriate psychosocial care models. This objective could be achieved by conducting rigorously designed dem-onstration projects that show how to successfully improve psychosocial care

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

Perc

ent y

es

50%

60%

70%

80%

90%

100%

Fall 2008N = 15,012

Fall 2009N = 15,841

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

Perc

ent y

es

50%

60%

70%

80%

90%

100%

Fall 2008N = 1,616

Fall 2009N = 2,461

Paul B. Jacobsen, PhD

ASCOPost.com | JANUARY 15, 2011 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 psycho-social care their patients receive and identify the need for quality improve-ment efforts. The next step will be to develop strategies that can be dissemi-nated readily to practices seeking guid-ance on how to improve the quality of psychosocial care they provide their patients. ■References

1. Adler NE, Page AEK (eds): Cancer care for the whole patient: Meeting psycho-social health needs. Washington, DC, Na-tional 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 Can-cer 84:1011-1015, 2001.

3. Institute of Medicine: Implementing cancer survivorship care planning. Washing-ton, DC, National Academies Press, 2007.

4. Jacobson JO, Neuss MN, McNiff KK, et al: Improvement in oncology practice performance through voluntary participa-tion in the Quality Oncology Practice Initia-tive. J Clin Oncol 26:1893-1898, 2008.

5. National Comprehensive Cancer Network: NCCN Clinical Practice Guide-lines in Oncology: Distress management, version 1.2011. Available at http://www.

nccn.org/professionals/physician_gls/PDF/distress.pdf.

6. Jacobsen PB, Shibata D, Siegel EM, et al: Evaluating the quality of psycho-social care in outpatient medical oncol-ogy 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.

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 Jim-mie Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center, New York.

PAGE 26 The ASCO Post | JANUARY 15, 2011

JOP Spotlight

Using detailed failure mode and ef-fects analyses (FMEAs), investiga-

tors at Dana-Farber Cancer Institute in Boston found that the medication-use processes associated with five oral che-motherapy agents were “surprisingly complex” and identified key vulnerabili-ties. These include “patient education about drug handling and adverse effects, prescription writing, patient self-admin-istration 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

common to all five oral chemotherapies studied, suggesting some common re-mediation strategies, such as improved patient education and using only elec-tronic prescribing. Results of the study

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

High-risk Failure ModesInterdisciplinary teams conducted

the failure mode and effects analyses for mercaptopurine (pediatric leuke-mia), temozolomide (brain cancer and melanoma), capecitabine (advanced colorectal and breast cancers), ima-

tinib (chronic myelogenous leukemia and GI stromal tumors [GIST]), and a phase II investigational agent used for treatment of GIST.

“The analyses included an evalu-ation of electronic and paper-based prescription writing, preparation and dispensing of medications on site and at community-based pharmacies, ad-ministration (largely at home by the patient or caregiver), and follow-up and symptom monitoring,” the au-thors 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 au-thors list them as: ■ Prescription writing errors resulting

from shortcuts, miscalculations, or illegible handwriting

■ Wrong tablets, liquid, dose, or num-ber of tablets dispensed in the phar-macy

■ Patient did not correctly adhere to regimen

■ Patient failed to or incompletely re-ported adverse effectsSome of the proposed remedia-

tion strategies were also common to all five study drugs. These include prohibiting handwritten and called-in prescriptions and using only electron-ic prescribing, and requiring written informed consent for all oral chemo-therapy treatment. Table 1 lists a repre-sentative set of additional recommen-dations.

Targeted Improvement EffortsThe 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 re-ally 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 clini-cal environment.” That included using

Table 1: Selected Recommendations to Address High-risk Failure Modes Affecting Five Oral ChemotherapiesRecommendation Source

Prescribing

Create checklists to guide and remind clinicians about key ele-ments 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

Adapted with permission from Weingart et al.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

