TAP Vol 3 Issue 15 by Harborside Press LLC

Viral Infection and Liver Cancer

| Treatment-related Cognitive Deficits

| Aspirin and Prostate Cancer Mortality

106

VOLUME 3, ISSUE 15

OCTOBER 15, 2012

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

2012 Breast Cancer Symposium

Breast Cancer Symposium Features Surgical Data, Updated Results from BOLERO-2, and Other Important News

On Mentoring: Looking Back with Gratitude and Paying It Forward

By Caroline Helwick

By Richard J. Boxer, MD, FACS

he annual Breast Cancer Symposium, held September 13 to 15 in San Francisco, is jointly sponsored by ASCO, the American Society for Radiation Oncology, the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Cancers, and the Society of Surgical Oncology. The conference allows for close interaction with thought leaders in multiple disciplines as well as an upfront view of advances in the field, a few of which are summarized in this meeting roundup.

Time to Specimen Fixation May Impact Tumor Estrogen Receptor Status See Page 110

A retrospective review of surgeries performed between 2008 and 2011 at the Mayo Clinic, Rochester,

showed that the time to tissue fixation varies significantly among surgeons and can affect estrogen receptor status of the tumor.9 Longer time to fixation (> 60 vs ≤ 60 minutes) was associated with greater odds of estrogen recepHope Rugo, MD tor negativity (64.6% vs 35.4%, P = .03). In a multivariate analysis, time to fixation was an independent predictor of estrogen receptor status. If prolonged, time to fixation leads to false-negative estrogen receptor staining, and patients may not receive appropriate treatment. In-service training was effective at shortening the time to fixation. continued on page 26

Issues in Oncology

Despite Progress, Chemotherapy Drug Shortages Still Vex the Oncology Community By Ronald Piana

ASCOPost.com

uring the first week of November 2011, President Obama signed an Executive Order directing the FDA to take steps to help resolve the drug shortages that were affecting patient care across the country. The oncology community was hit especially hard; many of the drug shortfalls were generic chemotherapy injectables such as vincristine, methotrexate, leucovorin, cytarabine, doxorubicin, and paclitaxel.

Fundamental Questions

Despite the Executive Order and widespread press coverage, drug shortages still exist, challenging the oncology community’s ability to deliver quality care to all our patients. A session at this year’s ASCO Annual Meeting attempted to answer two fundamental questions: Why is this happening, and how can we treat our patients? Session Chair Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer It is important to examine and Center, said that during the identify the root causes of these Q&A following a lecture he gave in 2010 at Rush Unidisturbing shortages in order to stave versity Medical Center, a off future problems. doctor asked what he could —Hagop M. Kantarjian, MD give his patient with newly diagnosed acute myeloid

pon graduation from medical school, doctors are given a gift that lasts a lifetime—the gift of respect. That respect needs to be re-earned every day, but it is accompanied by other rewards that come with caring for people: the ability to gain another’s trust, to reverse illness that alters the patient’s life, to hold fast an individual’s innermost secrets, and to gain enormous satisfaction in so doing. These are the rewards of being a physician. My father was a physician, approximately 40 of my direct relatives are or were physicians, and I am also the extraordinarily fortunate “son” of innumerable professors and mencontinued on page 10

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

MORE IN THIS ISSUE Oncology Meetings Coverage NCCN Hematologic Malignancies Congress �� 3–9 Best of ASCO® ’12 �� 15, 34, 53, 66,

68, 74, 84, 111 Breast Cancer Symposium �� 20–27 Direct from ASCO ��55–58 Bosutinib in CML ��46–51 FDA Update �� 2, 69–73, 116 Antioxidant Supplementation in Patients with Cancer �� 96 Dermatologic Events in Oncology �� 100 Letters to the Editor �� 118

continued on page 42

October is Breast Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | OCTOBER 15, 2012

PAGE 2

FDA Update

Regorafenib Approved for Advanced Colorectal Cancer

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 Philadelphia, Pennsylvania

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

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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 E. David Crawford, MD University of Colorado 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 John A. Fracchia, MD New York Urological Associates 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

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 Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

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

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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

Harborside Press® Publishing Staff

he FDA recently approved regorafenib (Stivarga) to treat patients with metastatic colorectal cancer that has progressed after treatment. Regorafenib is a multikinase inhibitor that blocks several enzymes that promote cancer growth. The drug was reviewed under the FDA’s priority review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. Regorafenib is being approved 1 month ahead of the product’s prescription drug user fee goal date of October 27, 2012, the date the agency was scheduled to complete review of the drug application. “[Regorafenib] is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past two months,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.

Clinical Study The safety and effectiveness of regorafenib were evaluated in a single clinical study of 760 patients with previously treated metastatic colorectal cancer. Pa-

tients were randomly assigned to receive regorafenib or placebo in addition to best supportive care. Patients received treatment until their cancers progressed or side effects became unacceptable. Study results showed patients treated with regorafenib plus best supportive care lived a median of 6.4 months compared to a median of 5 months in patients treated with placebo plus best supportive care. Results also showed patients treated with regorafenib plus best supportive care experienced a delay in tumor growth (progression-free survival) for a median of 2 months compared to a median of 1.7 months in patients receiving placebo plus best supportive care. Regorafenib is being approved with a Boxed Warning alerting patients and health-care professionals that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies. The most common side effects reported in patients treated with regorafenib include weakness or fatigue, loss of appetite, palmar-plantar erythrodysesthesia, diarrhea, mucositis, weight loss, infection, high blood pressure, and dysphonia.

■

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 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) 692-0805. Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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NCCN Hematologic Malignancies Congress

Developments in Hematologic Cancers Include New Considerations in Treating Challenging Leukemias and Multiple Myelomas By Alice Goodman

peakers at the National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies reviewed the current standard of care for various hematologic cancers and explored new concepts in treatment. Below are highlights from presentations on chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and multiple myeloma.

Suboptimal Response in CML For the first time, discussion of suboptimal response has been incorporated into the NCCN Chronic Myelogenous Leukemia Guidelines. Definitive treatment options are not recommended for patients in this subgroup, but the guidelines acknowledge that these patients “require careful monitoring and may benefit from alternative treatment options.”

Neil Shah, MD, PhD

Neil Shah, MD, PhD, UCSF Helen Diller Family Comprehensive Cancer Center, explained that the term “suboptimal response” is derived from the European LeukemiaNet guidelines. Patients with a suboptimal response to imatinib (Gleevec) may still have a substantial long-term benefit from treatment with dose-escalated imatinib or another approved tyrosine kinase inhibitor such as dasatinib (Sprycel), nilotinib (Tasigna), and the recently FDA-approved bosutinib (Bosulif ) but have a reduced likelihood of optimal response. Suboptimal responders at 3 and 12 months should be switched to a different tyrosine kinase inhibitor, Dr. Shah said. At 3 months, suboptimal response refers to lack of any cytogenetic response. At 12 months, suboptimal response is defined

as a partial, but not complete, cytogenetic response (and less than a partial response is considered “failure” by the European LeukemiaNet guidelines). In the early tyrosine kinase inhibitor experience, the 8-year overall survival rate on imatinib treatment was 85%. The majority of events related to disease progression or death occurred during the first 3 years of treatment, Dr. Shah said. Experience with imatinib showed that in general, the deeper the response, the better the long-term outcome. Patients with deep cytogenetic responses have better outcomes than those without a cytogenetic response. “Patients with 3-log reductions may also do better than those with lesser molecular responses, but this is an emerging concept,” he said. About 30% of patients fail to achieve a complete cytogenetic response at 12 months on imatinib. These patients should preferably be switched to a different tyrosine kinase inhibitor. Mutational testing is not recommended at baseline prior to treatment initiation, because drug-resistant mutations develop on treatment. The current recommendation is to perform mutational testing on a patient who fails to meet the 3-month, 12-month, or 18-month milestone. Mutations should also be assessed in patients with loss of response or disease progression at any time Thus far, all approved therapies fail to overcome resistance due to the T315I mutation. However, ponatinib, an investigational tyrosine kinase inhibitor in phase III trials, appears to

Javier Pinilla-Ibarz, MD

overcome resistance to T315I, and this drug should be approved early in 2013, he said.

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

Notes from the NCCN Hematology Meeting Chronic Myelogenous Leukemia

■■ “Suboptimal response” considerations have been incorporated into the CML Guidelines.

Acute Lymphoblastic Leukemia

■■ Stem cell transplantation remains the standard of care for relapsed/ refractory acute lymphoblastic leukemia.

■■ Adult patients with ALL should be risk-stratified at the time of diagnosis

and treated accordingly, and a transplant should be performed after the first complete remission is achieved for high-risk patients.

