tap vol 1 issue 4

A Harborside Press Publication

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

VOLUME 1, ISSUE 4

SEPTEMBER 2010

continued on page 2

Elderly women with estrogen receptor (ER)-positive early breast cancer may be able to safely forgo radia-

tion therapy after lumpectomy, according to data from a large Intergroup trial presented at the 2010 ASCO Annual Meeting. The only significant benefit for the addition of ra-diation therapy to tamoxifen was a small reduction in local recurrence—an absolute 7% decline compared to tamoxi-fen alone.

Radiation Therapy Not Necessary for Some Elderly Patients with ER-positive Breast Cancer By Caroline Helwick

Bosutinib May Have a Major Role in CML By Alice Goodman MORE IN THIS ISSUE

2010 ASCO Annual Meeting CoverageBreast cancer ..........................................1Hematology ............................................1Head and neck cancer .........................16Lung cancer .........................................25

Melanoma: A New Paradigm ......................3Direct from ASCO ....................................18

“At 10 years’ follow-up, 95% of the patients in each group had no distant metastases, which is essentially a 95% cure rate,” said Kevin S. Hughes, MD, a member of the Department of Surgical Oncology at Massachusetts Gen-eral Hospital, Boston.

The findings add further evidence that women aged 70 and older with early-stage breast cancer can undergo lumpectomy plus tamoxifen therapy alone without com-

promising their survival. Dr. Hughes made it clear, however, that the results cannot be applied to younger wom-en, for whom radiation therapy is the standard of care.

Dr. Hughes presented the results on behalf of the Cancer and Leu-kemia Group B (CALGB), the Ra-diation Therapy Oncology Group (RTOG), and the Eastern Coopera-tive Oncology Group (ECOG).

Recurrence Rate DifferedCALGB 9343 included 636

women age 70 and older with stage I (tumor size ≤ 2 cm), ER-positive (or ER-indeterminate), node-negative breast cancer who had a lumpectomy with negative margins. They were randomly assigned to receive tamoxi-fen (n = 319) or tamoxifen plus radia-

On the heels of the positive studies of nilotinib (Tasigna) and dasatinib (Sprycel) as first-line

therapy for chronic-phase chronic myeloid leukemia (CML), promising results for another tyrosine kinase inhibitor—bosutinib—were presented at the 2010 ASCO Annual Meeting. Two separate studies reported at the meeting showed that bosutinib was effective as

continued on page 8

Gabriel Hortobagyi, MD

The Oncologic Drugs Advisory Committee (ODAC)a of the FDA has recommended

that the Agency revoke approval of bevacizumab (Avastin) in first-line treatment of metastatic breast cancer. The FDA will decide whether or not to accept this recomendation later in the year. E2100, AVADO, and RIBBON-1 clearly showed that the addition of bevacizumab increases re-sponse rate and time to progression, although for reasons not yet clear, overall survival (OS) was not prolonged, nor was there an apparent non-significant trend for improved survival.

This makes the situation with bevacizumab continued on page 7

Leukemia

Breast Cancer

Fig. 1: Outcomes of radiotherapy/tamoxifen or tamoxifen alone after lumpectomy in elderly patients with estrogen receptor-positive breast cancer. Differences are small. Shaded green area represents 21 women (7%) who benefited by the addition of radiation compared to tamoxifen alone. Patient numbers (n) are actual numbers at 12 years’ follow-up, whereas percentages in parentheses represent the actuarial rate at 10 years. NS = not significant; Tam = tamoxifen; TamRT = tamoxifen/radiotherapy. Courtesy of Kevin S. Hughes, MD.

0.0

0.2

0.6

0.4

0.8

0 4 6 8 10 12 142

Prop

ortio

n

Years

Breast tumor recurrence

Death from other causes

Death from breast cancer

Ultimate mastectomy

Second primary cancer

Distant metastasis

Death

TamRTn = 317n (10 yr)

6 (2%)

4 (2%)

36 (12%)

21 (5%)

157 (33%)

145

12

Tamn = 319n (10 yr)

27 (9%)

10 (4%)

33 (9%)

16 (5%)

156 (33%)

148

8

P = .0001

NS

NS

NS

NS

NS

NS

21 women

Bevacizumab, ODAC, and the FDA

Important perspectives 2, 3, 6, 10, 11 | Oncology drug news 27 | Financial survival in oncology 30

Use your smartphone to view the original abstracts as presented at ASCO’s 2010 Annual Meeting.

See page 43 for more information about using 2D barcodes

second- and third-line therapy in patients for whom imatinib and other therapies have failed.

The first study found that half of the patients who were either imatinib-resistant or imatinib-intolerant achieved a complete cytogenetic response (CCyR) with bosutinib.1 The second study suggested that bosutinib was also effective as third-line therapy in chronic-phase CML, after failure on first-line imatinib and second-line dasatinib.2

“We see very good activity for bosutinib in both second- and third-line therapy, with high levels of re-sponse,” said lead author of the first study and senior author of the second study, Jorge E. Cortes, MD,

Dr. Hortobagyi attended the ODAC meeting as a consul-tant to Genentech and made a presentation in support of preserving and expanding the indications for bevacizumab. Dr. Hortobagyi indicated that “For this meeting [ODAC, July 20, 2010], the company [Genentech] pro-vided my travel and lodging expenses. I have otherwise no financial interest in the outcome of this meeting.”

aSee page 2 for perspective from ODAC members.

The full transcript of the July 20, 2010, ODAC meeting on bevacizumab may be obtained online at http://tiny.cc/2r9x6.

Or use your smartphone to access the transcript via the 2D barcode, above.

See page 43

The ASCO Post | SEPTEMBER 2010

Perspective

tion (n = 317), and then followed for a me-dian time of 12 years. The current analysis was of outcomes at 10 years.

No significant differences were ob-served between the groups with respect to breast preserva-tion rates, breast can-cer–specific survival, or overall survival

(Fig. 1), Dr. Hughes reported. In-breast recurrence, however, was inferior when radiation therapy was eliminated. Local recurrences were observed in 6/317 (2%) in the tamoxifen-radiotherapy arm and 27/319 (9%) in the tamoxifen-only arm (P = .0001).

Dr. Hughes remarked that this was a small benefit. “We would have to irradiate 319 women to prevent 21(7%) in-breast recurrences,” he noted.

Overall survival tended to be low be-

cause these were older women who died of other causes. ASCO President George Sledge, MD, of Indiana University School of Medicine, commented at a press brief-ing, “We have many elderly patients who have a hard time getting back and forth to radiotherapy appointments for 6 to 7 weeks. This study gives those patients real comfort that they are not missing out on a lifesaving treatment,” he said. “But there are going to be patients who look at the data and think that a 6% to 7% reduction

in in-breast recurrence is important to them because they want to avoid the need for retreatment. This study says that there are options for physicians and patients, and that is its value.” ■Reference

1. Hughes KS, Schnaper LA, Cirrincione C, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. 2010 ASCO Annual Meeting. Abstract 507. Presented June 7, 2010.

Radiation in Older Womencontinued from page 1

See page 43

ODAC Voting Members Discuss Panel’s Recommendation about Bevacizumab in Advanced Breast Cancer

The recent recommendation by the Oncologic Drugs Advisory Committee (ODAC) to withdraw

conditional approval of bevacizumab (Avastin) in com-bination with chemotherapy for previously untreated metastatic breast cancer has been received with contro-versy. While many are genuinely concerned about with-drawal of an effective drug, others—such as the author of a recent editorial in The Wall Street Journal (August 18, 2010)—have distorted the science and facts to ar-gue that the decision was political and that ODAC is beholden to the politics of the FDA and Congress. Un-

fortunately, these latter arguments serve no purpose but to promote an agenda at the expense of breast cancer patients.

It is important that the breast cancer community rest assured that ODAC is an independent, unbiased panel of experts in oncology whose mission is to provide their best objective scientific and clinical recommendations to the FDA for drug approval. In my experience on this panel, I have never witnessed improper influence from any government agency. In fact, the FDA has taken great steps to maintain the indepen-dence and objectivity of ODAC.

The FDA’s mandate is to protect the American public by approving drugs that are effective while posing acceptable risks. One need only remember events surround-ing the use of thalidomide in the 1950s—the drug caused immeasurable suffering in babies born without limbs, and the FDA blocked approval in the United States. Many more examples exist of the role the FDA serves in protecting the American public from unsafe drugs and/or indications and unscrupulous promotion. Indeed, given that fewer than 1% of drugs ever show significant benefit, it is essential that the American people feel confident that an approved drug will be of help to them and not promoted for economic purposes.

I present this as backdrop to the controversy over bevacizumab, which is a good example of a drug that has benefit but also significant side effects. When evaluat-ing a drug, one needs to weigh these factors within the context of the disease. For example, in lung and colon cancers, the therapeutic effect of bevacizumab on sur-vival was relatively short and the toxicity significant, but the benefit was nonethe-less meaningful because few drugs prolong survival in these devastating diseases. In breast cancer, however, patients experienced only a 1- to 2-month delay in disease progression—without improved survival—and had serious toxicity. The panel recognized that a drug may improve a patient’s quality of life without prolonging survival, and that is a very legitimate reason to approve a drug. Unfortunately, the manufacturer (Genentech) did not officially incorporate quality-of-life measure-ments in their investigations, and the quality-of-life data they did present suggested there was no improvement. In fact, Genentech’s response was, “We are not making patients worse.” This is not sufficient. We need to make patients better.

It is understandable that some oncologists may want bevacizumab to remain available with a breast cancer indication because it could benefit a subset of yet-to-be-identified patients. Of course, this requires controlled studies employing bio-markers and cannot be presaged through the art of medicine. Indeed, bevacizumab

does not target a specific driving oncogenic pathway. Angiogenesis is a complex phenotype, and all tumors show some degree of this process. We must not lose sight of the big picture, which is that most patients with metastatic breast cancer do not achieve meaningful benefit, and in the absence of benefit, only the potential of harm remains. Indeed, it is important to recognize that although many breast cancer survivors are currently benefiting from a combination of bevacizumab and chemotherapy, the results of the randomized studies indicate that it is the chemo-therapy drug and not bevacizumab that is providing the significant benefit. ■

—Wyndham Wilson, MD, PhD, ODAC Chair, Chief Lymphoid Therapeutics Section, Center for Cancer Research, National Cancer Institute

In December 2007, I voted to approve bevacizumab for advanced breast cancer on the basis of the E2100 study.

At the time, it was noted that the 22% response rate to pa-clitaxel was surprisingly low and the apparent difference with the combination might be exaggerated. The higher response rate with bevacizumab suggests drug activity. However, a 1% increased incidence of death with the combination observed in all the clinical trials weighed heavily not only on me, but on breast cancer advocates at the hearing.

E2100 was not meant to be a registration trial. Only grade 3–5 toxicities were reported, and there is no record of patients discontinuing therapy because of toxicity. The FDA review of the data found that 10% of patients lacked CT scans and approximately one-third of patients were not followed until pro-gression or end of study. E2100 is considered the most positive bevacizumab trial, and the missing data are of concern.

The additional data from AVADO and RIBBON-1 supported an increased response rate, but also confirmed the increased toxicity and lack of survival ad-vantage with bevacizumab. Like the majority of panel members, I could not rec-ommend approval. ■

—Joanne Mortimer, MD, Director of the Women’s Cancers’ Program and Professor of Medical Oncology and Experimental Therapeutics, City of Hope

Comprehensive Cancer Center, Duarte, California

See page 5 for perspective from members of the oncology community on the role of bevacizumab in breast cancer. Share your thoughts. Write to [email protected].

Wyndham Wilson, MD, PhD

Joanne Mortimer, MD

Disclosure of Potential Conflicts of InterestWyndham Wilson, MD, PhD: Dr. Wilson has no financial interest or other relationship with the manufacturers of any products discussed in this report.Joanne Mortimer, MD: Dr. Mortimer has no financial interest or other relationship with the manufacturers of any products discussed in this report. See page 43

ASCOPost.com | SEPTEMBER 2010 PAGE 3

Perspective

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

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

James L. Mulshine, MD Rush University Medical Center

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

George W. Sledge, MD Indiana University

Thomas J. Smith, MD Virginia Commonwealth University

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Lynn D. Wilson, MD Yale University School of Medicine

Stanley H. Winokur, MD Singer Island, Florida

INTERNATIONAL EDITORS

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

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

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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

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

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

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

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The past 4 decades have seen sub-stantial research on immuno-

therapy, particularly with vaccines, for treatment and prevention of mel-anoma recurrence. Reasons behind this research effort include the lack of effective conventional therapies for metastatic and high-risk melanoma, the now century-old observation that melanoma patients occasionally have dramatic responses to immu-nologic manipulations, and most im-portantly, our continually expanding understanding of the human immune system and the mechanisms of antitu-mor immune responses. But despite the enormous promise of vaccines to provide nontoxic protection against melanoma growth, the actual results have been disappointing, with several high-profile vaccine clinical trials fail-ing to demonstrate a benefit—and some actually suggesting vaccination was associated with a worse outcome.

Available vaccines have uniformly failed to produce significant levels of

objective response in patients with metastatic melanoma. A review of the National Cancer Institute experience with 440 patients (mostly melanoma patients) who received a total of 541 different vaccines demonstrated only four complete and nine partial re-sponses, for an overall response rate of 3%. A randomized trial compar-ing a peptide-pulsed dendritic cell vaccine to single-agent dacarbazine chemotherapy in patients with meta-

static melanoma showed a similarly low level of responses to the vaccine and disappointing median time to progression and median survival (3.2 and 9.0 months, respectively), which were no different from those for da-carbazine alone.

Putting Results in ContextThese disappointing clinical re-

sults are perhaps not so surprising when one considers that most vac-cines generate only weak immune responses, and it is likely that any immune responses we do detect are not directly relevant to immune-me-diated tumor destruction, because detection of an immune response to date has not correlated directly with tumor regression. It is fair to say that the entire paradigm of repeated vac-cination with tumor-associated anti-gens as a nontoxic way of stimulating the immune system to recognize and reject melanoma has failed to live up to expectations, and needs to be re-evaluated if not replaced.

The disappointing results of the past need to be placed in the context of exciting developments in our un-derstanding of the human immune system. Costimulatory molecules on T cells have been identified and shown to augment the T cell’s re-sponse to antigens, while inhibitory molecules have been found to rapidly turn off the same cell’s response. It has become increasingly apparent that the balance between these stimula-tory and inhibitory signals influences not only the magnitude of the antitu-mor immune response, but also the likelihood of toxicity, manifested in autoimmune adverse effects. This has allowed a new paradigm to emerge, namely “inhibiting the inhibitors,” or perhaps more colorfully put, “taking the brakes off the immune system.”

Toxicity–Response LinkThe first agents capable of inhib-

iting the inhibitory molecules on T cells to enter clinical trials in mela-noma have been the anti-CTLA4

Immunotherapy for Melanoma: Time for a New Paradigm?By Vernon K. Sondak, MD

We now have dramatic proof that ‘taking the brakes off the immune system’ can offer new hope to our patients with metastatic melanoma.

continued on page 4

Melanoma


Perspective

Page 1 Dr. Gabriel Hortobagyi offers his perspective on the recent recommendation by the Oncologic Drugs Advisory Committee (ODAC) that the breast cancer indication for bevacizumab be revoked.

Page 3 Dr. Vernon Sondak discusses the role of vaccines in the treatment of melanoma patients and explores a new paradigm for treating melanoma patients with immunotherapy.

The ASCO Post (ISSN 2154-3283) is published 12 times annually 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 Periodical Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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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.

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antibodies. CTLA4 has emerged as the prototypical inhibitory molecule, expressed almost as soon as T-cell ac-tivation by antigen begins, and its ab-sence or blockade is associated with severe autoimmune manifestations. In the earliest phases of clinical trials, treatment with even a single dose of anti-CTLA4 antibody—without any type of vaccine or other immunos-timulant—resulted in the arrest of melanoma growth and even in dra-matic tumor shrinkage in some cases. But it also resulted in profound au-toimmune toxicity in some patients, including immune-related colitis, hepatitis, and even hypophysitis (au-toimmune pituitary dysfunction). Repeatedly, it appeared that patients who experienced autoimmune tox-icities were also most likely to show benefit in terms of tumor response. Clearly, the success of CTLA4 block-ade represented a new paradigm, where toxicity of therapy was accept-ed—perhaps even desired—in order to stimulate a sufficiently robust im-mune response to check or even re-verse melanoma growth.

Dramatic ResultsThe value of this new paradigm over

the old one has now been established, with the recent presentation (at the 2010 ASCO Annual Meeting) of the results of a randomized phase III trial comparing patients with melanoma treated with a vaccine (gp100) to those treated with ipilimumab, one of two anti-CTLA4 antibodies to enter human testing, alone or with the gp100 vac-cine. In particular, it was hoped that the coadministration of the anti-CTLA4 antibody and the vaccine would “steer”

the immune system in the right direc-tion—and away from toxicity. The re-sults of this trial were dramatic—and in some ways unexpected. The gp100 vac-cine “control” arm, as in the past trials of vaccines, had a very low response rate and short progression-free and overall survival times, but limited toxicity. The two ipilimumab arms (alone or with vaccine), had far more toxicity but bet-ter response rates and, most important-ly, statistically significant improvement in overall survival compared to vaccine alone. Unexpectedly, adding the gp100 vaccine to the ipilimumab antibody did not improve the antitumor effects, nor did it lessen the autoimmune toxicity.

ConclusionOnly time will tell what role, if any,

vaccines will ultimately play in the treat-ment of melanoma patients. But there is no question that improvement in our understanding of the immune system and the development of antibodies ca-pable of both augmenting the immune response to self-antigens and blocking the negative regulatory influences on the antitumor immune response have resulted in a new paradigm for treat-ing melanoma patients with immuno-therapy. While there is a clear need for additional clinical trials, we now have dramatic proof that taking the brakes off the immune system can offer new hope to our patients with metastatic melanoma, and perhaps someday soon to patients with other stages and types of cancer. ■Suggested Reading

Gogas H, Ioannovich J, Dafni U, et al: Prognostic significance of autoimmunity during treatment of melanoma with interfe-ron. N Engl J Med 354:709-718, 2006.

Hodi FS, O’Day SJ, McDermott DF, et

al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med June 14, 2010 (epub ahead of print).

Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity indu-ced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with meta-static melanoma. Proc Natl Acad Sci USA 100:8372-8377, 2003.

Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: Moving beyond current vaccines. Nat Med 10:909-915, 2004.

Sarnaik AA, Weber JS: Recent advances using anti-CTLA-4 for the treatment of me-lanoma. Cancer J 15:169-173, 2009.

Schadendorf D, Ugurel S, Schuler-Thurner B, et al: Dacarbazine (DTIC) ver-

Immunotherapy for Melanomacontinued from page 3

sus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic mela-noma: A randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 17:563-570, 2006.

Viguier M, Lemaitre F, Verola O, et al: Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human meta-static melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immu-J Immu-nol 173:1444-1453, 2004.

Dr. Sondak is Chair, Department of Cutane-ous Oncology, H. Lee Moffitt Cancer Center and Research Institute, and Professor, Departments of Oncologic Sciences and Surgery, University of South Florida College of Medicine, Tampa, Florida.

Inside The ASCO Post – Don't miss these important perspectives:

Plus:Page 2 Dr. Wyndham Wilson and Dr. Joanne Mortimer offer their perspectives as voting members of ODAC about the Panel’s recent recommendation concerning bevacizumab in breast cancer.Page 6 Nine representatives of the breast cancer community speak about the role of bevacizumab in advanced breast cancer.Page 20 Direct from ASCO—Dr. Marilyn Heine discusses how oncologists need to advocate for their patients in the legislative arena as much as in the clinic.Page 28 Dr. Joseph Bailes answers questions about Medicare Drug Reimbursement and, in particular, emphasizes that all reimbursement issues pale in comparison to the lack of a solution for the sustainable growth rate problem.


News

The oncology community was recent-ly stirred with potentially practice-

changing news: the 12-to-1 vote by the FDA’s Oncologic Drugs Advisory Com-mittee (ODAC) to remove the advanced breast cancer indication for bevacizumab (Avastin). The Committee’s vote does not affect the current availability of the popular drug, but should the FDA fol-low ODAC’s recommendation—as is its usual practice—the management of many patients with breast cancer may change.

Bevacizumab is currently approved in combination with paclitaxel for the first-line treatment of advanced HER2-nega-tive breast cancer based on encouraging results of the E2100 trial.1 The FDA pro-visionally granted accelerated approval but requested confirmatory data, which Genentech supplied in November 2009 with the results of the AVADO and RIBBON-1 trials.2,3 On July 20, 2010, ODAC recommended against conver-sion to full approval.