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

Saul N. Weingart, MD, PhD

Drug Safety

ASCOPost.com | JANUARY 15, 2011 PAGE 27

JOP Spotlight

An Issue That Will Need Revisiting

Oral chemotherapy in ambulatory oncology poses a new and emerging area of risk,” the Dana-Farber Cancer Institute investigators noted in the intro-

duction to their report on medication safety analyses of oral chemotherapies. In an interview with The ASCO Post, Dr. Weingart said that continuing ef-

forts are needed to make sure that risks are more fully understood. “Oral che-motherapy is supplementing infusion therapy as part of the armamentarium,” he said, but “we are just beginning to understand the way that these new thera-pies 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 iden-tification 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.” ■

Safety vs Privacy

Some 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 prescrip-tion 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 in-formation. 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.” ■

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 enhance-ments 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 bet-ter 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 chemo-therapy. ■Reference

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

LIVER CANCER

Sorafenib plus DoxorubicinAdding sorafenib (Nexavar) to the

doxorubicin regimen used to treat pa-tients 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 com-pared 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 sys-temic treatment. Patients were randomly assigned to receive 60 mg/m2 of doxorubi-cin intravenously every 21 days for a maxi-mum 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 moni-toring 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 doxo-rubicin 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 indicat-ing a 51% reduction in the risk of death for patients in the doxorubicin/sorafenib group. The median progression-free sur-vival was 6 months among patients treat-ed with doxorubicin plus sorafenib vs 2.7 months among those who received doxorubicin plus placebo, with explor-atory 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 improve-ment in median time to progression, overall survival, and progression-free sur-vival “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 re-ceptor (ER)-positive invasive breast cancer in postmenopausal women with low bone density, according to a study published online in the Journal of the Na-tional Cancer Institute. In the Postmeno-pausal 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 ran-domly 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 statisti-cally 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 re-

duction for breast cancer with lasofox-ifene was similar to that reported for tamoxifen and raloxifene.

Attractive Option“The spectrum of activity for la-

sofoxifene, including the clinically and statistically significant reductions of non-vertebral fractures, stroke, and serious heart events, makes it an attractive option, particularly for use in postmenopausal women with osteoporosis or higher estra-diol 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 pla-cebo 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.

Emerging Clinical Data on Cancer ManagementIn the Literature

PAGE 28 The ASCO Post | JANUARY 15, 2011

Opinion

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 sus-pending 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 be-lief 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 vo-racious 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, di-agnose 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) avail-able to all, and solve the fundamental is-sue—that the cause of the health-care cri-sis 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 IsWhen 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 mon-ey”—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 coun-try will eventually be bankrupt, and even China will not be able to buy us out of it.

There must be consistency in our think-ing. Sipuleucel-T is a potentially valuable medication to a subpopulation of patients with metastatic prostate cancer refractory to hormones, for whom other chemother-apies have probably failed. These unfortu-nate individuals will gain an average of 4 months of life, although the quality of ex-tended life might not be very satisfying. If budgets are ever to be balanced, this ques-tionable benefit would likely result in oth-ers not being treated.

So let us have a real debate about the cost of health care and the choices (in-cluding 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. ■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.

Health-care Prioritiescontinued from page 1

ASCOPost.com | JANUARY 15, 2011 PAGE 29

Opinion

After surgery and adjuvant ther-apy, 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 deci-sions that affect the cost of care every day, in ways that may not be immedi-ately 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

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

Cancer Institute. In 2005, the United States spent $209  billion on overall costs for cancer care; by 2008, the fig-ure was $228 billion (Fig. 1), includ-ing $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 re-mained about the same as a percent-age 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 dis-ease categories.

Spending on cancer now accounts for about 5% of all medical treatment in the U.S. and about 10% of Medi-care 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 discus-sion 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 mar-ket, including preclinical and clinical testing, is approximately $1 billion.1

New imaging and radiation thera-py 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 re-ceiving 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 in-crease in cost.2

Beyond the cost to society, the cost of cancer treatment for individu-als is rising to a crippling level. Even when patients have insurance, they may still pay tens of thousands or even hundreds of thousands of dol-lars for treatment. Those without in-surance 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 diagno-sis, receive less aggressive treatment, and as a result, have shorter survival times.3)

Linking Positive Outcomes and Responsible Spending

The cost repercussions of clinical decisions can be profound for pa-tients 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 fami-lies: evidence-based medicine, appro-priate disease management, and com-passionate 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 in-formation available in the medical lit-erature reviewed by their peers. Many studies have shown that reducing the variation in care improves its qual-ity and diminishes errors. Although evidence-based medicine is relatively new in oncology, several organiza-tions have made great strides in cre-ating evidence-based pathways for cancer treatment, including ASCO, the National Comprehensive Cancer Network (NCCN), and the Ameri-can Society of Hematology (ASH).

