TAP Vol 2 Issue 11 by Harborside Press LLC

ASCO 2011 1, 3, 7, 8, 11, 14, 36

Malignant lymphoma 25

VOLUME 2, ISSUE 11

Subspecialization in oncology 34

JULY 15, 2011 ASCOPost.com

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

2011 ASCO Annual Meeting

Exemestane Prevents Invasive and Preinvasive Breast Cancers in MAP.3 Trial

Conflicts of Interest in Health-care Reform?

By Caroline Helwick

he aromatase inhibitor exemestane, takExemestane to Prevent Breast Cancer en for 5 years, significantly reduced invasive and pre■■ Taken for 5 years, exemestane led to a 65% reduction in invasive breast invasive breast cancers in cancers among postmenopausal women at risk for the tumor. postmenopausal women ■■ Exemestane also reduced the incidence of preinvasive cancers and at increased risk for the precursor lesions, and was very well tolerated. disease, in the large Canadian NCIC CTG MAP.3 potential for rare but serious side effects, including randomized trial. Results of the trial were presented venous thromboembolism and endometrial cancer. at the recent ASCO Annual Meeting by Paul Goss, 1 Exemestane is currently indicated for adjuvant enMD, PhD, of Harvard Medical School in Boston, and were subsequently published in The New England docrine treatment but is not FDA-approved for the Journal of Medicine.2 prevention of breast cancer. “Exemestane causes less “Our study not only showed an impressive reducbone loss than other aromatase inhibitors and thus tion in breast cancers, but also an was our first choice for a breast cancer prevention excellent side-effect profile,” said trial,” Dr. Goss noted. Dr. Goss, who noted that the curMAP.3 Study Details rently approved drugs for preventThe study is the first randomized trial to assess ing breast cancers—tamoxifen and SEE PAGE 38 continued on page 12 raloxifene—are associated with the Health-care Policy

Are Clinical Pathways Inevitable in Oncology’s Future? By Ronald Piana

ur health-care system is undergoing a gradual but inevitable sea change, shifting from traditional feefor-service to fee-for-value. A session at this year’s Association of Community Cancer Centers meeting in Washington, DC, shed light on how this trend will reshape incentives and the clinical behavior of providers. “After years of being viewed as the sacred cow, oncology is in the hot seat as payers target savings in this high-cost area,” said presenter Lesli D. Lord, Executive Director of On-

cology Physician Resource, PLLC. She added that while patient demographics contribute to rising cancer costs, clinical drivers account for the majority of the increase.

How Do We Know Pathways Are Coming? Close collaboration between payers and providers is likely to become even more critical in getting the most out of our limited financial resources, especially in a period of declining reimbursements. Ms. Lord said that evidence-based clinical pathways have emerged

Evidence-based clinical pathways have emerged as a primary model for driving more effective therapeutic spending. Lesli D. Lord

as a primary model for driving more effective therapeutic spending in oncology by modifying incentives and aligning providers around select treatment regimens. “Payers are looking for programs that achieve broad buy-in and provider compliance,” noted Ms. Lord. She said that payers want pathways that are specific and consistent across providers, and that have national credibility and are vetted with appropriate clinical standards. There also has to be a dem-

By Nora Janjan, MD, MPSA, MBA, and John Goodman, PhD

ast year’s health-care reform legislation, the Patient Protection and Affordable Care Act, was designed to incrementally roll out major new bureaucratic entities, oversight, and mandates for the practice of medicine between its enactment and 2013, after the next presidential election. A new lexicon for medical care was also introduced, including “accountable care organizations” and “meaningful use.” These changes to medical care systems make the physician first accountable to federal mandates that are intended to standardize care and advocate on behalf of the patient. This assumes that, prior to the passage of the legislation, continued on page 29

Dr. Janjan is Senior Fellow in Healthcare Policy and Dr. Goodman is President and CEO, National Center for Policy Analysis, a nonprofit think tank established in 1983 and headquartered in Dallas.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 ASCO Annual Meeting Renal Cell Carcinoma �� 3 Non–Small Cell Lung Cancer �� 7, 8 Myelofibrosis ��11 Breast Cancer �� 14 Prostate Cancer �� 36 11th International Conference on Malignant Lymphoma �� 25 Direct from ASCO �� 18 Oncology Worldwide �� 28 FDA Update �� 31, 32 Electronic Medical Records �� 40

continued on page 2

A Harborside Press® Publication

The ASCO Post | JULY 15, 2011

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Health-care Policy

Clinical Pathways continued from page 1

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France

Clinical Drivers of Oncology Costs

Long-term Goals

■■ Variations in therapeutics used ■■ High cost of newer drugs ■■ Low utilization of hospice care ■■ Increased utilization of hospital

As drug reimbursement for injectable chemotherapies continues to decline, community oncologists will need

■■ Inappropriate treatment mix ■■ Increased diagnostics and

to adopt new business models. Naturally, payers are interested in the concept of paying for adherence to pathways, but Ms. Lord pointed out that they are open to different payment types, especially in models that encourage oncologists to take more overall care and cost responsibility for managing their patients. “Payers also want tools and technology that enable efficient measurement of compliance to avoid significant and costly work,” said Ms. Lord.

Payer Requirements “Pathways will need to be continually extended to manage more than just drugs,” commented Ms. Lord. She identified several cost buckets with the po-

vs outpatient setting (recent)

imaging

tential to drive oncology savings. Under therapeutic management, she said, it is important to select pathways based on effectiveness, toxicity, and cost. Oncologists should also select pathways that reduce practice variation and that help to improve dosing practices. Studies have shown that timely initiation of hospice care enhances outcomes and saves money. Ms. Lord pointed to the recent ASCO statement on end-oflife care as an example of a continuum of cost-effective care that improves patient and caregiver awareness around treatcontinued on page 6

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0905. Copyright ©2011 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com.

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

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.

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

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $225; Individual International: $275; Institutional Domestic: $275; Institutional International $350. Contact subscriptions@harborsidepress.com.

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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onstrated savings potential in order to justify higher reimbursement. To that end, payers want periodic assessments of provider performance relative to designated spending targets.

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

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

ASCOPost.com | JULY 15, 2011

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2011 ASCO Annual Meeting Genitourinary Oncology

Axitinib Improves Progression-free Survival over Sorafenib in Advanced Renal Cell Carcinoma By Larry J. Rosenberg, PhD

randomized comparative effectiveness phase III trial demonstrated significantly superior efficacy for the tyrosine kinase inhibitor axitinib compared to sorafenib (Nexavar) in patients with advanced renal cell carcinoma

(RCC). These data suggest that axitinib may become a new standard of care for second-line treatment of metastatic RCC. The findings were presented at the 2011 ASCO Annual Meeting by Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute.1

also had been shown to be effective, no randomized trials had directly compared targeted agents in advanced RCC. AXIS was a global randomized phase III trial that enrolled 723 patients who had metastatic RCC with clear cell histology and disease progression following one treatment with a sunitinib (Sutent)-, bevacizumab (Avastin) plus interferon-alfa–, temsirolimus (Torisel)-, or cytokine-based regimen. Key eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, adequate renal, hepatic, and hematologic function, and at least 2 weeks since completion of prior systemic therapy (≥ 4 weeks for bevacizumab/interferon-alfa). Patients were treated with axitinib at 5 mg twice daily, which could be titrated to 7 or 10 mg twice daily; sorafenib was administered at 400 mg twice daily. The primary endpoint was progression-free survival, as assessed by a blinded independent review committee.

Axitinib and AXIS

Study Findings

Axitinib is an oral, selective, nextgeneration inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3. Compared with first-generation tyrosine kinase inhibitors such as sorafenib, axitinib inhibits VEGFR in vitro at substantially lower concentrations, with little inhibition of other kinases. In phase II trials, axitinib demonstrated activity in patients with SEE PAGE 38 cytokine-refractory RCC and sorafenib-refractory RCC, suggesting that it could be an effective therapy for second-line RCC. While sorafenib

Baseline characteristics were similar among patients on each treatment arm. Based on an intent-to-treat analysis, said Dr. Rini, “axitinib produced a median progression-free survival of 6.7 months, compared to 4.7 months for sorafenib; this corresponded to a stratified hazard ratio of 0.665 with a significant P value of .0001” (Table 1). Significantly greater progression-free survival with axitinib also was seen in patients who received prior cytokines (12.1 vs 6.5 months; P < .0001) or sunitinib therapy (4.8 vs 3.4 months; P = .0107). Forest plot analysis indicated that the survival benefit for axitinib was relatively preserved across

Brian Rini, MD

Expert Point of View

ccording to Eric Jonasch, MD, of The University of Texas MD Anderson Cancer Center, “These data show that treatment with a potent and specific antiangiogenic agent after immunotherapy does provide significant prolongation of progression-free survival, and that axitinib is clearly superior to sorafenib from a statistical and clinical perspective.” In the post–VEGF-targeted therapy scenario, he noted, the benefit of axitinib over sorafenib, while statistically significant, beEric Jonasch, MD comes somewhat less clinically relevant. “In tyrosine kinase inhibitor–refractory patients, everolimus provided a 4.9-month progression-free survival. Therefore, axitinib provides an alternative to everolimus in tyrosine kinase inhibitor–pretreated individuals, but it is not necessarily a paradigm shifting agent in that setting,” he added. “These data underscore the need for a better understanding of the resistance mechanisms after anti-VEGF therapy, which will guide our future therapy development,” said Dr. Jonasch.

■

Disclosure: Dr. Jonasch has served as a consultant for Pfizer, AVEO Pharmaceuticals, and GlaxoSmithKline, and has received research support from Pfizer, GlaxoSmithKline, and Novartis.

AXIS Trial in Renal Cell Carcinoma ■■ Axitinib resulted in statistically superior progression-free survival and response rate compared with sorafenib as second-line therapy in metastatic renal cell carcinoma, with comparable quality of life.

■■ Safety profiles were generally comparable for both agents, with most adverse events less than grade 3 in severity.

■■ These data suggest axitinib may be considered the new standard of care for second-line therapy of metastatic renal cell carcinoma.

patient subgroups when stratified by baseline characteristics and prognostic factors evaluated. The objective response rate was higher with axitinib compared to sorafenib (19.4% vs 9.4%; P = .0001). Patient-reported quality of life was comparable between the two treatment groups. Most adverse events were less

Table 1: Axitinib vs Sorafenib in Patients with Advanced Renal Cell Carcinomaa AXIS Trial

Axitinib (n = 361)

Sorafenib (n = 362)

Hazard Ratio

P Value

Median progression-free survival (95% CI)

6.7 mo (6.3–8.6)

4.7 mo (4.6–5.6)

0.665

< .0001

Prior sunitinib regimen (95% CI)

4.8 mo (4.5–6.4)

3.4 mo (2.8–4.7)

0.741

.0107

Prior cytokine regimen (95% CI)

12.1 mo (10.1–13.9)

6.5 mo (6.3–8.3)

0.464

< .0001

19.4%

9.4%

Stratified median progression-free survival

Objective response rate As assessed by Independent Review Committee.

.0001

than grade 3 in severity. This head-to-head comparison demonstrates that axitinib provided greater clinical benefit than sorafenib when used as second-line therapy for metastatic RCC, perhaps due to its more potent inhibition of the VEGFR. Results of the AXIS trial, concluded Dr. Rini, suggest that axitinib should be considered the new standard of care for second-line therapy of advanced RCC.

■

Disclosure: Dr. Rini is a consultant for AVEO, GlaxoSmithKline, and Pfizer, and has received research support from GlaxoSmithKline and Pfizer. Dr. Rosenberg is an employee of UBC Scientific Solutions and has previously provided medical writing support, which was funded by Pfizer Inc.

Reference 1. Rini BI, Escudier B, Tomczak P, et al: Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): Results of phase III AXIS trial. 2011 ASCO Annual Meeting. Abstract 4503. Presented June 6, 2011.

The ASCO Post | JULY 15, 2011

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News Health-care Policy

Clinical Pathways continued from page 2

ment options in advanced disease. “In all settings, pathways also need to help coordinate treatments to eliminate care fragmentation and guide utilization of lower cost options where the effectiveness of that option is war-

ranted,” noted Ms. Lord. Another area in which pathways can cut back on unnecessary costs is by decreasing hospital admissions. “When possible, shift delivery of patient services from hospitals to lower cost community settings. Also, utilize nurse coordination to reduce overall hospitalizations

and ER visits due to adverse reactions to therapy,” said Ms. Lord.

Changing Landscape As Ms. Lord stressed at the start of her presentation, our overburdened healthcare system is making a gradual but inevitable shift from traditional fee-for-service

to one in which value will become the operative term. We will reimburse providers in oncology by linking the reimbursement for the intervention to its clinical value; there would also be an added incentive to personalized medicine. Moreover, Ms. Lord said that new collaborative efforts and delivery models such as the patient-centered oncology medical home will emerge as instruments to foster output-based incentives to share savings as a measure of improving quality and reducing costs. “In short, the ‘pathways’ model has emerged as a primary method for driving more effective therapeutic spending in oncology, by modifying incentives and aligning providers around select treatment regimens,” concluded Ms. Lord.

■

Disclosure: Ms. Lord receives funding from Physician Resource Management, Inc, Oncology Physician Resource, PLLC, Southwest Oncology Network, LLC, and MOASC Purchasing Network, Inc. She has served as a consultant (compensated) to AmerisourceBergen Specialty Group.

News in Brief Final Decision on Sipuleucel-T

he Centers for Medicare & Mediaid Services (CMS) issued a final decision to cover FDA-approved indications of sipuleucel-T (Provenge) in prostate cancer, calling the treatment “reasonable and necessary.” The CMS final decision assures provider reimbursement of sipuleucel-T for Medicare beneficiaries effective immediately. Cost for the complete course of therapy is $93,000. FDA approved sipuleucel-T in April 2010 for asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer.

■

ODAC Again Recommends FDA Withdraw Its Approval of Bevacizumab for Metastatic Breast Cancer

n June 2011, a public hearing was convened to consider an appeal of the December 2010 recommendation by FDA to remove the breast cancer indication for bevacizumab (Avastin). FDA’s recommendation late last year was in accordance with a July 2010 recommendation by the Oncologic Drugs Advisory Committee (ODAC). Following the recent 2-day hearing, ODAC again voted to recommend that FDA reverse its earlier accelerated approval of bevacizumab in combination with paclitaxel for treatment of HER2-negative metastatic breast cancer. A final decision will be made by FDA Commissioner Margaret Hamburg.

■

ASCOPost.com | JULY 15, 2011

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2011 ASCO Annual Meeting Thoracic Oncology

Emerging Targeted Therapies Offer Glimmer of Hope for NSCLC but Biomarkers for Response Needed By Alice Goodman

mong the newer approaches to treatment of non–small cell lung cancer (NSCLC) are heat-shock protein 90 (Hsp90) inhibitors, toll-like receptor 2 (TLR2) agonists, and vasculardisrupting agents. So far, none appears to be a “home run,” but Hsp90 inhibition may be the most SEE PAGE 38 promising of the three approaches, according to presentations at a session on Emerging Novel Targets for Lung Cancer at the 2011 ASCO Annual Meeting. A theme that ran through the three presentations and discussions was the need for biomarkers to identify patients likely to respond (or not respond) to a given targeted therapy. Without such biomarkers, it is unlikely that targeted therapies can be exploited to best use.

Heat-shock Protein 90 A phase II study showed that the investigational Hsp90 inhibitor ganetespib (SA-9090) was well tolerated in patients with advanced pretreated non–small cell lung cancer (NSCLC), and the authors believe this drug holds promise as a single agent in molecularly selected subsets of NSCLC.1 All patients with a confirmed response had tumors harboring the ALK gene rearrangement, said Geoffrey Shapiro, MD, Dana-Farber Cancer Institute and Associate Professor at Harvard Medical School, Boston, who presented the study results.

eration Hsp90 inhibitors and does not have the hepatic toxicity associated with first-generation Hsp90 inhibitors or the ocular toxicity that has complicated the development of other second-generation Hsp90 inhibitors. It has been well tolerated in approximately 400 patients treated to date, with the most common adverse event being diarrhea, generally mild to manageable. In the phase II study, 76 patients with previously untreated stage IIIB/IV NSCLC were treated with ganetespib once weekly for 3 weeks of a 4-week cycle and were evaluable for response. Patients were stratified into four groups: 17 patients with EGFR mutations, 17 with mutated KRAS, 25 with wild-type EGFR and KRAS, and an additional 37 whose tumors were wild-type for EGFR and KRAS with adenocarcinoma only. At 16 weeks, the progression-free survival rate was 24.1%, and disease control rate was 54% (complete and partial response plus stable disease for 8 weeks or longer). In the EGFR wild-type, KRAS wildtype group, it is clear that patients whose tumors harbor ALK rearrangement can benefit from ganetespib. However, ad-

Suresh Ramalingam, MD

should be studied, and Hsp90 inhibition should be studied in crizotinib-resistant ALK-positive NSCLC. In the long and disappointing development history of Hsp90 inhibitors, we have reached an important and exciting turning point.”

TLR2 Agonist Results were less promising for immunotherapy with mycobacterium w (Cadi-05). The addition of a TLR2 agonist (Cadi-05), to standard paclitaxel plus cisplatin did not improve survival and showed a nonsignificant trend toward improved progression-free survival compared with paclitaxel/cisplatin alone in 221 patients with advanced NSCLC in a phase II trial reported at the meeting.2 However, a trend toward improved

Novel Targeted Agents in Lung Cancer ■■ Emerging strategies for non–small cell lung cancer include Hsp90

inhibitors, TLR2 agonists (immunotherapy), and vascular disruption.