Recent Studies Fail to Confirm Degree of Improvement in PFS

The panel concluded that bevaci-zumab plus commonly used chemo-therapy (taxane or anthracycline-based, or capecitabine [Xeloda]) increased progression-free survival (PFS) but not overall survival (OS). They noted that the two recent studies failed to confirm the magnitude of PFS improvement seen in E2100—5.5 months (HR = 0.48; P < .0001). PFS was improved in AVADO by 0.09 months in combination with docetaxel (HR = 0.62; P = .0003); and in RIBBON-1 by 1.2 months in combi-nation with taxane/anthracycline (HR = 0.64; P < .0001) and by 2.9 months in combination with capecitabine (HR = 0.69; P = .0002). In addition, the com-mittee expressed concern about toxicity.

Mixed Response“We are disappointed by the com-

mittee’s recommendation and believe [bevacizumab] should continue to be an option for women with this incur-able disease,” said Sandra Horning, MD, Senior Vice President and Global Head, Clinical Development Hematol-ogy/Oncology at Genentech. “We will continue to discuss the data from the more than 2,400 women who partici-pated in three phase III studies with the FDA. This recommendation does not

impact [bevacizumab’s] approved uses for other cancer types.”

In addition, the recommendation sparked mixed response from many in the

oncology community. In interviews with ODAC voting members (page 2), breast cancer specialists, oncologists in private practice, and a patient advocate (see

pages 6, 10, and 11), The ASCO Post cap-tured initial reactions to the recommen-dation and its potential consequences. ■

Bevacizumab in Advanced Breast Cancer: FDA Committee Ruling Sparks Response from Oncology Community By Caroline Helwick

references on page 7

Breast Cancer

© Centocor Ortho Biotech Inc. 2010 4/10 08ADA10011

Other pathways can contribute to prostate cancer promotion.5

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

46252ALT_TabIsland_v2 1 5/6/10 12:35 PM


Perspective

When there is initial enthusiasm regarding benefit of a new agent, the FDA has taken a pragmatic approach in recent years. Accelerated approval is granted, with full approval pending rapid confirmation with similarly robust data in additional trials. This did not occur with AVADO and RIBBON-1, leading to a unanimous negative ODAC vote. It would be disappointing, though, to lose this agent from our armamen-tarium. An option could be to keep the label restricted as it is now and rapidly conduct a trial that duplicates E2100 (and possibly also the capecitabine arm of RIBBON-1), which could then lead to full approval. At the same time, further study is needed to demonstrate clinically meaningful efficacy of bevacizumab in combination with other common chemotherapy agents and regimens in the front-line setting. ■

—Kathy S. Albain, MD, FACP, Professor of Medicine, and Director, Breast Research Program, Loyola University Chicago Stritch School of Medicine

“I believe we have to set the bar high for cancer drugs, even in the metastatic setting.”

I am as disappointed as anyone else to not see a survival benefit with bevacizumab, but I am willing to be hon-

est about the fundamental implications of the data. I be-lieve we have to set the bar high for cancer drugs, even in the metastatic setting. Patients expect survival advantag-es, and we should always try to produce this. In my view, expensive drugs like bevacizumab that do not produce a survival benefit should be put aside to allow us to focus

our energies on alternatives that may prove superior. Otherwise, our health-care dol-lars will be consumed by drugs that are not offering what our patients need. ■

—Matthew Ellis, MB, BChir, PhD, Professor of Medicine, Chief of Medical Oncology, Washington University School of Medicine, St. Louis

“If we only accepted cancer treatments that improve survival, we would severely limit options for our patients.”

I was surprised and disappointed over the advisory panel recommendation since the three major clinical

trials met their prespecified primary endpoint, PFS. The arguably simplistic view is that we want every new drug to give a statistically significant improvement in OS, but the situation is more complicated than this, which merits careful consideration. If we only accepted cancer treat-

ments that improve survival, we would severely limit options for our patients. For instance, in pancreatic cancer no agent improves survival, including gemcitabine, but this does not mean we don’t offer treatment to these patients. Turning to breast cancer, there are two regimens that have statistically improved OS, with data pub-lished in peer-reviewed journals and approved by the FDA (paclitaxel/gemcitabine and capecitabine/docetaxel), but we actually don’t use them very much. There are many treatments that have received regulatory agency approval for other endpoints outside of OS. An example is lapatinib’s approval with capecitabine in the refractory HER2 breast setting or in combination with letrozole as first-line treatment for pa-tients with HER2-positive and ER-positive advanced breast cancer based on PFS.

I feel that bevacizumab is perhaps being held to a higher standard than many oth-er agents in the setting of advanced cancers. Many of the treatments currently used and reimbursed are lacking formal phase III comparisons showing that they improve

“There has not been a single metric by which the FDA has reviewed drugs for advanced breast cancer.”

Back in 2005, when we saw the E2100 data, we had great hopes that we were entering an era when a new

class of drugs would be potent in advanced breast cancer. It’s fair to say that over the past 5 years, after five randomized controlled trials, the collective experience has suggested this drug is less impressive than we had hoped. That is a dif-ferent statement than a regulatory “yes or no” question,

but the recognition is that there may be less here than we first imagined. And though most breast cancer specialists believe bevacizumab (Avastin) is reasonably well toler-ated, there are side effects and it is costly. The FDA is not charged with assigning cost-benefit, but it is an unspoken though real issue when we are thinking about bevacizumab.

On the other hand, we use lots of drugs that have not been shown to improve survival, such as ixabepilone (Ixempra) and capecitabine (Xeloda), which was ap-proved based on response rate, and lapatinib (Tykerb), which was approved based on an increase in progression-free survival (PFS). Gemcitabine plus paclitaxel, how-ever, was approved based on a survival benefit. This suggests there has not been a single metric by which the FDA has reviewed drugs for advanced breast cancer.

In the wake of the recommendation from the Oncologic Drugs Advisory Com-mittee (ODAC), the breast cancer community of researchers, patient advocates, pharmaceutical sponsors, NCI, and the FDA should come together to articulate what should be the accepted clinical trial endpoint, what should be the most impor-tant treatment goal, and what predicts for overall survival (OS) and for symptom relief or for a better experience for patients. For bevacizumab, or any other drug, we should shift away from “good or bad, yes or no.” ■

—Harold J. Burstein, MD, Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, Boston

“It would be disappointing, though, to lose this agent [bevacizumab] from our armamentarium.”

The totality of evidence for first-line bevacizumab with chemotherapy supports an impact on PFS and a hint

of a survival benefit, but the degree of benefit may be che-motherapy drug- and schedule-dependent. The concern is that if the FDA removes the current label, we may be throwing the baby out with the bathwater. That is, bevaci-zumab may work best when combined with metronomic or continuous, regular dosing of a chemotherapy agent—

weekly paclitaxel as was used in E2100 (a 5.5-month prolongation of time to progres-sion), or capecitabine (Xeloda), the strongest signal in RIBBON-1. It is possible this form of chemotherapy dosing is also antiangiogenic, so a combination with bevaci-zumab would modulate angiogenesis even more effectively.

In contrast to E2100, the AVADO trial did not show a strong signal for bevaci-zumab added to every-3-week docetaxel, with a much shorter prolongation of re-sponse. So I choose a weekly taxane instead when selecting a bevacizumab regimen. And RIBBON-1 raised the concern that the placebo arm in the anthracycline/taxane (non-capecitabine) comparison performed slightly better than the bevacizumab arm, though not statistically significant. However, the capecitabine results were more en-couraging. Therefore, the focus should be the weekly paclitaxel regimen as in E2100, which gave an amount of time free of progression that is meaningful to our patients.

Harold J. Burstein, MD

Nine Members of the Oncology Community Speak Out about Bevacizumab’s Role in Metastatic Breast Cancer

continued on page 10

Kathy S. Albain, MD, FACP

Breast Cancer

See page 11 for contributors’ disclosures of potential conflicts of interest.

Edith A. Perez, MD

Matthew Ellis, MB, BChir, PhD


Opinion

somewhat different than what we have seen with a number of other drugs sub-mitted for FDA approval. But what is also different is the interesting quirk we see in terms of adverse events and tox-icity. They appear formidable on paper, yet the bulk of these events are hyper-tension and proteinuria, which are not only asymptomatic in most patients but are easily controlled. Testimony to this comes in the form of 800,000 patients exposed to this drug. Still, ODAC em-phasized its potential for toxicity.

Unbiased Review?From my perspective, the FDA re-

viewer’s presentation was disturbingly unfair. While the FDA must fulfill its function of protecting the public, deci-sions should be based on an unbiased review of the data. Such was not the case here. The reviewer noted, for example, that a hazard ratio for survival of 0.87 was not significant for bevacizumab. How-ever, she suggested that a hazard ratio of 1.003 “favored the placebo” arm. It was a subtle use of language that, in my opin-ion, introduced bias against the drug.

Similarly, while actual mortality was lower with bevacizumab, the reviewer concluded that drug-related mortal-ity was higher—regardless of the po-tential for serious toxicities (cardiac complications, bowel perforations) to be attributable to the anthracycline or taxane components. I felt this conclu-sion was thoughtless, disingenuous, ignorant, or clearly biased, and it sug-gests the reviewer’s agenda was to paint

Bevacizumab, ODAC, and the FDAcontinued from page 1

this drug in the most unfavorable light. Additionally, there is some unfairness

in the outcome in that Genentech was asked in 2008 to perform confirmatory trials that showed improvements in PFS without decrements in survival. Most reasonable observers would say Genen-tech satisfied this requirement. However, ODAC then questioned the clinical sig-

References1. Miller K, Wang M, Gralow J, et al:

Paclitaxel plus bevacizumab versus pacli-taxel for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007.

2. Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for first-line treatment of human epidermal growth factor receptor 2-nega-tive metastatic breast cancer. J Clin Oncol 28:3239-3247, 2010.

3. Robert NJ, Dieras V, Glaspy J, et al : RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of che-motherapy with or without bevacizumab for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. J Clin Oncol 27(15S; abstract 1005), 2009.

Response from Oncology Communitycontinued from page 5

nificance of findings, without providing a definition of such. A situation in which sponsors and investigators must guess at the FDA’s wishes is not transparent or predictable and is therefore unfair.

There is an urgent need for the FDA and the cancer community to agree upon exactly what qualifies a drug for ap-proval. Although there would certainly

be differences of opinion from the vari-ous corners as to the requisite degree of benefit, by having this conversation we should arrive at what is commensu-rate with the expectations for advanced breast cancer and deliver something that patients would consider of value. ■

—Gabriel Hortobagyi, MD M. D. Anderson Cancer Center, Houston

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9891320.4.28.lb.indd 1 5/4/10 12:16:54 PM


News

Chair of the CML Section, Department of Leukemia at M.D. Anderson Cancer Center in Houston. Noting that toxic-ity of bosutinib was acceptable in these studies, he commented, “Bosutinib is a contender for a major role in the treat-ment of CML.”

Bosutinib is 30 times more potent than imatinib. This drug inhibits BCR-ABL signaling in CML cells and is active against all imatinib-resistant mutations, with the exception of the T315-I clone. Pfizer is sponsoring a phase III study of bosutinib as first-line therapy for patients with newly diagnosed chronic-phase CML. The trial is currently accru-ing patients.

Second-line TherapyDr. Cortes presented a multicenter

phase I/II study in patients for whom prior imatinib therapy failed.1 Phase I was a dose-finding study that included 18 patients treated with bosutinib at 400, 500, or 600 mg/d. The phase II trial included 276 patients treated with bosutinib at 500 mg/d. The median age was 52 years, median time from diagnosis was 4 years, and patients had been on prior imatinib therapy for a median of 2.3 years. About 70% were imatinib-resistant, and 30% were imatinib-intolerant.

At a median follow-up of almost 3 years, median duration of bosutinib therapy was 13.7 months. Three-quar-

ters of patients had dose interruptions, and 45% required dose reductions. The dose of bosutinib was escalated to 600 mg in 33 patients (22%).

Of the 109 patients evaluable for best response, an overall response was seen in 102 (94%), and complete he-matologic response was observed in 99 (91%). Of the 214 patients analyzed for cytogenetic response (CyR), a major CyR was observed in 136 (64%) and complete CyR was seen in 106 (50%). Of the 151 patients evaluated for mo-lecular response, a major molecular re-sponse was seen in 79 patients (51%) and a complete molecular response was seen in 49 (32%).

Response rates were higher in imatinib-intolerant patients than in imatinib-resistant patients. Time to achieve a major CyR was about 6 months, but responses continue to im-prove over time, Dr. Cortes said, and are continuing well into the second and third years of therapy.

At 2 years, median progression-free survival (PFS) was 77% in imatinib-resistant patients and 86% in imatinib-intolerant patients. “The majority of patients are still alive,” Dr. Cortes said.

Adverse events on treatment includ-ed diarrhea in 84% (grade 3/4, 9%), rash in 34% (grade 3/4, 9%), nausea in 44% (grade 3/4, 2%), and vomiting in 36% (grade 3/4, 3%). Fluid retention was uncommon, and pleural effusion occurred in 3%. The rates of grade 3 or 4 myelosuppression were as follows:

Expert Point of ViewIn a separate interview, formal discussant of

one of the bosutinib trials at ASCO, Michael J. Mauro, MD, Associate Professor, Center for Hematologic Malignancies at the Knight Can-cer Institute at Oregon Health & Science Uni-versity in Portland, offered this opinion: “Bo-sutinib clearly represents another option for patients with CML. With multiple agents in the running, optimizing treatment algorithms and sequencing of therapy in the face of resistance or intolerance will become increasingly impor-tant and potentially easier, as the goal is to find the right drug for each pa-tient, to elicit or restore deep and long-lasting remission.”

Dr. Mauro noted that choosing the optimal initial therapy might be the most important decision. “The bar is set the highest for the agent to be used at diagnosis. Thus, forthcoming data on the front-line use of bosutinib will be eagerly received but very carefully scrutinized, given the long track re-cord of success with imatinib, the clear improvements made with nilotinib, and the ongoing challenge from dasatinib,” he stated. ■

Michael J. Mauro, MD

500 mg/d, with escalation to 600 mg if required. Median duration of treatment was 6.1 months in this ongoing phase II trial. Thus far, 3 patients have died and 14 have had disease progression. With a follow-up of 23 months, median overall survival was not reached in either resis-tant or intolerant patients. Responses were seen in patients with common BCR-ABL mutations, but not in those with T315I mutations. ■References

1. Cortes JE, Kantarjian H, Brummen-dorf T, et al: Safety and efficacy or bosu-tinib (SKI-606) in patients with chronic phase chronic myeloid leukemia following resistance or intolerance to imatinib. 2010 ASCO Annual Meeting. Abstract 6502. Presented June 7, 2010.

2. Khoury HJ, Kim D, Zaritskey A, et al: Safety and efficacy of third-line bosutinib in imatinib and dasatinib resistant or intoler-ant chronic phase chronic myeloid leuke-mia. 2010 ASCO Annual Meeting. Abstract 6514. Presented June 7, 2010

thrombocytopenia, 24%; neutropenia, 16%; and anemia, 12%.

Third-line TherapyA related poster focused on third-

line therapy with bosutinib.2 The poster, presented by Hanna J. Khoury, MD, Winship Cancer Institute at Emory University in Atlanta, showed that bo-sutinib was effective and well tolerated as third-line therapy in 90 patients with chronic-phase CML in whom both first-line imatinib and second-line dasatinib had failed. In imatinib- and dasatinib-resistant patients, a complete CyR was reported in 6 (22%) of 27 evaluable patients, a complete hematologic re-sponse was reported in 18 (86%) of 21 evaluable patients, and a major molecu-lar response was observed in 6 (27%) of 22 evaluable patients. Cytogenetic and molecular response rates were higher in the 23 patients who were on study due to intolerance to imatinib or dasatinib.

The starting dose of bosutinib was

Bosutinib in CMLcontinued from page 1

■ Bosutinib was effective as second-line therapy for chronic myeloid leukemia in imatinib-resistant and –intolerant patients.

■ A separate study showed efficacy for bosutinib as third-line therapy after first-line imatinib and second-line dasatinib had failed.

■ The eventual role of bosutinib in CML will emerge from further studies.

Bosutinib in Treatment-resistant CML


Perspective

OS, or even PFS or response rate. The concept of clinical benefit to the individual pa-tient or in the context of public health is sometimes not easily quantifiable, although we use response, PFS, and even OS as surrogates for that endpoint. Based on the data that have been available for many months, the three first-line trials of bevacizumab in breast cancer met the prespecified endpoints of improving median PFS. I am concerned that if registration studies are designed with a prespecified endpoint, the endpoint is met, and then a committee recommends to regulatory agencies not to formally approve the agent for physicians to consider as an option for their patients, it would put into question how trials are designed. This scenario could be a disturbing lesson for patients who volunteer for studies, for nonprofit funding groups, and for pharmaceutical companies who might invest years and millions of dollars to develop a drug in an area of unmet need, satisfy the endpoint required for registration, and then have the drug rejected by the FDA. I hope the advisory panel recommendation will not be a setback for drug discovery.

In addition, I respect the job that ODAC must perform, but I have to say that I was and remain concerned about the recent vote related to bevacizumab. I hope when the FDA meets later this year, they will vote at least to allow bevacizumab in combination with paclitaxel, and convert this regimen to full approval. In this case, their decision will not appear arbitrary but will be evidence-based. The FDA would come out a winner, and we would still have this regimen as an option for our patients.

As a disclosure, I have received research grants from Genentech and have served in the capacity of uncompensated advisor. ■

—Edith A. Perez, MD, Director Breast Cancer Program, Serene M. and Frances C. Durling Professor of Medicine, Mayo Clinic, Jacksonville

“If a drug is expensive, relative to its benefits, then we need to develop a dialogue to address this issue.”

I found it ironic that a representative of Genentech was in my office promoting bevacizumab for breast

cancer the same day the FDA committee voted against it. It’s important for us as physicians to try to resolve these different spins on information.

Right now, at Wilshire Oncology we use bevacizumab plus a taxane as front-line treatment for

metastatic disease in about 50% of patients. What I’ve been hoping for is the development of biomarkers of response to this drug, which would not only help us select appropriate patients for treatment but would also provide a subset of patients likely to demonstrate positive results in clinical trials of bevacizumab. Any future bevacizumab research should also focus on biomarkers.

At ASCO this year, we heard encouraging data in other tumor sites. The addition of bevacizumab to standard regimens extended PFS by 3.8 months in ovarian cancer, and in gastric cancer the geographic subset of Pan-American patients experienced a 4.7-month gain in overall survival (though the larger population including European patients did not benefit). In the context of the recommendation in breast cancer, will the FDA look favorably on these findings? I would hope so, but this raises concern about the use of bevacizumab in other tumors. We are looking for leadership at the FDA to help sort out these differences.

As a community physician, I want access to bevacizumab and any other drug that provides meaningful benefit. If it is expensive, relative to its benefits, then we need to develop a dialogue to address this issue. Perhaps manufacturers might be reimbursed proportionally to the benefit the drug provides, ie, have different payment schedules for bevacizumab in colon, breast, and lung cancers, where the magnitude of benefits varies. It’s a new approach, but without such innovations we may wind up with evi-

dence of varying benefits and lack of clinical access to the drugs with lesser benefits, and our ability to control disease will remain more limited. ■

—Cary Presant, MD, FACP, Director of Medical Oncology, Wilshire Oncology Medical Group, Los Angeles, and Past President,

Association of Community Cancer Centers

“Bevacizumab may be a good drug for a subset, but it should not be on the market for all HER2-negative patients until this is known.”

Since the ODAC vote, I’ve been monitoring the BCMets.org mailing list of over 1,000 women living

with metastatic breast cancer. Although you would think their immediate reaction might be negative, instead it is decidedly mixed, based on patients’ personal experi-ences with the drug’s activity, toxicities—and, of course, cost. There has been ambivalence about bevacizumab

from the beginning. In my experience, patients do not necessarily argue just for more options, but for more beneficial options—drugs that are better than what we have now or at least provide a unique benefit.

Many advocates believe OS should be the sole standard for drug approval, al-though OS is hard to prove due to crossovers and subsequent treatments, especially in the first-line setting. I do agree with ODAC that PFS is only a clinically meaningful endpoint when it represents a significant period of time, and when there is solid evi-dence that quality of life is not compromised. Some patients do well on bevacizumab, and others have a host of minor and major problems. Bevacizumab has significant toxicities, so it had better provide real benefit, and there is no good evidence of that.

Some women do appear to have strong responses, maintained even when the che-motherapy agent is discontinued. Preliminary findings from post hoc analysis of E2100 suggest that tumors with different VEGF mutations respond differently. We hope that Genentech will take the ODAC recommendation as an incentive to start looking at this issue more urgently. Bevacizumab may turn out to be a good drug for a subset of patients, but it should not be on the market for all those with HER2-negative disease until this is known. And I have real concerns about subjecting patients with early breast cancer in adjuvant trials to a potentially toxic drug with minimal benefit.

ODAC’s recommendation does show that the accelerated approval process works. Patient advocates were concerned that accelerated approval of bevacizumab would lead to an automatic full approval, despite problems with the drug. I was grati-fied to see that when confirmatory studies do not show meaningful clinical benefit, despite early promise, a drug can be removed from the market. ■

—Musa Mayer, Breast Cancer Survivor, Patient Advocate, Author, Creator of AdvancedBC.org

“My fear is that pharmaceutical companies will be discouraged from developing anticancer agents if they feel the bar they must jump over is simply too high.”