Multiple Myeloma

■■ A triple-drug combination incorporating a proteasome inhibitor and

an immunomodulatory drug for induction therapy is currently the best approach to newly diagnosed multiple myeloma.

■■ The risk of second malignancies should not dissuade oncologists from treating patients with lenalidomide maintenance therapy.

Overcoming Resistance in CML Another change in the 2012 version of this algorithm is incorporation of molecular testing at the 3-month treatment milestone for patients who fail to meet the threshold of BCR-ABL ≤ 10% on the International Scale on polymerase chain reaction testing. About 50% of patients with CML who develop resistance to tyrosine kinase inhibitors present a mutation in the abl kinase, and although more than 100 have been described, only 14 of them account for about 80% of all treatment-related mutations, explained Javier Pinilla-Ibarz, MD, H. Lee Moffitt Cancer Center, Tampa, Florida. The current NCCN recommendation is to perform BCR-ABL mutational analysis when patients fail to achieve treatment milestones. Higher-dose imatinib is no longer widely used to treat patients with suboptimal response or failure; instead, second-line therapy with a different tyrosine kinase inhibitor is recommended. In specific cases, some mutations may respond better to one of the available tyrosine kinase inhibitors. While V299L, T315A (different from T315I), and F317L/V/I/C mutations are better treated with nilotinib, Y253H, E255K/V, and F359V/C/I are more responsive to dasatinib. Bosutinib may also have better efficacy in cases of F359V/C/I and

F317L/V/I/C mutations. As noted earlier, experts in the field are hoping that the investigational drug ponatinib will fulfill its promise of overcoming the ubiquitous mutation T315I (different from T315A), which is resistant to all the currently available drugs. Data from the PACE trial of ponatinib recently presented at the ASCO Annual Meeting and the European Hematology Association Annual Congress are prom-

Joseph Alvarnas, MD

ising, showing a high complete cytogenetic response rate in heavily pretreated patients, including those who harbor the T315I mutation. The overall complete cytogenetic response rate in patients with chronic phase was 44%, which Dr. Pinilla-Ibarz called “remarkable.” There is still a role for allogeneic stem cell transplantation in CML, he continued. For imatinib failure in accontinued on page 6

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.

Indication VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other

medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a

cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death.

• Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group). • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases concentrations of VOTRIENT and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit juice. Concomitant use of strong CYP3A4 inducers (e.g., rifampin) should be avoided due to the potential to decrease concentrations of VOTRIENT. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of

concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions. The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs. 48%), diarrhea (59% vs. 15%), nausea (56% vs. 22%), decreased weight (48% vs. 15%), hypertension (42% vs. 6%), decreased appetite (40% vs. 19%), hair color changes (39% vs. 2%), vomiting (33% vs. 11%), tumor pain (29% vs. 21%), dysgeusia (28% vs. 3%), headache (23% vs. 8%), musculoskeletal pain (23% vs. 20%), myalgia (23% vs. 9%), gastrointestinal pain (23% vs. 9%), dyspnea (20% vs. 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in AST (51% vs. 22%), ALT (46% vs. 18%), glucose (45% vs. 35%), alkaline phosphatase (32% vs. 23%), total bilirubin (29% vs. 7%), and potassium (16% vs. 11%); decreases in albumin (34% vs. 21%) and sodium (31% vs. 20%); and leukopenia (44% vs. 15%), lymphocytopenia (43% vs. 36%), thrombocytopenia (36% vs. 6%), and neutropenia (33% vs. 7%). Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages. Reference: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.

VOTRIENT.com

The ASCO Post | OCTOBER 15, 2012

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B:11.75”

NCCN Hematologic Malignancies Congress Developments in Hematology continued from page 3

celerated or blast phase, he advised using a new tyrosine kinase inhibitor as a bridge to minimal residual disease and then going to stem cell transplantation as soon as possible. For patients with T315I mutation in

any phase, ponatinib (once it is approved by FDA) should be used as a bridge to minimal residual disease, and allogeneic stem cell transplantation should be performed until we have longer follow-up with this drug.

Relapsed/Refractory ALL Hematopoietic stem cell transplan-

T:10.5” S:8.75”

tation remains the standard of care for relapsed/refractory acute lymphoblastic leukemia, explained Joseph Alvarnas, MD, Associate Clinical Professor at City of Hope Comprehensive Cancer Center in Duarte, California. Experience in treating relapsed/refractory ALL shows that patients should be risk-stratified at the time of diagnosis and

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.2% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be

treated accordingly, and that transplant should be performed after the first complete remission is achieved. Another lesson from the experience at City of Hope is that unrelated donor transplants have similar outcomes as related donor transplants. “Don’t let the lack of sibling donor keep you from moving on to transplant,” Dr. Alvarnas told listeners.

used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10% compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient, treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour

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Several new agents under study may improve outcomes in relapsed/ refractory ALL. Nelarabine (Arranon), a prodrug of ara-G, and clofarabine (Clolar), a second-generation purine nucleoside analog, have had encouraging activity in phase II trials of patients with relapsed/refractory ALL. Each drug has toxicities. With ne-

larabine, neurologic toxicity is the key dose-limiting toxicity, and other significant toxicities include cytopenia, gastrointestinal effects, and pyrexia. Toxicities of clofarabine include elevations of liver enzymes, febrile neutropenia, skin rash, and cytomegalovirus reactivation. Dr. Alvarnas said that researchers are working on finding a monoclonal an-

urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache Musculoskeletal pain Myalgia Gastrointestinal pain Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorder b Skin hypopigmentation Stomatitis Chest pain a b

65 59 56 48 42 40 39 33 29 28 23 23 23 23 20 18 17 14 12 12 11 11 11 11 10

13 5 3 4 7 6 0 3 8 0 1 2 2 3 5 <1 <1 2 2 0 1 2 0 <1 2

1 0 0 0 0 0 0 0 0 0 0 0 0 0 <1 0 0 0 0 0 0 0 0 0 0

48 15 22 15 6 19 2 11 21 3 8 20 9 9 17 9 12 9 2 1 4 1 0 3 6

4 1 2 0 0 0 0 1 7 0 0 2 0 4 5 0 <1 2 0 0 0 0 0 0 0

1 0 0 0 0 0 0 0 2 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), nail disorder (5% versus 0%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased

44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45

5 8 <1

3 2 0

22 18 35

2 2 2

0 1 0

Albumin decreased

Alkaline phosphatase increased Sodium decreased Total bilirubin increased Potassium increased a

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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VOTRIENT

trial in relapsed/refractory ALL found that 26 of 36 patients achieved complete remission (72%), and median survival was 9 months (range, 8.2–15.8 months).4 Inotuzumab ozogamicin is an anti CD22 antibody conjugated with calicheamicin that induces double-stranded DNA breaks. A phase II trial of 40

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6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebocontrolled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

tibody in ALL that parallels rituximab (Rituxan) in lymphoma. Blinatumomab (AMG 103) and inotuzumab ozagamicin are active in relapsed/refractory ALL and well tolerated in preliminary studies. Blinatumomab is the first in a new class of agents called bi-specific T-cell engager (BiTE) antibodies that harness T cells to destroy the tumor cells. A phase II

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Developments in Hematology continued from page 7

patients with relapsed/refractory ALL treated with a median of two courses of therapy showed a complete remission rate of 56%; 70% of responders were alive at 6 months following therapy, and 12 patients went on to allogeneic stem

cell transplant.5 Grade 3 or 4 fever was reported in nine patients and grade 3 hypotension in one patient.

Overcoming Genetic Transformation in Multiple Myeloma Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Bos-

ton, emphasized two main points in his presentation.6 The first is that a triple-drug combination incorporating a proteasome inhibitor and an immunomodulatory drug for induction therapy is the best hope for achieving high frequency and extent of response in newly diagnosed multiple myeloma. After high-dose therapy and stem Kenneth C. Anderson, MD

• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, or severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:

cell transplantation, consolidation and maintenance therapy using these drugs can prolong progression-free survival. The second point he emphasized was that the risk of second malignancies should not dissuade oncologists from treating patients with lenalidomide (Revlimid) maintenance therapy. Dr. Anderson recommended a similar strategy in patients with newly diagnosed multiple myeloma who are not transplant candidates—that is, incorporating new drugs for induction therapy and maintenance therapy to prolong survival. One of the hurdles in treating multiple myeloma is its genetic complexity. At diagnosis, many mutations and other abnormalities are present, and at relapse new mutations arise, copy numbers changes, and translocations and other changes occur. He said that he is “passionate” about “not allowing this genetic evolution to occur in this hideously complex disease” and recommended a three-drug regimen incorporating novel agents as induction therapy followed by maintenance therapy. As the number of new drugs for multiple myeloma has increased, various combinations have been studied as treatment of newly diagnosed patients using drugs like bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide, and dexamethasone. Studies to date have shown that a four-drug combination was not an improvement over triple-drug therapy. The favored induction regimen at Dana-Farber Cancer Institute is RVD (lenalidomide, bortezomib, and dexamethasone), Dr. Anderson said. Building on success with RVD, the recently approved proteasome inhibitor carfilzomib substituted for bortezomib in that regimen may further improve outcomes, he noted. He was enthusiastic about results of a phase II study using the CRD regimen (carfilzomib, lenalidomide, dexamethasone), which were presented at the 2011 American Society of Hematology Annual Meeting.7 An oral proteasome inhibitor, S:12”

based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In preclinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state C max and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

ASCOPost.com | OCTOBER 15, 2012

PAGE 9

NCCN Hematologic Malignancies Congress MLN9708, is in clinical trials. If this drug is approved, then an all-oral three-drug combination would be possible, Dr. Anderson said.