■■ Of these, Hsp90 inhibition shows the most promise and will be studied

in phase III trials. Chemoimmunotherapy will be studied further, but vascular-disrupting agents do not appear to offer any benefit in NSCLC.

■■ The identification of biomarkers for response and failure on targeted therapies is a pressing need.

Geoffrey Shapiro, MD

“Additionally, the favorable safety profile and clinical activity in this difficult-to-treat patient population has prompted evaluation in a phase IIb/III trial of ganetespib in combination with docetaxel as second-line treatment for advanced NSCLC,” he said. Ganetespib is a potent Hsp90 inhibitor structurally unrelated to first-gen-

ditional biomarkers for treatment response are needed, and further analysis is ongoing to identify genetic profiles sensitive to ganetespib singe-agent treatment, Dr. Shapiro noted. The ganetespib study discussant, Suresh Ramalingam, MD, Associate Professor at Emory University, Atlanta, said that Hsp90 inhibitors have entered the therapeutic algorithm for ALK-positive NSCLC. The secondgeneration drugs have an improved safety profile, making them amenable to combination approaches. “Studies have clearly shown that most responders are crizotinib-naive,” Dr. Ramalingam told the audience. “The combination of crizotinib plus ganetespib

Professor of Medicine Penn State Milton S. Hershey Medical Center Deputy Director Penn State Hershey Cancer Institute, Hershey, Pennsylvania. Formal discussant of this trial, Raffit Hassan, MD, NCI, Rockville, Maryland, noted that Cadi-05 is one of several nonspecific immunomodulators being studied in NSCLC. Several trials of other vaccines are ongoing in patients with NSCLC. These vaccines include MAGE-A3, Stimuvax, and Lucanix.

progression-free and overall survival was observed in subsets of patients in the chemoimmunotherapy arm who completed four cycles of therapy and those with squamous histology, said presenting author Chandra Belani, MD, Miriam Beckner Distinguished

Chandra Belani, MD

Raffit Hassan, MD

“The present study was well designed, and the CADI-05 vaccine was incorporated in front-line therapy. However, CADI-05 did not improve survival, and overall survival was inferior compared with that reported in other multicenter trials. Use of nonspecific immunomodulators like CADI05 may be more useful in patients with lower tumor burden,” he said. “Immunomodulation [with an agent like CADI-05] is most likely to be successful if it is integrated with chemotherapy or radiation therapy, used in the adjuvant setting, and early in the metastatic disease setting or to maintain response. Several large randomized phase III trials of immunotherapy are ongoing, and these trials validate immunotherapy as an option,” Dr. Hassan stated.

Vascular-disrupting Agent ASA 404 (vadimezan), a small-molecule vascular-disrupting agent, failed to improve survival when added to paclitaxel/carboplatin vs paclitaxel/carboplatin alone as first-line therapy in the randomized phase III ATTRACT-1 trial.3 The study enrolled 1,545 patients with advanced-stage IIIB/IV NSCLC of all histologies and randomly assigned them to six cycles of chemotherapy plus vadimezan or chemotherapy alone. Patients in the experimental arm continued vadimezan after chemotherapy continued on page 8

The ASCO Post | JULY 15, 2011

PAGE 8

2011 ASCO Annual Meeting Thoracic Oncology

Maintenance Therapy Prolongs Progression-free Survival in Advanced NSCLC but Produces No Overall Survival Benefit By Alice Goodman

aintenance therapy with either pemetrexed (Alimta) or gefitinib (Iressa) achieved modest improvements in progression-free survival in patients with advanced non–small cell lung cancer (NSCLC). The magnitude of improved progression-free survival SEE PAGE 38 was 1.3 months and 2.2 months, respectively, in the two studies. No improvement in overall survival (OS) was found in the INFORM trial, and OS data were not reported for PARAMOUNT.

PARAMOUNT Trial Maintenance therapy with pemetrexed improved progression-free survival in patients with advanced

NSCLC who were treated with pemetrexed as part of their upfront chemotherapy regimen in the phase III randomized PARAMOUNT trial.1 “Pemetrexed has been shown to be effective maintenance therapy in patients with nonsquamous NSCLC who had not received the drug as part of chemotherapy. This trial includes patients who were already treated with four courses of pemetrexed as part of induction chemotherapy,” explained Luis G. Paz-Ares, MD, Virgen del Rocio University Hospital, Seville, Spain. “The study met its primary endpoint by showing significantly improved progression-free survival in patients continued on treatment with pemetrexed. We believe the magnitude of benefit is clinically significant and may support the use of peme-

PARAMOUNT and INFORM Trials ■■ Two randomized, phase III trials show a progression-free survival

benefit for maintenance therapy with pemetrexed and gefitinib, respectively, in patients with advanced non–small cell lung cancer.

■■ The magnitude of benefit was modest, between a 1.3- and 2.2-month gain in progression-free survival.

■■ No overall survival benefit was observed for maintenance therapy in the INFORM trial.

■■ It is not clear that maintenance therapy is superior to second-line therapy initiated at disease progression.

Targeted Therapies

Vadimezan did not add to the toxiccontinued from page 7 ity of chemotherapy. No clustering of until disease progression. The efficacy any specific events leading to death was analysis was based on 649 patients in observed in either treatment arm. the experimental arm and 650 in the “These disappointing results did not control arm. The safety analysis includbear out encouraging phase II results,” ed 628 and 626 patients, respectively. said presenting author Primo Lara, Median overall survival was 13.4 vs MD, University of California at Davis. 12.7 months for the experimental and “This study is another example of a discontrol arms, respectively. The Data and connect between positive phase II trials Safety Monitoring Committee closed and negative phase III trials. Vascular the study in March 2010 for futility. disruption as a therapeutic anti-cancer strategy remains unproven. Further development of vadimezan has been halted. The molecular target of this agent remains unknown.” Formal discussant of this trial, Jean-Charles Soria, MD, PhD, Institut GustaveRoussy, Paris, called the trial “completely negative.” He said Primo Lara, MD Jean-Charles Soria, MD, PhD that trials of vascular-disrupt-

trexed as maintenance therapy,” Dr. Paz-Ares stated. The trial enrolled 539 patients who responded to four cycles of pemetrexed plus cisplatin induction chemotherapy to receive continuing pemetrexed plus best supportive care or placebo plus best supportive care every 21 days in a 2:1 ratio. Both arms got folic acid and vitamin B12 supplementation. Maintenance therapy was continued until disease progression. Median age was 61 years, about 60% were males, the majority were Caucasian, and 80% were ever-smokers; 90% had stage IV NSCLC and 10% had stage IIIB disease; 88% had adenocarcinoma histology.

Key Data For the primary endpoint of investigator-assessed progression-free survival, pemetrexed was statistically superior to placebo: Median progression-free survival was 4.1 months in the pemetrexed arm vs 2.8 months with placebo (P = .00006), for a 38% reduction in risk of progression. These results held up in an independent review: Median progression-free survival was 3.9 vs 2.6 months, respectively (P = .0002), for a 36% reduction in risk of progression. Subgroup analysis showed that although all patients benefitted from pemetrexed, males, never-smokers, ing agents and other targeted therapies are plagued by a lack of predictive biomarkers to identify patients likely to respond and those with a high risk of treatment failure. “Molecular targeted agents are at very high risk of failure in phase III studies if no biomarker is identified. We have subjected about 27,000 patients to negative phase III trials over the past 10 years. We need to change the way we do clinical trials,” Dr. Soria stated.

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Disclosure: Dr. Belani and Dr. Hassan reported no potential conflicts of interest. Dr. Shapiro has received prior funding from Synta Pharmaceuticals. Dr. Ramalingam is a consultant/advisor for Abbott, Amgen, Genentech, GlaxoSmithKline, ImClone, Infinity, Lilly, and Pfizer. Dr. Lara is a consultant/advisor and has received honoraria and research funding from Novartis. Dr. Soria is an advisor/consultant for Abbott, Boehringer Ingelheim, Lilly, Merck, Pfizer, Roche, sanofi-aventis, SERVIER, and Wyeth, and has received honoraria from AstraZeneca and Bristol-Myers Squibb.

and responders appeared to do better. Quality-of-life analysis showed no significant difference between the two arms on the EQ-5D index score or visual analog scale.

Luis G. Paz-Ares, MD

Pemetrexed had an acceptable toxicity profile, Dr. Paz-Ares noted. The main differences in adverse events between the two arms were higher grade 3/4 toxicity rates for pemetrexed as follows: fatigue (4.2% vs 0.6%, respectively), anemia (4.5% vs 0.6%), and neutropenia (3.6% vs 0%). The study is fully powered for overall survival, and those results will be presented when the data mature.

INFORM Trial Maintenance therapy with gefitinib achieved significantly superior progression-free survival compared with placebo in the phase III, randomized, continued on page 10

References 1. Wong K, Koczywas M, Goldman JW, et al: An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract 7500. Presented June 4, 2011. 2. Belani C, Desai D, Khamar BM: Open-label randomized multicenter phase II clinical trial of a toll-like receptor 2 (TLR2) agonist mycobacterium w (Cadi-05) in combination with paclitaxel plus cisplatin versus paclitaxel plus cisplatin in advanced non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract 7501. Presented June 4, 2011. 3. Lara P, Douillard J, Nakagawa K, et al: Randomized phase III placebo-controlled trial of carboplatin/paclitaxel (CP) with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract 7502. Presented June 4, 2011.

Oncology with soul At Eisai, human health care is our goal. We give our first thoughts to patients and their families, and to increasing the benefits healthcare provides. Our therapies and diverse oncology pipeline are designed to make a difference and have an impact on patients’ lives. We are Eisai, where oncology is more than just our business—it’s our passion.

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May 2011

www.Eisai.com/us

The ASCO Post | JULY 15, 2011

PAGE 10

2011 ASCO Annual Meeting Thoracic Oncology

Maintenance Therapy continued from page 8

placebo-controlled, parallel-group INFORM study in Chinese patients with locally advanced NSCLC.2 No difference in overall survival was observed between the two arms of the study. “This is the first randomized maintenance therapy trial in Asian

Li Zhang, MD

patients with advanced NSCLC, and it met its primary endpoint of significant improvement in progressionfree survival with gefitinib maintenance,” stated Li Zhang, MD, Sun Yat-Sen University Cancer Center, Guangzhou, China. The study enrolled 296 patients with stage IIIB/IV NSCLC who completed four cycles of platinum-based first-line doublet chemotherapy without disease progression or unacceptable toxicity. Patients were randomly assigned to maintenance therapy with gefitinib or placebo and treated until disease progression.

Study Findings At a median follow-up of 16.8 months, median progression-free survival was 4.8 months for gefitinib vs 2.6 months for placebo (P < .0001), for a 58% reduction in risk of pro-

gression. The most common adverse events were rash (49.7%), diarrhea (25.2%), and increases in alanine transaminase (21.1%). These events were generally mild to moderate. Serious adverse events were reported in 6.8% of those treated with gefitinib vs 3.4% of the placebo group. Biomarker analysis was not mandated in this trial, but 27% of patients had EGFR mutation status analyzed; of these, 38% were EGFR mutation– positive. Progression-free survival was significantly longer with gefitinib in both the EGFR-positive and EGFR-negative groups. However, patients with EGFR mutations had the best outcome. Patients with EGFRunknown tumors also did well, Dr. Zhang said.

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Disclosure: Dr. Paz-Ares has been a scientific advisor for Lilly. Dr. Zhang reported no potential conflicts of interest.

References 1. Paz-Ares LG, De Marinis F, Dediu M, et al: PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract CRA7510. Presented June 5, 2011. 2. Zhang L, Shenglin M, Song X, et al: Efficacy, tolerability, and biomarker analysis from a phase III, randomized, placebo-controlled, parallel-group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC; INFORM; C-TONG 0804). 2011 ASCO Annual Meeting. Abstract LBA7511. Presented June 5, 2011.

Expert Point of View

aintenance therapy in NSCLC is an evercontentious issue,” stated formal discussant of these trials, Martin Edelman, MD, University of Maryland Greenebaum Cancer Center, Baltimore, at the ASCO Annual Meeting. “The maintenance approach is based on two observations: limited benefit from more than four courses of chemotherapy and improved outcomes with second-line chemotherapy.” There are two approaches: continued mainteMartin Edelman, MD nance (exemplified by the PARAMOUNT trial) and switch maintenance (the INFORM study). “These studies raise more questions than answers,” Dr. Edelman said. He questioned the value of progression-free survival as an endpoint. “It is subject to bias and doesn’t answer the question about overall survival. Is maintenance therapy really beneficial? The quality-of-life data are disappointing, with no difference between treatment arms. Maintenance therapy is not cost-free,” he continued.

Concerns and Conjectures His biggest concern is the fate of patients on the control arms of these trials. Many of these patients never get second-line therapy, yet we know that second-line therapy works, so the control arm results will be inferior. This is not a trivial issue. In my opinion, second-line therapy should be introduced when the tumor regrows,” he told listeners. It is not clear whether responders or nonresponders to induction therapy should go on to maintenance therapy. Also, almost all of the advantages with an EGFR tyrosine kinase inhibitor occur in patients with activating EGFR mutations. “I would like to see quality-of-life data on patients with activating EGFR mutations,” he said. EGFR mutations predict progression-free survival, not overall survival, he added. “We learned [from these trials] that the drugs work in patients who derive benefit from first-line chemotherapy. To date, there is no evidence that early introduction of therapy will improve survival compared to introducing second-line therapy at disease progression,” he said. Dr. Edelman said that future trials should mandate second-line therapy at progression, documentation of nontreatment in the control arm, and outcomes reporting for patients who get treatment on the control arm.

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Disclosure: Dr. Edelman has been a consultant for Amgen, Boehringer Ingelheim, BristolMyers Squibb, Endocyte, Genentech, Lilly, and OSI Pharmaceuticals, and has received research funding from Bristol-Myers Squibb, Lilly, and Tragara.

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2011 ASCO Annual Meeting Hematology

Novel JAK Inhibitor May Be an Option for Patients with Myelofibrosis By Alice Goodman

new approach to treating myelofibrosis appears to be paying off, according to several studies presented at the 2011 ASCO Annual Meeting. Treatment with a novel JAK inhibitor called ruxolitinib demonstrated significant and sustained improvement in splenomegaly and overall quality of life, functioning, and symptoms in patients with myelofibrosis, according SEE PAGE 38 to results of the phase III COMFORT-II trial that compared ruxolitinib vs best available therapy. A separate phase III trial comparing ruxolitinib to placebo (COMFORT-I) showed simi-

lar superiority for the novel JAK inhibitor. Myelofibrosis, which encompasses a group of diseases involving scar tissue buildup in the bone marrow, can sometimes transform to leukemia. The disorder involves dysregulation of JAK-STAT signaling, and thus, trials to test the effect of JAK inhibition have been conducted. Phase I/II trials showed good activity for JAK2 inhibition with ruxolitinib (see “Early Clinical Findings with JAK2 Inhibition”), and two phase III trials were mounted: COMFORT-I (a placebocontrolled trial) and COMFORTII (comparing ruxolitinib to best available therapy). At present, there are no FDA-approved agents for

Expert Point of View

oss Levine, MD, of Memorial Sloan-Kettering Cancer Center, New York, was the discussant of the COMFORT-I and COMFORT-II trials.1 He explained that 70% to 90% of patients with myelofibrosis have JAK2 mutations, which appear to be endemic. “This is a driver mutation, although not the only mutation in myelofibrosis,” he told listeners. “But I would argue that JAK2 is the most attractive target.” Ross Levine, MD Both COMFORT trials were based on phase I/ II trials showing that a majority of patients with myelofibrosis had rapid reduction in spleen size and reduction in associated clinical symptoms. “We don’t know if this is due to inhibition of JAK2 in the tumor cells or systemically,” he commented. Both phase III trials allowed crossover—COMFORT-I at 24 months and COMFORT-II at spleen enlargement—which may compromise the ability of these studies to show eventual differences in disease-free and overall survival, he continued.

Important Endpoint “Spleen size is an important endpoint. It is the major cause of morbidity and poor quality of life for patients with myelofibrosis, so a nonsurgical option to reduce spleen size without limiting toxicity would be of significant benefit for our patients,” Dr. Levine noted. “Both studies met their primary endpoints convincingly. Anemia and thrombocythemia occurred in about 30% of patients but were manageable,” he said. “[Ruxolitinib] fulfills an important unmet need for myelofibrosis patients. It is well tolerated, and the dosing is easily managed by hematologists/oncologists. This is the first demonstration of an effective targeted therapy in myelofibrosis, and will likely lead to JAK2 inhibition as a treatment for patients with myelofibrosis and splenomegaly,” he stated.

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Disclosure: Dr. Levine has served as a consultant or advisor with AstraZeneca, Incyte, and TargeGen, and has received honoraria from Novartis.

Reference 1. Levine RL: How do we find new mutations and develop novel therapies? 2011 ASCO Annual Meeting. Presented June 6, 2011.

the treatment of myelofibrosis, but some drugs are used in this setting off-label.

Early Clinical Findings with JAK2 Inhibition

Claire Harrison, MD

“Data from both COMFORT trials may result in a new standard of care for a large number of patients with myelofibrosis,” said Claire Harrison, MD, Guy’s and St. Thomas’ NHS Foundation Trust, London, presenting author of COMFORT-II.