Personally, I was not expecting ODAC to recom-mend full approval of bevacizumab, but I was

surprised that it recommended withdrawal of the indication. A number of drugs have been approved for breast cancer in recent years on the basis of mod-

Cary Presant, MD, FACP

Eric P. Winer, MD

Advocate Musa Mayer

Nine Members of the Oncology Community Speak Out about Bevacizumab’s Role in Metastatic Breast CancerContinued from page 6


Perspective

est benefit. “Modest benefit” does not mean that some patients don’t derive a more substantial benefit. Increasingly, however, many have wanted new drugs to show more benefit than older drugs, especially when treatment costs are high. The FDA is prohibited from considering cost, but society looks through a different lens—and this lens includes cost.

My fear is that pharmaceutical companies will be discouraged from de-veloping anticancer agents if they feel the bar they must jump over is simply too high. On the other hand, we don’t want to be in a situation where all that is being developed are drugs that add minimally to what we have. In truth, while PFS is probably a meaningful endpoint for some patients, ultimately our goal is to help patients live longer and better. If PFS doesn’t help them live longer, then the question becomes whether it helps them live better. I suspect that bevacizumab improves quality of life for some patients, but certainly not for all. Unfortunately, measuring quality of life is notoriously difficult.

Although I believe there are subpopulations that get substantial benefit and do particularly well with bevacizumab, I don’t know how to select those patients. Perhaps we will sort this question out in the adjuvant trials. It does seem that the FDA is sending a message to the oncology community, a mes-sage that drug approval in the future may look different than it has in the past. We will have to think carefully about drug development, and in this era of increasingly targeted therapies, it is our responsibility to identify populations that will benefit the most from new agents. ■

—Eric P. Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute and Professor of Medicine,

Harvard Medical School, Boston

“I think it unfortunate that insurance companies (including Medicare) have taken FDA approval as an indication of good medical practice.”

The details upon which ODAC based its decision are obvious: First and foremost, bevacizumab

does not prolong OS. But clearly there is biologic ac-tivity, perhaps a positive interaction with weekly pacli-taxel. I wish the system would let us give drugs the way we think they should be given, which in my practice

tends to be with weekly paclitaxel. Maybe because of how I give bevacizumab, I usually get results like those in E2100. The first patient I treated had a 2-year remission and excellent quality of life. Another had liver metastases disappear on MRI and has had a 7-month remission. Another patient is a 40-year-old with terrible organ disease, including liver and CNS metastases. I started her on the drug in March 2009 and she is still doing great. Now she asks me, ‘What will happen to me if the FDA takes [bevacizumab] away?’ While I could prescribe bevacizumab off-label, the price of the drug is unconscionable.

I think it unfortunate that insurance companies (including Medicare) have taken FDA approval as an indication of good medical practice, especially since the FDA tends to weigh one thing above the other in fairly arbitrary bureaucratic ways. The FDA review is a legally mandated adversary proceeding in which the drug company seeks approval and the FDA seeks evidence that the medication is both safe and effective. The FDA is not charged to, nor is it equipped to, set standards of medical care. Its job is to control marketing claims and protect con-sumers against dangerous drugs. Input from both patients and payers should be heard in open proceedings independent of the FDA review, which is, of ne-cessity, very detailed and technical. Such sessions, in which patient benefit is a major concern, are needed to help arrive at a fair evaluation of medical practice and what should be covered. ■

—Steven E. Vogl, MD, Private Practice, Bronx, NY

“The crux of the issue is whether overall survival should be the primary endpoint…though a survival benefit is increasingly hard to show.”

E2100 demonstrated several months’ increase in PFS with the addition of bevacizumab, while PFS

benefit was smaller in subsequent trials and an OS ben-efit was not shown. In some ways I can understand, therefore, where the FDA advisory committee was coming from in its recommendation. However, the pri-mary endpoint of the studies was PFS, and in all three

studies, PFS was statistically significantly improved. From this standpoint, bevaci-zumab should be approved, if this was the agreement with the FDA.

There is the more global picture, however, that we want our patients to actually survive longer. These studies bring up a major point; in fact, it is the crux of the is-sue, but it was not fully addressed at the hearing: whether OS should be the primary endpoint in metastatic breast cancer. Unfortunately, it is increasingly hard to show a survival benefit in a population that is living a median of at least 2 years now. One of the few positive trials in this regard was with trastuzumab (Herceptin), which is an extremely effective drug that has a definite target. If there is a survival benefit with bevacizumab, obviously it is not that large, at least in an unselected population.

We need better drugs, we need targeted drugs, and we need to understand the subset for which they are effective. There are definitely many patients who can ben-efit from bevacizumab—that has been shown in the data—but we have to learn how to identify them. I can see no reason to stop the adjuvant trials with bevacizumab. The agent clearly has activity in breast cancer, as shown by the increased response rate and PFS benefit. ■

—Sandra M. Swain, MD, Medical Director, Washington Cancer Institute, Washington, DC

Compiled and reported by Caroline Helwick.

Editor’s Note: FDA indicated it is the Agency’s policy not to comment on ODAC’s recom-mendations. The Agency will make a decision about whether to revoke the breast cancer indication later in the year. See page 2 for perspectives from ODAC voting members Wynd-ham Wilson, MD, and Joanne Mortimer, MD. Watch for further coverage in The ASCO Post.

Steven E. Vogl, MD Disclosure of Potential Conflicts of InterestHarold J. Burstein, MD: Dr. Burstein has no financial interest or other relationship with the manufacturers of any products discussed in this report.Kathy S. Albain, MD, FACP: Dr. Albain has disclosed: Attending a one-time advisory board meeting for Genentech (compensated) and a one-time advisory board meeting for Roche (compensated), pertaining to their pipeline but not dealing with bevacizumab.Matthew Ellis, MB, BCHir, PhD: Dr. Ellis has disclosed: Consultant, Genentech (<$10,000); Consultant, Roche (<$10,000)Edith A. Perez, MD: Dr. Perez has disclosed: Research grants, Genentech; Advisor, Genentech (uncompensated).Cary Presant, MD, FACP: Dr. Presant has disclosed: Research funding (Genentech, Roche, DiaTech Oncology); Consultant/advisor (Genentech). Musa Mayer: Ms. Mayer has disclosed: Consultant for programs supported by Genentech (uncompensated).Eric P. Winer, MD: Dr. Winer has disclosed: Principal investigator for a Genentech-sponsored trial at Dana-Farber Cancer Institute.Steven E. Vogl, MD: Dr. Vogl has no financial interest or other relationship with the manufacturers of any products discussed in this report.Sandra M. Swain, MD: Dr. Swain has disclosed: Research funding, Genentech; Advisory Board, Genentech/Roche (uncompensated).

Sandra M. Swain, MD

TORISEL—Significant overall survival benefit as first-line therapy1

Kaplan-Meier curves for overall survival (OS)*—TORISEL vs IFN�1

• Live vaccinations and close contact with those who received live vaccines should be avoided.• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL

therapy has stopped.• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%),

nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).

• In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion.

• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).

• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.

• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the brief summary of the full Prescribing Information on the next page.

References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. Data on file, Pfizer Inc. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

Change expectations

• Studied first-line in patients with ≥3 of 6 preselected prognostic risk factors1

The advanced RCC pivotal study included patients with2

• Clear-cell or non–clear-cell tumor histologyII • Any nephrectomy status

Median duration of treatment was 17 weeks (range 1-126 weeks) for the TORISEL arm and 8 weeks (range 1-124 weeks) for the IFN� arm.1

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

mTOR=mammalian target of rapamycin.IFN�=interferon alpha.CI=confidence interval.* Time from randomization to death.1† A comparison is considered statistically significant

if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1

‡ Based on log-rank test stratified by prior nephrectomyand region.1

§ Based on Cox proportional hazard model stratified by prior nephrectomy and region.1

II 82% and 82.5% of patients had known clear-cell histology for TORISEL and IFN�, respectively.2

¶ NCCN Category 1 recommendations are based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.3

# TORISEL was approved by the FDA in 2007.1

• Category 1 NCCN recommendation—first-line for poor-prognosis patients3¶

• >3 years experience since FDA approval#

Important Safety Information• TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild

hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN.

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

• Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in

the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of

infections, including opportunistic infections.• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented

with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic

acidosis, bloody stools, diarrhea, and/or acute abdomen.• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred

in patients who received TORISEL.• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy

may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

portant Safety Information

Change expectationsfor overall survival

With the fi rst and only IV mTOR inhibitor indicated for advanced renal cell carcinoma (RCC)1...

TUP100027_ASCO Post_Tabloid_FNL.indd 1-2 8/12/10 4:38 PM

TUP100027_ASCO Post_Tabloid_FNL.indd 3-4 8/12/10 4:38 PM


News

Zalutumumab significantly im-proved progression-free survival

(PFS) and disease control (response plus stable disease) compared with best supportive care in patients with ad-vanced squamous cell carcinoma of the head and neck in whom standard plat-inum-based chemotherapy had failed.1 The investigational drug improved overall survival (OS) compared with best supportive care, but the difference was not statistically significant.

Head & Neck Cancer

Zalutumumab Improved PFS in Squamous Cell Head and Neck Cancer, But Questions Remain about Drug’s True ValueBy Alice Goodman

awarded Fast Track status by the FDA for head and neck cancer patients in whom standard therapies have previously failed.

Study Details The open-label, parallel-group,

phase III ZALUTE trial randomly as-signed 286 patients with SCCHN to receive best supportive care plus the option to use methotrexate (n = 95) vs zalutumumab plus best supportive care and no methotrexate (n = 191). Imaging was performed every 8 weeks for assessment of treatment response.

Baseline characteristics were well balanced between treatment arms. Mean age was about 57 (range, 28–80). About 88% were males, and about 82% had an ECOG performance status of 0. Median duration of squamous cell car-cinoma of the head and neck was about 19 weeks at entry to the trial. About two-thirds had distant metastasis. About 40% received prior radiation, and about 55% underwent surgery. About 40% had concurrent chemo-radiation therapy, 16% had induction chemotherapy, and 83% had been treated with palliative chemotherapy.

Dr. Machiels explained that zalutu-mumab was titrated to grade 2 rash to obtain maximal efficacy (as rash is as-sociated with efficacy). The monoclo-nal antibody was given once a week, and patients were treated until disease progression. The dose was increased by 4 mg/kg every 2 weeks until the ap-pearance of rash.

■ Zalutumumab improved progression-free survival and disease control vs best supportive care in advanced squamous cell carcinoma of the head and neck after platinum-based chemotherapy has failed.

■ Survival was not statistically different with zalutumumab.

■ The cost of this EGFR inhibitor would equal approximately $709,000 per year of life gained.

Zalutumumab in Head and Neck Cancer

Jean-Pascal Machiels, MD, PhD

“ZALUTE is the first controlled study to show an EGFR antibody in-duces clinically meaningful improve-ment in progression-free survival,” said lead author Jean-Pascal Machiels, MD, PhD, of Cliniques Universitaires Saint-Luc-Université Catholique de Louvain, Belgium, at the 2010 ASCO Annual Meeting.

Zalutumumab, a fully humanized, high affinity monoclonal antibody tar-geted to epidermal growth factor recep-tor (EGFR), is under development by Genmab in Denmark. The drug has been

Expert Point of View

Despite the positive results of ZALUTE, formal discussant of this trial at the ASCO Annual Meeting, Alexander D. Colevas, MD, does not think this

drug will find a role in clinical practice. Dr. Colevas is an oncologist at Stanford University Cancer Center, Head and Neck Division, Palo Alto, California.

As the first randomized, controlled trial of EGFR inhibitor monotherapy in this setting, ZALUTE is worthy of note, Dr. Colevas commented. This study compared zalutumumab vs best supportive care plus methotrexate, and most patients got methotrexate “right out of the gate,” he said. But he ques-tioned the use of methotrexate as the control arm. “Is best supportive care plus methotrexate what oncologists are really doing? Most of us don’t reach for methotrexate in platinum failure,” he explained.

Even though there was a 1.5-week difference in median survival in this trial, Dr. Colevas said that it is not clear that patients’ quality of life is better on this drug. The slight separation of the overall survival curve favoring zalu-tumumab is “interesting, not definitive,” he noted.

Regarding the astronomic costs of new EGFR inhibitors, by his “back of the envelope” calculations, the drug would cost approximately $709,000 per year of life gained.

“This is not particularly cost-effective,” he commented.“Will we go home and do things differently with EGFR inhibitors in [squa-

mous cell carcinoma of the head and neck]? I am not going to. Despite the hype, is there a meaningful difference with these new drugs?… I don’t advo-cate larger trials of these agents. I think we would gain more from exploring new and different targets,” he stated. ■Zalutumumab did not signifi-

cantly improve OS: Median OS was 5.2 months for the control arm vs 6.7 months in the zalutumumab arm. Six-month OS was 42% in the control arm vs 57% in the zalutumumab arm. PFS was significantly better in the zalutumumab arm (P = .0010). Me-dian PFS was 8.4 weeks vs 9.9 weeks, respectively. The 26-week PFS was 7.3% in the control arm vs 20% in the zalutumumab arm.

PFS was consistently improved by zalutumumab in all subgroups, in-cluding age, sex, performance status, location of primary tumor, distant metastasis, duration of disease, and EGFR expression. Disease control was achieved in 48% vs 72%, respectively.

Adverse events (all grades) more fre-quently occurring with the monoclonal

antibody included skin rash (92% vs 0% in the control arm), anemia (25% vs 19%), pyrexia (22% vs 13%), head-ache (17% vs 6%), weight loss (16% vs 9%), diarrhea (13% vs 4%), and hypo-magnesemia (12% vs 2%). ■Reference

1. Machiels J-P, Subramanian S, Ruzsa A, et al: An open-label, randomized, phase III trial of zalutumumab, a human mono-clonal EGF receptor antibody, versus best supportive care, in patients with noncur-able squamous cell carcinoma (SCCHN) of the head and neck who have failed plat-inum-based chemotherapy (ZALUTE). 2010 ASCO Annual Meeting. Abstract LBA5506. Presented June 7, 2010.

Visit The ASCO Post website at:

ASCOPost.com

New!

See page 43


Appointments

Craig Thompson Named President of MSKCC

Craig B. Thompson, MD, has been named the new President and Chief Executive Officer of Memorial Sloan-Kettering Cancer Center (MSKCC)effective November 2, 2010. He suc-ceeds Harold Varmus, MD, who is now Director of the National Cancer Institute.

Rocky Mountain region’s only Na-tional Cancer Institute-designated comprehensive cancer center. “By di-recting an NCI–designated compre-hensive cancer center, I can contribute broadly in a way I’ve not been able to before,” said Dr. Theodorescu.

Dr. Theodorescu was recruited from his post as Director of the Mel-

lon Urologic Cancer Institute at the University of Virginia. As a bladder cancer expert, he focused his research on looking for biomarkers and new drugs that can lead to customized, targeted treatments for patients with bladder cancer.

Dr. Theodorescu has indicated his top priorities at UCCC will include:

Identifying genes that drive cancer to metastasis; cancer stem cell and re-generative medicine research and en-gineering; personalized medicine for predicting cancer outcome as well as response to therapy; and promoting the early phase clinical trials program at UCCC.

Craig Thompson, MD

Dr. Thompson has served as Direc-tor of the Abramson Cancer Center at the University of Pennsylvania and As-sociate Vice President for Cancer Ser-vices of the University of Pennsylvania Health System since 2006.

“We are at a time when transfor-mative developments in biomedical research are greatly expanding op-portunities to understand disease and to improve human health,” said Dr. Thompson. “I look forward to building on MSKCC’s achievements and tradi-tion of excellence and to working with my colleagues here in making progress in controlling and ultimately curing cancer.”

Dr. Thompson attended Dart-mouth College and completed his studies at Dartmouth Medical School. He received his MD degree from the University of Pennsylvania and com-pleted his residency at Harvard’s Peter Bent Brigham Hospital.

Dr. Thompson’s current research focuses on the role that metabolic changes play in the origin and progres-sion of cancer. ■UCCC Names New Director Dan Theodorescu

The University of Colorado Cancer Center (UCCC) has appointed Dan Theodorescu, MD, PhD, as the new Director of the UCCC consortium, effective July 1, 2010. Dr. Theodor-escu follows interim director Dr. Tim Byers, Associate Dean of the Colorado School of Public Health.

Dr. Theodorescu holds the Paul Bunn Chair in Cancer Research, named after the lung cancer pioneer who in 1988 founded UCCC, the


Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter

A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial

A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

Trial Currently Recruiting

Trial Currently Recruiting


Direct from ASCO

As an exclusive member benefit, ASCO members have advance

access to secure housing for the 2011 Annual Meeting 2 months prior to the general public. Members are en-couraged to take advantage of this benefit, as experience from previous meetings shows that highly sought-after hotels fill up within hours of the opening of housing and registration.

In late September, ASCO mem-bers can visit the Annual Meeting housing and registration website (www.asco.org/chicago2011) to se-lect their hotel for the meeting, June

3–7 in Chicago. An up-to-date inven-tory of available hotel rooms, descrip-tions of each hotel, and the distance to the convention center are provided online. Reservations may be changed or canceled without a fee if the change is made prior to a specified date listed online or on the housing confirmation.

Hotel reservations may be made without registering for the meeting at the same time, but both processes are linked for easy navigation. ■© 2010. American Society of Clinical Oncology. All rights reserved.

ASCO Members Have Advance Access to Hotels for 2011 Annual MeetingASCO Housing Block Opens to Members in September

June 3-7, 2011McCormick Place, Chicago

To reserve hotel space: www.asco.org/chicago2011

To become an ASCO member: www.asco.org/ASCOv2/Join+ASCO/Become+a+Member

The ASCO Cancer Foundation will soon begin accepting applications

for three types of awards created by the ASCO Diversity in Oncology Initiative and funded by Susan G. Komen for the Cure®. The awards support the program’s goals of addressing the lack of diversity in the oncology workforce and obstacles to oncology care in underserved com-munities. Applications for the Loan Repayment Program will open on Sep-tember 16. Applications for the Medical Student Rotation and Resident Travel Award will open on October 31.

Medical Student Rotation Award

The Medical Student Rotation Award provides an 8- to 10-week clinical or research oncology rotation for U.S. medical students from under-represented populations. Applicants must be enrolled in a U.S. allopathic or osteopathic medical school and be from an underrepresented population as defined by the eligibility criteria. Recipients are paired with a mentor who provides ongoing academic and career guidance. Each medical stu-dent receives a $5,000 stipend for the rotation plus $1,500 for future travel to the ASCO Annual Meeting. The student’s mentor receives $2,000.

Amanda Adeleye, one of six medi-cal students who received a Medical Student Rotation Award in 2010, was a first-year student at Columbia when she applied. The award allows the student to

2011 Diversity in Oncology Initiative Awards - Applications Opening SoonDue Dates: December 16 (LRP) and January 31 (MSR and RTA)

How to ApplyFor application forms and complete application criteria for all three awards, visit The ASCO Cancer Foundation website at www.ascocancerfoundation.org and click on “Awards.”

choose a mentor, so Ms. Adeleye picked Vincent L. Cryns, MD, of Northwest-ern University, a cancer researcher with whom she had worked for a summer after her freshman year in college. Cryns directs the physician scientist training program at the Feinberg School of Med-icine and also sees patients with breast cancer in a clinic at the SUCCEED Breast Cancer Survivorship Program.

Ms. Adeleye reports that during her rotation she “did a mix of research in the lab and seeing patients for 2 days each week.” She says that one of her most significant experiences during the rotation was a patient visit she par-ticipated in. “We met a woman who had been diagnosed with breast cancer a few days earlier. It was a quiet, pow-erful, humbling experience just to be there when someone is beginning to fight the fight of her life.” Adeleye plans a career in academic oncology.

Resident Travel AwardThe Resident Travel Award pro-

vides financial support for residents from underrepresented populations to attend the ASCO Annual Meeting. Ap-plicants must be residents in an ACG-ME-accredited residency program and must demonstrate an interest in pur-suing oncology as a career. The award includes complimentary meeting reg-istration and a $1,500 travel advance.

Frank Akwaa, MD, was one of 13 award recipients who received a Resi-dent Travel Award and attended the

2010 Annual Meeting in Chicago. He was in his final residency year at Johns Hopkins at that time and has recently started his oncology fellowship at the University of Rochester.

Dr. Akwaa had never attended the ASCO Annual Meeting before and says, “It was a great experience for me. Next time I go I’ll know how to navigate it.”

He explained that mentors as-signed as part of the award suggested sessions to attend and says, “I went to all of them and was glad I did.”

Dr. Akwaa’s advice to future appli-cants is “if you have the opportunity, jump on it. It’s a once-in-a-lifetime opportunity. I learned so much about current research and what options there are for careers in oncology.”