By relying on the principles of evi-dence-based medicine, physicians can make clinical decisions about proven treatment regimens, resulting in bet-ter outcomes for their patients. Using proven pathways that address the ma-jority of cancers decreases the vari-ability in costs as well, and in several cases offers proof that a less expensive drug is shown to have the same ben-efit 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 re-sults in an average cost savings of 35% over 12 months while demonstrating equivalent health outcomes.

Disease Management. Compre-hensive, timely disease management has demonstrated its effectiveness in improving health status, patient qual-ity of life, and financial outcomes. Al-though 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 manage-ment.

Implementing disease manage-ment as soon as a patient begins che-motherapy offers an opportunity to monitor drug reactions. If a patient is vomiting, he or she can report this

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

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

Ove

rall

canc

er c

osts

(in

billio

ns)

$170.0

$180.0

$190.0

$200.0

$210.0

$220.0

$230.0

2005

$209

2006

$206

2007

$219

2008

$228

$190.0

2004

Lost productivity, $135 billion

Direct medical costs,

$93 billion

Fig. 1: Overall U.S. Cancer Costs (in billions). Data courtesy of American Cancer Society and National Institutes of Health. continued on page 31

J. Russell Hoverman, MD, PhD Susan Russell

For personal service, please contact ASCO Member Services Monday through Friday, from 8:30 AM to 5:00 PM.

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Opinion

(usually to a call-center nurse) and receive a prescription for antinausea medication. When patients are able to receive medical support and ad-vice as needed, problems are caught earlier and fewer emergencies arise. Trips to the ER and hospital—expen-sive 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 to-ward costs associated with repeated hospitalizations. The 2008 Dart-mouth 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 actu-ally receive,” the report states.4 And although it is far from easy to deter-mine how much end-of-life care is too much, such care must begin with frank end-of-life conversations.

A recent study5 showed that de-spite 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, pa-tients who had these discussions were more likely to forgo aggressive medi-cal 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 pa-tient’s condition evolves.

It has been estimated that when a patient first receives a cancer diag-nosis, he or she recalls less than half of the conversation. Clearly the end-of-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 pa-tient’s wishes.

More Is Not BetterAlthough these pillars of respon-

sible 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 im-prove quality of care. Evidence-based pathways for cancer are now com-monly available. More and more pay-ers are offering access to disease man-agement for cancer. A compassionate end-of-life conversation can begin as soon as the patient’s condition war-rants it and the patient and family are ready to talk about it.

“Incredible advances in technol-ogy 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, —especial-ly 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 reason-able 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 help-ing make wise cost decisions as well as wise clinical decisions. ■References

1. Adams CP, Brantner VV: Estimat-ing 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 SEER-Medicare 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, Good-man DC, et al: Tracking the Care of Pa-tients 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 discus-sions, patient mental health, medical care near death, and caregiver bereave-ment adjustment. JAMA 300:1665-1673, 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.

Responsible Spendingcontinued from page 29

© Leo Cullum/The New Yorker Collection/www.cartoonbank.com

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

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

Scanning 2D codesWhen you see a code that you would like to scan, start the ScanLife application. The screen will look similar to camera mode.

Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically.

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

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BIOPPADC_40948_M03_ADC1Pager.indd7-26-2010 3:20 PM John Gluth / Craig Wong

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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

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibody–mediated

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activities may include prevention of signaling, antibody-dependent cellular cytotoxicity, and induction of apoptosis.3,5,6

the sum of its parts?

Antibody-drug conjugates (ADCs):

Can an ADC be greater than

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-specifi c 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. Ofl azoglu 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 specifi city 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.

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References:

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

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

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

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