COMFORT-II COMFORT-II enrolled 219 patients with intermediate or high-risk primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis and randomly assigned them in a 2:1 ratio to ruxolitinib at 15 or 20 mg twice daily vs best available therapy. The dose of ruxolitinib was determined by the patient’s platelet count. For the primary endpoint of achieving a 35% or greater reduction in spleen volume at week 48, ruxolitinib was significantly superior to best available therapy: 28.5% vs 0%, respectively (P < .0001). For the secondary endpoint (35% or greater reduction in spleen volume at week 24), ruxolitinib was also significantly superior to best available therapy: 31.9% vs 0%, respectively (P < .0001). Results showed that ruxolitinib significantly improved quality of life and symptoms associated with myelofibrosis from week 8 to week 48, as measured by the EORTC QLQ-C30 questionnaire. By contrast, the best available therapy group experienced progressive splenomegaly, worsening quality of life, and worsening symptoms over 48 weeks. Ruxolitinib had an acceptable safety profile compared with best available therapy. The most common adverse events were anemia and thrombocythemia. continued on page 12

wo small preliminary studies of JAK2 inhibitors CYT387 and SB1518 had encouraging results in patients with myelofibrosis, and these studies were reported in poster presentations at the Annual Meeting.1,2 Both drugs reduced splenomegaly and achieved improvement in constitutional symptoms. SB1518 demonstrated an

The JAK2 mutation as a potential cause of myelofibrosis is an important discovery. associated downmodulation in cytokines, and CYT387 was associated with an improvement in anemia. “The JAK2 mutation as a potential cause of myelofibrosis is an important discovery,” said Olatoyosi Odenike, MD, University of Chicago Medical Center, who was the discussant for the two poster presentations. She said that a number of JAK inhibitor ATP mimetics are in clinical trials for myelofibrosis. “There is a lack of effective therapy for patients with cytopenias, but JAK inhibitors achieve improvement in spleen size and constitutional symptoms. Novel agents are still desperately needed. We don’t quite understand how these agents are working, since responses are independent of JAK2 mutational status,” Dr. Odenike said.

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Disclosure: Dr. Odenike has been a consultant or advisor for Amgen, Cephalon, Incyte, and MGI Pharma. She has received research funding from MGI Pharma/ Eisai and Topotarget, and honoraria from Celgene and Genzyme.

References 1. Pardanani AD, Caramazza D, George G, et al: Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis. 2011 ASCO Annual Meeting. Abstract 6514. Presented June 3, 2011. 2. Deeg HJ, Odenike O, Scott BL, et al: Phase II study of SB1518, an orally available JAK2 inhibitor, in patients with myelofibrosis. 2011 ASCO Annual Meeting. Abstract 6515. Presented June 3, 2011.

The ASCO Post | JULY 15, 2011

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2011 ASCO Annual Meeting MAP.3 Trial continued from page 1

an aromatase inhibitor for breast cancer prevention in healthy women. The study enrolled 4,560 postmenopausal women from four countries who had at least one of the following risk factors: age ≥ 60 years; 5-year Gail risk score > 1.66%; prior atypical ductal hyperplasia, lobular hyperplasia, or lobular carcinoma in situ; or prior ductal carcinoma in situ (DCIS) with mastectomy. The study excluded BRCA1 and BRCA2 mutation carriers, women with DCIS who had undergone lumpectomy, and women with a history of cancer.

Paul Goss, MD, PhD

About half the population was considered at risk simply by virtue of being 60 years old or older, he noted. Subjects were randomly assigned to exemestane at 25 mg/d or placebo, for 5 years. At a median followup time of 3 years, 11 invasive breast cancers occurred in the exemestane group vs 32 in the placebo group, for annual incidence rates of 0.19% vs 0.55%, respectively, and resulting in a 65% reduction in invasive cancers with exemestane (P = .002), Dr. Goss reported.

JAK Inhibitor continued from page 11

COMFORT-I

At the same ASCO session, COMFORT-I results were presented by Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. COMFORT-I enrolled patients

The protective effect was striking for estrogen receptor–positive tumors, 7 of which developed in the exemestane group compared with 27 in the placebo arm, for a 73% relative risk reduction (P = .0008). In all subgroups analyzed, the incidence of invasive breast cancer was reduced with exemestane. The investigators also found a 53% reduction of invasive breast cancer and preinvasive DCIS, and fewer cases of cancer precursor lesions such as atypical ductal hyperplasia and atypical lobular hyperplasia with exemestane, he added. Serious toxicities over 3 years were not seen, particularly fractures, self-reported osteoporosis, cardiovascular toxicities, or second cancers. The exemestane group did report more bodily pain—46% vs 41% (P < .001)—and had minimal worsening of quality of life. In addition, 88% of the exemestane group reported an adverse event, as did 85% of the placebo group, “which because of the large numbers was statistically significant (P = .003), but the differences were really quite small,” he said. “Patients with as little as one report of ‘worsening’ of quality of life (eg, pain) were conservatively reported as ‘worsening’ even though in many this resolved after a single report for the rest of the treatment period,” Dr. Goss added.

‘Promising Option’ “The findings from MAP.3 indicate that exemestane is a promising new option for preventing breast canaccording to the same eligibility criteria as COMFORT-II and randomly assigned them to receive ruxolitinib vs placebo. At a median follow-up of 32 weeks, 41.9% of the ruxolitinib-treated patients vs 0.7% of the placebo group achieved the primary endpoint (ie, at least 35% shrinkage in spleen volume at week 24; P < .0001). Symptom burden was also significantly improved (P < .0001) with ruxolitinib vs placebo. More cases of thrombocythemia and anemia were observed in the ruxolitinib arm.

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Srdan Verstovsek, MD, PhD

Disclosure: Dr. Harrison has served as a consultant for Celgene, Incyte, Novartis, S*BIO, and Shire. Dr. Verstovsek has conducted research for AstraZeneca, Bristol-Myers Squibb, Celgene, Geron, Incyte, Lilly, Roche, and S*BIO.

Expert Point of View

ccording to Andrea De Censi, MD, of the E.O. Ospedali Galliera in Genoa, Italy, the invited discussant of the paper presented by Paul Goss, MD, PhD, at the 2011 ASCO Annual Meeting, “MAP.3 provides a paradigm shift for breast cancer prevention. Avoiding breast cancer with manageable toxicity is possible today.” Dr. De Censi maintained that the MAP.3 trial has altered the standard of preventive care by showing exemestane’s “potential impact on a Andrea De Censi, MD deadly disease.” While tamoxifen is still favored for at-risk premenopausal women, exemestane may be a preferred option in the postmenopausal group, given that the currently indicated drugs have not been well received due to concerns over adverse events, he said. “But we must remain aware that a drug that affects cell growth cannot be totally devoid of adverse effects,” he added. Individualized dosing and intermittent administration may help ameliorate toxicity.

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Disclosure: Dr. De Censi reported no potential conflicts of interest.

cer in menopausal women,” Dr. Goss commented. While acknowledging that the median follow-up of 3 years in MAP.3 is short, Dr. Goss noted that “in early breast cancer trials, benefits including prevention of new primaries are durable and indeed increase up to 5 years on therapy and are durable beyond cessation of treatment up to at least another 5 years that we know of.” Further, the analysis was intent-to-treat, and he speculated the benefit may actually be greater in patients who were compliant with the medication for the full 5 years. The number needed to treat to prevent one breast cancer over 5 years is just 26, compared to 95 with tamoxifen. Finally, the patent for exemes-

tane (Aromasin) recently expired, and a generic form is now available, providing an even more cost-effective means of chemoprevention, he added.

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Disclosure: Dr. Goss has received speaker’s honoraria from GlaxoSmithKline, Novartis, and Pfizer in the past.

References 1. Goss PE, Ingle JN, Ales-Martinez J, et al: Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial. 2011 ASCO Annual Meeting. Abstract LBA504. Presented June 5, 2011. 2. Goss PE, Ingle JN, Ales-Martinez J, et al: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364:2381-2391, 2011.

New Agents for Myelofibrosis ■■ New and effective treatments for myelofibrosis are an unmet need; inhibition of JAK2 appears to be a promising approach in this setting.

■■ Two phase III trials showed that ruxolitinib, the JAK2 inhibitor furthest along in clinical development, reduces splenomegaly and associated symptoms for many patients with myelofibrosis.

■■ Other JAK2 inhibitors are in various stages of development; CYT387 and SB1518 showed encouraging results in phase II trials.

References 1. Harrison C, et al: Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF, post-polycythemia vera-myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF).

2011 ASCO Annual Meeting. Abstract LBA6501. Presented June 6, 2011. 2. Verstovsek S, Mesa RA, Gotlib JR, et al: Results of COMFORT-I, a randomized double-blind phase III trial of JAK 1/2 inhibitor INCB18424 (424) versus placebo (PB) for patients with myelofibrosis (MF). 2011 ASCO Annual Meeting. Abstract 6500. Presented June 6, 2011.

The case for Vectibix® Q2W dosing schedule1

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

60-minute infusion1

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

Premedication not standardized1

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

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

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

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

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

The ASCO Post | JULY 15, 2011

PAGE 14

2011 ASCO Annual Meeting Important Briefs

Breast Cancer Studies Focus on Tailoring Therapy for Patient Subsets By Caroline Helwick

s part of our ongoing coverage of the 2011 ASCO Annual Meeting, The ASCO Post has provided substantive reports on key breast cancer trials, but others deserve attention.

Lapatinib/Capecitabine Controls Brain Metastases Results of the French phase II LANDSCAPE Trim:trial 7.875”found lapatinib Live: 7” (Tykerb) plus capecitabine (Xeloda) to be

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

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

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

MC46026-E

whole brain radiotherapy.1 For 43 patients followed a median of 14 months, at least an 80% reduction in central nervous system lesion volume was observed in 20.9% of patients, while 46.5% had a reduction of 50% to 80%, reported Thomas Bachelot, MD, of the Centre Léon Bérard in Lyon. SEE PAGE 38 Another 14% had a reduction of 20% to 50%, and 4.7% had less than a 20% reduction. Only 14% of patients had progressive disease as their best response, he said. Extra–central nervous system responses were also frequent, occurring in 42.9%; another 45.7% had stable clinical disease. Median time to progression was 5.5 months, and median time to whole brain radiotherapy was 7.8 months. Sixmonth overall survival was 90.9%. The benefit was robust in some cases, Dr. Bachelot noted. “One patient, for example, with 25 small brain metastases had a dramatic 98% volumetric reduction in lesions and is still on treatment after 13 months,” he reported. Nancy U. Lin, MD, of Harvard Medical School, Boston, commented that the study shows systemic approaches can be effective in treating HER2-positive brain metastases. “The results of LANDSCAPE raise the possibility that in the future, radiotherapy may be reserved for the salvage setting,” she said. “Continued active effort in this area is needed.” Trim: 10.75” Live: 10”

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

highly active against brain metastases in patients with HER2-positive metastatic breast cancer. The regimen produced a 67% central nervous system volumetric response rate and delayed the need for

Neoadjuvant Bevacizumab Increases Complete Responses In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial, bevacizumab (Avastin) added to regimens based on docetaxel followed by doxorubicin/cyclophosphamide significantly increased clinical and pathologic complete response rates, especially in the hormone receptor–positive subset. Neither capecitabine nor gemcitabine (Gemzar), however, conferred additional benefit when added to docetaxel but did contribute to toxicity, reported Harry D. Bear, MD, of Virginia Commonwealth University and the Massey Cancer Center, Richmond.2 The study enrolled 1,206 patients, 54% with tumors > 4 cm and 47% with positive lymph nodes. Clinical complete responses were observed in 64.3% in the bevacizumab arm vs 55.8% without bevacizumab (P = .006), and pathologic complete re-

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2011 ASCO Annual Meeting sponses were achieved in 34.5% and 28.4%, respectively (P = .027). Among hormone receptor–positive women, pathologic complete responses were seen in 23.3% and 15.2%, respectively, a significant (P = .008) increase with the addition of bevacizumab. Approximately 50% of the triple-negative subset responded to either regimen. Although neoadjuvant bevacizumab did not significantly increase pathologic complete responses in the triplenegative subset of NSABP B-40, it did improve responses among patients with triple-negative breast cancer in the GeparQuinto study, which was presented by Bernd Gerber, MD, of Rostock, Germany.3 The 684 patients were randomly assigned to epirubicin/cyclophosphamide followed by docetaxel (EC-Doc) with or without bevacizumab. The pathologic complete response rate was 36.4% for the bevacizumab arm vs 27.8% for the EC-Doc arm (P = .021). By the two main definitions of pathologic complete response, the rates were 44.6% vs 36.5%, respectively, when evaluated according to the NSABP definition (no invasive residual disease in the breast; P = .04), and 40.1% vs 32.7%, respectively, by the MD Anderson definition (no invasive residual disease in the breast or nodes; P = .059), Dr. Gerber reported. The addition of bevacizumab, young age, grade 3 disease, and small tumor size independently predicted pathologic complete response in the multivariate analysis. He noted that bevacizumab did not lead to a higher pathologic complete response rate in the overall population, only among those with triple-negative breast cancer.

Bevacizumab Prolongs Remission in Triple-negative Subset of RIBBON-2 The addition of bevacizumab to second-line chemotherapy improved progression-free survival in patients with triple-negative breast cancer in RIBBON-2, reported Adam Brufsky, MD, PhD, of the University of Pittsburgh.4 RIBBON-2 enrolled 684 HER2negative locally advanced or metastatic patients with one prior chemotherapy regimen to second-line chemotherapy (physician’s choice) with or without bevacizumab. His presentation focused on the 159 patients with triplenegative breast cancer. Median progression-free survival was 6.0 months with bevacizumab/chemotherapy compared with 2.7 months with che-

motherapy alone, for a highly significant 51% reduction in risk (P = .0006). Objective response rates were 41% and 18%, respectively (P = .0078). “Despite the immature data and small sample size, there was also a trend toward improved overall survival, from 12.6 months with chemotherapy to 17.9 months with bevacizumab,” Dr. Brufsky reported (hazard ratio = 0.624; P = .0534).

Platinum Monotherapy Is Active in Triple-negative Disease Both carboplatin and cisplatin, given as single agents, showed significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer in a study of 86 patients

Lack of Adjuvant Endocrine Therapy Oncologists need to pay increased attention to side effects related to endocrine treatments and perhaps adjust their message to patients. This was the conclusion of the Cancer Surveillance and Outcomes Team (CanSORT) study, led by T. May Pini, MD, MPH, of the University of Michigan, Ann Arbor, who evaluated reasons why compliance rates are poor with tamoxifen and aromatase inhibitors.5 They surveyed 503 women 4 years after diagnosis of invasive hormoneresponsive breast cancer, and looked at the percentage of noninitiators (who never started therapy), nonpersistors (who started but discontinued), and

New Breast Cancer Findings ■■ In HER2-positive patients with brain metastases, a regimen of lapatanib plus capecitabine produced a 67% central nervous system volumetric response rate and delayed the need for radiotherapy.

■■ Bevacizumab added to standard neoadjuvant regimens improved clinical and pathologic response rates in NSABP B-40 and in the triple-negative subset of GeparQuinto.

■■ Single-agent treatment with carboplatin or cisplatin led to a 30%

response rate in patients with metastatic triple-negative breast cancer in a study by the Translational Breast Cancer Research Consortium.

■■ In the triple-negative subset of RIBBON-2, bevacizumab combined with second-line chemotherapy reduced the risk of progression by 51% and doubled response rates.

■■ Patients prescribed endocrine therapy often discontinue, not only due to side effects, but also due to cost and because of physician influence.

by the Translational Breast Cancer Research Consortium, TBCRC009.4 Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital, Boston, reported that the overall response rate to the compounds was 30.2%, including 4.7% complete responses. Subgroup analyses of the multicenter single-arm trial showed higher responses with cisplatin (37%) than carboplatin (23%), but absent a randomized comparison, Dr. Isakoff cautioned against making treatment decisions based on this difference. “Platinum is a reasonable option for metastatic triple-negative breast cancer, but we still don’t know whether triplenegative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy,” he pointed out. “I think it will take some of the randomized studies now going on in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there is something special about triplenegative disease and platinum.”

persistors (who continued on treatment). Dr. Pini and colleagues also asked patients about the reasons why they never initiated therapy, as well as why they stopped prior to completion of a full course. Among patients who did not initiate treatment (n = 56), women expressed concerns about side effects (27%) or chose not to take their physician’s recommendation (16%); concerns about costs were less common (5%). (Note: responses were not mutually exclusive.) The most common reason for failure to start treatment, however, was that “the doctor said therapy was not needed” (39%); several (4%) reported their physicians did not even discuss endocrine therapy. Of the 447 women who initiated therapy, 83% were persistors and 17% were nonpersistors. Nonpersistence was related to side effects (27%); cost (18%), with less prescription medication coverage associated with an increased likelihood of nonpersistence;

and concerns about adverse effects (16%). Patients also cited a dislike of being on medications (17%) and the need to “move on” from the cancer (11%). Almost one out of six patients (16%) said they were “told to stop” by their physician. Women whose physicians were not medical oncologists had nearly a threefold higher likelihood of nonpersistence. “Decreasing out-of-pocket costs may increase persistence with adjuvant endocrine therapy. Doctors also need to focus attention on the challenging issue of treatment side effects,” Dr. Pini said. Research should aim to identify modifiable aspects of physician-patient communication that could improve rates of initiating and persisting with therapy.

■

Disclosure: Dr. Bachelot has done research and served as a consultant for GlaxoSmithKline. Dr. Lin has received research funding from Genentech and GlaxoSmithKline. Dr. Bear has received honoraria from Genentech and Roche. Dr. Gerber has received honoraria from AstraZeneca, GlaxoSmithKline, Novartis, Roche, and sanofi-aventis, and research funding from Novartis. Dr. Brufsky, Dr. Isakoff, and Dr. Pini reported no potential conflicts of interest.