Loan Repayment ProgramThe Loan Repayment Program

provides repayment of qualifying educational debt to oncologists or oncology fellows who commit to practicing oncology in a medically underserved region of the United States (as designated by the U.S. Health Resources and Services Ad-ministration as a Health Professional Shortage Area or Medically Under-served Area). Applicants must be an Associate or Active ASCO member or submit a membership application with the award application. The pro-gram will repay up to $35,000 per year for 2 years (up to $70,000 total) of qualifying education debt.

Brooke Gillett, DO, was among three physicians who received an award in the Loan Repayment Pro-gram. After completing her fellowship at the University of Utah in Salt Lake City, Gillett joined Oncology Hema-tology Associates in Springfield, Mis-souri. She had decided she wanted to practice in a smaller community be-fore she saw a poster about the ASCO Loan Repayment Program in the fel-lowship office. “I wanted to live in a smaller community, I wanted to be busy, and I love going where I’m really needed and it will be really fulfilling.”

Her practice serves patients in all of southern Missouri and in northern Arkansas. She says that without ac-cess to oncology care in Springfield, patients would have to drive 6 hours to St. Louis. ■Selected portions reprinted from ASCO News & Forum. © American Society of Clinical Oncology. (“ASCO’s Diversity in On-cology Initiative.” ASCO News & Forum, October 2009: 26-31). All rights reserved.


Direct from ASCODirect from ASCO

ASCO and Advocates: Partners in Patient Advocacy

ASCO and ASCO members work hand-in-hand with pa-

tient advocates to address a wide array of issues affecting people with cancer, including the advancement of cancer research, legislative and regulatory matters related to cancer care and research, improving the quality of cancer care, raising public awareness of the disease, and pro-viding support to those living with cancer. Whether advocates are op-erating from an individual or orga-nizational level, locally or nationally, ASCO supports their efforts and of-fers opportunities and resources to promote all types of advocacy for people with cancer. Independent of their particular focus, patient ad-vocates share a common goal with ASCO: addressing the needs and concerns of people with cancer and ultimately accelerating progress against cancer.

ASCO Programs for Patient Advocates

ASCO’s mission has always cen-tered on improving the treatment and care of people living with cancer. This mission includes serving not only the educational needs of the profes-sional oncology community, but also the educational needs of the patient and survivor communities as well. As such, ASCO provides the opportuni-ty for advocates to attend the ASCO Annual Meeting and ASCO Sympo-sia to gain the education, knowledge, and skills necessary to participate in the cancer research process. ASCO meetings also enable advocacy orga-nizations to promote their programs,

services, and resources to the profes-sional oncology community. As an added benefit, ASCO meetings are great places for advocates to network with one another as well as with on-cology professionals.

ASCO’s Annual Meeting Patient Advocate Programs have developed significantly over the past 7 years to reflect the Society’s commitment

to working with the advocacy com-munity. Approximately 350 patient advocates attended the 2010 ASCO Annual Meeting, representing well over 100 patient advocacy organiza-tions. Twenty organizations exhib-ited in the ASCO-sponsored Patient Advocacy Booth, prominently situat-ed at the front of the Oncology Pro-fessionals Hall. Established in 1992, this booth allows organizations to promote their mission and programs to meeting attendees. In addition, about 30 other patient advocacy or-

ganizations exhibit at each ASCO Annual Meeting.

Beyond exhibit opportunities, programs offered for advocates at ASCO’s Annual Meeting include: ■ A teleconference for patient ad-

vocates that takes place in mid-May, highlighting studies that will be presented at the meeting and answering advocates’ ques-

tions related to the research ■ Discounted registration rate ■ Discounted subscription to ASCO’s

Virtual Meeting and Podcast ■ Research Review Sessions, dur-

ing which ASCO members re-view disease-specific topics pre-sented at the meeting, explain how the research is relevant to patients, and answer questions

■ Patient advocate scholarships, made possible by The ASCO Cancer Foundation

■ A lounge for patient advocates

ASCO Resources for Patient Advocates

One of ASCO’s shared goals with the patient advocacy community is to increase the accessibility of ac-curate and current information to people living with cancer.

ASCO’s doctor-approved pa-tient information website, Cancer.Net, includes a section dedicated to Advocacy and Policy. Here, visitors can learn about ASCO’s programs for patient advocates, read about what it means to be a cancer advo-cate, find information about current policy issues, and learn how to ef-fectively communicate with elected officials.

A comprehensive section lists Cancer-Specific Resources—na-tional, not-for-profit organizations that provide additional informa-tion, services, and support. The Cancer News and Meetings section includes easy-to-read summaries that put top scientific news from ASCO meetings into context for patients. Videos and podcasts with national and international cancer experts are included as well, break-ing down the science into specific disease areas and explaining what the studies mean for people with cancer.

These and other resources are freely available on Cancer.Net. Ad-ditional information about ASCO’s patient advocate programs can be obtained by contacting [email protected]. ■© 2010. American Society of Clinical Oncology. All Rights Reserved.

Save the DateDecember 9-11, 2010

ChicagoChicago Multidisciplinary

Symposium in Thoracic Oncology

www.astro.org/Meetings

January 20-22, 2011San Francisco

Gastrointestinal Cancers Symposium

www.gicasymposium.org

February 17-19, 2011Orlando, Florida

Genitourinary Cancers Symposium

www.gucasymposium.org

ASCO and Advocates: Partners in Patient Advocacy


Direct from ASCO

Medicare reimbursement. Med-ical liability reform. Stem cell

research. Insurance coverage for investigative drugs. These are but a few examples of the hundreds of areas in which legislation and regu-

lations affect medical practice and patient care.

Marilyn Heine, MD, a member of Regional Hematology Oncology Associates in Langhorne, Pennsyl-vania, thinks that physicians can

make a difference in public policy and have a responsibility to do so. “I firmly believe that just as we ad-vocate for our patients in the clini-cal arena, it’s imperative that we advocate for them in the legislative

Marilyn Heine, MD

arena,” she said. Dr. Heine practices what she

preaches. She is the coordinator of a physician advisory group that communicates regularly with their congressman, Patrick Murphy. She organized the group years ago at the request of a member of the U.S. House of Representatives on whose campaign she had worked. His suc-cessors were aware of this resource and have continued to use it.

Education, Rapport Important

Legislators want help in un-derstanding the implications of health-care policies, according to Dr. Heine.

“The essential thing in advocacy is education. Just as we educate our patients about the best treatment for them, we can educate our poli-cymakers on what would be the best position for them to take to benefit their constituency. The vignettes we provide about our patients and how issues affect them put a face on these issues.”

An occasional message to leg-islators is not as effective as devel-oping an ongoing relationship, Dr. Heine noted. She suggests getting to know lawmakers’ senior staff in their home office as well as their legislative aides in Washington. One activity that she found very productive was hosting a tour of her oncology practice.

“We described the activities in the different areas where we pro-vide care and the many support services provided daily, most of which are uncompensated,” Dr. He-ine reported. She commented that this exposure to a real practice with real patients helped illustrate how Medicare payments are already fall-ing short of the cost of care of on-cology patients.

Oncologist Urges Political Advocacy at Grass Roots Level

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Tips and Tools for Political Advocacy

Dr. Heine has several sugges-tions for oncologists interested in developing a dialog with members of Congress. One is to engage in the legislator’s campaign. “Volunteer, contribute, and encourage others to support the candidate. If you are inter-ested, host a fundraiser or a ‘meet and greet,’” she said.

To arrange a meeting or to host the legislator at your practice, call the legislator’s scheduler. Dr. Heine cautioned that you have to be de-

termined—it often takes more than one call. But, she noted, persever-ance pays off.

“I have seen positive results, such as a member of Congress modify-ing his position and becoming a champion of a bill,” she said. “Last year, Representative Patrick Mur-phy sent a ‘Dear Colleague’ letter to other members of the House, urg-ing passage of the bill to reform the Medicare sustainable growth rate payment system for physicians. In another instance, I was fortunate in securing a congressionally autho-

rized research grant.” Dr. Heine also encouraged using

ASCO resources. She has found the ASCO staff and online tools to be extremely helpful in her advocacy efforts.

“ASCO provides updates on is-sues and excellent talking points that help you formulate an agenda,” she noted. For oncologists interested in becoming a public policy advocate she suggested joining ASCO’s Ad-vocacy Network at http://capwiz.com/asco/home.

Finally, Dr. Heine noted that pro-

moting public and patient awareness of issues can help move the policy agenda. She writes letters to the editor of both the local paper and the Phila-delphia Inquirer, and her office has information available in the waiting room for patients interested in advo-cating access to care and other issues.

Dr. Heine said, “As physicians, we have a unique role in advancing the advocacy agenda for cancer care issues.” ■© 2010. American Society of Clinical On-cology. All Rights Reserved.

Neal J. Meropol, MD

What strategies work effectively in reaching full enrollment

in clinical trials? That was the ques-tion addressed at a 1½-day sympo-sium held in Bethesda, Maryland, last April. With a limit of 300 par-ticipants, many who wanted to at-tend had to be turned away. “There was tremendous enthusiasm for the conference among investigators at both academic medical centers and community sites,” said Neal J. Me-ropol, MD, from University Hospi-tals Case Medical Center and Case Western Reserve University, one of four cochairs of the event.

The “launch pad” for the NCI-ASCO Cancer Trial Accrual Sympo-sium: Science and Solutions, accord-ing to Dr. Meropol, was the premise that everyone understands what the barriers are. With that as the foun-dation, the symposium focused on empirical research that had tested ways to overcome obstacles to clini-cal trial enrollment. “This was the first national meeting in which the explicit focus was on solutions to barriers in clinical trial recruitment,” he pointed out.

Successful Strategies Presented

Representatives from sites ac-tively engaged in clinical trial re-cruitment presented research and interventions that had enhanced accrual among a variety of patient populations and types of trials. In breakout sessions, research was pre-sented about specific aspects of ac-crual, such as recruitment planning, community outreach, leadership, organizational culture, and minority recruitment.

“I was excited to see some of the successes that organizations had by using strategies with doctors as well as patients,” Dr. Meropol said. As an example, a three-pronged approach used successfully at Ohio State University Comprehensive Cancer Center (OSUCCC) involved inter-ventions with patients and family members, referring physicians, and the faculty and staff of the cancer center. During the 4-year period 2004-2007, accruals to therapeu-tic clinical trials had stagnated at about 700 accruals each year. To counter this, OSUCCC developed a campaign called “2010 by 2010” with the ambitious goal of enroll-ing 2,010 patients during the year 2010. Using a variety of strategies, including staff and faculty training, new communication methods with patients and referring physicians, and revised management systems in the Clinical Trials Office, annual patient accrual at OSUCCC has al-ready increased 69% and is on track

to exceed its goal for the year 2010 by 695 patients.

Commenting on the OSUCCC experience, which was one of four presented in a plenary session at the symposium, Dr. Meropol said, “The notion that institutional culture plays a big role in accrual success re-ally resonated with the participants at the symposium.”

He identified several take-home messages that emerged at the sym-posium: ■ Site-specific applicability:

Some interventions are more appropriate and effective in the community, whereas others work better in academic medical centers.

■ Awareness: Any steps that im-prove awareness about clinical trials among communities, phy-sicians, and patients can be use-ful.

■ Organizational culture: Any changes to institutional culture that promote the importance of clinical trials among stakeholders at all levels can be helpful.

■ Infrastructure: Basic changes in clinical trial infrastructure are needed to decrease impediments to physicians and patients to par-ticipate in clinical trials. Such infrastructure changes may in-clude increased reimbursement to cover administrative costs of participation, wider insurance coverage for patients, and reduc-tion in regulatory and paperwork requirements.

■ Recruitment planning: In plan-ning a clinical trial, more atten-tion should be given to develop-ing recruitment strategies and making sure that eligibility re-quirements are applicable to the patients seen in routine practice.Dr. Meropol noted that funding

for clinical trials was not addressed, in that it was outside the scope of the symposium.

Disseminating Results and Next Steps

A report summarizing the find-ings of the meeting is being prepared for submission to a cancer-related journal, Dr. Meropol stated. The document will incorporate literature references for the reader to refer to in developing accrual strategies. The success of the symposium has also generated enthusiasm for having similar meetings in the future, per-haps every other year.

One of the goals of the meeting was to identify recommendations for future research about accrual. To that end, each breakout group identi-fied specific topics related to clinical trial accrual for which more research is needed. The report of the sympo-sium will include recommendations for a research agenda related to clini-cal trial recruitment.

Slides presented at the meeting can be viewed on ASCO’s website at www.university.asco.org/CT2010. ■© 2010. American Society of Clinical On-cology. All Rights Reserved.

First-of-its-kind Symposium Focuses on Solutions to Obstacles in Clinical Trial AccrualEvent Cosponsored by ASCO and the National Cancer Institute


Special Feature

The epidermal growth factor receptor (EGFR) is dysregulated by a variety

of mechanisms in non–small cell lung can-cer (NSCLC). Drugs that target EGFR, therefore, have become an integral com-ponent of care, although their optimal use is still being refined. Two experts in this area addressed some of the relevant clini-cal conundrums, at an Education Session held at the 2010 ASCO Annual Meeting.

Tony Mok, MD, Professor of On-cology at the Chinese University of Hong Kong, said randomized studies have established the key driver of re-sponse to EGFR-targeted therapy to be the activating EGFR mutations, not Asian ethnicity. In the pivotal Iressa Pan-Asia Study,1 response rates to ge-fitinib (Iressa) were 71% for patients with mutations compared to 1% for those without. Perhaps as importantly, Dr. Mok added, the Pan-Asia study showed that for treatment-naive pa-tients, chemotherapy is superior to a tyrosine kinase inhibitor (TKI) in the absence of EGFR mutations.

Targeting EGFR in Lung Cancer in 2010Studies are better defining mutations and evaluating strategies for tackling resistance.By Caroline Helwick

pooled analysis of 1,809 patients, howev-er, found median PFS to be 13.2 months with erlotinib (Tarceva) and 9.8 months with gefitinib (5.9 months with chemo-therapy),6 offering a “suggestion” of en-hanced benefit with erlotinib, but further studies are needed, according to Dr. Mok.

Treating Beyond ProgressionResearch is focusing on better un-

derstanding mechanisms of resistance to TKIs and strategies to overcome them, said David M. Jackman, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

Dr. Jackman noted that when TKIs are stopped, patients could have worsening of disease. Therefore, progression should be measured while the patient is on treat-ment. “We don’t want to misinterpret ra-diologic worsening as tumor progression related to resistance. It might just be, for example, because the drug was held for treatment of a rash,” he pointed out.

Similarly, progression in the cen-tral nervous system may not represent

nase, mTOR, heat shock protein 90, or c-MET. Amplification of c-MET is a key mechanism of resistance, and recent phase II data suggested dual in-hibition with erlotinib and the c-MET inhibitor ARQ197 might be effective.8

Meanwhile, clinicians should re-member that EGFR mutations also predict for response to chemotherapy, “so standard chemotherapy is of value in the second-line setting,” Dr. Jackman said. “The larger question is whether to keep the patient on the TKI,” he add-ed. “In patients with indolent disease, sometimes continuing the TKI alone can provide long-term benefit. When you remove the TKI, tumors threaten to flare. My bias is to keep the TKI and give chemotherapy on top of this, rath-er than make a wholesale switch.”

Sloan-Kettering Genotyping All Lung Adenocarcinomas

Clearly, the key to optimally treating NSCLC is to unravel the genetic makeup of the patient’s tumor. The Lung Cancer Molecular Analysis Project at Memo-rial Sloan-Kettering Cancer Center (MSKCC) is seeking to do just that by routinely testing all NSCLC specimens for mutations in EGFR and KRAS, which are the most common, along with 40 ad-ditional abnormalities in seven genes.

EGFR mutations are found in approxi-mately 19% to 26% of adenocarcinomas, making them highly sensitive to EGFR inhibitors. About 23% to 30% of tumors have KRAS mutations, which appear to be associated with treatment resistance.

MSKCC oncologists use the test results to select patients for treatment

with erlotinib or gefitinib and to iden-tify patients’ eligibility for biomarker-driven clinical trials, said Mark Kris, MD, Chief of the Thoracic Oncology Service at MSKCC, at a poster presen-tation at the Annual Meeting.9 Table 1 shows the frequency of various muta-tions revealed in data on 541 tumors assessed by the lung cancer molecular analysis project (Table 1).

“The [lung cancer-molecular analy-sis] program has permitted molecular testing in 96% of patients with available tissue. We detected a driver mutation in 6%, and the program guided the selec-tion of therapy in 18% of patients with EGFR, KRAS, and EML4-ALK muta-tions. The [lung cancer-molecular anal-ysis project] findings support making upfront genotyping of lung adenocarci-nomas part of routine care,” Dr. Kris said.

Protocols for agents targeting BRAF, MEK1, HER2, and PIK3CA are in the approval process, and the investigators will collaborate with Lung Cancer Muta-tion Consortium institutions to complete trials of agents targeting these mutations.

Elsewhere, Oncologists Slow to Order Molecular Tests

While NSCLC patients at MSKCC are tested for an array of molecular alter-ations, the average American oncologist takes the opposite approach. According to a survey conducted by Xcenda, LLC, a full-service consultancy, market re-search, and managed markets agency in the healthcare space, 62% of American medical oncologists would not order molecular testing before treating a hy-

Table 1: Mutations in 541 Lung Adenocarcinomas Assessed in LC-MAP

Mutation NumberPercent of Specimens

(95% CI)

KRAS 143 26% (23%–30%)

EGFR* 119 22% (19%–26%)

EML4-ALK 8 8% (4%–16%)

PIK3CA 3 0.7% (0.1%–2%)

MEK1 2 0.4% (0%–1%)

BRAF 1 0.2% (0%–1%)

HER2 0 0% (0%–0.8%)

AKT1 0 0% (0%–0.8%)

* Primarily exon 10 deletion (n = 55) and exon 21 mutation (n = 49). LC-MAP = Lung Cancer Molecular Analysis Project. Courtesy of Mark Kris, MD.


Lung Cancer

“This study informed us that we have to select patients for their biomarkers before putting them on an EGFR TKI in the first-line setting,” he noted.

Emerging data would suggest that the exon 19 deletion may be more pre-dictive of response to EGFR TKIs than exon 21 mutation, as this group has better response rates and progression-free survival (PFS),2,3 although a recent study found no differences.4 Zeroing in on the mutations would help define candidates for anti-EGFR treatments.

The Japanese NEJGSG002 study,5 the WJTOG3405 study,4 and the Spanish Lung Cancer Group trial3 confirmed the benefits of TKIs in patients with EGFR mutations, but no large comparative study has established the superiority of one agent over the other, he added. A recent

a genetic change associated with re-sistance, but rather, insufficient pen-etration of drug into a sanctuary site. In this case, increasing the dose may achieve the proper concentration. “We have induced cytologic clearance of lung cancer cells from the cerebrospi-nal fluid using daily high-dose gefitinib for 2 weeks, followed by 2 weeks of maintenance gefitinib,” he reported.

Novel means of overcoming resis-tance are in development, including three irreversible EGFR inhibitors: PF299804, BIBW2992, and HKI-272. Other potential approaches are to com-bine a TKI with cetuximab (Erbitux), a strategy that reduced tumor burden in a study presented at the 2010 ASCO Annual Meeting.7 TKIs might also be combined with inhibitors of PI3 ki-

We have to select patients for their biomarkers before putting them on an EGFR TKI in the first-line setting...

– Tony Mok, MD


Special Feature

ASCOPost.com | JULY 2010

PAGE 53TAP Caucus

Should Oncologists Own Imaging Services?


Physician-owned Imaging Centers

Offer High-quality, Integrated ServicesBy Robert M. Langdon, MD

The efficiency of an oncology imaging center

within a multidisciplinary freestanding cancer

center is extraordinary.

T he ability of an oncology practice to own and

operate its own imaging center provides patients

with higher quality, better efficiency, lower costs,

and consistent care. Physician-owned imaging cen-

ters provide improved quality through collaborative

work with oncologic radiologists who are dedicated

to reading scans from a cancer view. These centers

can ensure quality through accreditation with orga-

nizations such as the American College of Radiology.

The practicing oncologist can immediately consult

with on-site radiologists to review the patient’s stud-

ies and make special requests in regard to issues under question. During clinical tri-

als, these radiologists are attuned to providing accurate tumor measurements and

characteristics to meet Response Evaluation Criteria in Solid Tumors (RECIST)

and other criteria set forth in the trial. The affiliated facility provides for reduction

in patient migration from imaging center to imaging center for procedures. This

allows easy access for the imaging procedure to consistently assess accurate

staging and tumor response on therapy. It also provides a rapid comparison

when there are questions of relapse, progression, or a new malignancy.

Full-spectrum Care Under One RoofThe efficiency of an oncology imaging center within a multidisciplinary

freestanding cancer center is extraordinary. The patient has the convenience

of receiving the full spectrum of outpatient oncology care under a single roof.

Patients commonly come into the imaging center for all of their imaging stud-

ies as well as a medical oncology visit and treatment on the same day, whether

on active treatment or during follow-up in support groups and survivorship

programs, all in a single facility. Because the multidisciplinary physicians—

specifically the radiologist and medical and radiation oncologists—meet un-

der the same roof, the patient benefits from open collaboration and assess-

ment in a timely manner. This is in contradistinction to outpatient situations

in many facilities, where the assessment, radiology, and scanning needs to be

done in a minimum of one day in advance of the patient’s visit.