■

Disclosure: Drs. Shah, Pinilla-Ibarz, Alvarnas, and Anderson reported no potential conflicts of interest.

References 1. Shah NP: How to respond to a suboptimal response in CML (and by the way, what is a suboptimal response?). NCCN 7th Annual Congress: Hematologic Malig-

nancies. Presented September 14-15, 2012. 2. Pinilla-Ibarz J: Overcoming resistance to TKI in Ph+ leukemias. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012. 3. Alvarnas JC: New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012. 4. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab

on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012. 5. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamicin (IO; CMC544), a CD22 monoclonal antibody attached to calicheamycin, produces complete response (CR) plus complete marrow response (mCR) of greater than 50% in refractory relapse (R-R) acute lymphocytic leukemia (ALL). 2011 ASCO Annual Meet-

ing. Abstract 6507. Presented June 6, 2011. 6. Anderson KC: Evidence-based treatment of newly-diagnosed multiple myeloma: Does one treatment fit all? NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012. 7. Jakubowiak A, Dytfeld D, Jagannath S, et al: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and lowdose dexamethasone (CRd) in multiple myeloma (MM). 53rd ASH Annual Meeting. Abstract 631. Presented December 12, 2011.

NCCN Appoints Dr. Robert Carlson as Chief Executive Officer

he National Comprehensive Cancer Network (NCCN) has appointed Robert W. Carlson, MD, a leading expert in the field of breast medical oncology, as Chief Executive Officer. “Dr. Carlson is highly regarded in the oncology community, and NCCN is extremely pleased to appoint him as CEO. Over the last 17 years, he has brought to NCCN a remarkable devotion to advancing the NCCN Clinical Guidelines, as well as a collegial leadership style,” said Thomas D’Amico, MD, Chair of the Board of Directors of NCCN. “Dr. Carlson’s years of expertise in oncology have afforded him the ability to lead within a world-class academic cancer institute and develop long-standing relationships and collaborations with other national and international organizations and com-

mittees, patient advocacy groups, and institutions working to proliferate the science behind cancer treatment and improve patient outcomes.”

Leadership Positions Dr. Carlson comes to NCCN from Stanford University Medical Center, where he has served as Professor of Medicine in the Division of Oncology and Stanford Medical Informatics, first joining the faculty in 1983. He is the Medical Director of inpatient oncology and hematology at Stanford Cancer Institute—one of the 21 NCCN Member Institutions (see sidebar). In addition, Dr. Carlson has held or holds numerous leadership positions within the Stanford Cancer Institute and Stanford Hospital and Clinics. Dr. Carlson is a graduate of Stan-

NCCN Member Institutions ■■ City of Hope Comprehensive Cancer Center

■■ Dana-Farber/Brigham and

Women’s Cancer Center Massachusetts General Hospital Cancer Center

■■ Duke Cancer Institute ■■ Fox Chase Cancer Center ■■ Huntsman Cancer Institute at the University of Utah

■■ Fred Hutchinson Cancer Research

Center / Seattle Cancer Care Alliance

■■ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

■■ Robert H. Lurie Comprehensive Cancer Center of Northwestern University

James Cancer Hospital and Solove Research Institute

■■ Roswell Park Cancer Institute ■■ Siteman Cancer Center at BarnesJewish Hospital and Washington University School of Medicine

■■ St. Jude Children’s Research

Hospital / University of Tennessee Cancer Institute

■■ Stanford Cancer Institute ■■ University of Alabama at

Birmingham Comprehensive Cancer Center

■■ UCSF Helen Diller Family

Comprehensive Cancer Center

■■ University of Michigan

Comprehensive Cancer Center

■■ Memorial Sloan-Kettering Cancer

■■ UNMC Eppley Cancer Center at

■■ Moffitt Cancer Center ■■ The Ohio State University

■■ The University of Texas MD

Center

Comprehensive Cancer Center -

The Nebraska Medical Center Anderson Cancer Center

■■ Vanderbilt-Ingram Cancer Center

I am excited to expand my role in NCCN and to work with each and every one of the world-class member institutions, committees and panels, and the superb headquarters staff to improve the lives of people with cancer. —Robert W. Carlson, MD

ford University Medical School, and he completed his internship and junior residency in internal medicine at Barnes Hospital Group in St. Louis, Missouri, and his senior residency in internal medicine at Stanford University.

Long-standing Collaboration Dr. Carlson began his long-standing collaboration with NCCN when the organization was founded in 1995, and since has held numerous leadership roles, most notably, Representative to the NCCN Board of Directors, Chair of the Breast Cancer Guidelines Panel, Member and Founding Chair of the Breast Cancer Risk Reduction Guidelines Panel, and Chair of the Survivorship Guidelines Panel. Dr. Carlson has chaired numerous task forces at NCCN,

has been presented the NCCN Guidelines Achievement Award and the Rodger Winn Award, and has received special recognition and appointment to the NCCN Board of Producers. Dr. Carlson has served in numerous capacities for NCCN over the past 17 years. “My work with NCCN is one of the most rewarding aspects of my career,” he said. “I am excited to expand my role in NCCN and to work with each and every one of the world-class member institutions, committees and panels, and the superb headquarters staff to improve the lives of people with cancer. We will also work hard to develop collaborative relationships with other organizations that share our goals.” Dr. Carlson will officially join NCCN on January 2, 2013.

■

View Our Special Webcast

Case Studies in Rare Lymphomas The ASCO Post announces availability of a special online program featuring cases in Hodgkin lymphoma and systemic anaplastic large cell lymphoma. An expert panel includes moderator James O. Armitage, MD, with faculty Joseph M. Connors, MD, Andreas Engert, MD, and Steven M. Horwitz, MD.

To view the webcast, visit ASCOPost.com/lymphomaweb/ or access the presentation using your smartphone via the QR code shown here.

The ASCO Post | OCTOBER 15, 2012

PAGE 10

Opinion

On Mentoring continued from page 1

tors who educated me. How do I repay those who came before me and gave me so much?

Repaying Our Benefactors When I asked if I might repay my father for providing me with the opportu-

nities for a great public school and medical education, he said the only repayment necessary was to see to the education of my children, and I have. But what is my responsibility to those, in addition to my daughter, who followed me into medicine? As far back as Hippocrates, doctors have been given the responsibility to not only care for others but also to teach and

mentor the “sons” and “daughters” who enter medical practice after them. Our schools also deserve our gratitude. We may have been excellent, hard-working students, but the schools we attended did not have to admit us, educate us, and pass their imprimaturs onto us. We owe those schools our support, both in thanks for our edu-

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Trebananib (AMG 386) With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Trebananib IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel IV QW (3 on/1 off)

R A N D O M I Z A T I O N

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Primary

PFS

2:1 randomization

Placebo IV QW Monotherapy

Key Secondary

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

Trebananib is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20090508) • www.ClinicalTrials.gov (NCT01204749)

Compassion and Wisdom The answers in medicine constantly change, but most of the questions never do. Likewise, there will always be a place for the art of medicine, built on compassion and judgment. Keeping current in the science of medicine never replaces the need for compassion, and the art of medicine is a special gift that must be conveyed to younger physicians. It is our responsibility to convert those who do not know the art of medicine to those who understand and practice this essential skill. As we grow older, hopefully we grow wiser. Wisdom, in my estimation, is knowledge plus experience. One cannot have the judgment to know when and when not to treat without having treated many before and learning from the experience. The patient relies upon that wisdom the doctor derives from experience. We can help so many more by passing on what we have learned; old mistakes need not be repeated. Our hands may not be as steady, our stamina may not be as reliable, but we can still identify symptoms and help make diagnoses, and patients as well as a future generation of physicians can profit from our insight.