References 1. Bachelot TD, Romieu G, Campone M, et al: LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2positive metastatic breast cancer before whole brain radiotherapy. 2011 ASCO Annual Meeting. Abstract 509. Presented June 5, 2011. 2. Bear HD, Tang G, Rastogi R, et al: The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. 2011 ASCO Annual Meeting. Abstract LBA1005. Presented June 6, 2011. 3. Gerber B, Eidtmann H, Rezai M, et al: Neoadjuvant bevacizumab and anthracyclinetaxane-based chemotherapy in 686 triplenegative primary breast cancers: Secondary endpoint analysis of the GEPARQUINTO study. 2011 ASCO Annual Meeting. Abstract 1006. Presented June 6, 2011. 4. Brufsky A, Valero V, Tiangco B, et al: Impact of bevacizumab on efficacy of secondline chemotherapy for triple-negative breast cancer: Analysis of RIBBON-2. 2011 ASCO Annual Meeting. Abstract 1010. Presented June 6, 2011. 5. Isakoff SJ, Goss PE, Mayer EL, et al: TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triplenegative breast cancer and evaluation of p63/ p73 as a biomarker of response. 2011 ASCO Annual Meeting. Abstract 1025. Presented June 4, 2011. 6. Pini TM, Griggs JJ, Hamilton AS, et al: Patterns and correlates of adjuvant breast cancer endocrine therapy use. 2011 ASCO Annual Meeting. Abstract 510. Presented June 5, 2011.

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Spotlight on Research Gynecologic Oncology

NCI Clinical Investigator Team Leadership Awards: Conversations in Gynecologic Oncology By Jo Cavallo

he National Cancer Institute recognized Cheryl Saenz, MD, and Linda R. Duska, MD, among others,

B:8.625 in

late last yearT:7.625 within a Cancer Clinical Investigator Team Leadership Award. The S:6.75 in 2-year award includes $50,000 in funding

for cancer research programs at NCI-designated cancer centers. The ASCO Post recently talked with Dr. Saenz and Dr.

Duska about their work and how their respective grants are helping to further their research goals in gynecologic oncology.

CHERYL SAENZ, MD What appealed most to Cheryl Saenz, MD, about specializing in gynecologic oncology was the opportunity it gave her to offer her patients comprehensive care. “When I first rotated on the gynecologic oncology service, it was the most all-encompassing field in oncology because as gynecologic oncologists we operate on our patients, prescribe chemotherapy, and work with the radiation oncologists to treat our patients,” says Dr. Saenz. “It allowed me to take care of my patient from the time

Cheryl Saenz, MD

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

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

B:11.25 in

Despite advances in targeted cancer therapy,

T:10.5 in

S:9.75 in

of her cancer diagnosis until her cure or end of life. And that’s not really available in any of the other oncology specialties.” Now Clinical Professor of Gynecologic Oncology at the University of California, San Diego, School of Medicine, Dr. Saenz focuses on educating women about the prevention of gynecologic cancers and being a facilitator between researchers and clinicians to enable patients to get the most effective treatments for their cancer.

Counseling Patients One of your areas of interest is the prevention of gynecologic cancers. How do you educate women about their risk for cervical, uterine, and ovarian cancers? Dr. Saenz: Each of those malignancies has different risks associated with it. Some risks are hereditary, while others are environmental. With all of these cancers, however, what’s incredibly important is to take a thorough family history, particularly at the patient’s first visit but then at follow-up visits as well, because family history is very dynamic, especially when you have a patient for years and other members of her family are di-

ASCOPost.com | JULY 15, 2011

PAGE 17

Spotlight on Research

agnosed with other malignancies in the interim. And from that information, you can start to put together a picture of a patient’s family history and what her individual risk factors may be. When we talk about a woman with endometrial cancer, it’s important that we not only talk about her family history of ovarian and endometrial cancers and perhaps breast cancer, but colon cancer as well, because colon cancer and endometrial cancer are genetically linked. That’s one of the ways that we focus on prevention. We also focus on preventing environmental malignancies, particularly cervical cancer—which is related to the human papillomavirus (HPV)—especially now that there is a vaccine available to help prevent HPV-driven malignancies. We educate patients about their risk of exposure to HPV and help them discuss the risks with family members.

Research-Clinic Bridge Presently you are not directly involved in clinical trial research. Why were you a recipient of the NCI Cancer Clinical Investigator Team Leadership Award? Dr. Saenz: Although I have not been in the laboratory for several years, the NCI grant was given to me so I could continue acting as a facilitator or as a bridge between the basic and translational research going on here and the clinical activities of the gynecologic cancer service we provide at UC San Diego. For example, when clinicians see patients they may not always be thinking of the latest research and whether some of their clinical questions could be answered in the laboratory. Conversely, researchers may not always be aware of what we’re seeing clinically. Attending meetings with the researchers allows me to bring them relevant clinical findings. We are also one of the sites for the Oncofertility Consortium, an NIH-funded program, which looks at fertility preservation in women undergoing cancer treatment. As part of the consortium, we actually identify young women who may be at risk for infertility and offer them the opportunity to have one of their ovaries removed and frozen for their potential later use in harvesting eggs for in vitro fertilization. When I heard that the program was ongoing, I volunteered to be the surgeon on the protocol. Once we identify an eligible patient, I get the woman into the operating room within 5 to 7 days after diagnosis so that she doesn’t have any subsequent delay in her cancer treatment. So I see myself as someone with a foot in each arena. Having worked in a

molecular biology laboratory for many years and now as a clinician, I have a much greater appreciation for those two areas. As a result, I’m able to bring the two fields together.

Inroads of Success In the future, will it be possible to cure gynecologic cancers or is turning them into chronic diseases the best we can hope for? Dr. Saenz: Of course, my hope is that we could cure these diseases. On the other hand, if we could extend patients’ overall survival, that in itself would be a success. That’s what we have done reasonably well with ovarian cancer. As much as people see ovarian cancer as a horrible disease—and so it is, with 50% of women diagnosed with ovarian cancer dying from the disease—the truth is that we have achieved a long overall survival rate in this population, more so than in patients with a diagnosis of stage III or IV gastric or colon cancer. The greatest inroads of success in ovarian cancer have been in prolonging disease-free intervals.

LINDA R. DUSKA, MD The combination of a better understanding of the molecular and cellular basis of cancer and the near completion of the human genome project is working to turn gynecologic cancers, such as ovarian cancer, into chronic diseases. Finding

includes translational studies intended to help us learn more about gynecologic cancers and biologic treatment effect. In collaboration with my colleagues, Drs. Sally Parsons, Paula Fracasso, and Gina Petroni, we are currently developing a phase 0 study in endometrial cancer. I am very grateful for the scientific, biostatistical, and clinical trial design expertise available at UVA for collaborations in developing a complex trial such as this one. In this trial, we will give a biologic drug to patients prior to hysterectomy and then look at both their endometrial cancer tissue and blood samples to see if the drug is targeting what we think it’s targeting in the endometrial cancer tissue. We’ll also see if we can measure the drug in tumor tissue and correlate this measurement with serum levels. In addition, with my collaborators Drs. Jill Slack-Davis and Jennifer Scalici, we’re conducting a pilot study investigating VCAM, a new potential marker for ovarian cancer in serum. VCAM is measurable in serum but also lights up in the peritoneum of patients with advanced ovarian cancer, and we’re looking at the VCAM response to chemotherapy in the peritoneum and in the blood. Another one of our scientists, Jae Lee, PhD, has developed the COXEN algorithm, which predicts drug sensitivity based on gene-expression analysis. The algorithm was originally devel-

Clinicians need to work more closely with the basic scientists to develop better therapies, so ultimately we’re able to individualize cancer care. more effective targeted treatments that allow patients to maintain a high quality of life is the goal of Linda R. Duska, MD, Associate Professor of Obstetrics and Gynecology and the Gynecologic Oncology Fellowship Director at the University of Virginia (UVA) in Charlottesville. To achieve that goal, Dr. Duska is helping build the clinical trial program in gynecology/oncology at UVA, including NCI-initiated group trials and investigator-initiated trials. One of these trials is an investigator-initiated phase 0 trial in patients with endometrial cancer. Phase 0 trials use pharmacodynamic biomarker assays to evaluate whether a new agent is hitting its intended molecular target.

Based on your research findings, will new treatments for gynecologic cancers be available in the clinic soon? Dr. Duska: I’m very optimistic about that. We’ve made so much progress in our understanding of cancer biology and genetics, and we’re just sitting at the edge of breakthroughs now, but there’s so much more to learn. Clinicians like me need to work more closely with the basic scientists to develop better therapies, so ultimately we’re able to individualize cancer care.

Translational Research

NCI Grant

How is your research resulting in more effective treatments for gynecologic cancers? Dr. Duska: A lot of our clinical work

How will the NCI award help further your work? Dr. Duska: My job isn’t just focused

oped to predict chemosensitivity for bladder cancer, but we’re translating it for use in recurrent ovarian cancer in a phase II prospective design.

Linda R. Duska, MD

on the clinical trial program. I’m a practicing gynecologic oncologist, and I perform complex gynecologic cancer surgeries as well as administer chemotherapy for my patients. I’m also the Fellowship Director for Gynecologic Oncology, and in that role, I see my job as training not only excellent clinicians but also future clinical trialists in the advancement of care for gynecologic cancers. So far, I’ve had the opportunity to mentor two of my fellows in designing and implementing their own clinical trials. The NCI award will allow me to build on both our internal relationships with clinical investigators and basic scientists here at UVA and our external relationships with other cancer centers to launch clinical trials. The UVA Cancer Center has been supportive to me in this regard, from both a mentoring and a financial standpoint, and has allowed me to carve out time to carry out this work. The NCI grant, which UVA is matching, is going to give me the support I need to achieve those goals. In addition to the support for my salary, the UVA Cancer Center has been instrumental in supporting my investigator-initiated trials. Without the Cancer Center’s support, I would not be able to do these studies.

Chronic Illness vs Cure With the progress being made in the understanding of the molecular pathogenesis of gynecologic cancers, do you think these cancers can be turned into chronic illnesses, or will it be possible to cure them? Dr. Duska: That’s a good question. In the case of ovarian cancer, right now for many patients with advanced disease we are able to achieve a “chronic disease” state, which is much better than where we were 10 years ago. Cure is the ultimate goal but living longer and living well with disease is an integral step in this process. We also have to focus more on quality-of-life issues and develop treatments that are not so toxic. I definitely think we’re making progress.

■

Disclosure: Dr. Saenz and Dr. Duska reported no potential conflicts of interest.

The ASCO Post | JULY 15, 2011

PAGE 18

Direct from ASCO

ASCO University® Launches New Programs

couple of convenient new educational opportunities are now available on the ASCO University® website (http://university.asco.org).

Cardiac Comorbidity Boards ASCO University® is now offering a pilot series that focuses on cardiovascular disease and cancer treatment–related toxicities. Each module in this online program features a patient case that is presented and discussed by expert faculty and an open discussion forum that facilitates continued interaction and dialogue between online participants and the faculty. Planning Group members Sandra Swain, MD, Director of the Washington Cancer Center in Washington, DC, and Richard Steingart, MD,

FACC, FSGC, Chief of Cardiology Service at Memorial Sloan-Kettering Cancer Center in New York, collaborate to identify topic areas for each module and identify experts in cardiology and oncology to present the case discussion. “This new series addresses some of the difficult cardiac issues that must be managed in our patients,” Dr. Swain said. Two case topics are currently available; the first deals with toxicities associated with trastuzumab (Herceptin) and anthracycline therapy, and the second focuses on hypertension and vascular endothelial growth factor (VEGF) signaling pathway inhibitors. A third module will be released in the fall and will address issues related to treatment

Special Award Recipients Honored at 2011 ASCO Annual Meeting

ach year, as a way to recognize enhancements in cancer care, ASCO honors individuals who have made significant contributions to the Society, the practice of oncology, and patients with cancer. At this year’s Annual Meeting, ASCO was pleased to recognize the 2011 Special Award recipients: Kenneth C. Anderson, MD, received the David A. Karnofsky Memorial Award and Lecture, for his achievements in cancer research. Dr. Anderson’s studies on novel biologically based therapies for multiple myeloma have helped to transform myeloma therapy.

Kenneth C. Anderson, MD

The Science of Oncology Award and Lecture was presented to Robert A. Weinberg, PhD, for furthering the understanding of cancer through innovative and groundbreaking research. Dr. Weinberg is best known for his discovery of the first human oncogene,

ras, which causes normal cells to form tumors, and for the isolation of Rb, the first known tumor-suppressor gene. For her pioneering work in palliative

with tyrosine kinase inhibitors. The Cardiac Comorbidity Boards can be accessed at http:// university.asco.org/cardiac

New Webinar Series ASCO is also offering live, 1-hour webinars as part of a new Monthly Webinar Series on the ASCO University® website. This new series shares key scientific and educational presentations and focuses on highlights from ASCO’s thematic meetings. Webinar topics include: ■■ The Role of the Primary Care Provider in the Care of Adolescents and Young Adults with Cancer ■■ 2011 Gastrointestinal Cancers Symposium Highlights ■■ 2011 Genitourinary Cancers Symposium Highlights

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

■■ Tumor Oncology: Challenging Cases ■■ Lymph Node Dissection in Breast Cancer ■■ 2011 Annual Meeting Highlights (gastrointestinal, genitourinary, breast) ■■ 2011 Annual Meeting Highlights (lung, melanoma, lymphoma ) Webinars are available for purchase at university.asco.org/webinars. A discount is available for all ASCO members.

■

Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “New Cardiac Comorbidity Boards on ASCO University®” and “New Webinar Series from ASCO University®” Available at ASCO.org/dn. All rights reserved.

What’s Hot in

JCO

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

JCO.org

Jamie H. Von Roenn, MD

medicine, Jamie H. Von Roenn, MD, was awarded the ASCO-American Cancer Society Award and Lecture. Dr. Von Roenn has focused her career on the integration of palliative medicine skills and principles into oncology care. The Gianni Bonadonna Breast Cancer Award and Lecture recognized Luca Gianni, MD, for research that has led to the definition of a successful new regimen for breast cancer, and for the clarification of relevant aspects of the pharmacology of paclitaxel and the mechanisms of drug– drug enhancement with doxorubicin. Dr. Gianni will receive the award and present his lecture at the upcoming 2011 Breast Cancer Symposium.

1. Breast Cancer Adjuvant Therapy: Time to Consider Its TimeDependent Effects Ismail Jatoi, et al 29(17): 2301

6. Future of Treatment for LowRisk Prostate Cancer: For All, for Some, or for None? Anthony V. D’Amico 29(15): 1940

2. How Long Is Long Enough? Andrew D. Seidman 29(16): 2129

7. Genetic Testing for Lung Cancer: Reflex Versus Clinical Selection Paul A. Bunn Jr, et al 29(15): 1943

3. Vatalanib in Advanced Colorectal Cancer: Two Studies With Identical Results Alberto F. Sobrero, et al 29(15): 1938 4. Mesorectal Fascia Instead of Circumferential Resection Margin in Preoperative Staging of Rectal Cancer Bengt Glimelius, et al 29(16): 2142 5. Lymphocyte Infiltration in Breast Cancer: A Key Prognostic Factor That Should Not Be Ignored Roger Mouawad, et al 29(15): 1935

8. Hope and Realism: The Perfect Balance? Shirish M. Gadgeel 29(16): 2291 9. Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and MetaAnalysis of Randomized Clinical Trials Alessandra Gennari, et al 29(16): 2144 10. Myelodysplastic Syndromes: Dissecting the Heterogeneity Peter L. Greenberg 29(15): 1937

ASCOPost.com | JULY 15, 2011

PAGE 19

Direct from ASCO

The Honorable Sherrod Brown, the senior U.S. Senator from Ohio, received the Public Service Award for his efforts to ensure that the new healthcare law included important consumer protections requiring insurance plans to cover routine care for patients undergoing cancer clinical trials. In recognition of his distinguished

Luca Gianni, MD

leadership in geriatric oncology, John M. Bennett, MD, received the B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology. Dr. Bennett was a founding member of the International Society for Geriatric Oncology and the first Chair of the Myelodysplastic Syndromes Foundation. Lee J. Helman, MD, received the Pediatric Oncology Award and Lecture, for his focus on the biology and treatment of pediatric sarcomas, specifically Ewing’s sarcoma, rhabdomyosarcoma, and osteosarcoma. Benjamin O. Anderson, MD, was honored with the Partners in Progress Award for his efforts to improve the quality of care women receive around the world. Over the past decade, he has been a leading voice in the international breast cancer clinical improvement and best practices movement through the establishment of the Breast Health Global Initiative (BHGI). For his efforts to improve cancer treatment and awareness in France and abroad, David Khayat, MD, PhD, received the Distinguished Achievement Award. Dr. Khayat organized the French Federation of Medical Oncologists and was the Co-Founder of the World Summit Against Cancer, which gathered more than 100 international leaders to reaffirm their commitment to the eradication of cancer. Dr. Khayat was the first president of the French National Cancer Institute. Daniel G. Haller, MD, received the Special Recognition Award for his outstanding contributions to clinical oncology and cancer research and for his dedicated service to the oncology com-

munity. At this year’s Annual Meeting, Dr. Haller concluded 10 years of service as the Editor-in-Chief of the Journal of Clinical Oncology, the official journal of ASCO. Finally, the ASCO Statesman Award honored 20 ASCO members

who have demonstrated extraordinary volunteer service, dedication, and commitment to ASCO, through 20 years of volunteer service. A full list of recipients can be found at http://chicago2011.asco.org/AbouttheMeeting/SpecialAwardWinners/

ASCOStatesmenAwardWinners.aspx. ASCO congratulates the 2011 Special Award winners for their outstanding achievements.