Convenience and CostThe convenience of working in a dedicated oncology imaging center is that

the staff becomes intimately acquainted with each patient and understands his

or her individual needs, anxieties, and clinical situation. Adjustments in timing

of procedures and approach can be individualized. The freestanding facility can

provide urgent procedures without the patient ever having to leave the outpa-

tient cancer center. These procedures include the primary diagnosis of deep-vein

thrombosis, pulmonary emboli, pericardial effusions, and superior vena cava

syndrome. The diagnosis can be confirmed within the outpatient facility without

undue and sometimes unnecessary movement to a hospital-based facility. In the

era of frequent precertification, this process can be streamlined and performed in

an efficient fashion. A dedicated staff that is knowledgeable about an individual

Robert M. Langdon, MD

P hysicians should not own their own imaging centers. Period. End of story. The United States spends more of its GDP on health care than any other country, and that share is rising. Support-ers of our health-care system point to the

large and increasing maze of regulatory requirements as an important compo-

nent of health-care costs—and unnecessary costs at that—accounting for be-

tween $58 billion and $340 billion annually. Another estimate is that $8 billion

annually is derived from physicians’ additional income that results from owner-

ship of outpatient facilities, including diagnostic imaging centers, testing labora-

tories, day-surgery facilities, and procedure laboratories.Conflict of Interest and Overuse of Facilities

Conflict-of-interest concerns affect the entire economy, not just health care.

Empirical studies in medicine concerning conflict of interest are particularly

powerful. They consistently show that when physicians own their own labora-

tories, imaging equipment, pharmacies, and surgical centers, there is marked

excess in the use of these facilities.1 Using the quality-of-care paradigm outlined

Physicians Should Not Own Imaging CentersBy Charles L. Bennett, MD, PhD, MPP, and E.W. Lingle, PhD

by Mark Chassin, MD, the current President of the Joint Commission, this ex-

cess almost always represents overuse of these facilities (as opposed to underuse

or misuse).2 Although regulatory approaches including Independent Diagnos-

tic Testing Facility Performance Standards are designed to prevent meaningful

responses to overutilization, it is not clear in practice that these standards are

workable or even meaningful.3Safety and Legal IssuesA second concern reflects patient safety. Recent studies have reported on the

long-term safety risks of CT scans.4 Excessive use of CT scanning appears to

be a significant cause of preventable cancers. These safety concerns will only

increase as the rates of utilization of outpatient imaging centers increase.

A third concern is legal—physician-owned imaging centers are increasingly

targets in the coming health-care reform setting, and have been targets histori-

cally. Multiple concerns related to self-referral, including conflict of interest and

increased costs to the Medicare program, resulted in a ban on self-referral ar-

rangements under the Medicare program. Under health-care reform, oversight

of physician-owned imaging centers will expand in ways yet to be determined.

Violations of Stark provisions are increasingly difficult to prevent among physi-

cians who own imaging centers.5,6Competition and TransparencyA fourth concern involves competition. For markets to run efficiently, there must

be fair competitive practices and transparent pricing options. Health-care econo-

mists recognize that the U.S. health-care system does not meet the criteria to cat-

Charles L. Bennett, MD, PhD, MPP

E.W. Lingle, PhD

Physician-owned imaging centers are as far

away from transparency as one can get.


ASCOPost.com | JUNE 2010

PAGE 73

TAP Caucus

The ASCO Post invites you to comment on the subject of physician-assisted suicide, or physican-aid-

ed dying, a controversial, but very real issue in caring for patients with incurable cancer. Send your

thoughts to Dr. James Armitage, c/o [email protected]. Selected responses will be pub-

lished online and in future issues of The ASCO Post.


W hy do I no longer use the phrase “physi-

cian-assisted suicide”? It is simply inac-

curate. The phrase emerged to distinguish the

practice from euthanasia, which suggests lack of

choice on the part of the patient. But “physician-

assisted suicide” has its own connotation prob-

lems.In Oregon and Washington, physician-aided

dying is regulated by nearly identical Death with

Dignity Acts (DWDA) that pertain specifically to

physician support in achieving a peaceful death.

In both states, the DWDA does not regulate assisting in a suicide, because

that is still a crime.

We do not use the word “suicide” to describe similar medical practices

like allowing patients to choose to withdraw or withhold medical treatment

that will cause death. Current medical practice allows physicians to pre-

scribe medication that sedates the patient into unconsciousness while food

and hydration is withheld, thus hastening death.

Physician-assisted Suicide Is

Unnecessary, Ineffective, and

Increasingly Dangerous

By Kevin Olson, MD

In Support of Physician-aided Dying

By Nancy Crumpacker, MD

More Than a Linguistic Distinction

The distinction is not just linguistic. The word “suicide” demeans people

who wish a choice in the timing and manner of their imminent deaths. Peo-

ple using the DWDA and those who would commit suicide are opposites:

■ The suicidal person is generally physically healthy but does not wish to

live. The person who uses the DWDA is dying but wishes to live.

■ Typical suicides bring shock and tragedy to loved ones. DWDA deaths

bring closure and are supported by family and friends.

■ Suicides are often impulsive and violent. Dying under our law allows

planning for a peaceful death.

■ Suicide is an expression of despair and futility. DWDA deaths are em-

powering acts.

I have prescribed medications under the DWDA for a few of my patients.

I did it because I respect those who are dying and possibly experiencing

suffering that I may not be able to ameliorate. I watched as these patients

gained a sense of control that had eluded them during months to years of

terminal illness. I reminded myself that I am not able to fully understand how

Nancy Crumpacker, MD

I have prescribed medications

under the DWDA for a few patients

because I respect those who are

dying and possibly experiencing

suffering that I may not be able to

ameliorate. For every 100 individuals who ask

about physician-assisted suicide,

only 10 pursue the legal process of

obtaining a prescription, and only

2 of those 10 follow through and

obtain a prescription.


My opposition to physician-assisted suicide

(PAS) stems less from purely ethical or reli-

gious ideology and more from pragmatic concerns

about the delivery of this kind of care. My perspec-

tive comes as a full-time practicing hematology/

oncology physician for the past 16 years and as the

leader of a group of 40 private practice oncologists

for the past 10. The PAS challenge has had many

beneficial consequences in Oregon including im-

proved focus on palliative care at the end of life,

improved hospice utilization (Oregon ranks among

the nation’s leaders in this regard), improved training and expertise in the man-

agement of pain, and a reduced fear of painful death by those near the end of

life—even for those who pursue a hastened death via PAS. However, three main

issues drive my opposition to PAS: It is not needed, it is not always effective, and

it is dangerous in an increasingly complex medical care delivery system.

Not NeededPAS is not needed for patients with cancer because it is rarely used. When

asked about the frequency of requests for PAS, I use the “100-10-2-1” rule. That

is, for every 100 individuals who ask about the option (often in the panic of be-

ing informed of a terminal diagnosis), only 10 begin to pursue the legal process

of obtaining a prescription. Of those 10, only 2 follow through completely with

the process and obtain a prescription (often because the dying process inter-

venes without the need for a hastened death). For the two who get prescriptions,

one will actually use it.

Physician-assisted Suicide

Although a few of my patients have received a prescription as part of the PAS

process, none has used it. Of the roughly 30,000 deaths that occur in Oregon

each year, only 40 to 60 deaths occur as part of a PAS treatment. Most who par-

ticipated in PAS over the past 2 years cite loss of autonomy and loss of dignity

as their major motivation for the request. Fear of painful death was the primary

concern in PAS patients in the early years of the program. Clearly, the health-

care system evolved to address and relieve these pain concerns, and it is possible

Kevin Olson, MD

The ASCO Post’s TAP CaucusJune 2010: Should oncologists participate in physician-assisted suicide?

July 2010: Should oncologists own imaging services?

View the debates by visiting ASCOPost.com.

We encourage you to share your opinions on these and other important issues in oncology. Send your thoughts to Editor-in-Chief, Dr. James

Armitage, at [email protected]. Your letters will be published in future issues of The ASCO Post.

See page 41 for this issue’s debate, “Is accelerated partial-breast irradiation acceptable care in patients receiving breast-conserving treatment?”

pothetical stage IV NSCLC patient.10

“Only a minority of consultants planned to order specific testing to assess possible chemosensitiv-

ity (ERCC-1) or KRAS or EGFR status,” said Mark R. Green, MD, Chief Medical Offi-cer of Xcenda, Palm

Harbor, Florida, at another poster pre-sentation at the Annual Meeting.

He and his colleagues queried 585 oncologists as to how they incorpo-rate marker testing in their treatment planning for a hypothetical 58-year-old female, former smoker presenting with stage IV lung adenocarcinoma. Three-quarters of respondents were in community practice and one-quarter practiced in academic centers or teach-ing hospitals. About half had practiced for at least 11 years and saw at least one new NSCLC patient per week.

Participants were asked whether they would request special marker

studies on the tissue before finalizing their management plans, and were pre-sented with 10 testing options.

Prior to treating, 60% of oncologists would order no molecular tests, includ-ing 64% of those in community practice and 51% in academic settings (Fig. 1). For those who would test, the single most com-mon choice was for EGFR status, which was selected by just 10% of respondents; 9% would order at least two of the follow-ing: EGFR, KRAS, or ERCC-1. No clear correlation was seen between time out of training or volume of lung cancer patients and plans for more frequent testing.

“The notion here, among nearly 600 medical oncologists, is ‘I am not per-suaded by the discussion, the data, and the analyses [in support of testing] that the clinical impact is enough to consider these tests mandatory for optimum treat-ment,’” Dr. Green told The ASCO Post.

While he proposed a number of reasons for their reluctance, he said, “The bottom line is that from March through September 2009, the major-ity of oncologists, who had substantial lung cancer experience, were not plan-ning to use molecular studies as a basis

for finalizing their management plans.” It should be noted that most respon-

dents were surveyed prior to the publi-cation of two high-profile studies1,3 and a relevant editorial in The New England Journal of Medicine.11 Dr. Green acknowl-edged that if surveyed today, some on-cologists might answer differently. In-deed, over time there was an increase in the proportion of physicians who would order at least one test, from 28% initially to 46% by mid-September 2009.

Commenting on the findings, Dr. Kris suggested, “There is a widely held but unsubstantiated belief that erlotinib is helpful, regardless of mu-tation status. Many physicians are giving erlotinib, especially second-line, without testing. But the data are incontrovertible that any benefit is trivial in unselected patients. Plus, the maintenance benefit of chemotherapy is twice that of erlotinib, and from the [Pan-Asia] study we know that a TKI may actually be detrimental in wild-type patients. You need to test these patients, and as time goes on I think more doctors will realize this.”

Xcenda is continuing to survey on-cologists on this and related issues in order to create “a matrix of informa-tion” that will guide the personaliza-tion of NSCLC care, Dr. Green said. ■References

1. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.

2. Fukuoka M, Wu Y, Thongprasert S, et al: Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia. 2010 ASCO Annual Meeting. Abstract 8006. Presented May 31, 2010.

3. Rosell R, Moran T, Queralt C, et al:

Screening for epidermal growth factor re-ceptor mutations in lung cancer. N Engl J Med 361:958-967, 2009.

4. Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomized phase 3 trial. Lancet Oncol 11:121-128, 2010.

5. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR. N Engl J Med 362:2380-2388, 2010.

6. Paz-Ares L, Soulières D, Melezinek I, et al: Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 14:51-69, 2010.

7. Riely GJ, Janjigian YY, Azzoli CG, et al: Phase II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. 2010 ASCO Annual Meeting. Abstract 7557. Presented June 6, 2010.

8. Schiller JH, Akerley WL, Brugger W, et al: Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer. 2010 ASCO Annual Meeting. Ab-stract LBA7502. Presented June 5, 2010.

9. Kris MG, Lau CY, Ang D, et al: Initial results of LC-MAP: An institutional pro-gram to routinely profile tumor specimens for the presence of mutations in targetable pathways in all patients with lung adeno-carcinoma. 2010 ASCO Annual Meeting. Abstract 7009. Presented June 8, 2010.

10. Green MR, Wozniak AJ, Willey J, et al: Plans of American medical oncologists to or-der molecular testing before starting first-line therapy for patients with stage IV non-small cell lung cancer. 2010 ASCO Annual Meet-ing. Abstract 7568. Presented June 6, 2010.

11. Gazdar AF: Personalized medicine and inhibition of EGFR signaling in lung cancer. N Engl J Med 361:1018-1020, 2009.

0%

10%

20%

30%

40%

50%

60%

70%

51%

9% 11%

64%

8% 10%

Academic or Teaching Institution(n = 57)

Community Practice(n = 191)

No

Yes, ERCC-1

Yes, KRAS mutation status

Yes, EGFR by IHC

Yes, at least 2 of the 3 studies(ERCC-1, KRAS, EGFR)

Yes, all 3 studies

Yes, EGFR copy number by FISH

Yes, EGFR mutation testing

Yes, KRAS and EGFR by IHC andEGFR by FISH or mutation testing

Yes, other

Fig. 1: Survey results according to practice venue, for a subset of all medical oncology consul-tants surveyed, from 3 of 8 live research events (results were similar for the remainder of the total population). Respondents were asked whether they would order any of several marker studies for a hypothetical 58-year-old female, former smoker presenting with stage IV lung adenocarcinoma. EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridization; IHC = immunohis-tochemistry. Courtesy of Mark R. Green, MD.

Targeting EGFR in Lung Cancercontinued from page 25

See page 43


FDA Update

FDA Grants Priority Review to Denosumab

The FDA has granted priority review designation to Amgen’s denosumab (Prolia), a subcutaneous RANK ligand inhibitor, for the treatment of bone metastases to reduce skeletal-related events in patients with cancer. Filed in mid-May with the FDA, the Biologics License Application (BLA) submission summarizes clinical experience from nearly 6,900 patients across 18 clinical studies, including approximately 5,700 patients with advanced cancer in the three pivotal phase III head-to-head trials vs zoledronic acid (Zometa). De-nosumab is the first therapy to target the RANK/RANKL pathway, which is believed to play a central role in cancer-induced bone destruction.

New Docetaxel Formulation Approved

The FDA has approved a new one-vial formulation of sanofi-aventis’s docetaxel (Taxotere Injection Concentrate). The 1-vial docetaxel is anticipated to become available to cancer treatment clinics and hospitals nationwide in the fall in both 80- and 20-mg dosages. Previously, docetaxel was available in a two-vial formulation—one containing the drug and the other with the diluent. The 1-vial docetaxel eliminates the need for the initial dilution step with the diluent. The pharmaceutical ingredients of docetaxel and the 1-hour IV infusion administration remain the same.

Perifosine Receives Orphan Drug Designation in Neuroblastoma

Perifosine (licensed by Keryx from Aeterna Zentaris in the United States) has received Orphan Drug designation from the FDA for the treatment of neu-roblastoma, a cancer of the nervous sys-tem affecting mostly children and infants for which there are no FDA-approved therapies. Phase I data of perifosine in recurrent pediatric solid tumors, includ-ing neuroblastoma, was presented at the 2010 ASCO Annual Meeting. Investiga-tors concluded that perifosine was safe and well tolerated in children with ad-vanced solid tumors and that perifosine may have antitumor clinical activity as a single agent in neuroblastoma.

Phase III Bone Marrow Transplant Trial on Track after FDA Meeting

An Australian biotechnology com-pany, Mesoblast Ltd, provided market

Oncology Drug Newsguidance on its bone marrow transplant program following a formal meeting with the FDA. For this phase III program, patented allo-geneic adult mesenchymal precursor cells (MPCs) will be used under an Orphan Drug designation

to expand unrelated donor hemato-poietic stem and progenitor cell num-

bers for use in patients with hematologic malignancies. In the meeting with the FDA,

Mesoblast proposed a phase III clini-cal trial whose design, size, duration,

and primary endpoints were based on results from the 25-patient pilot trial performed at The University of Texas M. D. Anderson Cancer Center. Me-soblast will seek to obtain a binding Special Protocol Assessment prior to commencing the trial. ■

TrimSize: 7.625” x 10.5” 731US10AB00705 - Publication:

©2010 Bristol-Myers Squibb. All rights reserved. 731US10AB00705 4/10

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Expert’s Corner

At the 2010 ASCO Annual Meet-ing’s Reimbursement Forum,

Joseph S. Bailes, MD, of Texas On-cology, Austin, described the 2010 changes to Medicare reimbursements and made some predictions regarding future reimbursement issues.

Prompt Pay DiscountsWhat is happening with regard to

“prompt pay” discounts?Dr. Bailes: Prompt pay discounts

confound average sales price (ASP) calcu-lations. ASCO is advocating the amend-ment of the Medicare ASP calculation to exclude them (H.R. 1392/S. 1221), which would increase the ASP and the Medicare payment. Congress has already excluded prompt pay discounts from the average manufacturer price (AMP), which is used to calculate Medicaid pay-ment rates. The House included a provi-sion to exclude prompt pay discounts under Medicare within H.R. 3200, a near-final version of the health-care re-form bill, but the provision did not sur-vive in the final legislation.

BiosimilarsAs biologics go off-patent and generics

come on board, what will be the reimburse-ment policy for the so-called biosimilars?

Dr. Bailes: Health-care reform leg-

A Conversation with Joseph S. Bailes, MD, ASCO Immediate Past Chair of Government Relations Medicare Drug Reimbursement RoundupBy Caroline Helwick

islation created a new pathway for bio-similars. Medicare reimbursement for these products reflects a compromise, differing from the payment method-ology used for traditional generics. The original reference biologic will be paid at ASP plus 6% based on its own sales data—nothing changes. The bio-similar product will be paid the sum of 100% of ASP from its own sales data plus 6% ASP from the reference prod-uct’s sales data.

Chemotherapy AdministrationHow has reimbursement for chemo-

therapy administration been affected?Dr. Bailes: For 2010, the Centers

for Medicare and Medicaid Services (CMS) implemented cuts in payment levels for chemotherapy administra-tion codes. CMS used new data for determining practice expenses and relied on a survey administered by the American Medical Association, the Physician Practice Information Sur-vey (PPIS). However, the survey had significant flaws, and we secured some relief when CMS agreed to instead use the Gallup survey for oncology. De-spite this, the adverse impact of the PPIS data from other specialties result-ed in net decreases for chemotherapy administration within the fixed pool.

CMS has agreed to phase in changes over a 4-year period (2010-2013). For 2010, this results in an overall estimat-ed 1% cut for oncology.

Medical MalpracticeIs there any relief to be found within

the medical malpractice relative value units (RVUs)?

Dr. Bailes: CMS proposed the re-duction of malpractice RVUs assigned to codes with zero physician work val-ues to near zero levels. This approach failed to recognize the malpractice risk associated with chemotherapy admin-istration codes. CMS agreed to modify the proposed changes to reflect the as-sociated amount of clinical labor. This mitigated the reductions, although some decline occurred in these codes, particularly in the malpractice risk part.

Consultation CodesWhat are the changes in consultation

codes? Dr. Bailes: There has been con-

tinuing debate as to when and how to use these codes. CMS eliminated pay-ment under Medicare fee-for-service for consultation codes (except for tele-health consultation codes), effective January 1, 2010. This follows a history of unclear guidance from CMS and the Office of the Inspector General on when to use the consultation codes vs codes for new patient visits or hos-pital admissions. CMS redistributed the RVUs for consultation codes in a budget-neutral manner to the codes for new and established patient visits. The consultation codes still exist, and other payers (including Medicare Ad-vantage) may still use them, but that does not mitigate their elimination from Medicare.

Competitive Acquisition Program

Is the Competitive Acquisition Program (CAP) for Medicare Part B drugs dead?

Dr. Bailes: Congress is still inter-ested in CAP, so we need to keep an eye on this. The intention of CAP is to remove financial pressures associated with the profit or loss of providing a drug therapy. Congress originally envi-sioned competing vendors that would serve physician offices and compete

‘We Need to Permanently Fix SGR’

All other reimbursement issues pale in com-parison to the lack of a permanent fix for

the sustainable growth rate (SGR). With each go-round on the subject, “Congress just kicks the can down the road,” said Joseph S. Bailes, MD, ASCO’s Immediate Past Chair of Govern-ment Relations.

“Congressional interventions over the years have merely delayed the impact of the SGR mechanism rather than reset the base. As a re-sult, the cuts from prior years have continued to

accumulate,” he said, noting that the cost of enacting a permanent fix is now reaching $250 billion. “We all have SGR fatigue, and so does Capitol Hill.”

On June 24, the House of Representatives voted once again—this time, 417 to 1—to delay the 21.3% reduction in Medicare pay for physicians through November 30, but by December 1 the mandated SGR cut is expect-ed to occur. ASCO continues to advocate for a permanent legislative fix that removes the accumulation of delayed cuts from the mechanism and puts an end to the “month-to-month patches” long endured by oncologists. ■

Joseph S. Bailes, MD

on the basis of quality. Vendors would negotiate pricing with manufacturers, and vendor bids to CMS would be less than ASP plus 6% for each drug. CMS struggled to get CAP up and running, but only a single vendor was secured and CAP was suspended, although it remains a dormant authority that CMS can restart at any time.