Our Legacy

Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

cation and in the interest of educating future students.

So once we are entrusted with the gift of being a doctor, we owe it to our parents, our teachers, our profession, and ourselves to pay it forward. Mentoring is the link from the past to the future. Our legacy should be to prepare our children and the physicians of succeeding generations, for the benefit of all.

■

The ASCO Post

Trebananib is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20101129) • www.ClinicalTrials.gov (NCT01493505)

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facebook.com/TheASCOPost

ASCOPost.com | OCTOBER 15, 2012

PAGE 11

Perspective Hepatocellular Carcinoma

Viral Infection and Liver Cancer: A Global Health Crisis By Ronald Piana

t is estimated that at least 15% of all cancers worldwide can be attributed to infectious etiologies, mostly viral infections. At this year’s ASCO Annual Meeting, an intriguing session on virally induced cancers provided critical clues that could be of real practical value in advancing our battle against cancer, both in the clinic and on the prevention front.1

John D. Groopman, PhD

Moreover, virally induced cancers will have a predominant impact on the world’s rising cancers rates, especially in the economically developing nations. John D. Groopman, PhD, Johns Hopkins University, Baltimore, opened with a sobering worldview of cancer epidemiology. “Currently, almost 50% of the world’s cancer deaths occur in Asia, and by 2050, that percentage will rise to about 70%.”

(HBV) carriers worldwide that will convert into about 100�� million cancer deaths during the rest of the 21st century. “This looming crisis is something that we probably won’t be able to attenuate in the near future, given the disease’s etiology and our lack of broad-based intervention strategies. Right now, about 95% of liver cancer’s etiology is known; however, translating that knowledge into actionable therapies and prevention is our huge challenge,” noted Dr. Groopman. He then gave an overview of our current knowledge of hepatocellular carcinoma. “The classic prospective study by Beasley and colleagues of 22,707 Chinese men in Taiwan, was one of the first analyses to demonstrate the power of an immunologic biomarker by showing that the presence of the HBV antigen was major driving force in the relative risk of developing liver cancer,” said Dr. Groopman. “However, when we looked at these different populations, a geo-

accounting for approximately 300,000 deaths per year.

■■ Men with liver cancer in China have less than a 10% 1-year survival rate; in some regions, the average time to death after diagnosis is 2.6 months.

HBV and Aflatoxin: A Deadly Synergy Over the past 20 years, Dr. Groopman and colleagues have prospectively followed more than 18,240 men. “Using the HBV surface antigen as a biomarker along with a number of aflatoxin biomarkers, particularly the DNA damage products of aflatoxin, we found a statistically significant increase in liver cancer in those that were HBVpositive (relative risk = 7.3) or aflatoxin-positive (relative risk = 3.4). However, in those individuals who were HBV-positive and aflatoxin-positive, there was a greater than multiplicative relative interaction between the virus antigen and the environmental mycotoxin, leading to a relative risk value of 60 for developing [hepatocellular car-

—John D. Groopman, PhD

graphic variation of hepatocellular carcinoma in male HBV carriers suggested that the incidence of [the disease] is not driven solely by the HBV infection, in fact, environmental risk factors play a large role. This finding led to a number of prospective studies in the early 1980s in areas of China where liver cancer incidence is exceedingly high,” said Dr. Groopman.

Viral Transmission in the Third World In developing countries, common modes of virus transmission include:

■■ Perinatal (from mother to baby at birth) ■■ Early childhood infections (unapparent infection through close interpersonal contact with infected household contacts)

■■ Unsafe injection practices ■■ Unsafe blood transfusions ■■ Unprotected sexual contact

■■ About 50% of the world’s liver cancer deaths occur in China. ■■ Liver cancer is the second leading cause of cancer death in China,

About 95% of liver cancer’s etiology is known; however, translating that knowledge into actionable therapies and prevention is our huge challenge.

Clear Demographic Connection To illustrate the viral connection to cancer prevalence, Dr. Groopman focused on liver cancer, which is a major killer of men in Southeast Asia and sub-Saharan Africa. “In terms of its global impact, liver cancer is the third leading cause of cancer death, with more than 80% of these deaths occurring in the world’s economically developing regions,” said Dr. Groopman. He added that there are approximately 500 million hepatitis B virus

Liver Cancer among Men in China

cinoma],” said Dr. Groopman. “Over the past decades, we have gained a lot of knowledge about HBV, in particular, the mutations on the Xgene, which produces a protein, called the X-protein that embellishes the development and proliferation of HBV, which in turn leads to the sequential infection of the hepatocytes in people,” explained Dr. Groopman. Dr. Groopman commented that we are able to detect this biomarker up to 20 years prior to the development of hepatocellular carcinoma. “This is critically important because, in Africa and Asia, children are infected with HBV before the age of 2 years. So, if you don’t have a health-care mechanism for vaccinating children at birth, these children are going to be infected, and consequently will have a high lifetime risk of liver cancer,” said Dr. Groopman.

Prevention Strategies One of major public health challenges in dealing with virally induced liver cancer is that much of the incidence of HBV infection is in regions of the world where economic and political hurdles impede effective strategies. Moreover, the global recession has reduced the funding of major health-care bodies, limiting their ability to launch vaccination programs. “About 79% of [World Health Organization] member states have adopted universal childhood HBV vaccination policies as of 2005. However, according to the latest birth cohort data, less than one-third of the world’s children younger than 1 year of age have been vaccinated for HBV,” said Dr. Groopman, adding that in the two regions with the highest incidence of liver cancer—south eastern Asia and Africa—the percentages of children vaccinated for HBV are 9% and 6%, respectively. The frustration for public healthcare professionals is that much of the world’s liver cancer is preventable. Dr. Groopman pointed to a 20-year follow-up study published in the Journal of the National Cancer Institute in 2009.2 “The study revealed about a 70% drop in liver cancer cases among 6- to 19-year-olds who were vaccinated for the hepatitis B virus at birth. But it is going to take the rest of the century for vaccination strategies to eradicate this virus,” said Dr. Groopman.

■

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

References 1. Groopman J: Virally mediated oncogenesis: Liver cancer and hepatitis. 2012 ASCO Annual Meeting. Extended Education Session. Presented June 1, 2012. 2. Chang MH, You SL, Chen CJ, et al: Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: A 20year follow-up study. J Natl Cancer Inst 101:1348-1355, 2009.

PERJETA: for the first-line treatment of HER2+* metastatic breast cancer Indication

PERJETA™ (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity

• Exposure to PERJETA can result in embryofetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Additional Important Safety Information Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and trastuzumab and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further

6.1-Month Improvement in Median IRF†-Assessed PFS‡1 Placebo + trastuzumab + docetaxel

PERJETA + trastuzumab + docetaxel

100 90 80

18.5

MONTHS

60 PFS (%)

HR = 0.62 95% CI [0.51-0.75] P< 0.0001

12.4

40 30

MONTHS

20 10 0

P+T+D Pl+T+D

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk IRF = independent review facility. PFS = progression-free survival.

† ‡

Select Important Safety Information: Most Common Adverse Reactions

The most common adverse reactions (>30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.1 Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information. For more information, scan the QR code or visit www.PERJETA.com.

Reference: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. *HER2+ = human epidermal growth factor receptor 2 positive.

HER0000955000

Printed in USA.

(06/12)

PERJETA™ (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status 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 specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial Placebo PERJETA Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA™ (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

ASCOPost.com | OCTOBER 15, 2012

PAGE 15

Best of ASCO® Annual Meeting ‘12 Gastrointestinal Oncology

Noncolorectal GI Cancer Evidence Incorporated into Guidelines By Susan London

he noncolorectal gastrointestinal cancer studies selected for this year’s Best of ASCO meetings include some whose results are being folded into practice guidelines or are good candidates for incorporation, according to Alexandria T. Phan, MD, Associate Professor at The University of Texas MD Anderson Cancer Center, Houston, who presented the data at Best of ASCO San Diego.