■

The ASCO Post | JULY 15, 2011

PAGE 20

Direct from ASCO

Stephen Cannistra, MD, Takes Over as Editor-in-Chief of Journal of Clinical Oncology

ince 1989, Stephen Cannistra, MD, has been working to make the Journal of Clinical Oncology ( JCO) the most credible, authoritative resource for disseminating significant clinical oncology research while acting as a reviewer, Consultant Editor, Associate Editor, Editorial Board Member, and as of June, Editor-in-Chief. Even before his new duties officially began, Dr. Cannistra was developing and implementing “many substantive initiatives… that represent a continued commitment to providing timely service to [the] readership, authors, and patients whom [oncologists] treat.”1 Rapid Review: High-profile, practice-changing studies submitted to JCO will now be eligible for a Rapid Review track. For papers identified as being appropriate for Rapid Review, JCO will provide authors with the first decision within approximately 72 hours from the time the manuscript is assigned to an Editor. Once a Rapid Review manuscript is officially accepted for publication, it will be published online in only

ASCO Celebrates

30,000th Member Milestone

4 to 6 weeks. In an effort to provide Protocol Redactions: As initiated the oncology community with the by former Editor-in-Chief Daniel G. most up-to-date information availHaller, MD, in conjunction with Dr. able, all manuscripts published on a Cannistra, JCO is providing readers Rapid Review track will with a redaction of the be available on an open protocol for all randomaccess basis, accessible to ized phase II and phase nonsubscribers as well as III studies. This material subscribers to JCO. is uploaded as a suppleUnderstanding the mental file at www.JCO. Pathway: JCO is introorg to provide readers ducing a new article type with as much clinically that describes the biology relevant information as underlying the findings of possible. The redactions Stephen Cannistra, MD will include the followoriginal reports. This section, which will be called ing information: ■■ Selection of patients, including Understanding the Pathway (UTP), both eligibility and ineligibility will comprise a two-page summary criteria that will accompany a given original ■■ Schema and treatment plan, report in order to highlight salient sciincluding administration schedule entific aspects for a clinical audience ■■ Rules for dose modification interested in translational research. ■■ Measurement of treatment The goal of the UTP section is to proeffect, including response vide a concise description of the uncriteria, definitions of response derlying pathway or biologic process, and survival, and methods of explain its relevance to the original remeasurement port, and highlight future therapeutic ■■ Reasons for early cessation of or investigational directions pertaintrial therapy ing to the pathway in cancer.

■■ Objectives and entire statistical section (including endpoints) Correspondence: The Correspondence section, which until recently was available online only, has returned to the print issues of JCO. “I have always considered the Correspondence section to represent an ongoing discussion of an original report,” explains Dr. Cannistra; “it is a platform that encourages readers to provide alternative interpretations, uncover flaws in the analysis, and clarify issues that were not fully addressed in the original article. It recognizes the fact that an article’s impact does not end at the time of publication but is shaped by readership opinion.”1 Returning the Correspondence section to print is an effort to ensure that all readers have access to this important section.

■

SCO recently celebrated an important milestone in its 47-year history—the addition of its 30,000th member. ASCO is an incredibly diverse organization, with members practicing in all disease sites, specialties, and settings, plus thousands of members practicing in countries outside the United States. At the 2011 ASCO Annual Meeting six new members were chosen from among the oncology disciplines to represent the Society’s 30,000 members and the “Face of ASCO.”

■

Cancer.Net Mobile App for Patients

escribed as “a gem of a freebie,” Cancer.Net’s new app is the mobile companion for patients to stay informed about cancer and to organize important personal data often needed for doctor visits. It includes interactive tools to help patients get

answers to important questions, track side effects, and manage medications. Direct your patients to www.cancer.net/app to download the Cancer.Net mobile app. © 2011. American Society of Clinical Oncology. All Rights Reserved.

SAVE THE DATE Breast Cancer Symposium 2011

EORTC-NCI-ASCO Annual Meeting on Molecular Markers in Cancer

September 8-10, 2011

October 27-29, 2011

San Francisco Marriott Marquis San Francisco, California

Brussels Meeting Center Brussels, Belgium

To confront a

Common Threat in the 2 leading causes of cancer death1...

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Think Avastin First-line metastatic non-squamous NSCLC: 19% increase in median OS in combination with PC (Study E4599)2

1-year survival:

Percentage Surviving

100

51% vs 44%2

2-year survival:

23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months)

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; HR=hazard ratio; CI=confidence interval.

Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)2 Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)3

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed

AVA0000488100

Printed in USA.

(06/11)

Hemorrhage — Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included: — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included: — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

Most common adverse events Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate: — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

Because overall survival matters Proven to extend overall survival (OS) in the 2 cancers with the highest mortalities1

Percentage Surviving

First-line MCRC: 30% increase in median OS in combination with IV 5-FU–based chemotherapy (Study 2107)4,5

100

First-line median OS:

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

20.3 vs 15.6 months

60 40 20

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

0 6

18 12 OS (Months)

MCRC=metastatic colorectal cancer; IV=intravenous; 5-FU=5-fluorouracil; IFL=5-FU/leucovorin (LV)/irinotecan.

OS in second-line MCRC Study E3200: Median OS of 13.0 months with Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)2,6

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Based on animal data, Avastin may cause fetal harm and may impair fertility Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%),

abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intraabdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy– sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. American Cancer Society. Cancer Facts and Figures 2010. http://www.cancer. org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 21, 2011. 2. Avastin Prescribing Information. Genentech, Inc. February 2011. 3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 4. Data on file. Genentech, Inc. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.

www.avastin.com

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

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Speciﬁc Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone. The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients). Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

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

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. NCI-CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued. System Organ Class/ IFN-α + Placebo IFN-α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5-FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1. Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1). Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected. Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin. Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under-estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. (3% vs. 0%). In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone. (3% vs. 0.3%) and proteinuria (3% vs. 0%). 8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).] Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established. Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose-related and were partially Metabolic/Nutrition reversible upon cessation of treatment. Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients. Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).] In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients. Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).] (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients. 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 ® hemorrhage, and traumatic hematoma). 1 DNA Way Avastin is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus South San Francisco, CA 94080-4990 ©2011 Genentech, Inc. Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

ASCOPost.com | JULY 15, 2011

PAGE 25

11th International Conference on Malignant Lymphoma Hematology

Intergroup Study Evaluates Outcomes of Elderly vs Younger Patients Treated for Advanced Hodgkin Lymphoma By Matthew Stenger

he 11th International Conference on Malignant Lymphoma was held June 15–18 in Lugano, Switzerland. Topics of discussion included lymphoma staging in the new millennium, lymphoma and its microenvironment, and lymphoma cure vs control. The ASCO Post summarized several key presentations in the July 1, 2011, issue. Here is continued coverage of the conference.

Study Design In the Intergroup E2496 trial,1 patients with advanced-stage Hodgkin lymphoma were randomly assigned to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for six to eight cycles plus radiation therapy for bulky mediastinal disease or the Stanford V regimen (doxorubicin, vinblastine, mustard, vincristine, bleomycin, etoposide, prednisone) consisting of 12 weeks of chemotherapy and radiation of 36 Gy to sites greater than 5 cm. Among 812 patients enrolled, 43 were aged 60 years or older (median age of 65 years, 69% with stage III disease, 47% with B symptoms, and 16% with International Prognostic Index ≥ 4), with 23 randomly assigned to ABVD and 22 to Stanford V. In an analysis of characteristics and outcomes in this older group, Andrew M. Evens, DO, MSc, and colleagues from the Intergroup E2496 study found a number of dif-

ferences between older and younger patients, including a greater frequency of mixed cellularity type (35% vs 13%, P = .0004) and lower proportion with ECOG performance status of 0 (35% vs 58%, P = .004). Dose reductions were required in 84% of elderly patients. There were no statistically significant differences in grade 3 or 4 toxicities (by CTCAE criteria) between older and younger patients; however, the incidence of bleomycin lung toxicity occurred in 26% of older patients, which had an associated mortality rate of 18%. Furthermore, the treatment-related morality rate was 9.3% for elderly patients (2 deaths in each arm, 2 due to bleomycin

treatment arms were thus pooled for an exploratory comparison of outcomes between older and younger patients. There were no differences between older and younger patients in overall response rate (70% vs 78%, P = NS) or complete response rate (65% vs 71%, P = NS), but 3-year (55% vs 76%) and 5-year (46% vs 74%) failure-free survival (P = .0014) and 3-year (69% vs 93%) and 5-year (56% vs 90%) overall survival (P < .0001) were significantly lower in older patients.

Results Favor Younger Patients According to Dr. Evens, who is Associate Professor of Medicine at the University of Massachusetts and lead au-

This is one of the first reports from the United States in the past 10 to 15 years of a prospective clinical study in Hodgkin lymphoma that included elderly patients. – Andrew M. Evens, MD

lung toxicity) compared with 0.3% for patients < 60 years old (P < .0001).

A Focus on Elderly Patients Among all elderly patients, there were no differences between the two treatment groups with regard to patient characteristics, overall response rate, complete response rate, failurefree survival, or overall survival; the

thor of the analysis, “This is one of the first reports from the United States in the past 10 to 15 years of a prospective clinical study in Hodgkin lymphoma that included elderly patients. Hodgkin lymphoma is relatively uncommon in the elderly, with most patients being diagnosed in their 20s or 30s.” Dr. Evens said, “This analysis showed that although approximately

The ASCO Post

Wants to Hear from You

Andrew M. Evens, MD

half of the elderly patients are cured with ABVD or Stanford V therapy, progression-free survival and overall survival rates are significantly inferior to those in younger patients. Furthermore, the older vs younger survival rates appear to be disproportionately inferior compared with what we observe in other lymphoid malignancies. This report also confirms prior observations that elderly Hodgkin patients appear to have different disease biology and appear to endure more treatment-related toxicities, notably bleomycin lung toxicity. We need to continue to explore novel therapeutic options for elderly patients.”

■

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

Reference 1. Evens AM, et al: Efficacy and tolerability of ABVD and Stanford V for elderly advanced-stage Hodgkin lymphoma (HL): Analysis from the phase III randomized US intergroup trial E2496 (Abstract 107).

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

The ASCO Post | JULY 15, 2011

PAGE 26

Journal Spotlight Genitourinary Oncology

Studies Explore Potential Benefits of Sunitinib before Nephrectomy in Metastatic Clear Cell Renal Cancer By Matthew Stenger

he multitargeted tyrosine kinase inhibitor sunitinib (Sutent) is established as first-line therapy in metastatic clear cell renal cancer. Data supporting use of cytoreductive nephrectomy in metastatic clear cell renal cancer come from the pre–targeted therapy era, when less-effective immune therapy was standard of care, and the role of nephrectomy in the setting of targeted therapy has not been well established. Most patients in randomized trials of sunitinib had undergone nephrectomy prior to receiving sunitinib treatment. Treatment with sunitinib prior to nephrectomy may pose a number of important advantages, including disease control and potential tumor downstaging that could facilitate surgery and selection of patients with rapidly progressive disease who may not be expected to have optimal benefit from nephrectomy. On the other hand, presurgical treatment could also be associated with such adverse consequences as delayed wound healing, local progression during the treatment interval prior to surgery, and tumor regrowth in the interval off treatment during the nephrectomy period.

Two Studies In a recent issue of the Annals of Oncology,1 Thomas Powles, MD, and colleagues, from St. Bartholomew’s Hospital, University College Hospital London, Whipps Cross Hospital, and The Royal Free Hospital in London, and The Netherlands Cancer Institute in Amsterdam, reported findings from two single-arm phase II studies of sunitinib prior to planned nephrectomy that help shed light on what might be expected from this approach. The two trials were nearly identical in terms of patient characteristics, design, and endpoints, but differed in number of cycles of sunitinib and duration of sunitinib-free interval prior to nephrectomy. Previously untreated patients with newly diagnosed metastatic clear cell renal cancer received either two (study A, n = 19) or three (study B, n = 33) cycles of oral sunitinib at 50 mg/d for 4 weeks on/2 weeks off before planned nephrectomy, with surgery taking place 24 hours (study A) or 14 days (study B) after the last

dose of sunitinib; sunitinib treatment resumed after 21 days (study A) or a minimum of 14 days (study B) after surgery. Among all 52 patients, 77% were male, median age was 60.5 years, median longest diameter of primary tumor before treatment was 9.45 cm, 71% of patients had two or more metastatic sites, and 33% had Memorial Sloan-Kettering Cancer Center (MSKCC) poor-risk disease; more patients in study B (50% vs 5%) had poor-risk disease. With regard to overall patient outcomes, median progression-free survival was 8 months and median overall survival had not been reached at the time of reporting. Number of metastatic sites was the only factor significantly associated with shorter progression-free survival, whereas such factors as study design, MSKCC prognostic group, gender, and age had no significant impact on outcome.

Radiologic Outcomes with Upfront Sunitinib Sunitinib treatment was associated with a 12% median reduction (range: 8%–35%) of the longest diameter of the primary tumor. Partial response of the primary tumor by response evaluation criteria in solid tumors (RECIST v1.1) occurred in 6% of 49 evaluable patients, with 94% having stable disease. No patients had progression or became ineligible for surgery on the basis of changes to the primary tumor. Reduction of the primary tumor was not significantly affected by the number of cycles of sunitinib. Overall, clinical benefit by RECIST criteria occurred in 38 (73%) of patients (79% in study A and 70% in study B), with 5 patients (10%) achieving an overall partial response; 12 (24%) had progression of disease at the time of surgery. The partial response rate for metastatic sites (27%) was higher than that for the primary tumor. The number of cycles of sunitinib prior to therapy did not have a significant effect on overall response rate. There was no difference in outcome between patients with MSKCC poor-risk disease and those with intermediate-risk disease. Grade 3 or worse toxicity occurred

Primary Tumor

20%

-20%

3 cycles of sunitinib 2 cycles of sunitinib

-40%

Metastatic Site

40% 20% 0% -20% -40% -60%

3 cycles of sunitinib 2 cycles of sunitinib

-80% Fig. 1: Percentage change in size of tumors with sunitinib, at (A) primary tumor (longest diameter) and (B) metastatic site (combined metastatic sites, by RECIST v1.1). Reprinted from Powles et al,1 by permission of Oxford University Press, on behalf of the European Society for Medical Oncology.

in 30% of patients with upfront sunitinib, with 21% having a dose reduction. The most common toxicities were mucositis (15%), hand-foot syndrome (11%), fatigue (9%), hypertension (6%), and diarrhea (6%). Toxicity did not delay scheduled surgery in any patient.

Surgical Outcomes A total of 37 patients (70%) underwent radical nephrectomy, with reasons for not undergoing surgery including progression of systemic disease (n = 9), patient choice (n = 3), and being unfit for surgery (n = 2). As noted by the investigators, the patients who declined or were considered unfit for nephrectomy “were benefitting from sunitinib and it was felt that the risks of interrupting treatment and surgery outweighed the benefits.” The majority of tumors were grade 2 or 3. In total, 49% of tumors

contained greater than 50% necrosis. Tissue fibrosis was a prominent feature in 13 patients (62%) in study B, but was not observed in patients in study A. Median blood loss during surgery was 725 mL, median duration of surgery was 189 minutes, and median hospital stay was 8 days. Plasma creatinine level increased significantly (from 78 to 109 µmol/L) after surgery. Surgical complications occurred in 10 patients (27%), including delayed wound healing in 5 and postoperative edema, bleeding requiring surgical reintervention, renal failure requiring dialysis, and postoperative hypotension requiring intensive care unit admission in 1 patient each. Postoperative death due to respiratory failure occurred in 1 patient. There was no difference in surgical complications according to whether presurgical duration off sunitinib was 1 or 14 days.

ASCOPost.com | JULY 15, 2011

PAGE 27

Journal Spotlight

Postoperative Sunitinib The median time from nephrectomy to restarting sunitinib was 21 days. Of 32 patients, 8 exhibited progression of disease by RECIST criteria during the postsurgery time off treatment. Among those with progression, reintroduction of sunitinib resulted in disease stabilization in 5 of 7 patients when compared with metastatic sites at the last staging before nephrectomy. As stated by the investigators, results of this experience with presurgical sunitinib indicate that the approach is “surgically safe and associated with promising efficacy, with the majority [of patients] obtaining a clinical benefit…. Despite [the relative lack of responses] in the primary tumor, the majority SEE PAGE 38 of patients obtained some tumor shrinkage and none became inoperable, which is reassuring.” The finding that 1 day off drug prior to surgery was

not associated with any greater surgical risk is also reassuring; such an approach would permit reduced time off sunitinib therapy. Although there appeared to be no difference in outcomes between patients receiving two cycles (study A)

study (European Organisation for Research and Treatment of Cancer 30073, ClinicalTrials.gov identifier NCT01099423) evaluating immediate nephrectomy vs delayed surgery with preoperative sunitinib in metastatic clear cell renal cancer.2 In this

This experience with presurgical sunitinib indicates that the approach is surgically safe and associated with promising efficacy. of upfront sunitinib and those receiving three cycles (study B), a smaller percentage of those receiving three cycles underwent surgery, and patients receiving three cycles exhibited a high frequency of peritumoral fibrosis. It is unclear whether this finding is associated with the greater time on sunitinib therapy or the greater percentage of poor-risk patients in study B. Findings in these studies contributed to the design of a phase III

ACTIVITY OVERVIEW APNs are critical members of the multidisciplinary team that provides treatment for patients with MM. APNs and physicians need to be aware of the factors that optimize patient outcomes, especially as new therapies become available. This series of half-day conferences will highlight the latest data on the treatment of MM in the frontline and relapsed/refractory settings. The curriculum will include emerging evidence about novel agents, expert commentary on the clinical implications of new research, and case study discussions to provide real-world context. The role of APNs in improving practice management efficiencies as members of the multidisciplinary team will also be explored.