Outpatient Prospective Payment System

What changes were made for drug reimbursement through the Outpatient Prospective Payment System (OPPS)?

Dr. Bailes: The OPPS allows for more expensive drugs to be paid for separately, whereas payment for less expensive drugs is bundled. CMS has a great deal of discretion in implement-ing changes in the drug payment for-mula in the hospital outpatient setting. For 2010, the package threshold is $65 and the methodology for establishing drug payment levels remains at ASP plus 4%, which was set in 2009. One significant change was in reimburse-ment for 5-HT3 receptor antagonist antiemetics. These drugs were origi-nally paid separately, regardless of the threshold. For 2010, however, CMS reversed this determination, and Medi-care no longer pays separately for any oral or injectable 5-HT3 receptor an-tagonist except for palonosetron (Al-oxi), which exceeds the $65 threshold.

RadiopharmaceuticalsHow are therapeutic radiopharma-

ceuticals paid?Dr. Bailes: For 2010, these were

moved to ASP plus 6% reimburse-ment. Separate payment for these products was maintained, and the expense of making the product into a “patient ready” form is covered. Di-agnostic radiopharmaceuticals remain packaged within payment for services.

Off-label UseWhat’s new in coverage of off-label use

of cancer drugs?Dr. Bailes: The list of compendia

and peer-reviewed journals as a basis for determining coverage was recently updated, largely a result of ASCO’s ef-forts. This is good news, but in some instances Medicare contractors are

Reimbursement


Expert’s Corner

imposing burdensome documentation requirements to provide information from all four compendia to support claims. Difficulties remain in securing access to off-label uses not reflected in the compendia, especially under Medicare Part D.

Other CoverageWhat’s the future of coverage for end-

of-life care and patient education?Dr. Bailes: There were provisions

included in the House version of the health-care reform bill that would have helped cover decision aids for indi-viduals with cancer as they decided on treatment. This coverage (advanced cancer care consultation) pertains to consultations about advance direc-tives, continuum of end-of-life services

(including palliative care and hospice), and related issues. These end-of-life provisions were excluded from the fi-nal version of the bill because of the highly politicized rhetoric that became associated with the issue. It is impor-tant, however, to have decision aids for patients as they look at therapy, and these decision aids are certainly a ben-

efit that should be covered. The issue is likely to resurface in the future.

Regarding hospice, there is a budget neutrality provision—that is, payment may be limited to current hospice pay-ment levels, the current language sug-gests. Demonstration projects current-ly underway should inform the issue of hospice reimbursement. Regarding

patient education, ASCO is support-ing a proposal by the Oncology Nurs-ing Society to establish separate Medi-care coverage for nursing time spent on education about cancer treatment and symptom management. The leg-islation would also expand federal re-search in this area and establish a study by the Institute of Medicine. ■

Contact The ASCO PostEditorial CorrespondenceJames O. Armitage, MD Editor-in-Chief email: [email protected]

Cara H. Glynn, Director of Editorial email: [email protected] Phone: 631.935.7654

Andrew Nash, Assoc. Director of Editorial email: [email protected] Phone: 631.935.7657

Advertising Rates, reprints, or supplements

Leslie Dubin email: [email protected] Phone: 631.935.7660

Rights and Permissionsemail: [email protected]

Editorial OfficeHarborside Press 37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Information You Can Trust

and Your Patients Can Understand

Cancer.Net Guides to CancerDetailed guides about specific types of cancer, including: symptoms, risk factors, diagnosis, staging, treatment, clinical trial resources, side effects, after-treatment, current research, and questions to ask the doctor.

ASCO Answers Fact SheetsA double-sided page introducing a cancer type.

ASCO Patient EducationEach cancer education resource uses illustrations to aid comprehension and is updated annually or as needed by a 150-member editorial board of practicing oncologists, nurses, social workers, and patient advocates.

For discussions with patients about their cancer care and treatment, you want to be sure that the information you provide is not just the best available, but also easy to understand. That’s why ASCO offers a variety of oncologist-approved educational materials for doctors to share with their patients.

Whether you need a comprehensive guide to a specific kind of cancer or just a list of available resources, ASCO can help:

Cancer.Net Promotional MaterialsAll promotional materials are offered free-of-charge.

Cancer.Net is your resource for the most trusted and up-to-date cancer information, developed by the world’s leading cancer doctors.

Cancer.Net is made possible by The ASCO Cancer Foundation which provides support for cutting-edge cancer research, education, and patient information.

Cancer.Net provides you with doctor-approved information in one comprehensive website:

• Guides to over 100 types of cancer• Find a doctor database• Clinical trial resources• Coping with cancer• Caregiving• Survivorship• Questions to ask the doctor• Podcasts• Information in Spanish

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Cancer.Net is your resource for the most trusted and up-to-date cancer information, developed by the world’s leading cancer doctors. Cancer.Net brings the expertise and resources of the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians, to people living with cancer and those who care for and care about them.

For information about ASCO’s patient information resources, call toll-free 888-651-3038.

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091265JCOprintAd_fullpg Final.indd 1 11/23/09 2:46:25 PM


News

Community oncologists are de-vising ways to stay afloat as they

brace for the “perfect economic storm” making landfall on their practices. At a 2010 ASCO Annual Meeting ses-sion called “The Challenge of Finan-cial Survival,” speakers described their view of these uncharted waters.

‘Financial Survival’ a Challenge to OncologistsBy Caroline Helwick

Health Economics

physicians or hospital employees, 5% were physician-owned but had a hos-pital or corporate affiliation, 2% were affiliated with US Oncology, 1% were academic-affiliated and 2% reported “other” practice settings.

Perhaps more telling were their pre-dictions: only 15% envisioned their practices/business structure remaining “unchanged and viable” for at least 5 years, while 19% said they are “changing now” and 53% predicted they will be stable only for “the foreseeable future.”

Eye of the Storm Oncologists considering a new busi-

ness model are mainly concerned about declining physician compensation, the survey suggested. This was cited as a reason for change by 54% of the survey respondents, while others cited loss of referrals due to competition (19%) and the need to reduce practice overhead (15%). Interestingly, only 4% said re-duced reimbursements were a reason for change and just 3% listed lower drug cost margins.

But oncologists have seen drug mar-gin as a percentage of total revenue in-creasingly fall, from 45% in 2002 to just 9% today, according to Ms. Towle, who said this contributes to the “dramatic de-cline” in the funds available to run one’s practice. Revenue related to drugs is more important than ever, she maintained (see Fig. 1), adding, “If drug management is not a core competency in your practice, you are losing revenue. The ‘new normal’ is low-margin, high-volume.”

More Problems and PressuresThe “perfect storm” is also fueled

by greater regulatory exposure, infor-mation overload, scarcity of resources, increased practice size, and an emerg-ing patient profile in which more and more Medicare patients lack secondary

insurance. As a result, oncologists are increasing their referral of patients for chemotherapy visits outside of their of-fices. In the survey, 33% of oncologists referred up to 400 visits in 2009, and 9% referred more than 1,000.

More drain on resources comes from the handling of insurance and payer is-sues, with the average practice employ-ing 1.2 billing staff for every physician and 0.4 patient financial advocates.

Time to Start Adapting “Pay-for-service is going away;

new systems will pay for quality and

Radiation7%

Infusion8%

Imaging3%

Lab2%

Evaluation and management

8%Nonmedical

3%

Drugs69% Drug Management must be a

core competency in your practice

Fig. 1: Revenue mix in a typical oncology practice. Revenue related to drugs is more important than ever. Adapted with permission from Elaine L. Towle, CMPE.

Elaine L. Towle, CMPE

Indeed, many practices are feeling the pinch of a difficult economy and are being forced to evolve, said Elaine L. Towle, CMPE, Director of Oncol-ogy Services at Oncology Metrics, a division of Altos Solutions, Los Altos, California. This is clear from the Na-tional Practice Benchmark, an annual survey of some 200 U.S. practices that her company conducts.

“Total collected revenue in these practices increased 6% from 2007 to 2008, and at first glance this is good news. However, total practice expense increased 16% over the same period, resulting in fewer dollars available to support practice operations,” she said. “When practice expenses rise more rapidly than revenue, the result is lower physician incomes.”

The most recent survey (2009) re-vealed a shifting practice landscape. Some 73% of respondents were still in-dependent physician-owned practices but many were consolidating: 11% were practicing oncology within a multispe-cialty group, 6% were hospital-owned

Hospitals as Partners: Oasis or Refuge?

More and more oncologists are leaving practice to join hospital-based can-cer centers and clinics, “seeking refuge from the seemingly endless buf-

fetings of 7 years of health-care ‘reform,’” said Jeffrey C. Ward, MD, an oncolo-gist/hematologist with Puget Sound Cancer Centers, Edmonds, Washington, who participated in the ASCO session, “The Challenge of Financial Survival.”

“Oncologists who have made this transition report no disruption to patient care, only minor limitations to physician autonomy, decreased stress, and a rela-tively high level of satisfaction with their current practice circumstances,” noted Dr. Ward, drawing from surveys by the Washington State Medical Oncology Society and his personal observations.

What Are the Hospital-based Options?The professional services agreement is the simplest. Under this model there

are fully integrated clinical services, but the physicians and/or practice remain an independent contractor. Several structures are possible: (1) the hospital contracts with the practice for global payment, and the practice provides management; (2) the hospital employs physicians, but the practice remains physician-owned and contracts with the hospital; (3) the hospital owns the practice and contracts with physicians for professional services; or (4) the hospital employs or contracts with physicians, and the practice is spun off into a joint venture.

Professional service agreements make sense for a number of reasons, Dr. Ward maintained. Practice and hospital incentives are aligned, physicians retain a mea-sure of independence and control, some measure of exclusivity is allowed, and the structure is relatively simple. But, he added, hospitals may pay only the “fair mar-ket value of the practice,” Stark laws and anti-kickback statutes may come into play, and independent contractors must provide their own benefits and malpractice coverage. Under this model, 340B drug pricing may or may not be allowed, which can be an advantage or disadvantage depending on one’s perspective, he added.

The advantages of full employment, on the other hand, are independence from drug revenue and the “stigma” of drug revenue, financial stability, shared malpractice risk, freer lifestyle, infrastructure support, full benefits, and other things lacking under a professional services agreement system.

“But you lose independence and flexibility, it requires a common vision, there is no guarantee of long-term financial success, it is difficult to reverse, and it takes lots of time and effort to make it happen,” Dr. Ward pointed out.

Regardless of one’s preference, he concluded, partnering with a hospital in some fashion or another “may prove to be the only reality available to people in practice” and offers hidden opportunities.

“Hospitals need physician partners, not just employees,” he explained, “and whether they know it or not, hospitals desperately need physician leadership. If oncologists who have run a practice leave that skill set behind when they join a hospital, both the oncologist and the hospital will miss opportunities.” ■

outcomes,” Ms. Towle emphasized. Many practices have started adapting, and good first steps are to become in-volved in a demonstration project, initiate clinical process measurements, and perhaps partner with others to increase efficiency. Partnering is espe-cially beneficial in areas that require capital or specialized, highly paid staff for procedures such as radiotherapy, imaging, and infusion therapy.

The main point, she concluded, is, “The good ol’ days are gone. New prac-tice models are developing. Investigate and embrace them.” ■

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

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TAP on Technology

Multiparameter Gene Profile Assays for Predicting Recurrence of Colon CancerBy Matthew Stenger

761 candidate genes in samples from 1,851 patients in four colon cancer treatment studies. The seven genes used in the assay were selected from among 76 showing statistical associa-tions with recurrence in these studies.

Whole Genome oligonucleotide micro-arrays. Multivariate analysis identified a 38-gene signature associated with risk of development of distant metastases.

The signature was validated in an independent group of 178 stage II or

This year saw the introduction of the first commercially available

multiparameter gene profile assay for predicting risk of recurrence of colon cancer after surgery. The Oncotype DX colon cancer assay (Genomic Health) for predicting risk of recur-rence in patients with stage II disease was launched in January 2010, and the ColoPrint assay (Agendia) is likely to be available soon. Methods for better quantifying risk of recurrence after surgery in patients with stage II disease are needed, because patients at higher risk of recurrence may experience a relatively greater benefit from adju-vant chemotherapy. Such treatment is associated with only a small absolute survival benefit in this setting, while posing a risk of toxicity in all who re-ceive it.

Oncotype DXLike the Oncotype DX breast can-

cer assay, the Oncotype DX colon can-cer assay uses real-time reverse tran-scription polymerase chain reaction (RT-PCR) technology to measure lev-els of select cancer-related genes com-pared with reference genes. RNA is ex-tracted from manually microdissected formalin-fixed, paraffin-embedded tumor tissue, and DNase I treatment is used to eliminate DNA contamina-tion (Fig. 1). RT-PCR is performed to quantify expression of seven cancer-related genes, and expression is nor-malized to expression of a set of five reference genes, providing the basis for calculating a recurrence score (0–100). The seven cancer-related genes (Ki-67, C-MYC, MYBL2, FAP, BGN, INHBA, GADD45B) include cell-cy-cle and stromal genes that were con-sistently associated with a recurrence-free interval in development studies.

The availability of high-throughput RT-PCR made it possible to evaluate

therapy is in combination with estab-lished clinicopathologic factors. ■Additional Resources on Oncotype DX

Kerr D, Gray R, Quirke P, et al: A quan-titative multigene RT-PCR assay for predic-

In a validation study involving 1,436 pa-tients with stage II disease, the continu-ous recurrence score was significantly and nearly linearly associated with recurrence risk (P = .004). The 3-year recurrence risk ranged from 9% to 11% at low recurrence score (< 30, 44% of patients) to 25% to 27% at high recur-rence score (≥ 41, 26% of patients). On multivariate analysis, recurrence score, T stage, and mismatch repair (MMR) status were the most important inde-pendent predictors of recurrence.

ColoPrintLike the Agendia MammaPrint

breast cancer assay, the ColoPrint assay uses DNA microarray technology to determine levels of expression of can-cer-related genes in fresh frozen tumor samples. In development studies, gene expression in frozen tumor tissue from 188 colon cancer patients with stage I to III disease was measured on Agilent 44K

III samples and in in-silico data sets (n = 322). In the validation study, pa-tients identified by the ColoPrint sig-nature as high-risk (39% of patients) had a significantly greater risk of dis-tant metastases (HR = 3.2, P = 8.5e-4) compared with low-risk patients (61% of patients). The 5-year distant me-tastasis-free survival rate was 89% for low-risk patients and 62% for high-risk patients. Prediction of recurrence with the ColoPrint signature was significant in both stage II disease (P = .0058) and stage III disease (P = .036). Multivari-ate analysis showed the signature to be the most prognostic factor. To make the test suitable for clinical use, the profile was translated into a diagnos-tic test using an Agilent 8-pack format that supports high throughput.

These assays help to refine risk of recurrence in early-stage colon cancer. For the present, their optimal use in selecting patients for adjuvant chemo-

Fig. 1: Technology underlying gene profile assays to predict colon cancer recurrence. RNA is extracted from tumor tissue, and DNA microassays are used to determine levels of expression of cancer-related genes.

For more information on gene profiling in colorectal cancer, use your smartphone to follow the links in the above barcode.

See page 43

tion of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospec-tively designed QUASAR validation study 2009 ASCO Annual Meeting. Abstract 4000. Abstract presented May 31, 2009.

Glas AM, Roepman P, Salazar R, et al: Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients. 2009 ASCO Annual Meeting. Abstract 4036. Abstract presented May 30, 2009.

Additional Resources on ColoPrintSalazar R, Marshall J, Stork-Sloots L, et

al: The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint. 2010 ASCO Annual Meeting. Abstract TPS199. Poster presented June 7, 2010.

Rosenberg R, Maak M, Nitsche U, et al: Independent validation of a prognostic ge-nomic profile (ColoPrint) for stage II colon cancer (CC) patients. 2010 ASCO Annual Meeting. Abstract 3513. Poster presented June 8, 2010.

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Appointments

Dr. Theodorescu trained as a urologic oncologist at Memorial-Sloan Kettering Cancer Center in New York. He received his PhD degree in molecular and cell biol-ogy from the University of Toronto under the mentorship of internationally known cancer biologist Dr. Robert Kerbel. ■

Fred Hutchinson Cancer Research Center Announces New President and Director, Lawrence Corey

The Fred Hutchinson Cancer Research Center board of trustees has an-

UCCC Names New Directorcontinued from page 17

nounced the selection of Lawrence Corey, MD, an internationally re-nowned expert in virology, immunol-ogy, and vaccine development, as its new President and Director. Dr. Corey is expected to begin responsibilities as the Center’s new leader on January 1, 2011.

Dr. Corey is known internationally for his research in infectious disease-related cancers, HIV infection, and medical complications of patients with compromised immune systems.

“It will be a great privilege to work with our faculty, staff, and board members to extend and expand the Center’s excellence,” said Dr. Corey, whose academic medical career spans more than 3 decades. He is perhaps best known for his expertise in lead-ing complex scientific coalitions and partnerships in the United States and abroad, including an international clinical trials network dedicated to HIV-vaccine development.

Dr. Corey’s research focuses on novel therapies and vaccines for hu-man viral infections, in particular herpesviruses, HIV, and infections re-lated to cancer. He is also particularly interested in expanding the Center’s research in understanding the role can-cer plays in global health.

Dr. Corey also is principal inves-tigator of the Hutchinson Center–based HIV Vaccine Trials Network, an international collaboration of sci-entists and institutions that combines clinical trials and laboratory-based research to accelerate the develop-ment of HIV vaccines. In addition to his research, Dr. Corey is an infectious disease physician at the Seattle Cancer Care Alliance.

Dr. Corey earned his bachelor’s and medical degrees from the Uni-versity of Michigan. He received his infectious diseases training at the Uni-versity of Washington School of Medi-cine, where he joined the faculty in 1978. He moved his laboratory to the Hutchinson Center in 1997. ■

Dan Theodorescu, MD, PhD Lawrence Corey, MD

TAP CaucusIs accelerated partial-breast irradiation acceptable care

in patients receiving breast-conserving treatment?

See page 41 in this issue and share your thoughts by writing

to [email protected].

* The Eigenfactor Project is a non-commercial academic research project sponsored by the Bergstrom

lab in the Department of Biology at the University of Washington. The Eigenfactor method considers

the past five years’ Thomson Reuters journal-to-journal citation network, excluding self-citations, so

that highly cited journals affect the score more than lesser cited journals.

To Submit a manuscript, contact JCO Editorial

PHONE: (703) 797-1900 | E-MAIL: [email protected] | ONLINE: www.submit.jco.org

17.793 Higher Impact, Higher Value

Journal of Clinical Oncology (JCO) has strengthened its position as publisher of

the most important clinical oncology research, with higher scores recorded in all

key measures of a journal’s impact on the scientific community.

As reported by Thomson Reuters in its just-released 2009 Journal Citation

Reports®:

• JCO’s impact factor has increased, for the fifth year in a row, to 17.793, ranking

it 4th among 165 oncology journals surveyed

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News

The FDA’s Oncologic Drugs Advi-sory Committee (ODAC) con-

cluded that bevacizumab (Avastin) conveys little benefit in advanced breast cancer, but the occasional patient has prolonged remission with little toxicity. This is the patient subset that may stand to lose the most, should the FDA with-draw the label for bevacizumab.

Lori Baur, a patient with triple-neg-ative breast cancer from Sleepy Hollow, New York, belongs to this group. She told The ASCO Post, “I’m just 41 years old and I have an aggressive cancer, including brain lesions that have disappeared but will probably rebound if I go off [bevaci-zumab]. I am pleading with the FDA not to take this drug away from patients like me who are responding to it.”

But interviews with several private insurers offer some reassurance to pa-tients like Ms. Baur, and the oncolo-gists who treat them. Lee Newcomer, MD, Senior Vice President, Oncology, at UnitedHealthcare, told this newspa-per that he agrees with ODAC’s recom-mendation, but his company will not stop covering bevacizumab for current responders.

“We think ODAC’s opinion was important. We never felt bevacizumab should have been approved originally because the data show no increase in overall survival (OS), and now there is the emergence of toxicity. The drug is an important step scientifically, but it is not ready for the clinic in breast can-cer,” he said in an interview.

Coverage DecisionsDr. Newcomer’s personal opinion

aside, UnitedHealthcare bases cover-

age decisions on the recommendations of the National Comprehensive Can-cer Network (NCCN), he pointed out. “This takes the decision-making to the academic experts who we feel are best qualified to make the call, and secondly, the process is transparent,” he said. “So for us, the NCCN would also need to withdraw its recommendation, which I am sure it will consider if the FDA sides with the panel. If the NCCN still believes we should cover bevacizumab, we will.”

erage. Meanwhile, any patient insured by UnitedHealthcare who has been started on bevacizumab, regardless of future policy changes, will be allowed to continue until disease progression, he emphasized.