Alexandria T. Phan, MD

Chemoradiation in Anal Cancer In the ACT II trial, 940 patients with treatment-naive anal carcinoma of clinical stage T3-4, N0-3 or T12, N1-3 were randomly assigned at study entry, and treatment was based on a 2×2 factorial design. Patients were randomly assigned into four arms: mitomycin plus radiation therapy with chemotherapy maintenance, mitomycin plus radiation therapy without chemotherapy maintenance, cisplatin plus radiation therapy with chemotherapy maintenance, and cisplatin plus radiation therapy without chemotherapy maintenance. The rate of complete response at 26 weeks was statistically indistinguishable between mitomycin and cisplatin (83% vs 84%). “There is internal consistency, with an excellent complete

response rate,” Dr. Phan commented. In the entire trial population, patients who had a complete response had superior progression-free survival (83% vs 45%, HR = 0.21, P < .001) and overall survival (93% vs 61%; HR = 0.21, P < .001). Importantly, the rate of complete response increased with time. “The timing of when response is assessed makes a difference,” noted Dr. Phan. Fully 60% of patients who had not achieved a complete response at 11 weeks had achieved one by 26 weeks (Table 1). Meanwhile, complete response remained a significant predictor of outcome (Table 2). “The complete response rate is a good surrogate marker for progression-free survival and overall survival if measured at the right time,” Dr. Phan commented. “In anal cancer, you should wait for 26 weeks postchemoradiation before you do a biopsy and surgery because of continuing disease regression,” she recommended, noting that National Comprehensive Cancer Network guidelines now call for repeated evaluation in patients with persistent disease.2

FOLFOX4 in Chemoradiation for Esophageal Cancer In the PRODIGE 5/ACCORD 17 trial, 267 patients with untreated esophageal cancer who were not surgical candidates were randomly assigned evenly to definitive chemoradiation using FOLFOX4 (leucovorin, fluorouracil [5-FU], oxaliplatin) vs definitive chemoradiation using cisplatin and 5-FU, each followed by more of the same chemotherapy.3 In contrast to results of an earlier phase II trial,4 this phase III trial

Key Noncolorectal GI Cancer Findings Presented at Best of ASCO® ‘12 ■■ Mitomycin- and cisplatin-containing chemoradiation have similar efficacy in anal cancer. Complete response predicts better outcomes; the optimal time to assess response is 26 weeks after chemoradiation.

■■ FOLFOX4 is not superior to cisplatin/5-FU in definitive chemoradiation for esophageal cancer, but it may be less toxic.

■■ Adding panitumumab to chemotherapy worsens outcomes in patients with advanced esophagogastric cancer.

■■ In patients with hepatocellular carcinoma starting sorafenib, prophylactic

use of a urea-based cream reduces the incidence and severity of hand-foot skin reaction.

found that the Table 1: Timing of Complete Response Assessment in the FOLFOX4 and ACT II Trial ci splatin/5-FU CR Rate % Patients Absolute Risk groups did not Week with CR MMC CiSP Difference differ significantly with respect to 11 426 65.2 58.1 7.1% (-0.1, +14.5) median progresP = .05 sion-free sur526 75.4 76.9 1.5% (-7.9, +4.8) vival (9.7 vs 9.4 18 P = .64 months) or over584 84.1 85.0 0.9% (-6.3, +4.5) all survival (20.2 26 P = .74 vs 17.5 months). However, there a In 691 patients with data at all three time points. were fewer deaths CR = complete response; MMC = mitomycin; CisP = cisplatin; OS = overall due to toxicity on survival; PFS = progression-free survival. 1 FOLFOX4 (one Adapted with permission from Glynne-Jones et al. vs six). Table 2: Complete Response as Predictor of Outcome “This was a HR (95% CI) negative study.… (CR vs not CR) In esophageal cancer, nothing has Week PFS OS changed: Concur- 11 0.71 (0.53, 0.95) 0.70 (0.49, 0.99) rent chemoradiaP = .02 P = .046 tion with cisplatin 0.52 (0.38, 0.71) 0.48 (0.34, 0.70) and 5-FU is still 18 P < .001 P < .001 the standard,” Dr. Phan asserted. 26 0.21 (0.15, 0.29) 0.21 (0.15, 0.31) P < .001 P < .001 “But FOLFOX with radiation a In 691 patients with data at all three time points. may be preferred CR = complete response; MMC = mitomycin; CisP = cisplatin; OS = overall for patients with a survival; PFS = progression-free survival. 1 borderline ECOG Adapted with permission from Glynne-Jones et al. [performance sta=�� .01) and memonths, HR = 1.37, P �� tus],” and “the fact that there are fewer dian progression-free survival (6.0 vs toxic deaths with FOLFOX-radiation 7.4 months, HR = 1.22, P = .068). The may allow for a better platform to add rate of objective response did not differ other radiosensitizing drugs in the fusignificantly between groups. ture,” she noted. “The final outcome is disappoint“Early promising results from raning.… There is no benefit of panitudomized phase II trials should always mumab in unselected patients,” Dr. be confirmed in a larger randomized Phan commented. phase III trial,” Dr. Phan added. “So what went wrong with the Panitumumab in Advanced REAL3 trial?” she Esophagogastric Cancer asked. “Perhaps it’s The REAL3 trial tested addition of the wrong biologipanitumumab (Vectibix), an antibody cal subgroup that we to epidermal growth factor receptor picked. There may See Page 110 (EGFR), to the EOX chemotherahave been too many py regimen (epirubicin, oxaliplatin, toxicities. Perhaps capecitabine [Xeloda]) in 553 patients the modified EOX was too low in dose with advanced cancer of the esophaintensity compared to the EOX. And gus, gastroesophageal junction, or maybe we picked the wrong chemostomach.5 “The EOX doses had to be therapy backbone—maybe it should modified because of toxicity to accombe irinotecan,” she suggested. modate the addition of panitumumab,” “In advanced gastroesophageal adeDr. Phan noted. nocarcinoma, the EGFR pathway may Compared with chemotherapy not be relevant,” Dr. Phan concluded, alone, chemotherapy plus panitumumnoting that the similar EXPAND trial, ab was actually associated with worse which used cetuximab (Erbitux) incontinued on page 18 median overall survival (8.8 vs 11.3

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving

Important Safety Information

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. ÂŠ 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6397 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND... • 37% reduction in risk of death vs placebo

(P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 – In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (≥ 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot flush, headache, and upper respiratory tract infection1

XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

Learn more at XtandiHCP.com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; OCTOBER 15, 2012

PAGE 18

Best of ASCOÂŽ Annual Meeting â&#x20AC;&#x2DC;12 Noncolorectal GI Cancer continued from page 15

stead, recently reported negative results as well.6

Preventing Sorafenib Skin Reaction In a phase II trialâ&#x20AC;&#x201D;the largest ever of a supportive measure in patients re-

ceiving anticancer drugsâ&#x20AC;&#x201D;investigators randomly assigned 871 patients starting sorafenib (Nexavar) for advanced hepatocellular carcinoma to prophylactic urea-based skin cream (Eucerin, 10% urea) three times daily plus best supportive care, or to best supportive care alone.7 The group given the urea-based

cream had a lower 12-week incidence of any-grade hand-foot skin reaction (56% vs 74%, PÂ ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ <ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ Â ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ďż˝ .0001) and of grade 2/3 reaction (21% vs 29%, PÂ =Â .004). There was also a prolongation of time to onset (median, 84 vs 34 days; PÂ <Â .0001). The severity of hand-foot symptoms was lower in the urea-based cream group compared with the con-

trol group from week 4 onward, but the impact on daily activities was reduced only transiently. â&#x20AC;&#x153;To me, this is actually the most useful study because it was very impressive how many patients were enrolled in this.â&#x20AC;Ś Itâ&#x20AC;&#x2122;s called a phaseÂ II trial, but it actually should be called a phaseÂ III,â&#x20AC;? Dr. Phan maintained.

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------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 WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders 9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; OCTOBER 15, 2012

PAGE 19

Best of ASCOÂŽ Annual Meeting â&#x20AC;&#x2DC;12 She noted that it was unclear who was assessing the hand-foot skin reaction in the trial, but it ultimately did not matter because patient-reported quality of life was better with the cream. â&#x20AC;&#x153;The urea-based cream is already recommended for grade 1 hand and foot skin reaction,â&#x20AC;? Dr. Phan pointed out.8 â&#x20AC;&#x153;The cost of the urea-based cream

is so much cheaper than the cost of seeing the dermatologist to get treatment for hand and foot skin reaction. Therefore, I think itâ&#x20AC;&#x2122;s reasonable to say that urea-based cream should be used prophylactically for all patients starting on sorafenib.â&#x20AC;?

â&#x2013;

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

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

References 1. Glynne-Jones R, James R, Meadows H, et al: Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II. 2012 ASCO Annual Meeting.