LEARNING OBJECTIVES Upon completion of this activity, participants should be better able to: • Identify patient- and disease-related characteristics that influence selection of appropriate treatment for MM • Assess the latest data on the safety and efficacy of various frontline regimens • Explain recent clinical trial data on novel agents including regimens for relapsed/refractory MM • Apply collaborative approaches for physicians and APNs in toxicity assessment, monitoring, and treatment to help patients achieve positive clinical outcomes • Describe the long-term psychosocial and physical issues that survivors face and how to craft an effective multidisciplinary survivorship care plan • Outline how APNs can be more effectively integrated into the multidisciplinary team that treats patients with MM

References 1. Powles T, Kayani I, Blank C, et al: The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. Ann Oncol 22:10411047, 2011. 2. ClinicalTrials.gov: Immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer. Available at http://clinicaltrials. gov/show/NCT01099423.

CRYSTAL GATEWAY MARRIOTT 1700 JEFFERSON DAVIS HIGHWAY • ARLINGTON, VA 22202

SATURDAY, DECEMBER 3, 2011 REGISTRATION: 8:00 AM • PROGRAM: 8:30 AM

A HALF-DAY CME/CE-CERTIFIED REGIONAL CONFERENCE

This activity has been designed to meet the educational needs of hematology/oncology physicians and advanced practice nurses (APNs) involved in the treatment of patients with multiple myeloma (MM).

Disclosure: Among the authors of the Annals of Oncology article, Drs. Powles and Bex reported participating in advisory boards for Pfizer in 2009. In addition, Pfizer supplied research grants to support the work reported in the Annals article.

SATURDAY, OCTOBER 29, 2011 REGISTRATION: 8:00 AM • PROGRAM: 8:30 AM

EFFICIENCY, REVENUE, AND PATIENT OUTCOMES

TARGET AUDIENCE

■

study, which currently is recruiting patients, an estimated 458 patients are being randomly assigned to immediate or deferred nephrectomy. In the immediate-nephrectomy arm, patients are to receive sunitinib once daily on days 1 to 28 starting 4 weeks after surgery, with postsurgical treatment repeating every 6 weeks for four courses in the absence of disease progression or unacceptable toxicity. In the deferred-nephrectomy arm, patients are to receive preoperative suni-

COLLABORATIVE PRACTICE MODELS FOR PHYSICIANS AND ADVANCED PRACTITIONERS IN MULTIPLE MYELOMA: MAXIMIZING

tinib on days 1 to 28 every 6 weeks for three courses and undergo nephrectomy 1 day after completing sunitinib treatment. Postoperative sunitinib is given on days 1 to 28 every 6 weeks for two courses. The primary outcome measure is overall progression-free survival. The phase III study was initiated in April 2010, and its estimated completion date is in 2014.

SHERATON ANN ARBOR HOTEL 3200 BOARDWALK • ANN ARBOR, MI 48108 ACCREDITATION STATEMENT

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Postgraduate Institute for Medicine and the Institute for Medical Education & Research. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. A statement of credit will be issued only upon receipt of a completed activity evaluation form.

CREDIT DESIGNATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of 3.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

GNA/ANCC

This educational activity for 3.75 contact hours is provided by the Institute for Medical Education & Research, Inc. (IMER). IMER is an approved provider of continuing nursing education by the Georgia Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. There is no fee for this educational activity.

To register please go to www.IMERonline.com/736_mm

FACULTY William I. Bensinger, MD (Co-Chairperson) Fred Hutchinson Cancer Research Center, University of Washington School of Medicine Kristen Detweiler Short, MS, RN, CNP (Co-Chairperson) University of Michigan Comprehensive Cancer Center Jointly sponsored/co-provided by: This activity is supported by an independent educational grant from Millennium Pharmaceuticals, Inc.

The ASCO Post | JULY 15, 2011

PAGE 28

OncologyWorldwide A Prominent Oncologist Retraces Her Steps from Baghdad By Ronald Piana

Maha Hussain, MD, FACP

Maha Hussain, MD, FACP, Professor of Medicine and Urology, is the Associate Director for Clinical Research at the University of Michigan Comprehensive Cancer Center (UMCCC) and Co-leader of its Prostate Cancer/GU Oncology program. Dr. Hussain recently spoke with The ASCO Post about becoming a doctor in her native country of Iraq and the events that propelled her eminent career in oncology.

Career Beginnings Was there a seminal influence that primed your decision to become a doctor? As far back as I can remember I always wanted to be a doctor. My father understood the value of a medical profession— not only as a fulfilling career but also as an opportunity to make a difference—and he encouraged my siblings and me to become doctors. I think inspiration from my three uncles, who were physicians, also played a significant role in my decision. Was it a difficult process getting into medical school in Iraq? In Iraq, like the United States, admission to medical school was very competitive. However, the distinction is that students take a one-time national exam, and the absolute score alone determines ones eligibility for admission. By default, medical school entry requires the highest-ranking scores, and the University of Baghdad College of Medicine gets the highestranking students. In my case, that worked out perfectly because I scored very well and was accepted directly to the University of Baghdad College of Medicine.

Medical School Experience Most students from your generation in U.S. medical programs were men. What

was it like being a female medical student in Iraq? I went to medical school from 1974 to 1980, and at that time I had female professors who were graduates from the 1960s and 1970s. I also knew women from my parent’s generation who had graduated in the 1950s. More than one-third of my class—over 300 students—were women. A starting doctor’s life was not easy, and there were demanding requirements during the first few years of training, including mandatory service in rural areas and several years of intense training before one would think of opening a practice. For women this could have been a huge burden, especially if they decided to marry and have children. Despite these potentially limiting variables, many women went to medical school. We were proud to have earned our places as physicians, and in my experience none of us felt as though we were different or in any way discriminated against. I suppose that this was a manifestation of the progressive attitudes in the urban centers in Iraq at that time and a reflection of the value that Iraqi society put on education.

Gradual Specialization What steered you to oncology? My preference toward a career in oncology developed over time while in the United States. During my clinical training at the different hospitals in Baghdad, oncology was in its infancy and not a developed field in Iraq, by comparison with other subspecialties. At that time, smoking was quite prevalent and preventive cancer care was nonexistent. Those variables coupled with other socioeconomic and cultural factors contributed to patients presenting with far advanced tumors. Baghdad hosted the country’s major medical centers, and as students we saw some of the most complex and advanced instances of cancer. At the time, it struck me that something was wrong with cancer care in Iraq. People shouldn’t have to wait that long to have care, and early detection and prevention of potentially preventable cancers should be a priority. However, my true momentum to-

ward oncology was built during medical training at Wayne State University. There, I was exposed to a broad oncology experience and had the good fortune to closely connect with several members of the hem/onc faculty whom I considered my mentors. In that challenging environment, my interest in oncology intensified. Remember, this was the time when a cure for testes cancer was becoming possible, better systemic treatments were emerging for a variety of advanced cancers, organ preservation strategies were being tested, and clinical and basic research was expanding. The space and opportunity to contribute became apparent, and to date I have never regretted my decision.

Moving to America Leaving one’s homeland is a major life decision. What was the driving factor in your decision, and what brought you to the United States? Getting a higher degree in the West was a professional priority for my husband and me—an objective fostered by our families. However, perhaps the most consequential twist in our lives was that we left Iraq to pursue these opportunities 3 weeks before the start of the Iraq/Iran war. Experiencing the freedoms, opportunities, and potential that the United States provided, we made a conscious decision to make this country our homeland. Our first landing after leaving Iraq was actually the UK. After the first year there, it became clear that while there were opportunities to train, they were not the ones for which we were looking. That coupled with strong encouragement from my uncles (practicing physicians in the United States) was the ultimate catalyst for the decision to move to America. Having just left our homes in Baghdad, we were weary and reluctant to move again, but it was one of the best decisions that we ever made.

Returning to Iraq Do you plan to visit Iraq? This coming August will be 31 years since I left Iraq. I have not gone back but I would love to return for a visit. In fact, as things settle, I may take my

Maha Hussain’s Career Highlights ■■ 1994-present: Co-Chair,

Prostate Cancer Subcommittee, SWOG

■■ 2007-2008: Chair, FDA/Onco-

logic Drugs Advisory Committee

■■ 2009: Chair, ASCO Cancer Education Committee

■■ 2010: Associate Director for

Clinical Research, University of Michigan Comprehensive Cancer Center

■■ 2011: Chair, ASCO/American

Society for Radiation Oncology/ Society of Urologic Oncology Genitourinary Cancers Symposium Program Committee

sabbatical there. This will give me the opportunity to contribute to oncology education or help contribute to the restructuring of the national cancer care system. On a personal note, however severe the changes may be, I would be remiss if I did not acknowledge the desire to return simply to see the place I grew up in.

Last Thoughts Any last thoughts on your oncologic journey? This has actually been a great exercise in reflection! As I look back, I can see that my career was in part being shaped by my personal and professional experiences in Iraq but clearly matured and focused in the United States. I have been fortunate in that I have experienced two different cultures and systems and had several role models and mentors over the years. I’m a doctor at heart—I want to help sick people—but I continue to be curious and intellectually stimulated by the ever-expanding science at the foundation of medicine, starting from my early research experience as a fellow. When I interact with residents, I try my hardest to recruit them into the incredibly exciting and rewarding career of oncology.

■

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

ASCOPost.com | JULY 15, 2011

PAGE 29

Opinion Health-care Policy

Conflicts of Interest continued from page 1

physicians were not accountable, and that the health care delivered had no meaningful impact on patient outcomes. But the ethics of medicine hold duty to the patient first and foremost; it is the patient who holds the physician accountable for the quality of care delivered.

Survival and Chronic Disease The steady advancements in U.S. medical care have had a meaningful impact that increased both quality-oflife and survival rates, as evidenced by a burgeoning retirement age population. According to the Congressional Research Service, the average life expectancy was 49 years in 1900, 59 years in 1930, 70 years in 1960, 75 years in 1990, and 77 years in 2003. In 2009, the World Bank posted the U.S. average life expectancy as 79 years. Early leaps in survival resulted from the control and treatment of infectious diseases with vaccines and antibiotics. Since the 1960s, incremental increases have resulted from advances in the diagnosis and treatment of heart disease and cancer. The fastest growing segment of the U.S. population comprises those aged 80 years and older, with a growth rate four times that of the total population. Perhaps physicians and health-care systems have done their job too well. The diagnosis and treatment of chronic disease, however, has become the more prominent issue, as approximately 75% of all health-care costs relate to the treatment of chronic disease. The rapidly expanding population over the age of 65 years, and the use of Medicare and Social Security payroll tax revenue within general government revenues, has placed significant financial strain on these social programs.

Role of Government For all the debate regarding the cost of health care, however, only 31% of the cost is attributed to hospital care, 21% to physician/clinical services, and 10% to prescription drugs (Fig. 1). The remaining 39% of national health expenditures includes 7% for administrative costs for billing and regulatory compliance—almost as much as that spent on all prescription drugs in the United States. An additional 7% includes investment in new technologies and in health information technology systems.1 The government has, incrementally, assumed a dominant role in health care. With the creation of Medicare and Medicaid in 1964, the federal government rapidly increased its share of health-care spend-

ing from 10% to nearly 25% in 1965. Currently, over 35 million Americans are enrolled in Medicare. Over 50 million Americans now receive Medicaid, at a cost of $273 billion—a 36% jump since 2008 due to the failing economy—and 16 million more will be added to Medicaid by 2014 under the new Affordable Care Act criteria. More than half of all Americans are now enrolled in a federal health-care insurance program.

More about Cost, Less about Quality As the debate over the budget and debt ceilings intensifies, the Medicare issue is really more about the cost and less about the quality of U.S. medical care. The passage of the Patient Protection and Government public health activities 3% Program administration 7%

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■■ ■■

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closer to or below fee-for-service levels (10-year savings of $135 billion). Medicare payments to hospitals that serve a large number of low-income patients, known as disproportionate share hospitals, will be reduced (10year savings of $22 billion). A high-income adjustment will be made for Part B premiums (10year savings of $25 billion). An Independent Payment Advisory Board was created to further reduce Medicare payment rates (10-year savings of $16 billion). A new hospital insurance tax on taxable wages over $200,000 per year for single filers/$250,000 for joint filers will raise $87 billion between FY2013 and FY2019. Investment 7%

Other retail products 3%

Hospital care 31%

Prescription drugs 10% Home health care 3% Nursing home care 6% Dental 4%

Physician/clinical services 21%

Other professional services 6%

Fig. 1: National health expenditures, 2008. Total = $2.3 trillion. Source: Centers for Medicare & Medicaid Services.1

Affordable Care Act begs the question, affordable to whom? The Congressional Budget Office has reported that the coverage provisions will cost $1.445 trillion between FY2012 and FY2021, despite the $500 billion cut in Medicare benefits. Under the legislation, the $500 billion cut in Medicare targets reimbursement of health-care providers, and will be achieved through the following2: ■■ Permanent reductions are being made in the annual updates to Medicare’s fee-for-service payment rates (10-year savings of $196.3 billion). ■■ Maximum payment rates in the Medicare Advantage program are

■■ A new tax on investment income will raise an additional $123 billion over 10 years.

New Payment Models Under the Affordable Care Act, government sanctioned accountable care organizations will require health-care systems to be accountable for the cost as well as the quality of health care. The new model is charged with “restructuring traditional Medicare coverage” and must create a prospective budget and resource assessment. Compliance with the 15 core measures under meaningful use requires significant investment in

health information technology and administrative staff, and will further strain the financials of health-care systems.3 New payment models are established, and Section 3022 of the Affordable Care Act requires participation in a Medicare Shared Savings Program by January 1, 2012. The Shared Savings Program will shift from volume-based to value-based rewards. Centers for Medicare & Medicaid Services (CMS) Director Donald Berwick indicated that financial opportunities for accountable care organizations to achieve shared savings “will vary according to its initial tolerance for risk.”3 The accountable care organization payment models, Shared Savings Program, Partial Capitation Model, and Fully Capitated Model are based on the level of risk and patient population. Capitated models were widely used in the 1990s with private sector health maintenance organizations, which caused significant problems with access to specialty care. The difference now is that the government, rather than a private sector entity, is the gatekeeper for access to medical care. The Shared Savings Program must meet cost targets and is better suited to lowest-risk populations. The Partial Capitation Model places the accountable care organization at risk for the cost of some Medicare services. Finally, the Fully Capitated Model provides global payments, at the discretion of the Secretary of Health and Human Services, for services delivered to high-risk populations. To make up for lost reimbursement and meet the criteria set in the Affordable Care Act, health-care systems must improve efficiency, optimize bed capacity, and invest heavily in health information technology.4

Can Efficiency Be Improved Adequately? The ability of health-care systems to sufficiently improve efficiency to make up for the Affordable Care Act’s reimbursement cuts is in question. The results of a Medicare Physician Group Practice Demonstration Project between 2005 and 2010, involving 10 large physician groups with high information technology penetration and financial solvency, are concerning. Targeting coronary artery disease, diabetes, congestive heart failure, and preventive care, the criteria were met in only 2 of the 10 groups at the end of year 1, 4 groups in year 2, and in only half of the groups by year 3 of the project. To meet the criteria, the groups made an average $1.7 million infrastructure investment, and most of these physician group practices did not break even continued on page 30

The ASCO Post | JULY 15, 2011

PAGE 30

Opinion

Conflicts of Interest continued from page 29

on their initial investment. The calculated operating margins required to recover costs were 20% over 3 years, 13% for 5 years, and 8% for a 10-year payback.5 At the end of 5 years, only 6 of 10 groups produced a savings totaling $78 million over 5 years. On average, this is a savings of $2.6 million per year per group for those that were successful in cost savings. CMS Director Berwick, however, indicated that it was necessary to spend resources to reduce unnecessary services, health information technology was critical, and physician leadership was necessary to motivate implementation of the changes in practice. The newly created Center for Medicare/Medicaid Innovation concurrently is launching “aggressive testing” of nationwide technical support for accountable care organizations to complement ongoing private sector efforts.3

Disclosure: Dr. Janjan has served as a consultant to Bayer Pharmaceuticals.

References 1. Centers for Medicare and Medicaid Services: National health expenditures by type of service and source of funds, CY 1960–2009. Available at http://www.cms.gov. Accessed June 8, 2011.

2. Davis PA, Hahn J, Morgan PC, et al: Medicare provisions in PPACA (P.L. 111148). Congressional Research Service. April 21, 2010. Available at http://assets.opencrs. com/rpts/11-148_20100421.pdf. Accessed June 8, 2011. 3. Berwick DM: Launching accountable care organizations—the proposed rule for the Medicare shared savings program. N Engl J

Med 364(16):e32. Epub March 31, 2011. 4. Berkowitz SA, Miller ED: Accountable care at academic medical centers—lessons from Johns Hopkins. N Engl J Med 364(7):e12. Epub Feb 2, 2011. 5. Haywood TT, Kosel KC: The ACO model—a three-year financial loss? N Engl J Med 364(14):e27. Epub Mar 23, 2011.