Aetna’s position is similar. “If breast cancer is removed by the FDA as an in-dication for bevacizumab, Aetna would consider removing coverage, but we would also consider the position of the NCCN on this issue, as we have cov-

termination. We would continue to cover bevacizumab for breast cancer where mandated by applicable legal requirements of a state, or CMS re-quirements for Medicare and Medicaid members,” he told The ASCO Post.

NCCN Guideline ProcessThe importance of the NCCN Breast

Cancer Panel, therefore, becomes clear. Panel member Harold Burstein, MD, PhD, of Dana-Farber Cancer Institute, Boston, said that should the FDA with-draw the indication, as part of its regular review the NCCN panel would recon-sider the appropriateness of keeping bevacizumab plus paclitaxel as an ac-ceptable regimen.

“The NCCN has a sophisticated guideline process, and there will be op-portunities to review any FDA decision. We meet annually to review recent data and hear new opinions. And we often meet ad hoc when the FDA approves a new drug, though I can’t say we have ever met because the FDA withdrew a drug,” Dr. Burstein said. He noted that FDA ap-proval does not dictate the NCCN’s rec-ommendations. “There are breast cancer drugs on our list of recommended treat-ments for advanced breast cancer that are not FDA-approved for this indica-tion. For example, we list as single agents doxorubicin, epirubicin, pegylated li-posomal doxorubicin (Doxil), vinorel-bine, and cisplatin, which are not FDA-approved, and gemcitabine, which is approved only in combination. We also list paclitaxel/carboplatin/trastu-zumab (Herceptin) and trastuzumab/capecitabine, which are not FDA-ap-proved regimens.” ■

Lee Newcomer, MD James Cross, MD Harold Burstein, MD, PhD

UnitedHealthcare is currently de-veloping a new review process for beva-cizumab using NCCN recommenda-tions. “We are no longer just matching the drug with the diagnosis. We are looking at three other specific things that NCCN recommends: which drug it is paired with, what line of therapy, and when to discontinue it [upon pro-gression],” he said.

In 2009, UnitedHealthcare pro-vided coverage for bevacizumab to 55% of patients not meeting all the NCCN recommendations. The com-pany will now enforce all three recom-mendations as a requirement for cov-

ered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater,” said James Cross, MD, Head of National Medical Policy and Operations.

Aetna will make provisions to al-low continued coverage, however, for persons already completing a course of therapy, he added. Otherwise, the drug would not be covered. “Participating physicians who wish to prescribe beva-cizumab for breast cancer would have to inform patients in writing that this would not be covered by their health plan, and they would be afforded the opportunity to appeal any adverse de-

For Bevacizumab, Third-party Payers Look to NCCNBy Caroline Helwick

Breast Cancer

Coming in the October 2010 issue of

■ News from the 2010 UICC World Cancer Congress, Shenzhen, China

■ News from Best of ASCO

■ TAP Caucus: Do Patients with Limited-stage Hodgkin Lymphoma Require Radiotherapy?

■ Plus, Direct from ASCO, Important Perspectives, Oncology Drug News, and more

Be sure to visit The ASCO Post online at ASCOPost.com.


In the News

used in one arm of the RIBBON-1 study, should also be an option for women with metastatic breast cancer.

Is Progression-free Survival a Meaningful Endpoint?

Dr. Robert attended the ODAC

meeting as an observer. “It was an in-teresting process,” he remarked, “be-cause there seemed to be a few things going on that are frankly unresolved. One is the debate about progression-free survival vs overall survival. A number of us in the breast cancer community who do research feel that progression-free survival is potentially a clinically meaningful endpoint.” Dr. Robert noted that progression-free survival was the primary endpoint for the three trials the FDA used in mak-ing its decision on bevacizumab for advanced breast cancer—the E2100 trial that prompted the accelerated ap-proval and the follow-up RIBBON-1 and AVADO trials.

In all three trials, the drug com-binations used were active and “suc-ceeded achieving the endpoint of each trial, which was progression-free sur-vival statistically, and that was never a debate,” Dr. Robert said. “No one argued that the progression-free sur-vival data were not robust. The issue

The Challenge of Overall SurvivalMost trials in metastatic breast cancer do not use over-

all survival as the primary endpoint, according to Dr. Robert. “It’s a very uncommon endpoint,” he said. “It is always

nice to see [an improvement in overall survival] achieved, but I don’t think it should be the sole metric or a necessary metric if you see a significant progres-sion-free survival with accept-able toxicity.”

Using overall survival as an endpoint “is a very big chal-lenge for a number of reasons,” he noted. While a crossover

design “is a bit of a carrot to encourage people to partici-pate in a clinical trial,” it also means “you are reducing the chance of showing an impact on overall survival, because there may be some benefit in second-line treatment.” That was actually demonstrated in RIBBON-2, where every-body gets first-line chemotherapy, and then is randomly assigned to chemotherapy or chemotherapy plus bevaci-zumab. Thus, some patients are getting bevacizumab in the second-line setting, where there was a progression-free survival of about 2 months.

Another reason overall survival is challenging as an endpoint is because breast cancer is quite heterogeneous, Dr. Robert said. Although median survival is 2 to 3 years, many patients are living even longer. ■Nicholas Robert, MD

Expect QuestionsThe widespread reporting of the recommendation to withdraw FDA ap-

proval of bevacizumab for the treatment of metastatic breast cancer is sure to raise questions among concerned patients. Some of the answers will depend on the FDA’s decision, but here’s what we know now.What did ODAC recommend?

The Oncologic Drugs Advisory Committee of the FDA recommended that bevacizumab no longer be approved for women with metastatic breast cancer. The committee voted unanimously that two new studies that were required for bevacizumab to complete the approval process (following an accelerated approval in 2008) do not “provide confirmatory evidence of clinical benefit of bevacizumab in combination with paclitaxel for the initial treatment of [metastatic breast cancers].” The committee voted 12 to 1 that “the indication for treatment of metastatic breast cancer be removed from the Avastin label.”When will the FDA make its decision?

The FDA is expected to decide later in the year whether or not to accept ODAC’s recommendation.If FDA decides to go along with ODAC, will bevacizumab still be available to patients with advanced breast cancer?

Yes. Physicians would still be able to use bevacizumab off label to treat patients with metastatic breast cancer. The use of bevacizumab off-label rather than for an FDA-approved indication, however, might affect costs and insurance coverage for bevacizumab, which could in turn limit its acces-sibility for patients (see page 35 for more on insurance implications).Does the FDA’s decision affect other indications for the use of bevacizumab?

No. The FDA’s decision on the use of bevacizumab for metastatic breast cancer will not affect the drug’s FDA-approved indications for metastatic colorectal cancer, metastatic nonsquamous non–small cell lung cancer, and metastatic renal cell carcinoma. ■

Answering Questions Your Patients May Ask about the Role of Bevacizumab in Metastatic Breast CancerBy Charlotte Bath

In the News focuses on media re-ports that your patients may have questions about at their next visit. This continuing column will pro-vide summaries of articles in the popular press that may prompt such questions, as well as com-ments from colleagues in the field.

Breast Cancer

tinue to stay on the drug? That, of course, may depend on what FDA says, but it is hard if you have someone that has meta-static breast cancer and is doing well on a bevacizumab regimen to stop that regi-men.” Dr. Robert is Associate Chair of the Breast Committee of US Oncology, a physician practice management group with about 1,200 oncologists, Chair of the Cancer Committee at INOVA Fairfax Hospital in Virginia, and an ASCO Uni-versity faculty member. He also served as principal investigator of RIBBON-1, one of the two new studies ODAC analyzed before making its recommendations.

“For patients who are tolerating treat-ment and responding, it would probably be prudent for the FDA to permit them to stay on treatment until they experience disease progression or develop a com-plication,” Dr. Robert said. “It would be pretty tough from a patient perspective to stop a regimen if you are doing well on it.” In the US Oncology practice, that would primarily involve patients using first-line paclitaxel and bevacizumab, the combi-nation used in the E2100 study that led to FDA’s accelerated approval in 2008 of bevacizumab for advanced breast cancer.

“I was the principal investigator for the RIBBON-1 study and serve as a consultant and lecturer for Roche, so I am familiar with both research and clinical considerations. From a clinical perspective, I do think weekly paclitaxel with bevacizumab should still be avail-able, and I think that opinion is shared by a lot of people in the breast cancer community,” Dr. Robert said. He added that the combination of capecitabine (Xeloda) and bevacizumab, which was

When the FDA issued an acceler-ated approval for the use of beva-

cizumab (Avastin) for metastatic breast cancer, the approval was contingent on additional clinical trials demonstrating efficacy for that indication. Now, nearly 2½ years later, the results of those trials have prompted FDA’s Oncologic Drugs Advisory Committee (ODAC) to rec-ommend that the FDA withdraw its approval of bevacizumab for metastatic breast cancer. The recommendation

was widely reported by national news organizations, in-cluding the business press, which specu-lated on the poten-

tial economic impact if bevacizumab loses its FDA-approved indication for metastatic breast cancer, and the medical media, which looked at what it might mean to patients and physicians if the FDA decides to accept ODAC’s recommendations.

Patients Want Answers“I’m getting questions from patients

who are on bevacizumab about what this will mean for them,” said Nicholas Robert, MD. “Will they be able to con-

See page 43


In the News

was the trade-off with side effects, and the problem I had was that all of the trials were put into one category.” He argued that “another approach” would have been to look at the data for the dif-ferent drug regimens and approve the combination regimens that produced clinically meaningful results, which he considers to be paclitaxel with bevaci-zumab, as used in the E2100 trial, and capecitabine plus bevacizumab, as used in one arm of the RIBBON-1 trial.

What about Toxicity?“The other big issue” discussed by

ODAC, Dr. Robert noted, “was the concern about toxicity, which is real.” Hypertension is not uncommon as a side effect of bevacizumab, he said, “but we are all internists—oncolo-gists in this country are specialists in internal medicine first. We can man-age hypertension. We can manage neutropenia and febrile neutropenia. Those are complications of treatment, and it’s our job to manage the com-plications. I’ve not had a patient for whom I’ve had to hold bevacizumab for hypertension, because we monitor patients for that and we treat it,” he said. “All of the drugs we use for che-motherapy have risks for toxicity, and it is really an art in terms of how to use them carefully so you don’t produce harm. It is the art of managing pa-tients with metastatic breast cancer, the art of oncology.”

Dr. Robert argued that the toxic-ity “is acceptable given the gains” of an additional 5.5 months of pro-gression-free survival in the E2100 study, and an additional 2.9 months of progression-free survival in the capecitabine arm of the RIBBON-1 study. “For me that would have passed muster as a risk-benefit ratio that was acceptable, worthy of use, and worthy of being available in clin-ical practice,” he said.

What Is the Chronic Disease Model?

“The more drugs we have available, the more treatments we have available for the patient, the better chance we have of keeping the patient’s disease under control for a longer period of time,” Dr. Robert said. “The rationale is that we think of metastatic breast can-cer as a chronic disease, and we give se-quential treatment, moving from one drug to another drug.” According to this rationale, “if a drug produces a few more months of controlled cancer,” it could be useful as part of the sequen-

tial strategy. Registry data show that “women are living longer with stage IV breast cancer today than 20 years ago, and that is partly due to having multi-ple treatments available so you can use that strategy,” he added.

All of the women in the cited stud-ies were HER2-negative and therefore not candidates for hormonal therapy.

For more perspectives on the role of

bevacizumab in advanced breast cancer,

see pages 2, 10, and 11.

“So you only have chemotherapy,” Dr. Robert pointed out. Paclitaxel and capecitabine without bevacizumab also “are very reasonable regimens,” he said. “If bevacizumab is not available, we will continue to use the arsenal of agents we have available and continue to use single agents. We have other drugs.” ■

(Stimulating Targeted Antigenic Responses To NSCLC)

EMD Serono, Inc. is anaffiliate of Merck KGaA,Darmstadt, Germany


In the Literature

Emerging Clinical Data on Cancer Diagnosis and Management

BREAST CANCER

Triple-negative Breast Cancer More Common in African and African-American Women

Women of African ancestry are more likely to have breast cancers that are negative for estrogen recep-tor (ER), progesterone receptor (PR), and HER2/neu, according to a study published online in the journal Can-cer. The primary study population in-cluded 581 African-American women and 1,008 white women diagnosed with breast cancer at the Henry Ford Health System in Detroit, and a com-parison group of 75 African women diagnosed at the Komfo Anokye Teaching Hospital in Ghana. Of these patients, 82% of the African women were triple-negative, compared to 26% of the African-Americans, and 16% of the white Americans. Researchers also found that the Ghanaian women were diagnosed at a younger age than American women, and with larger tu-mors and more advanced cancer. In addition, the Ghanaian women were more likely to test negative for each of the three markers.

Increasing Outcome Disparities“The most significant recent ad-

vances in breast cancer treatment have involved targeting these three recep-tors. But these treatments do not help women with triple-negative breast can-cer. Outcome disparities are therefore likely to increase, because fewer Afri-can-American women are candidates for these newer treatments,” remarked Lisa A. Newman, MD, MPH, one of the study authors. Dr. Newman is Director of the Breast Care Center at the Univer-sity of Michigan Comprehensive Can-cer Center, and Professor of Surgery at the University’s medical school.

“Our study documented provoca-tive patterns of increasing frequency for early onset/younger age at diag-nosis, ER-negative/PR-negative, and triple-negative breast cancers in asso-ciation with presumed increasing ex-tent of African ancestry. These patterns suggest that further study of the breast cancer burden in African women could lead to the identification of tumor or germline markers associated with high-risk breast cancer,” the investiga-tors wrote. “Hopefully, these markers will ultimately have potential utility for targeted therapy of the triple-negative

phenotype, for which we are currently limited to chemotherapy as systemic treatment.”

Stark A, et al: Cancer July 13, 2010 (epub ahead of print)

Genetic Risk Scores for Breast Cancer Are Highly Predictive of ER-positive Disease

An analysis of breast cancer risk, overall and by tumor subtype, in rela-tion to 14 individual single-nucleotide polymorphisms (SNPs) and to a poly-genic risk score found that the poly-genic risk score was highly predictive of estrogen receptor–positive disease. Investigators from the United Kingdom and France estimated the per-allele odds ratio for individual SNPs and the cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. The study included 10,306 women with breast cancer (average age at diagnosis, 58 years) and 10,393 women without breast cancer, who in 2005–2008 pro-vided blood samples for genotyping.

The odds ratios for breast cancer were greatest for the SNPs FGFR2-rs2981582 and TNRC9-rs3803662 and, for these two SNPs, were sig-nificantly greater for ER-positive than for ER-negative disease—both in the data from this study and in meta-analyses of other published data. The next strongest association was for 2q-rs13387042, for which the per-allele odds ratio was significantly greater for bilateral than unilateral disease and for lobular than ductal tumors.

Subdivision by Risk“When the effects of the seven

SNPs most strongly associated with overall breast cancer risk in these data were combined using a polygenic risk score, the cumulative risk of breast cancer to age 70 years among women in the top fifth was twice that in the bottom fifth (8.8% vs 4.4%). Both the relative and, particularly, the abso-lute difference was much greater for ER-positive disease (7.4% vs 3.4%) than for ER-negative disease (1.4% vs 1.0%),” the authors wrote.

“Certain established risk factors for breast cancer have similar, or even greater, effects on breast cancer inci-dence than the differences seen here between women in the highest vs the lowest fifth of polygenic risk score. Indeed, our estimate of the cumula-

tive incidence of breast cancer to age 70 years in women in the top fifth for polygenic risk score (8.8%) is similar to that for women in developed coun-tries with one first-degree relative with breast cancer (9.1%), and considerably less than that for women with two af-fected first-degree relatives (15.4%),” the researchers concluded. “Further-more, no interactions have been found between the effects of the genes inves-tigated here and the other risk factors for breast cancer. Hence, as others have suggested, subdividing women on the basis of their polygenic risk is, at this stage, not a useful tool for pop-ulation-based breast cancer screening programs but may be useful for under-standing disease mechanisms.”

Reeves GK, et al: JAMA 304:426-434, 2010.

PROSTATE CANCER

Sipuleucel-T Prolongs Survival in Men with Castrate-resistant Metastatic Prostate Cancer

Men with metastatic castration-resistant prostate cancer who received sipuleucel-T (Provenge) had a 22% rela-tive reduction the risk of death (P = .03), representing a 4.1-month improvement in median survival, compared with the placebo group in a multicenter phase III trial reported in The New England Jour-nal of Medicine. The authors concluded that among men with asymptomatic or minimally symptomatic metastatic cas-tration-resistant prostate cancer, sipu-leucel-T prolonged overall survival, the primary endpoint of the trial. No effect from sipuleucel-T was observed for the secondary endpoint of time to objective disease progression.

Sipuleucel-T is an active cellular im-munotherapy that has shown survival benefit in previous trials. For this dou-ble-blind study, known as the Immuno-therapy for Prostate Adenocarcinoma Treatment (IMPACT) study, 512 pa-tients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) ad-ministered intravenously every 2 weeks, for a total of three infusions. All patients had previously received androgen-de-privation therapy. Median survival was 25.8 months in the sipuleucel-T group vs 21.7 months in the placebo group. The 36-month survival probability was 31.7% in the sipuleucel-T group vs 23.0% in the placebo group.

Consistent Results Across Subgroups

“In our study, the effect of sipuleu-cel-T on survival was observed consis-tently across subgroups of patients, in-cluding those with prognostic factors known to be adversely correlated with overall survival, such as increased lev-els of PSA, lactate dehydrogenase, and alkaline phosphatase, as well as an in-creased number of bone metastases, an increased Gleason score, a decreased performance status, and the presence of pain,” the authors wrote. The treat-ment effect of sipuleucel-T was also observed after adjusting for use of docetaxel, which most patients in both groups received following use of the study therapy. The authors stated that sipuleucel-T was well tolerated.

In an editorial in the same issue of The New England Journal of Medicine, Dan L. Longo, MD, noted that the results of the clinical trial reported by Kantoff el al, “helped convince the FDA to approve sipuleucel-T for clini-cal use.” He added that other immuni-zation strategies being tested for pa-tients with prostate cancer include the vaccines GVAX and PROSTVAC-VF and the experimental drug MDV3100. “The prospects for improved therapy for prostate cancer have never been so encouraging,” he commented.

Kantoff PW, et al: N Engl J Med 363:411-422, 2010.

Longo DL: N Engl J Med 363:479-483, 2010.

LYMPHOMA

Relapsed/Refractory NHL Study Shows High Rates of Responses with Anti-CD22 Fractionated Radiotherapy

An objective response (OR) rate of 62% was achieved among patients with relapsed/refractory non-Hodk-gin lymphoma (NHL) who received two or three weekly infusions of yttri-um-90 (90Y)-epratuzumab tetraxetan (humanized anti-CD22 antibody) in a phase I/II trial. Median progression-free survival (PFS) was 9.5 months.

The multicenter trial involved pa-tients at several European centers as well as the Garden State Cancer Center in Belleville, New Jersey, and included 17 patients who had prior autologous stem cell transplantation (ASCT). Within the overall OR rate of 62% for 61 evaluable patients, 48% of patients


In the Literature

achieved a complete response (CR) or complete response unconfirmed (CRu). Patients without prior ASCT had higher OR rates—71%, with a CR/Cru rate of 55% —across all NHL subtypes and 90Y doses. This was true even in poor-risk categories. For ex-ample, patients with disease refractory to their last anti-CD20–containing regimen had a 73% OR rate and a 60% CR/CRu rate, and those with bulky disease had a 71% OR rate and a 43% CR/Cru rate.

Patients who had previously had ASCT received lower doses of radio-immunotherapy and achieved an OR rate of 41% (CR/CRu, 29%). For pa-tients with follicular lymphoma (FL),

OR rates and median PFS increased with total 90Y dose, reaching 100% OR (CR/CRu, 92%) and 24.6 months PFS at the highest dose levels (> 30 mCi/m2 total 90Y dose [1,110 MBq/m2]). Patients with FL refractory to prior anti-CD20–containing regimens achieved 90% OR and CR/CRu rates

and a median PFS of 21.5 months. Most treatment-related adverse ef-

fects were mild to moderate (grade 1 or 2). The exceptions were two cases of severe neutropenia, one with febrile neutropenia.

The high rates of durable CR/CRus achieved with high total doses of 90Y fractionated anti-CD22 radioimmu-notherapy in patients with relapsed/refractory NHL resulted in recom-mendations that 20 mCi/m2 × 2 weeks be used as the dose in future studies.

The authors also noted that 90Y-epratu-zumab tetraxetan could also be used as part of a combination approach for relapsed/refractory NHL.

Morschhauser F, et al: J Clin Oncol 28:3709-3716, 2010.