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Abstract 4004. Presented June 2, 2012. 2. NCCN Clinical Practice Guidelines in Oncology. Anal carcinoma. Version 2.2012. Available at http://www.nccn. org/professionals/physician_gls/pdf/ anal.pdf. Accessed August 28, 2012. 3. Conroy T, Galais M-P, Raoul J-L, et al: Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE 5/ACCORD 17 trial. 2012 ASCO Annual Meeting. Abstract LBA4003. Presented June 2, 2012. 4. Conroy T, YataghĂ¨ne Y, Etienne PL, et al: Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer. Br J Cancer 103:1349-1355, 2010. 5. Waddell TS, Chau I, Barbachano Y, et al: A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). 2012 ASCO Annual Meeting. Abstract LBA4000. Presented June 2, 2012. 6. Merck Serono: EXPAND trial of erbitux in advanced gastric cancer does not meet primary endpoint [press release], July 5, 2012. Available at http://www.merckserono.com/corp.merckserono_2011/ en/images/20120705_en_EXPAND_ tcm1494_96884.pdf. Accessed August 28, 2012. 7. Ren Z, Zhu K, Kang H, et al: A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. 2012 ASCO Annual Meeting. Abstract 4008. Presented June 2, 2012. 8. Lacouture ME, Wu S, Robert C, et al: Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001-1011, 2008.

The ASCO Post Follow us on Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only ÂŠ 2012 Astellas Pharma US, Inc. XTANDIÂŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

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The ASCO Post | OCTOBER 15, 2012

PAGE 20

2012 Breast Cancer Symposium Anthracycline Use Steadily Declining in Early Breast Cancer Population By Caroline Helwick

nthracycline use in early-stage breast cancer has been steadily declining, especially for patients with stage I/II or HER2-positive disease, according to an analysis of patients treated at the University of California, San Francisco (UCSF) School of Medicine.1

including nausea, vomiting, cardiomyopathy, and secondary leukemias. There has been interest in identifying equally effective non–anthracyclinecontaining regimens, and evidence now supports the use of TC (docetaxel/cyclophosphamide) and TCH (docetaxel/carboplatin/trastuzumab [Herceptin]). Both of these regimens have been shown to produce diseasefree and overall survival benefits.2,3

Study Design

Katherine M. Serrurier

Treatment Alternatives Lead author Katherine M. Serrurier, Clinical Research Coordinator at the UCSF Breast Care Center, presented the results at the 2012 Breast Cancer Symposium. The study’s senior author was Hope S. Rugo, MD. “Over the second half of the last decade, the use of anthracycline-based

Ms. Serrurier and colleagues sought to determine if these data have led to changes in chemotherapy prescribing patterns, and to evaluate the impact of TC and TCH on the use of anthracycline-containing regimens based on stage, age, and tumor subtype. They reviewed 1,116 charts of patients treated between 2000 and 2010. Approximately half the patients had stage II tumors, while about a quarter had stage I and a quarter had stage III disease. One-fourth of the tumors were HER2-positive. Variations in regimens were examined based on hormone receptor and

EXPERT POINT OF VIEW

n a debate about the benefit of anthracycline therapy at the Symposium, Stephen E. Jones, MD, of US Oncology Research, The Woodlands, Texas, advocated for greater use of non–anthracycline-containing regimens. Dr. Jones was the principal investigator of US Oncology Research Trial 9735,1 which found superior overall survival with TC (docetaxel/cyclophosphamide) vs classic anthracycline chemotherapy (87% vs 82%) as well as superior disease-free survival (81% Stephen E. Jones, MD vs 75%, respectively). They also found fewer instances of congestive heart failure and bone marrow damage in the TC arm, he pointed out. “Since the publication of this study, the use of the TC regimen in the United States has increased dramatically, thereby sparing many women the exposure to anthracyclines,” he said. Dr. Jones said the ideal number of cycles of TC chemotherapy has still not been determined, but six cycles are being evaluated in prospective studies. “I believe that the TC regimen will be equal to anthracycline regimens for most women with HER-2-negative disease,” he said. “However, whether there is a subset of patients who benefit from anthracyclines (eg, triple-negative disease) based on some mechanism of action other than topoisomerase II alpha gene expression remains to be answered.” Studies are underway to help answer this question, he said.

■

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

Reference 1. Jones SE, Holmes FA, O’Shaughnessy JA, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of U.S. Oncology Research Trial 9735. J Clin Oncol 27:1177-1183, 2009.

decade from 2000 to 2010 showed that 80% of chemotherapy was anthracycline-based. However, for the earlier time period, vs the most recent 5 years, the use of anthracycline-based regimens decreased from 95% to 65%, while non–anthracycline-containing regimens increased from 5% to 35% of all chemotherapy treatments, she reported (Fig. 1).

in the treatment of stage I disease (61% reduction) and HER2-positive disease (66% reducSee Page 110 tion). More than 90% of stage�� III patients, however, continue to receive anthracyclines, with only a 6% reduction observed.

Anthracycline Use in Early Breast Cancer Fig. 1: Decreasing use of anthracyclines at University of California, San Francisco, 2000–2010. A = anthracycline; AC = doxorubicin/cyclophosphamide; NA = nonanthracycline; TC = docetaxel/cyclophosphamide; TCH = docetaxel/cyclophosphamide/trastuzumab. Courtesy of Serrurier KM, et al.1

regimens has significantly decreased,” said Ms. Serrurier. “This reduction parallels the presentation of treatment alternatives for the treatment of earlystage breast cancer.” Anthracycline-based combination chemotherapy is a standard of care for treating early-stage breast cancer, but these agents are associated with significant short- and long-term toxicity,

HER2 status, tumor stage, and age at diagnosis. The use of anthracyclinecontaining vs non–anthracycline-containing regimens was evaluated for an earlier time period (2000–2005) and a more recent time period (2006–2010).

One-third Now Receive Nonanthracycline Regimens The overall analysis of use for the

■■ Between the time periods 2000–2005 and 2006–2010, the use of

anthracyclines in treating early breast cancer dropped from 95% to 65% in the University of California, San Francisco, Cancer Registry database.

■■ The greatest reduction in use was in patients with stage I (61%) or HER2positive (66%) disease.

■■ More than 90% of patients with stage III breast cancer still receive anthracycline-based regimens.

The decrease in anthracycline use was observed across all ages, biologic subsets, and in stage�� I and stage�� II disease. The biggest decrease was seen

Interestingly, she added, the use of anthracyclines dropped at this academic institution that receives many refercontinued on page 22

Resistance or intolerance to CML therapy may occur. In some cases, repeatedly. Even today, with a number of available options for treating resistant/intolerant chronic phase chronic myeloid leukemia (CP-CML), a gap in therapy exists. One post-imatinib study found 42% of patients discontinued dasatinib as a second-line therapy by 6 years due to disease progression and/or study drug toxicity.1 Another post-imatinib study found 47% of patients discontinued nilotinib by 4 years due to disease progression and/or drug-related adverse events. 2 Itâ&#x20AC;&#x2122;s clear that for these patients, unmet medical needs persist.

Visit CMLResponseProject.com to learn more. References: 1. Rea D, Vellenga E, Junghanss C, et al. Six-year follow-up of patients with imatinib-resistant or imatinib-intolerant chronic-phase chronic myeloid leukemia (CP-CML) receiving dasatinib. Poster presented at: 17th EHA Annual Congress; June 14-17, 2012; Amsterdam, The Netherlands. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. ÂŠ2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5347112

The ASCO Post | OCTOBER 15, 2012

PAGE 22

2012 Breast Cancer Symposium Novel Device May Eliminate Need for Re-excision after Lumpectomy By Caroline Helwick

novel device employed during breast surgery reduces the need for re-excision due to positive margins. This lessens patient anxiety, lowers treatment costs, and helps preserve the cosmetic appearance of the breast, according to a large prospective study reported at the 2012 Breast Cancer Symposium.1

Intraoperative Identification The MarginProbe (Dune Medical Devices, Inc) provides surgeons with real-time, immediate intraoperative detection of cancerous tissue at the margin of the excised specimen. An FDA advisory panel recently recommended its approval.

excised specimen relies upon visual examination and palpation. Numerous techniques have been tried to improve intraoperative identification, but no significant improvements have been seen in 25 years.” The pathology report, therefore, provides the margin status 1 or 2 weeks postsurgery. In 20% to 40% of cases, it indicates the presence of positive margins and the patient must undergo a second excision, she said. The MarginProbe utilizes radiofrequency electrical fields to identify cancer on the surface of excised tissue specimens, which has a different electrical property from normal tissue.