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

Select ERBITUX + RT

Other Requirements While a significant investment in health information technology will be needed by some health-care entities, additional administrative staff will also be required to ensure compliance with the 15 core meaningful use measures, and for the submission of reports to the federal government. Under the concept of meaningful use, physicians must have the capacity to “submit electronic syndrome surveillance data to public health agencies and actual submission according to applicable law and practice.” Additionally, more than 80% of patients must have a problem list of active diagnoses. Lists must be generated for quality improvement, reduction of disparities, research, and outreach. Physicians initially must implement one clinical decision “relevant to the medical specialty or a high clinical priority, along with the ability to track compliance”; and there should be clinical decision support that is “intelligently filtered and organized to enhance health and health care,” although “CMS will not issue additional guidance” along these lines. Improvements in medical care, along with a strong tradition of the doctorpatient relationship, have significantly improved the lives of Americans. This relationship determined meaningful patient-centered medical care based on individual circumstances. Under the Patient Protection and Affordable Care Act, accountability of care and meaningful medical practice is now under the control of the payer, ie, the government.

■

ERBITUX Indications ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck ■ ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

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

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

ASCOPost.com | JULY 15, 2011

PAGE 31

FDA Update

First Fentanyl Nasal Spray Approved for Cancer Breakthrough Pain

he FDA has approved fentanyl nasal spray (Lazanda) for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy

for their underlying persistent cancer pain. This marks the first FDA product approval for Archimedes Pharma. The new product will be available in the second half of this year through a

Risk Evaluation and Mitigation Strategy (REMS) program. Pharmacies, distributors, and health-care professionals who prescribe to outpatients are required to enroll in the program to dispense, distribute, and prescribe

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

RT alone (n=213)

Median overall survival 49.0 months

29.3 months

45%

19.7

month improvement

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

3-year survival rate 55% P=0.05

22%

improvement†

EGFR=epidermal growth factor receptor; MAb=monoclonal antibody; RT=radiation therapy; HR=hazard ratio; CI=confidence interval. * A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration of locoregional control. Secondary endpoints included overall survival.1,2 † Relative increase in improvement, from 45% to 55%; ([55-45]/45) x 100=22. Median follow-up=54 months.2

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

ERBITUX Safety Information ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

fentanyl nasal spray. For more information, see www.lazanda.com.

■

The ASCO Post | JULY 15, 2011

PAGE 32

FDA Update

FDA Issues Updated Safety Data on Silicone Gel–filled Breast Implants

he FDA has released a report updating the clinical and scientific information for silicone gel–filled breast implants, including preliminary safety data from studies conducted by the manufacturers (Allergan and

entor) as a condition of their NoM vember 2006 approval. While the report confirms that silicone gel–filled breast implants are safe and effective when used as intended, women should fully understand the risks prior to

considering silicone gel–filled breast implants for breast augmentation or reconstruction. Based on the report, women should know that breast implants are not lifetime devices. The longer a woman has

silicone gel–filled breast implants, the more likely she is to experience complications. The most frequently observed complications and outcomes are capsular contracture, reoperation, and implant removal. Preliminary data do not

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

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

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

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

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

ASCOPost.com | JULY 15, 2011

PAGE 33

FDA Update

indicate that silicone gel–filled breast implants cause breast cancer, reproductive problems, or connective tissue disease. The report includes preliminary safety data from post approval studies conducted by the manufacturers, a summary and analysis of adverse events received over the years by the

FDA, and a comprehensive review of publications that discuss the safety and effectiveness of silicone gel–filled breast implants. The report is part of the FDA’s ongoing effort to ensure that women who have or who may be considering breast implants

are informed of all possible complications and outcomes. The agency has also redesigned its website to include comprehensive information on silicone gel–filled and saline-filled breast implants (www.fda. gov/breastimplants).

■

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

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

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

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2011. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

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

© 2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US11AB05808

5/11

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

The ASCO Post | JULY 15, 2011

PAGE 34

JOP Spotlight Community Oncology

Is Subspecialization an Option or a Necessity in Community Practices? By Charlotte Bath

hould oncologists in community practices subspecialize? What would that mean for them and for their patients? These are some of the issues tackled in a

Journal of Oncology Practice ( JOP) Strategies for Career Success article entitled “Subspecialization in Community Oncology: Option or Necessity?”

What Drives Subspecialization? “The pressure that practitioners feel because of the explosion of knowledge in medical oncology has to a great extent driven subspecialization,”

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

wrote Dean H. Gesme, MD, an oncologist with Minnesota Oncology in Minneapolis, and Marian Wiseman, MA, of Wiseman Communications in Washington, DC. “Patients’

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

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

3 4

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

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

ASCOPost.com | JULY 15, 2011

PAGE 35

JOP Spotlight

Dean H. Gesme, MD

growing sophistication has produced pressure, too.” In an interview with The ASCO Post, Dr. Gesme said he could easily understand the patient’s perspective. “If I had a personal medical problem, I would certainly want to see someone who had not only a lot of intellectual

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

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

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

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

knowledge, but also a lot of experience dealing with whatever the condition was. Because there is just no substitute for experience in clinical medicine.” As Larry J. Geier, MD, an oncologist in a large community practice in Kansas City, Missouri, stated in the JOP article, “Patients want this. They

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group. Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older. OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

want to feel like they are going to someone who really knows their stuff.” Dr. Geier, who specializes in cancer genetics and risk assessment, said that subspecialization improves the quality of care. “If you do it all day every day, you are going to get better and better.”

Barbara McAneny, MD

Generalists Still Needed Not everyone thought subspecialization was needed or helpful. “A subspecialist is what the patients need if they happen to have the disease that is specialized in,” stated private oncologist Barbara McAneny, MD, CEO of an Albuquerque, New Mexico, practice with eight medical oncologists. “We need community oncologists who are continued on page 36

Pros and Cons of Subspecializing Pros

■■ Easier to stay current in

focused area; possibly increases quality of care in subspecialty area

■■ Affords comfort level and confidence in patient management

■■ Fosters efficiency in tumor board attendance

■■ Provides readily available

consultant, go-to expert in group

■■ Promotes consultation, referrals

■■ Cultivates clinical team’s depth of expertise, knowledge

Cons

■■ Harder to stay abreast in other areas; possibly decreases level of care in other areas

■■ Not possible in small practices ■■ Not possible in rural areas with low volume of patients

■■ Deprives subspecialist of variety in patient mix

■■ Requires group compensation

plan that obviates competition for patients

ER-B0001A-03-11

Rev March 2011

■■ May exacerbate workforce shortages

The ASCO Post | JULY 15, 2011

PAGE 36

JOP Spotlight

Subspecialization in Community Oncology continued from page 35

comfortable taking care of everyone,” she said. “The need for subspecialization is also made less essential by the ease of internet information searches. While there is no substitute for personal experience, I have found that most experts in unusual tumors are happy to e-mail or talk with SEE PAGE 38 us, especially when we have read their papers. Genetically driven personalized medicine will be too much for anyone to keep track of when the field reaches its full potential. I feel that electronic decision support may provide better care than even a referral to a subspecialist,” she said. “I certainly feel that there is a very big role for the oncology generalist. There are areas like breast cancer, co-

lon cancer, lung cancer, where all of us who are practicing in the community are going to have to have a modicum of awareness, experience, and scientific knowledge and have to deal with those issues,” Dr. Gesme said. “Most of us need a broad base. And then on top of that, many of us, particularly in large practices, can focus on areas where we have greater depth of knowledge.” He compared it to training in internal medicine before becoming an oncologist. “All of us still use those internal medicine skills to a certain degree,” he said. Subspecialty skills “will be added on top, not necessarily as an alternative to being a generalist or a specialist.”

Deliberate Departure or Gradual Evolution? Subspecialization can be a deliberate departure from general oncology—meant to deal with the explosion of knowledge and expectations of patients—or it can evolve, Dr. Gesme said.

“Five years ago I talked to my group of physicians and they all agreed they really didn’t want to designate themselves as subspecialists. That was the group think,” Dr. Gesme said. “I look back at this past year and essentially everyone in the group now has some kind of a subspecialty area. We’ve never written it down, but it just evolved that way because we do have a large group and we are actively participating in many different multidisciplinary teams.” Dr. Gesme’s group includes 59 oncologists throughout the urban Minneapolis area, with 13 oncologists at the site where he practices. “I’ve got some areas that I emphasize, esophageal and head and neck cancer,” he said. “Another physician specializes in melanoma, and many of us, if we have a melanoma patient, will refer the patient to him early on and get his direction. He is very good about sending the patient back. We manage the patient until a specific issue or dilemma arises and then [our

Cabozantinib Shows Encouraging Activity in Metastatic Castrate‑resistant Prostate Cancer

melanoma specialist] will again see the patient and help us decide exactly what to do if it is a difficult situation,” he said. “Whether they embrace subspecialization or lament it, individuals see subspecialization as a growing trend, driven by the increasing complexity of cancer care, the changing delivery systems, and patient demand,” the article concludes. Will that trigger new designations and certifications by professional organizations and specialty societies? “I think it is premature to do anything immediately,” Dr. Gesme commented, “but I think that is the direction it certainly is going. Studying the issue and being ahead of the curve for professional organizations definitely is something that would make sense.”

■

Reference 1. Gesme DH, Wiseman M: Subspecialization in community oncology: Option or necessity? J Oncol Pract 7:199-201, 2011. Genitourinary Oncology

By Larry J. Rosenberg, PhD

abozantinib, a dual inhibitor of MET kinase and the vascular endothelial growth factor (VEGF) receptor, exhibits high, early single-agent activity in men with metastatic castrate-resistant prostate cancer, according to Maha Hussain, MD, FACP, who presented these findings at the 2011 ASCO Annual Meeting.1 Dr. Hussain, of the University of Michigan in Ann Arbor, reported that cabozantinib therapy resulted in a 76% rate of complete or partial resolution of bone scans, with objective disease control seen in 68% of patients at 12 weeks. Cabozantinib (XL184) is a potent oral inhibitor of the MET, VEGFR2, and RET tyrosine kinases. In a phase I study, cabozantinib demonstrated clin-

ical activity in patients with medullary thyroid cancer. MET and its ligand HGF are believed to promote tumor growth, invasion, and metastasis, and MET expression is often observed in bone metastases and in advanced prostate cancer. Preclinical studies have demonstrated that inhibition of MET reduces cell proliferation in mouse xenograft models of prostate cancer.2 These data led to the current study of cabozantinib in patients with metastatic castrate-resistant prostate cancer.

Study Design In this randomized discontinuation phase II trial, patients with multiple solid tumors were administered oral cabozantinib at a daily dose of

MET Kinase/VEGF Inhibitor in Prostate Cancer ■■ Cabozantinib showed high clinical activity in men with metastatic

castrate-resistant prostate cancer, regardless of prior docetaxel therapy, with evidence of tumor regression seen in 74% of treated patients.

■■ Approximately 76% of patients with bone disease showed complete or partial resolution of bone lesions, as measured by bone scan.

■■ Tumor response and improvements in bone scans seen with cabozantinib therapy were accompanied by reductions in pain and narcotic use for bone pain in evaluable patients, and improvements in bone turnover markers.

100 mg for a 12-week lead-in stage. Subsequent continuation of therapy was based on observed response at 12 weeks: patients with a partial response continued receiving open-label cabozantinib, men with stable disease were randomized to cabozantinib or placebo, while those with progressive disease discontinued therapy. The primary endpoint was objective response rate per modified Response Evaluation Criteria in Solid Tumors (mRECIST v. 1.0) in the lead-in stage. Up to 200 patients could be enrolled to target 70 patients for randomization, for a power of 0.80 to detect a hazard ratio of 0.50. Patients in the metastatic castrateresistant prostate cancer cohort were required to have progressive measurable disease (mRECIST v. 1.0) and could have received one prior chemotherapy regimen (or none), excluding other experimental treatments. Median age was 68 years; ECOG performance status was 0 in 52% of patients and 1 in 48%; 37% had visceral disease. Bone disease was present in 87% of patients, and 43% were pretreated with docetaxel. Randomization was halted at 122 patients based on the high rate of clinical activity observed. A total of 177 patients were accrued.

Key Results There were 7 confirmed partial responses in the lead-in stage (with an additional 3 partial responses subsequently observed), and stable disease was seen in 135 patients (79%), for a disease control rate (partial responses plus stable disease) of 68%. However, 74% of treated patients SEE PAGE 38 showed measurable tumor regression, which was independent of prior treatment. Post-randomization progression-free survival was 21 weeks for patients on cabozantinib vs 6 weeks on placebo (HR = 0.13; logrank P = .0007). With a median followup of 4 months (range 1–15 months), the overall median progression-free survival is 29 weeks. By week 12 of the study, complete resolution of bone scans was observed in 19% of patients and partial resolution in 56% of patients. Additionally, noted Dr. Hussain, in 67 patients receiving narcotics for bone pain, 70% had improved pain, and 56% of assessable patients had decreased or halted narcotics as determined by an investigator. Improvements in bone turnover continued on page 39

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The ASCO Post | JULY 15, 2011

PAGE 38

Perspective

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

Scanning the Codes 1 2

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My First of Many ASCO Meetings By Richard J. Boxer, MD

n June, I attended my first ASCO Annual Meeting. Although I have been practicing and teaching urology for 35 years with a specific interest in genitourinary oncology and I have attended dozens of national meetings, the ASCO Annual Meetings were not on my radar.

Focus on the Patient The opportunity to interact with and learn from the multidisciplinary scholarly colleagues that ASCO brings together is invaluable. While the Annual Meeting may seem overwhelming—11,600 papers, 35,000 attendees, and more than 400 exhibitors—the quality and ease of interaction allows the maximum amount of learning to occur. Bringing to bear the experience of medical, surgical, and radiation oncologists upon both esoteric and common medical issues, ASCO enlightens the professional for the sake of the patient. In the May 1, 2011, issue of The ASCO Post, I wrote: At this year’s ASCO Annual Meeting, we will be introduced to new ideas, discoveries that open windows of opportunity for improving our patients’ quality and quantity of life, and creative methods of reducing the ravages of disease. Data, statistics, facts, and erudite discussions will inundate our week. But we must realize that all of this new information and all the biotechnologic marvels that are displayed in the convention hall are meaningless to the person with cancer unless we are patient-focused.

If my concerns were valid and I had any cause for uneasiness that the information may not be patient-centered, the meeting dashed those concerns, proving that a focus on the patient and scholarly research are compatible efforts, not competitive or mutually exclusive.

My Top Learning Experiences

In an excellent session titled “Treating Genitourinary Malignancies (Prostate, Kidney, and Urothelial Cancers): The Latest and Greatest,” I was educated about “Advances in Prostate Cancer Therapeutics” by Gary R MacVicar, MD, from Northwestern University. For the first time, he was able to report an increase in survival of patients with metastatic castrate-resistant prostate cancer using sipuleucel-T (Provenge), abiraterone (Zytiga), or cabazitaxel ( Jevtana). Christopher Sweeney,

Richard J. Boxer, MD

MBBS, of the Dana-Farber Cancer Institute discussed “What’s New in Urothelial Cancer.” Unfortunately, there is not much new in this setting, but the future is bright with enormous efforts in clinical trials. Dr. Sweeney then summarized the state of the art in treating testicular and bladder cancer. Finally, Elisabeth Heath, MD, of the Karmanos Cancer Institute gave a review titled “Update on Renal Carcinoma: Treatment Options for the Practicing Oncologist.” Her overview of the FDA-approved therapeutics for treating renal cell carcinoma was aimed directly at the oncology community closest to the patient. The clinical science that Dr. MacVicar reviewed was explained in great detail by Charles Ryan, MD, of the University of California, San Francisco, in the Clinical Science session, “Translational Science Advancing AR Targeting in Prostate Cancer.” Dr. Ryan authored the paper on a phase II study on abiraterone. He clearly discussed the findings that have excited the community about the prospect of making advances on a particularly difficult problem, metastatic castrate-resistant prostate cancer. The educational session, “Dutasteride, Finasteride, Micronutrients, and Vitamins for Prostate Cancer Prevention: How Do We Apply What We Have Learned to the Community?” led by Ian Thompson, MD, of the University of Texas Cancer Center in San Antonio, Gerald Andriole, MD, of Washington University in St. Louis, and Otis Brawley, MD, the Medical Director of the American Cancer Society, was a tour de force of the present thinking on prevention of prostate cancer. Again, the emphasis was on the pragmatic approach for practicing oncologists and urologists who care for these patients. The next session that addressed my interest, “The Changing Face of Castration-resistant Prostate Cancer: Standard Therapy and New Targets,” featured Kim N. Chi, MD, from the Vancouver

ASCOPost.com | JULY 15, 2011

PAGE 39

Perspective

Cancer Centre, Charles G. Drake, MD, PhD, from the Sidney Kimmel Comprehensive Cancer Center, and Thomas W. Flaig, MD, from the University of Colorado. The topics of emerging investigational therapies, immunotherapy, and new standards in medical management of metastatic castrate-resistant prostate cancer brought the audience up to date on all the newest (and future) approaches to our most difficult cases of patients with prostate cancer. Finally, the oral abstract session,

Cabozantinib in Castrateresistant Prostate Cancer continued from page 36

markers were also observed, with the majority of patients experiencing decreases of ≥ 50% in plasma Ctelopeptide. In addition, declines in total alkaline phosphatase of ≥ 50% were observed in the majority of patients with increased baseline levels. “Patients who had complete or partial bone scan resolution had higher rates of target lesion regression, higher rates of progression-free survival at 6 months, greater pain improvement, higher reduction in narcotic use, and greater reduction in bone turnover markers,” said Dr. Hussain. The most common grade 3 toxicities during lead-in stage regardless of causality were fatigue (16%), hypertension (6%), and hand-foot syndrome (6%). Dose reductions for adverse events occurred in 51% of patients, and discontinuations due to adverse events in 15% during the 12week lead-in stage. Dr. Hussain concluded that in patients with progressive castrate-resistant prostate cancer, “cabozantinib has substantial antitumor activity,” with significant rates of disease regression and objective disease control, and complete or partial resolution of bone scans at 12 weeks. Cabozantinib is currently undergoing further evaluation in docetaxelpretreated patients in this setting.