SURVIVORSHIP

Two Studies Mine Long-term Data on Health Risks among Childhood Cancer Survivors

Two studies—one reported in the Journal of the American Medical Asso-ciation (JAMA) and the other in the Journal of the National Cancer Institute (JNCI)—confirm that survivors of childhood cancer are at increased risk of subsequent cancers and provide more details on the long-range impact of childhood cancer and its treatment. The JAMA study found that childhood cancer survivors had excess mortality from second primary cancer and circu-latory disease beyond 25 years from di-

agnosis. The JNCI study concluded that survivors of Hodgkin lymphoma are at greatest risk of developing another neo-plasm. Other factors associated with increased risk in the JNCI study were being female, older age at time of di-agnosis, receiving therapy in an earlier treatment era, and receiving radiation therapy.

Expanded AnalysisThe JNCI study represents an ex-

panded analysis of the Childhood Cancer Survivor Study. For the analy-sis, the incidence of and risk for subse-quent neoplasms occurring 5 years or more after the childhood cancer diag-nosis were determined among 14,359 people treated from 1970 through 1986. Their median age was 30 years, with a range of 5 to 56. Among these survivors, 1,402 subsequently devel-oped 2,703 neoplasms. The calculated cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% for all subsequent neoplasms, 7.9% for second malignant neoplasms (excluding nonmelanoma skin can-cer), 9.1% for nonmelanoma skin can-cer, and 3.1% for meningioma.

“Excess risk was evident for all pri-mary diagnoses,” the authors reported, “with the highest being for Hodgkin lymphoma and Ewing sarcoma.”

For the cohort of patients treated for cancer between 1970 and 1986, “it is clear that continued surveillance for subsequent neoplasms is essential, as their risk continues to increase as these survivors enter their third and subse-quent decades of life,” the authors con-cluded. “The continued surveillance is of particular importance because many adult survivors do not appreciate the health risks that are related to their childhood cancer and so do not have regular medical follow-up or practice recommended screening.”

Largest Study of Its KindThe JAMA study used data from

the British Childhood Cancer Survi-vor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. The authors noted that it “is the largest population-based cohort study to comprehensively examine the late effects of childhood cancer and its treatment.”

Overall, 3,049 deaths were ob-served, which was 11 times the num-ber expected based on cause-specific standardized mortality ratios. That

ratio declined with follow-up, but was still three times higher than expected 45 years from diagnosis. The absolute excess risk for deaths from recurrence declined from 97 extra deaths per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths be-yond 45 years from diagnosis. During the same periods of follow-up, the ab-solute excess risk for deaths from sec-ond primary cancers increased from 8 extra deaths to 58 extra deaths, and the absolute excess risk from circula-tory causes (which includes cardiac and cerebrovascular deaths) increased from 2 extra deaths to 29 extra deaths. Beyond 45 years from diagnosis, recur-rence accounted for 7% of the excess number of deaths observed, whereas second primary cancers and circulato-ry deaths together accounted for 77%.

“These findings confirm the impor-tance of very long-term outcome data and that survivors should be able to access health-care programs even de-cades after treatment,” the investiga-tors commented.

“The excess morality due to second primary cancers and circulatory dis-eases is likely attributable to late com-plications of treatment,” they added. They acknowledged, however, that a potential limitation of the study is the lack of detailed data on radiotherapy and chemotherapy exposures. In addi-tion, they noted, survivors in the study were treated between 1940 and 1991, and “findings may not be translatable to survivors treated in more recent years.”

Friedman DL, et al: J Natl Cancer Inst 102:1083-1096, 2010.

Reulen RC, et al: JAMA 304:172-179, 2010.

GUIDELINES

Guideline Summaries Offer Quick Synopses for Clinicians

Two Guideline Summaries published in the July issue of the Journal of Oncol-ogy Practice provide outlines of clinical recommendations recently issued by ASCO. Condensing key patient manage-ment recommendations to a few pages, JOP Guideline Summaries are intended to assist busy oncology practitioners in clinical decision-making.

A summary by Elizabeth Ham-mond, MD, and coauthors offers an overview and discussion of recom-mendations for immunohistochemical (IHC) testing of estrogen and proges-terone receptors in patients with breast cancer. Jointly developed by ASCO and the College of American Patholo-gists, these guidelines are aimed at im-proving the accuracy of IHC.

In the same spirit, Timothy Gil-ligan, MD, and colleagues present a summary of ASCO’s clinical practice guideline on the use of serum tu-mor markers in men with germ cell tumors. The authors address screen-ing, diagnosis, monitoring during treatment, and post-therapy surveil-lance of patients with seminoma and nonseminomatous germ cell tumors.

Hammond MEH, et al: J Oncol Pract 6:195-197, 2010.

Gilligan TD, et al: J Oncol Pract 6:199-202, 2010. ■

© Michael Maslin/The New Yorker Collection/www.cartoonbank.com

From the preface:

In addition to providing treat-

ment, oncologists need to re-

spond to the very personal and

human needs of patients and

their loved ones. How does an

oncologist honestly, yet com-

passionately, tell patients and

their families that things are not

going well; that there is no lon-

ger any useful anticancer thera-

py left to give; that it is time to

focus on symptom control rather

than anticancer therapy? How

do physicians, who are trained to

treat disease, instead talk about

death and loss? And, for those

fortunate enough to survive,

how do doctors discuss the

long-term consequences of

treatment? Additionally, how do

oncologists deal with their own

emotions and grief?

A strength of the collection is its potential to allow patients to better understand

issues faced by their oncologists.

-Dr. L. James Maher III, Mayo Clinic

These writings present voices of the physician experience that are sadly not heard often

enough–perspectives that are authentic, sensitive, and truly focused on thoughtful

delivery of patient care.

-Germaine Tupper, Senior Biotechnology Manager

At a time when the science of oncology is burgeoning with new information and practice-

changing advances, it is easy to overlook the importance of the art of oncology, the

focus on the meaning of the cancer and the experience to the patient as well as the

importance of the relationship between doctor and patient.

-Cynthia Chauhan, Patient Advocate

Art of Oncology is a collection of 30 brief articles that address

issues related to end-of-life care, symptom control, ethics,

and communication with patients. The essays

collected in this volume first appeared in the

monthly Art of Oncology section of Journal of

Clinical Oncology (JCO), the world’s leading

peer-reviewed journal for doctors who treat

patients with cancer.

Just Published on KindleArt of Oncology:Honest and Compassionate Responses to the Daily Struggles of People Living with Cancer-Edited by Charles L. Loprinzi, MD, Regis Professor of Breast Cancer Research, Mayo Clinic

Available for purchase at www.jco.org/kindle.


TAP Caucus

Is Accelerated Partial-breast Irradiation Acceptable Care in Patients Receiving Breast-conserving Treatment?By Simon Powell, MD, PhD, and Lawrence J. Solin, MD, FACR, FASTRO


The rationale for the use of APBI is that 85% to 90% of recurrences after wide local excision alone occur in the same quadrant of the breast as the initial cancer.

PRO One of the major recent changes in radiotherapy for early-stage breast

cancer is the selective use of accelerated partial-breast irradiation (APBI). The attraction of APBI is the accelerated delivery of treatment, which in most cases condenses the traditional 6-week course of treatment into just 1 week. A shorter treatment time is feasible because the target of therapy is limited to the affected quadrant rather than the entire breast.

The rationale for the use of APBI is that 85% to 90% of recurrences after wide local excision alone occur in the same quadrant of the breast as the initial cancer.1 In this classic study, the use of radiation therapy resulted in a significant reduction in breast cancer deaths, although

not in overall survival. This discrepancy potentially suggests that the use of ra-diation therapy carries with it some long-term survival risks, which have been reported for postmastectomy radiation.

Meta-analysis of the use of radiation therapy in conjunction with conservative surgery also shows a survival benefit.2 The conclusion is that radiation therapy can reduce breast cancer recurrence and improve breast cancer survival, but can the same be achieved with less radiation and potentially fewer long-term complications?

Which Breast Cancer Patients Are Appropriate for APBI?Not even the most ardent supporter of APBI feels that all patients receiv-

ing conservative breast surgery are suitable for APBI. The current U.S.-based randomized trial of APBI vs conventional whole-breast irradiation allows en-rollment of patients with tumors up to 3 cm in size and up to three positive axillary lymph nodes.3 However, many institutionally based studies use more stringent entry criteria, such as only T1N0 patients.4 Based on recruitment to the randomized trial, less than 5% of the patients have positive nodes, so there is a degree of selection being carried out by the accruing physicians.

I would argue that the presence of lymphatic invasion or positive lymph nodes puts the whole breast and adjacent chest wall (including the skin) potentially at risk. Given that many would consider administering postmastectomy radiother-apy in this setting, APBI would logically be less appropriate. The opponents of adopting APBI may focus on the difficulty in selecting the appropriate patient, but the factors influencing local control or multifocal disease within the breast are well defined. When present, these factors make the patient less suitable for APBI.

Another potential criticism of APBI is that case selection makes the need for radiotherapy debatable. However, in a study of wide local excision without radio-therapy for good-risk T1N0 breast cancer, the projected recurrence rate was over 20% at 5 years.5 The results of the initial studies of APBI have been reported with actuarial follow-up of 9.5 years,6 and the local control rate is over 95%, equivalent to matched pairs of patients treated with conventional whole-breast irradiation.

Accurate Planning and Delivery Becomes an Important Factor in Breast Radiotherapy

The use of APBI is associated with more detailed three-dimensional map-ping of the target volume than has been traditional in breast cancer radio-

Simon Powell, MD, PhD

CON For the patient with early-stage breast cancer, the gold standard for

radiation treatment after breast-conservation sur-gery remains whole-breast radiation (often with a boost), not accelerated partial-breast irradia-tion (APBI). Breast-conservation treatment with whole-breast radiation has been studied in many randomized clinical trials conducted worldwide, with data from tens of thousands of treated pa-tients.1 These clinical trials have demonstrated equivalent survival for breast-conservation treat-

ment with radiation compared to mastectomy with 20 years or more of follow-up. Adding whole-breast radiation after breast-conservation surgery (lumpec-tomy) improves the rate of local control in the treated breast, and leads to an improvement in breast cancer mortality and overall survival. In addition to primary endpoints of local control and survival, a great deal is known about secondary endpoints after breast-conservation treatment, such as detection and treatment of local recurrence, optimization of cosmetic outcome, minimi-zation of complications, and timing and integration of radiation with surgery and systemic therapy.

Limitations of Supporting ArgumentsAPBI is a change in the paradigm for delivering radiation treatment after

lumpectomy for patients with early-stage breast cancer. Arguments typically cited to support the use of ABPI are that nonrandomized phase I/II trials substitute for randomized phase III trials, and that other new technologies have been implement-

ed without randomized clinical trials. These arguments are of course scientifically invalid, and randomized clinical trials remain the gold standard for evidence-based medicine. Consensus statements and expert opinion cannot substitute for scien-tific evidence. A number of ongoing randomized clinical trials in Europe, Canada, and the United States are comparing standard whole-breast radiation treatment to APBI. In the United States, an open randomized clinical trial is being conducted jointly by the National Surgical Adjuvant Breast and Bowel Project and the Radia-tion Therapy Oncology Group (NSABP B-39/RTOG-0413).

Another argument commonly cited to support APBI is patient conve-nience, given the reduced overall treatment time. There are now accelerated whole-breast radiation treatment regimens that substantially shorten overall treatment time, but with supporting scientific evidence from randomized clinical trials that report up to 12-year outcomes.2-4 One commonly used ac-celerated whole-breast radiation treatment regimen uses 16 fractions, not much greater than the 10 fractions used in many APBI regimens.

Other Practical ConcernsPublished reports of APBI have shown large variations for patient selection,

radiation dose fractionation, and techniques for radiation delivery. Far too little is known about the long-term consequences of APBI, including detec-tion of local recurrence, salvage treatment for local recurrence, mammogram findings, and late complications. Late complications are a particular concern when, as in APBI, large radiation fractions are used.5 In two older randomized trials of APBI, the rate of local recurrence was higher for APBI in comparison to

Lawrence J. Solin, MD, FACR, FASTRO


Pro/Con

Rather than using theory to debate whether APBI is clinically valid, the focus should be on accruing patients to ongoing randomized clinical trials.


TAP Caucus

therapy. One of the reasons for the success of APBI may be better target delineation by planning and, although not required for the randomized trial, the use of image-guided radiotherapy (IGRT) for more precise delivery of

Partial-breast Irradiation Is an Acceptable Optioncontinued from page 41

treatment if external beams are used.7 The optimum dose, delivery schedule, and target volume for APBI are yet to be finalized, although 32 to 40 Gy giv-en over 4 to 5 days in not more than 4 Gy per fraction is the current practice in the United States. The target volume receiving the prescribed dose can vary widely by the applied technique.

As a physician who supports the use of APBI in selected patients with early-stage breast cancer, I would ad-vocate that further research is needed to define the optimum method for de-livering APBI. Patients should contin-ue to accrue to appropriate clinical tri-als so that we can continue to perfect this alternative method of radiother-

apy, which patients find so appealing in its brevity and lack of side effects. In 2010, there is sufficient evidence to support that APBI is acceptable care in conjunction with conservative surgery for selected patients with early-stage breast cancer.8

References1. Fisher B, Anderson S, Bryant J, et al:

Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpec-tomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002.

2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.

3. NSABP B-39, RTOG 0413: A ran-domized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. Clin Adv Hematol Oncol 4:719-721, 2006.

4. Lawenda BD, Taghian AG, Kachnic LA, et al: Dose-volume analysis of radio-therapy for T1N0 invasive breast cancer treated by local excision and partial breast irradiation by low-dose-rate interstitial im-plant. Int J Radiat Oncol Biol Phys 56:671-680, 2003.

5. Schnitt SJ, Hayman J, Gelman R, et al: A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer. Cancer 77:1094-1100, 1996.

6. Vicini FA, Kestin L, Chen P, et al: Limited-field radiation therapy in the man-agement of early-stage breast cancer. J Natl Cancer Inst 95:1205-1210, 2003.

7. Bert C, Metheany KG, Doppke KP, et al: Clinical experience with a 3D surface patient setup system for alignment of par-tial-breast irradiation patients. Int J Radiat Oncol Biol Phys 64:1265-1274, 2006.

8. Smith BD, Arthur DW, Buchholz TA, et al: Accelerated partial breast irradiation consensus statement from the American So-ciety for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 74:987-1001, 2009.

Dr. Powell is Chair of the Department of Ra-diation Oncology at Memorial Sloan-Ketter-ing Cancer Center, New York.

Tell Us What You Think

Write to [email protected] and share your viewpoint on APBI. Selected responses will be published in a future issue.

Order your copy at www.asco.org/store or call 1-703-519-1430

A Print Publication with:

• 22 chapters covering the most current understanding of oncology, including all of the major disease areas and general topics such as symptom management

• Expanded coverage of:• Clinical Trials and Statistics• Multiple Myeloma• Palliative and End-of-Life Care

• 165 practice questions to aid self-study — 79 are NEW

• Detailed answer rationales with references

An Online Question Bank on ASCO University™ with:

• The 165 practice questions from the Print Publication

• 90 bonus questions

• Detailed answer rationales with links to relevant references

• Expanded Coverage

• Even More Practice Questions

As always, all content has been written and peer-reviewed by the experts at ASCO.

The 2nd Edition of ASCO-SEP offers:

NEW ASCO-SEP,® 2nd Edition

10119_SEPIntleditionFP FNL.indd 1 3/4/10 2:02:50 PM


TAP Caucus

Important: Getting the applicationThere are 3 ways to download the ScanLife application.

1. Simply text the word “scan” to 43588.

Or

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

Or

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

The application is free, though standard data rates for your phone do apply.

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.

A short audio chime will indicate a successful scan and the phone will contact the server for further instructions. This may take up to a minute depending on data speeds and phone type.

two-dimensional (2D) barcode, also known as a matrix code, is a graphic image that contains information stored both horizontally (like the one-dimensional UPC used in supermarkets) and vertically. The added dimension in a 2D

barcode enables the image to represent thousands of char-acters—essentially a portable database—compared with only 10 to 20 characters stored in the conventional unidi-mensional barcode. Given that added capacity, 2D barcodes are increasingly being used for fast data access in a variety of settings, and in documents from drivers’ licenses to tax returns.

Perhaps not surprisingly, the real boom in 2D barcode use has been in mobile marketing. Companies have developed technology that enables camera phones to scan matrix codes from a website, print publication, or poster. The con-sumer can then access content embedded in the code or be redirected to targeted content via the phone’s Web browser.

The 2D barcodes used in this issue of The ASCO Post will con-nect readers to further information about the articles they are reading. For instance, a report from the ASCO Annual Meeting may include a barcode that will connect readers online to the original abstract of the study discussed. In this way, the editors of The ASCO Post hope to provide readers with further resources and validated information about the news in these pages.

Find examples of 2D barcodes on the pages of this issue. Using the ScanLife application (see right), scan these codes with your camera phone, and see where they bring you. Watch for more barcodes in future issues of The ASCO Post.

What Are Two-Dimensional Barcodes?

What’s this?

whole-breast radiation treatment.6,7 Two more recent trials of APBI showed no dif-ference in local recurrence, although they reported local recurrence at only 5 years and 4 years, respectively, and acknowl-edged the need for longer follow-up.8,9

Rather than using theory to debate whether APBI is clinically valid, the fo-cus should be on accruing patients to ongoing randomized clinical trials. Such trials would provide evidence-based outcomes with which physicians and patients could make informed decisions about local treatment options. Unfortu-nately, some physicians have promoted the rapid introduction of this new tech-

Partial-breast Irradiation Is Not an Acceptable Standard of Carecontinued from page 41

nology into clinical practice without ad-equate scientific evidence, even though randomized clinical trials can be prop-erly conducted and reported. Physicians would best serve patients by supporting randomized trials of APBI.

References1. Clarke M, Collins R, Darby S, et al:

Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.

2. Whelan TJ, Pignol J-P, Levine MN, et al: Long-term results of hypofraction-ated radiation therapy for breast cancer. N Engl J Med 362:513-520, 2010.

3. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al: The UK Stan-

dardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A ran-domised trial. Lancet Oncol 9:331-341, 2008.

4. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al: The UK Stan-dardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A ran-domised trial. Lancet 371:1098-1107, 2008.

5. Bentzen SM, Yarnold JR. Reports of unexpected late side effects of accelerated partial breast irradiation—radiobiologi-cal considerations. Int J Radiat Oncol Biol Phys 77:969-973, 2010.

6. Dodwell DJ, Dyker K, Brown J, et al: A randomised study of whole-breast vs. tu-mour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol (R Coll Radiol) 17:618-622, 2005.

7. Ribeiro GG, Magee B, Swindell R, et al: The Christie Hospital breast conservation tri-al: An update at 8 years from inception. Clin Oncol (R Coll Radiol) 5:278-283, 1993.

8. Polgar C, Fodor J, Major, T et al: Breast-conserving treatment with partial or whole breast irradiation for low-risk in-vasive breast carcinoma—5-year results of a randomized trial. Int J Radiat Oncol Biol Phys 69:694-702, 2007.

9. Vaidya JS, Joseph DJ, Tobias JS, et al: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, pro-spective, randomised, non-inferiority phase 3 trial. Lancet 376:91-102, 2010.

Dr. Solin is Chairman of the Department of Ra-diation Oncology, Albert Einstein Medical Cen-ter, Philadelphia.

After multiple lines of HER2+ MBC treatment

What’s next?

When faced with how to treat advanced HER2+ metastatic breast cancer, the answer is never simple. While there is a wide variety of agents used in this patient population, there is no accepted standard of care in the management of HER2+ metastatic breast cancer once the disease has progressed after multiple lines of treatment.1-3 Without clear consensus guidelines, and with no data to support the superiority of one regimen over another, treating these patients can be particularly challenging.2-5

Difficult choicesTherapies that target HER2-overexpressing tumor cells have revolutionized treatment for women with HER2+ disease. However, once these patients progress after several lines of therapy, existing treatment options offer limited efficacy and may not be tolerated well by patients.2,4,6 Some patients may stop responding to treatment altogether, or may refuse active treatment, valuing quality of life over the limited results they are likely to achieve.4,7

New answers are requiredPatients with heavily pretreated HER2+ metastatic breast cancer need treatment options that can give you clearer answers the next time you ask yourself, “What’s next?”

A pioneer in HER-signaling research, Genentech remains committed to the discovery and development of medicines that help improve the lives of women with HER2+ breast cancer throughout all stages of disease. References: 1. Cardoso F, Castiglione M. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(suppl 4):iv15-iv18. 2. Wardley A. The need for advanced breast cancer treatment guidelines: results of an internet-based survey. Breast. 2008;17:275-281. 3. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. V.1.2009. http://www.nccn.org. Accessed October 20, 2009. 4. Cardoso F, Di Leo A, Lohrisch C, Bernard C, Ferreira F, Piccart MJ. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Ann Oncol. 2002;13:197-207. 5. Kalaja VV, for the ESMO Guidelines Working Group. Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2007;18(suppl 2):ii9-ii11. 6. Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamide-methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243-1252. 7. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. In: Yu D, Hung M-C, eds. Breast Cancer Chemosensitivity. New York, NY: Springer-Verlag. 2007:1-22. Advances in Experimental Medicine and Biology; vol 608.

Options can run out for patients with HER2+ metastatic breast cancer

www.BioOncology.com

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