Study Details

Susan K. Boolbol, MD

“In breast-conserving surgery, which is performed in 60% to 75% of patients with early breast cancer, it is incredibly important to obtain clear margins,” said senior investigator Susan K. Boolbol, MD, of Beth Israel Medical Center, New York. “Intraoperative identification of residual disease at the margins of the

The study involved 495 patients with pure ductal carcinoma in situ (DCIS) or invasive cancer with a DCIS component enrolled at 21 sites. Patients underwent lumpectomy; excised tissue was inspected and palpated, with further excision if the surgeon deemed it necessary. At this point, patients were randomly assigned to having tissue evaluated intraoperatively or not with the probe, as an adjunct to standard of care. “The probe was able to identify positive margins that required reexcision intraoperatively, and the intraoperative evaluation for positive margins usually minimized the total tissue that had to be resected,” Dr. Boolbol reported. “By using the probe both in the pure DCIS popula-

Intraoperative Cancer Detection ■■ In a recent study in patients with early breast cancer, a new device

(MarginProbe) identified positive margins requiring re-excision intraoperatively. The intraoperative evaluation for positive margins usually minimized the total tissue that had to be resected.

■■ Use of the device significantly reduced the number of candidates for reexcision.

■■ Results with the device are dependent on the definition of adequate margins, about which there is no national consensus.

Anthracycline Use continued from page 20

rals and difficult cases that would suggest the need for aggressive treatment. “We are now evaluating this trend in the Northern California Cancer Registry and in the [National Comprehensive Cancer Network (NCCN)] breast

cancer database,” Ms. Serrurier said. “These analyses will for allow for more accurate association of regimen with specific subtype, and most importantly will allow correlations with outcomes over time.”

■

Disclosure: Ms. Serrurier reported no potential conflicts of interest.

tion and in the invasive cancer–plusDCIS group, we reduced the number of times we needed to go back to the operating room.” The intraoperative assessment essentially cut the need for re-excision by half. In the pure DCIS subgroup, repeat surgery was necessary in 37% of the control arm vs 13% of the device arm. In the invasive/DCIS subset, repeat procedures fell from 33% to 17%. The one-stop procedure was no different from the standard approach in the amount of total tissue volume removed, which averaged 85 cc in the device arm and 76 cc in the control arm among the pure DCIS group and 94 cc and 90 cc, respectively, in the invasive/DCIS subset, showing statistical noninferiority of the novel approach in preserving tissue volume. “These are very impressive results,” Dr. Boolbol commented at a press briefing. “Further clinical studies are needed, but this appears to be a novel device that can potentially affect the way we perform lumpectomies.”

Bigger Issue Andrew D. Seidman, MD, of Memorial Sloan-Kettering Cancer Center, New York, agreed that the interval between surgery and receipt of the pathology report is a stressful time for patients, and said, “any device that can reduce anxiety, cost, time, expense, and effort for patients by getting it right the first time is welcome news.” Monica Morrow, MD, the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan-Kettering Cancer Center, however, noted, “The margin issue is much more complicated.” Dr. Morrow, a breast surgeon, told The ASCO Post, “The reoperation rate is completely dependent on how an ‘inadequate margin’ is defined, and there is no consensus on this. If References 1. Serrurier KM, Hwang J, McGuire JP, et al: Chemotherapy treatment patterns for early-stage breast cancer: Decreasing use of anthracycline-based regimens. 2012 Breast Cancer Symposium. Abstract 141. Presented September 14, 2012. 2. Jones S, Holmes FA, O’Shaughnessy

Monica Morrow, MD

your definition is ‘tumor not touching ink,’ then it appears this probe will help to reduce the reoperation rate. If your definition is 5 mm, then it may or may not. It depends on what your baseline positive margin rate is.” Dr. Morrow further pointed out that the manner in which the specimen is processed also affects the positive margin rate. “At Memorial we have processed them in three different ways over the past 10 years. Our positive margin See Page 110 rate was 50% with one approach, 18% with another, and with the way we do it now—which is to take separate margin specimens from around the cavity—it has dropped to 6%,” she said. “The single most important thing to reducing positive margin rates is to come to a national consensus on the definition of an adequate margin,” she emphasized. A consensus conference will tackle this issue later this year.

■

Disclosure: Dr. Boolbol was an investigator in the clinical trial and served as a consultant for Dune Medical during the FDA approval hearing. Drs. Seidman and Morrow reported no potential conflicts of interest.

Reference 1. Freedman BC, Boolbol SK, Cocilovo C, et al: Reduced re-excisions while conserving tissue volume resected in DCIS patients. 2012 Breast Cancer Symposium. Abstract 144. Presented September 13, 2012. J, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:11771183, 2009. 3. Slamon D, Eiermann W. Robert N, et al: Adjuvant trastuzumab in HER2-positive patients. N Engl J Med 365:1273-1283, 2011.

FOCUSED ON YOUR

PATIENTS

February 2012

ZOM-1036266

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PAGE 24

2012 Breast Cancer Symposium 21-gene Recurrence Score Predicts Outcomes of Node-positive, ER-positive Patients after Adjuvant Chemoendocrine Therapy By Caroline Helwick

he 21-gene recurrence score (obtained with Oncotype DX) can help identify patients with estrogen receptor (ER)-positive, node-positive breast cancer who do not respond well to adjuvant chemoendocrine therapy, according to a retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 study presented at the 2012 Breast Cancer Symposium.1

Eleftherios P. Mamounas, MD

Refining Risk “Our findings help to refine residual risk of recurrence in node-positive, estrogen receptor–positive patients, and may help tailor the extent of adjuvant chemotherapy. These data may also identify appropriate candidates for clinical research protocols evaluating new adjuvant treatments,” said lead investigator Eleftherios P. Mamounas, MD, of Aultman Cancer Center in Canton, Ohio. Of course, the recurrence score has been related to outcomes in several patient populations already, but most data are from estrogen receptor–positive node-negative patients. The current study shows that “we can apply those findings to ER-positive patients with any number of positive nodes, treated with chemotherapy as well as endocrine therapy, and find that the recurrence score is still prognostic across the spectrum,” he said. Oncotype DX is currently indicated for use in patients with estrogen receptor–positive, node-negative breast cancer to determine prognosis and estimate whether the addition of chemotherapy to endocrine therapy would be beneficial. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines extend this recommendation to patients with micrometastases in the sentinel node.

Study Details The study included 1,065 patients treated with adjuvant doxorubicin/cyclophosphamide (AC) with or without paclitaxel plus adjuvant tamoxifen in the randomized NSABP B-28 trial. Researchers calculated recurrence score using tissue specimens from past breast surgeries and then correlated the score with outcomes. Median follow-up was 11.2 years. Recurrence score was shown to be low (< 18) in 36%, intermediate (18– 30) in 34%, and high (≥ 31%) in 30% of patients. The distribution of the recurrence score was not statistically significantly different by treatment, type of surgery, or number of positive nodes. However, older patients and patients with small tumors were significantly more likely to have a low recurrence score.

Independent Predictor of Outcomes In the univariate analysis, the recurrence score was a significant predictor of disease-free survival, distant recurrence–free interval, breast cancer–specific survival, and overall survival. In multivariate analysis, the recurrence score provided independent prognostic information for all three endpoints beyond clinical and pathologic factors, including treatment, age, tumor size, tumor grade, number of positive nodes, and type of surgery (P < .001), Dr. Mamounas reported.

EXPERT POINT OF VIEW

ndrew D. Seidman, MD, of Memorial Sloan-Kettering Cancer Center, New York, said the study “highlights the fact that despite hormone receptor positivity and HER2 negativity, many patients will have a high risk of recurrence despite receiving chemotherapy and appropriate endocrine therapy. This gene assay represents a biological tool that may be useful in the future in stratifying patients for clinical trials and in identifying candidates whose outcomes Andrew D. Seidman, MD can be improved.” This work extends the observation that the recurrence score has the unique prognostic power above and beyond standard prognostic factors,” he continued. “I am particularly struck by the fact that it provides unique information in the multivariate analysis. As such, it can determine which patients are well served by an anthracycline-based regimen and an antiestrogen, and conversely, can identify those remaining at high residual risk of relapse, for whom we need to find better treatments, perhaps by overcoming resistance to endocrine therapy.”

■

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

score,” he said. “More importantly, overall survival was 90% for the low recurrence score group, vs 63% for the high recurrence score patients,” he added. “It is also interesting to note that patients with four or more positive nodes and a low recurrence score had better outcomes than those with one to three positive nodes and a high recurrence score,” he said. “And by treatment assignment, outcomes were very similar between treatment arms in patients with low recurrence score, with the benefit of paclitaxel seen mainly in the intermediate– and

Recurrence Score in Breast Cancer ■■ The 21-gene recurrence score (Oncotype DX) may have clinical utility in

patients who are estrogen receptor–positive with any number of positive lymph nodes.

■■ The recurrence score predicted which patients were likely to recur

after chemotherapy and who therefore might benefit from additional treatment.