■

Disclosure: Dr. Hussain has served as an uncompensated consultant for Exelixis.

References 1. Hussain M, Smith MR, Sweeney C, et al: Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. 2011 ASCO Annual Meeting. Abstract 4516. Presented June 6, 2011. 2. Tu WH, Zhu C, Clark C, et al: Efficacy of c-Met inhibitor for advanced prostate cancer. BMC Cancer 10:556, 2010.

Genitourinary Cancer (Nonprostate), co-chaired by Evan Y. Yu, MD, and Carsten Bokemeyer, MD, offered the audience a comprehensive look at renal cell, germ cell, and urothelial cancers. Once again, the Genitourinary Tract Planning and Educational Committee brought together the most interesting

and thought-provoking series of papers, clearly presented by forward-thinking educators and scholars. My first ASCO meeting gave me a much better understanding of state-ofthe-art care for patients with genitourinary tract malignancies and will serve my patients and students well. I look

forward to ASCO 2012 in Chicago.

■

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

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

The ASCO Post | JULY 15, 2011

PAGE 40

Expert’s Corner Electronic Medical Records

A Conversation with David Henry, MD

Despite initial disruption, EMRs improve oncology practice. By Ronald Piana iKnowMed Integrated Oncology Systems, and in 2010 we switched over to the MOSAIQ system.

iven the intricate nature of oncology workflow, terminology, cancer staging, and the high risk associated with chemotherapy administration, an oncology electronic medical record (EMR) system needs to be much more than a storehouse of patient information. According to David Henry, MD, Clinical Professor of Medicine, Pennsylvania Hospital, Philadelphia, and community oncologist, adopting these complex systems is well worth the initial costs and discomfort.

Why did you switch systems after several years? The iKnowMed was very good. However, the central reason for changing to MOSAIQ was the added functionality of data mining, which our first system didn’t do as well. To provide high-level care you need the ability to ask the system certain questions about how you’re treating patients. For instance, we’ll look at the last 100 patients with bone metastases and see if we treated them with bisphosphonates or denosumab (Xgeva). Our current system allows us to see what we did in managing patients and how we could have improved our treatment of these patients. It is a very important functionality for driving better cancer care patterns.

System Advantage

Initial Adoption

When did you first integrate an EMR system into your clinical practice? Our seven-doctor hem/onc practice has been using an EMR system for about 6 years. Our first EMR was the

We’ve heard varying reports on initial adoption of EMRs. What was your experience? Most oncology EMRs on the market are fairly similar in certain core functionalities, but the amount of learning required depends on the specific practice dynamics. Our current system was clearly written by a computer genius without a doctor or nurse within a 20-mile radius. It is full of complicated computer jargon, which ultimately you learn, but at the beginning it’s like trying to speak a new language. So the accepted wisdom—that EMR adoption is initially painful, but after 3 to 6 months that pain decreases—has been borne out by our experience. But the early learning curve associated with electronic medical systems is well worth it. That said, you should anticipate a major disruption to your office practice. In fact, I would recommend that you cut the hour-per-day patient flow by 50% during the transition. You simply cannot operate as fast as you did prior to adoption. However, if you decide not to cut your volume, then you need to have one of the so-called fluent “superusers” at your elbow every day in the clinic for a few weeks to guide the transition.

David Henry, MD

An oncology-specific EMR/EHR should have: ■■ Chemotherapy automation

with alerts and correct dosing

■■ Specific oncology EMR/EHR templates

■■ Reporting capabilities for both internal and external needs

■■ Automated cancer registry reporting

■■ Clinical trial component ■■ Laboratory result interface ■■ Automated lab result tracking ■■ User-friendly flow sheets, screens, and graphs

■■ Medication inventory tracking ■■ Coding integration ■■ Automation of charging and billing

■■ Direct link to patient education materials and resources

■■ Document scanning ■■ Patient accessibility

Specific System Needs Is your current system designed to be oncology-specific? Absolutely. Oncologists should be getting a totally oncology-specific system. Our system keeps excellent records of basic patient encounters, performs safe and crosschecked chemotherapy order writing, orders lab tests well, and of course compiles a database, so if I want to check to see whether a patient’s platelet count has changed over the past 6 months, I can just pull up the e-chart, and there are the data. Given the complex nature of cancer care, it is vital that practices adopt oncology-specific systems. What are your system upgrade needs? Naturally we are at the mercy of the vendor, who seems to roll out additions to the system in no particular order. The next function that’s going to be released is the e-prescribing module, which we really need. The system itself is modular, so the upgrades and

EMR vs EHR

key difference between an electronic medical record (EMR) and electronic health record (EHR) is that EHRs have all the functions of an EMR but provide a more comprehensive view into a patient’s health and history by pulling and sharing information from other electronic health systems.

■

ish my notes at 9:00 or 10:00 PM; there’s a tremendous amount of typing involved. However, we’re piloting a new voice recognition functionality that could significantly improve our time efficiencies. We’re adopting software called Dragon Naturally Speaking (see “Speeding Up the Patient Chart Process”), which is rolling out its 11th edition. We are currently in the testing

Speeding Up the Patient Chart Process

ragon Naturally Speaking is a speech recognition software package that has three primary functions: taking dictation, converting text to speech, and executing command input. That is, the user can have speech transcribed as written text, have a document synthesized as an audio stream, or issue commands (say, to open an application, edit text, or search the Web) that are recognized as such and performed by the program.

■

add-ons are seamless, without any disruption to the practice.

stage, but so far we are very happy with its performance.

Recommendations for Conversion

Closing Thoughts

What suggestions would you give to a colleague who is readying to take the plunge into the EMR world? The prospect is analogous to considering which smartphone to buy. All of them have different functionalities, and it depends on the personality of your particular practice as to which system best serves your needs. Naturally, smaller practices have different needs than larger, more complex organizations. So a lot of research is involved, but most important, when you get ready to transition to an EMR you must do a lot of critical self-evaluation about the true needs of your practice. After the growing pains, does the EMR save time? An EMR is not time-neutral. I fin-

Any last thoughts about the place of electronic technologies in oncology? Electronic health-care technologies are here to stay, for one thing, because these machines increase safety—not only in chemo ordering but also by giving the ability to treat patients from multiple sites. For example, this weekend I’m on call, so if a patient of one of my partners contacts me and says he doesn’t feel well, I can pull up all of the clinical information on that patient and make a timely and accurate treatment decision. Prior to EMRs, that wasn’t the case. These technologies will continue to evolve and become an ever-more integral part of practicing medicine.

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

ASCOPost.com | JULY 15, 2011

PAGE 41

In the News Gynecologic Oncology

Cervical Cancer Screening Study Should Reassure Physicians and Patients that a 3-Year Screening Interval Is Safe and Effective By Charlotte Bath

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

esults of a large-scale cervical cancer screening study using concurrent human papillomavirus (HPV) and Pap testing should “reassure” women over 30 who test negative for HPV and have normal Pap tests that “it is extremely safe to go 3 years” before being tested again, Barnett S. Kramer, MD, MPH, said in an interview with The ASCO Post. Dr. Kramer is Editorin-Chief of the Journal of the National Cancer Institute and the screening and prevention editorial board of Physician Data Query (PDQ), and recently retired as Associate Director for Disease Prevention at the National Institutes of Health. Initiated by the NCI, the screening investigation was called a “real world” study because it was done in a community setting among 33,818 women receiving concurrent SEE PAGE 38 HPV and Pap testing at Kaiser Permanente Northern California. Investigators estimated 5-year cumulative evidence of cervical cancer and cervical intraepithelial neoplasia grade 3. Among their conclusions was that concurrent testing allowed screening intervals to be safely extended to 3 years for women who had negative HPV tests and normal Pap smears and “reduced the burden of screening on women and clinicians.” Details of the study were reported at the recent ASCO Annual Meeting1 and in the

June 15 edition of The ASCO Post.2 “Initial studies of any diagnostic or screening tests often take place in more controlled settings, where you optimize the performance and so they tell you whether the screening test could work,” Dr. Kramer commented. “I think [the NCI study findings are] a good indicator that in the real world, you don’t need to do an HPV and a Pap test every year. There probably would be no additional benefit, but there could be additional harm resulting from unnecessary biopsies, unnecessary investigation.”

Overcoming Reluctance The study validates current cervical cancer screening recommendations from several groups, including the American Congress of Obstetricians and Gynecologists. Reported reluctance to adopt these guidelines and abandon routine annual testing can be attributed to a combination of factors. “There is an established American medical culture, and if a new test comes along, it often simply gets added to whatever is being done at that time. Physicians who rely on a routine schedule may be reluctant to change it,” Dr. Kramer said. He added that the “very strong evidence” from the study about concurrent testing being safe and effective for women with a negative HPV test and a normal Pap smear, “undercuts the strategy to do it every year no matter what.” In addition, “for most of their adult lives, women are used to getting the test every year, and so they don’t question continuing to get it every year, even though new information becomes available that shows it is quite safe and may even be safer to add a test, but space out the testing. You often hear that if you change it to every 3 years instead of every 1 year, women will be less inclined to get it. I don’t

Why Only for Women over 30?

omen under 30 years old frequently get transient HPV infections that will clear without treatment, according to Dr. Kramer, and that it is why the HPV test “is not used or not recommended for women under 30,” he said. “More often than not, a positive HPV test in younger women is just an indicator of a transient infection that occurred relatively recently and will be cleared without doing anything. You don’t want to overtreat these women.”

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Expect Questions from Your Patients

he study of concurrent HPV and Pap testing for cervical cancer was widely reported even before the recent ASCO Annual Meeting. In an interview with The ASCO Post, Barnett Kramer, MD, was asked how physicians can respond to questions about the study from patients. “You can tell a woman over the age of 30 that if she is HPV-negative, she has an exceedingly low chance of developing a serious cervical abnormality over the next 3 years, and it is okay to screen her Barnett Kramer, MD again in 3 years,” Dr. Kramer replied. “There is virtually one cause of cervical cancer, and that is HPV infection with a carcinogenic strain,” he explained. “So if you are HPV-negative, you are not infected with the cause of cervical cancer, and it is extremely unlikely— even if you do get infected subsequently—that an abnormality and cancer would develop within 3 years and be missed. If you are not infected with a carcinogenic strain of HPV, then the chances that you would get infected and develop a serious cervical abnormality are extremely low within the next 3 years,” he said. The study results are “reassuring,” he added. “You can reassure a woman that based on a negative HPV, it is extremely safe to go 3 years” before the next test.

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know of any evidence to substantiate that,” Dr. Kramer said. The study also concluded, “In routine clinical practice, a single HPV test was clearly superior to a single Pap smear in women age 30 and above for predicting who would develop [cervical intraepithelial neoplasia grade 3] or cervical cancer within 5 years.” Dr. Kramer noted that while the HPV test is more sensitive than a Pap smear, a Pap smear is more specific, and that is why it adds import to a positive HPV finding. “The risk of developing [cervical intraepithelial neoplasia grade 3], higher-grade lesions, or cancer was elevated considerably in women who were HPV-positive. But the risk was highest if they were not only HPVpositive, but also Pap smear–positive.”

Current and Future Testing As previously reported in The ASCO Post,2 “Based on their findings, the authors suggest that a screening program with a single HPV test could be used first, and if negative, no additional testing would be needed for at least 3 years; the Pap test would be reserved only for women who were HPV-positive.” They cautioned, however, that this hypothesis still needs to be tested.

“Although it may someday be shown that it’s perfectly legitimate to use HPV as the primary and the Pap test as the triage,” Dr. Kramer said, “we’re not there yet; it would take more information. But it is conceivable that if you have an HPV as the primary test and it is negative, then you can be confident that the risk will be very low over the next 3 years, so you can stop there. If it is positive, then you can do a Pap test to see if treatment is needed right then and there. Or if the Pap is negative, you could wait 1 year and see if the HPV infection clears, because many HPV infections will clear.” Dr. Kramer noted that currently, HPV testing has only been approved by the FDA in two circumstances. One approved use, which was not tested in this study, is “if a woman has minor abnormalities on the Pap smear, you can triage her to either be treated or to observation with an HPV test. If the HPV test is positive, then you would go on to treatment or colposcopy. If it is negative, then it is safe to follow her and see if the abnormality clears,” Dr. Kramer explained. “The only other approved use is the concurrent use of both HPV and a Pap test, which was the design of this study, continued on page 42

The ASCO Post | JULY 15, 2011

PAGE 42

In the News

Cervical Cancer Screening continued from page 41

which reaffirms that in the community setting, that is a perfectly safe, legitimate strategy,” he said. “It works wells, and it shows how good HPV is as a primary screen when combined with Pap smears.”

While the study concluded that concurrent screening at 3-year intervals “reduced the burden of screening on women and clinicians,” Dr. Kramer pointed out, “you could also decrease the burden considerably if ultimately you showed that you can use HPV as the primary and the Pap test as the tri-

Our New 2010 Impact Factor

age.” Self-collection of an HPV sample by women who didn’t need a Pap test would ultimately “be the most convenient, if it were proven to be just as safe,” he added. While there would need to be safeguards to ensure that samples were collected and submitted properly, there is precedence in the

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community setting for patients collecting screening samples—for example, stool samples for colon cancer screening—and then mailing or bringing the samples to a medical center.

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

References 1. Katki HA, Kinney WK, Fetterman B, et al: Cervical cancer risk for 330,000 women undergoing concurrent HPV testing and cervical cytology in routine clinical practice. 2011 ASCO Annual Meeting. Abstract 1508. Presented June 6, 2011. 2. Goodman A: 2001 3-year screening interval safe for women with HPV-negative and normal Pap tests, data show. The ASCO Post, June 15, 2011.

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PAGE 43

Patient’s Corner Quality of Life

Stalked by Cancer: One Woman’s Story

I lived with the worry that breast cancer would enter my life. I just didn’t know when. By Elyse Spatz Caplan, MA, as told to Jo Cavallo

ancer has been stalking me all my life. My mother’s mother had died of breast cancer at a relatively young age. My mother was diagnosed with breast cancer in the early 1960s, when she was 35 and I was just 5 years old. Although she was told that she probably wouldn’t live more than 2 years, she survived and lived another 26 years cancer-free, until 1989, when she was diagnosed with lung cancer. She died 2 years later. It was while taking care of my mother during her last few weeks of life that I discovered I, too, had breast cancer. I had felt a lump in my left breast while taking a shower in my parents’ home and immediately knew what it meant. Just as I was turning 34, the disease had come for me.

Proactive Stance Because of my family history of cancer—my brother had both Hodgkin and non-Hodgkin lymphoma and died from a rare pancreatic neuroendocrine cancer, and my father also died from pancreatic cancer—even before getting my diagnosis, I had decided to be as proactive as I could to protect my health. I had seen a breast surgeon only 2 months before my diagnosis to map

out a surveillance plan for me to start mammogram and ultrasound screenings, to stay ahead of the cancer. Even though I had been expecting a breast cancer diagnosis, when it finally came I was terrified. I had three young sons— aged 7, 5, and 2—and I thought, “These children need their mother; I cannot die.” My cancer was classified stage IIB multicentric disease, and I was given a mastectomy and four rounds of combination therapy with doxorubicin and cyclophosphamide. Because of my cancer history, I also decided

had, I had to deal with it. I can live without breasts but I can’t live without my life.

Changes in Being a Cancer Survivor Because my professional training is in speech/language pathology and psychology, I decided to use my experience with cancer to help others coping with the disease. When I became the psychosocial program coordinator at a major cancer center nearly 20 years ago, the term “quality of life” was just becoming part of the vernac-

Today, we can more clearly talk to patients about what a good quality of life means to them as they live with cancer. to have a prophylactic contralateral mastectomy, something unheard of at the time. Although my surgeon was against the surgery, I didn’t want to wait for the other shoe to drop. I needed to raise my sons and see them grow up. I’d always lived with the worry that breast cancer would enter into my life, and now that it

ular, but no one could really define what it meant. Today, we can more clearly talk to patients about what a good quality of life means to them as they live with cancer. Is it important for survivors to continue with their careers? To keep their hair as they go through treatment? To see their children graduate from college or get

Coming in Future Issues of ■■ Continued Comprehensive Coverage of the 2011 ASCO Annual Meeting and

Important News from 2011 Best of ASCO Meetings

■■ Comparative Effectiveness Research and Patient Centered Outcomes in Oncology ■■ Special Series on Rising Costs of Cancer Care: It’s More Than Drugs ■■ TAP on Technology: Potential Circulating Tumor Cell Assay for Predicting Prognosis

in Squamous Cell Head and Neck Carcinoma

■■ Integrative Oncology: A Need for More Research ■■ Psychosocial Oncology: Evaluating Suicidal Risk in Persons Diagnosed/Living with Cancer ■■ Columns and Perspectives by Oncology Experts

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

Elyse Spatz Caplan, MA

married? The availability of less toxic, more effective targeted treatments is giving patients the kinds of options I never had. And patients are much better informed about their disease than I was when I was diagnosed 2 decades ago. They go into their oncologist’s office armed with information that needs to be distilled down and personalized for each patient. As a result, physicians need to spend more time with patients, answering their questions and listening to their concerns, and then tailoring treatment based not just on their cancer but on their quality-of-life needs as well.

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Elyse Spatz Caplan, MA, is Director of Programs and Partnerships for Living Beyond Breast Cancer, in Haverford, Pennsylvania.

Antibody-drug conjugates (ADCs):

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

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

Monoclonal antibody

Stable linker

Cytotoxic

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

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

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

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

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