■■ The recurrence score may also identify low-risk estrogen receptor–positive, node-positive patients who might be sufficiently treated less aggressively.

“The recurrence score was a significant predictor. For patients with a low score, disease-free survival at 10 years was close to 76%, while it dropped to 48% for those with a high

high–recurrence score groups.” The hazard ratios for the prognostic impact of the recurrence score were 2.53 for disease-free survival, 2.42 for distant recurrence-free inter-

val, 3.09 for overall survival, and 3.38 for breast cancer–specific survival, all highly significant (P < .001). The recurrence score was strongly related to 10-year risks of recurrence, with disease-free survival events occurring in 54% of patients in the high end of the recurrence score See Page 110 group vs 17% of those in the low end of the recurrence score. Breast cancer–specific deaths occurred in 33% and 2%, respectively, Dr. Mamounas further reported. In an exploratory analysis, the recurrence score remained an independent predictor of all outcomes in patients with HER2-negative/equivocal tumors. In this subgroup of 937 patients, patients with high vs low recurrence score had more than a sixfold increase in breast cancer–specific mortality (P < .001).

Treatment Decisions The recurrence score provides information regarding residual risk of recurrence after chemotherapy. Therefore, the study’s findings can potentially help in making treatment decisions, Dr. Mamounas maintained. continued on page 25

ASCOPost.com | OCTOBER 15, 2012

PAGE 25

2012 Breast Cancer Symposium Adjuvant Chemotherapy for Breast Cancer Not Linked to Acute Myeloid Leukemia and Myelodysplastic Syndromes By Caroline Helwick

Neelima Denduluri, MD

ontradicting what some previous investigations have found, a study from The US Oncology Network found that adjuvant chemotherapy for breast cancer does not increase the risk of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS), at least within the first 3�� years of treatment.1 The study was presented at the 2012 Breast Cancer Symposium by Neelima Denduluri, MD, of Virginia Cancer Specialists, Arlington, Virginia. “The rates of AML/MDS were found to be low after adjuvant chemotherapy, and similar to those noted in non– See Page 110 chemotherapy-treated patients,” Dr. Denduluri reported. She acknowledged that the followup time is short. However, she pointed out, “the majority of topoisomerase-

induced leukemias are detected within the first 3 years.” The risk of developing AML/MDS after breast cancer treatment has been estimated at approximately 1% overall, though higher risks may be incurred by patients who are older and those who have received anthracyclines, high cumulative doses of cyclophosphamide, or radiotherapy. It has not been established whether granulocyte colonystimulating factors or taxanes are correlated with increased risk. The goal of this study was to evaluate risk among the population of 20,900 breast cancer patients in the oncology-specific electronic health record, iKnowMed.

No Increased Risk from Chemotherapy At a median follow-up of about 3 years, 12 cases of AML/MDS were identified among 11,295 chemotherapy recipients (0.106%), including 11 cases among 8,829 patients receiving pegfilgrastim (Neulasta) and 1 case among 2,466 patients not receiving pegfilgrastim. Among 9,605 patients not receiving chemotherapy, there were 16 cases (0.167%, P = .26). Of the 12 cases of AML/MDS in chemotherapy-treated patients, 8 patients had received anthracycline-contain-

Adjuvant Chemotherapy and AML/MDS Risk ■■ A large population-based study found that the risk of secondary acute myeloid leukemia and myelodysplastic syndromes following adjuvant chemotherapy is not increased, compared to patients not receiving chemotherapy.

Recurrence Score continued from page 24

“We can identify patients with high residual risk in spite of receiving chemotherapy. We can try to find a better treatment for them or enroll them in clinical trials evaluating novel adjuvant therapies. On the other hand, patients with low residual risk may do well with shorter duration of chemo-

therapy and will not be the best candidates for such clinical trials.” He suggested that for low-risk patients it might be sufficient to treat with four cycles of AC, rather than a full course of eight cycles, including a taxane, though this will require further confirmation. Existing data already suggest, he added, that low-risk patients may not benefit from che-

ing therapy. The median time to onset of AML/ MDS was 1.8 years in the chemotherapy group and 2.2 years in the nochemotherapy group. Among patients for whom cytogenetic information was available, abnormal cytogenetics were identified in 8 of 11 chemotherapytreated patients with AML/MDS and in 3 of 15 cases with no prior chemotherapy.

■

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

Reference 1. Denduluri N: Risk of acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy for early breast cancer in the community setting. 2012 Breast Cancer Symposium. Abstract 62. Presented September 14, 2012.

EXPERT POINT OF VIEW

lifford A. Hudis, MD, of Memorial SloanKettering Cancer Center, New York, said that the findings of the US Oncology study should be “very reassuring” to physicians and patients. “Several recent publications and SEER (Surveillance, Epidemiology, and End Results) database analyses have reported what strike some of us as remarkably high rates of AML/MDS,” he Clifford A. Hudis, MD told The ASCO Post. The current study results are much more in line with clinical trial data (such as the pivotal Cancer and Leukemia Group B [CALGB] 9741 trial of dose-dense chemotherapy1) that show the risk to be “a fraction of a percentage,” he said. Dr. Hudis added, “I think studies based on SEER data are overestimating the real risk. Dr. Denduluri showed data that are more in line with what the prospective randomized trials have reported. My argument has always been that prospective randomized clinical trials are the right way to identify this toxicity, and not Medicare claims.”

■

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

Reference 1. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Tiral 9741. J Clin Oncol 21:1431-1439, 2003.

motherapy at all, and this is being further tested in a prospective Southwest Oncology Group (SWOG) trial (RxPONDER). The NSABP B-28 analysis indicates that the extent of chemotherapy might be tailored according to the estimation of residual risk, he said.

■

Disclosure: Dr. Mamounas serves as consultant (advisory board) and speaker for Genomic Health, Inc.

Reference 1. Mamounas EP, Tang G, Paik S, et al: Prognostic impact of the 21-gene recurrence score on disease-free and overall survival of node-positive, ER-positive patients with breast cancer treated with adjuvant chemotherapy: Results from NSABP B-28. 2012 Breast Cancer Symposium. Abstract 1. Presented September 13, 2011.

The ASCO Post | OCTOBER 15, 2012

PAGE 26

2012 Breast Cancer Symposium Updated Results continued from page 1

BOLERO-2: 18-month Data Updated results from the pivotal phase III BOLERO-2 trial continue to show that everolimus (Afinitor) added to exemestane in metastatic breast cancer significantly delays disease progression.1 Median progression-

free survival by local assessment was 7.8 months with everolimus/exemestane vs 3.2 months with exemestane alone, for a 55% reduction in risk. By central review, median progressionB:8.625” free survivalT:7.625” was 11.0 vs 4.1 months, respectively,S:6.75” for a 62% reduction in risk. The differences in each analysis were highly significant (P < .0001).

While no significant differences in overall survival have emerged, with 200 deaths overall there were 6.8% more deaths with single-agent therapy, reported Hope Rugo, MD, of the University of California, San Francisco. An exploratory analysis of the trial suggested that adding everolimus has beneficial effects on bone turnover and breast

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases

cancer progression in the bone.2 Bone marker levels at 6 and 12 weeks increased over baseline levels with placebo, but decreased with everolimus, for an absolute difference of 66%. At day 60, the cumulative incidence rate of progressive disease in the bone was also lower with everolimus (3.03% vs 6.16%), and this trend was sustained beyond 6�� months. The investigators suggested that everolimus is overcoming the negative effects that exemestane is known to have on bone. “In the overall population, we saw less progression in the bone in patients getting everolimus, and in the subgroup with bone metastases at baseline— which is about three-quarters of patients—we saw this as well,” Dr. Rugo said. “This is a very interesting difference that suggests there is a site-specific effect with everolimus, and we have not seen this much with other targeted agents.”

Final Analysis of RIBBON-2

CabOzantinib MET Inhibition CRPC Efficacy Trials KEY ELIGIBILITY CRITERIA •Diagnosis of CRPC •Presence of bone metastases •Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) •No limit to the number of prior therapies

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib (60 mg qd) Randomization Prednisone

Randomized, double-blind, controlled trial

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib (60 mg qd) Randomization Mitoxantrone + Prednisone

Randomized, double-blind, controlled trial

B:11.25”

PRIMARY ENDPOINT

S:9.75”

COMET-2

T:10.875”

COMET-1

The final overall survival and safety analysis of the RIBBON-2 trial revealed no improvement in overall survival (a secondary endpoint) with the addition of bevacizumab (Avastin) to secondline chemotherapy in patients with HER2-negative, bevacizumab-naive metastatic breast cancer.3 Of the 684 patients, 82% in each arm have died. Median overall survival was 17.8 months with chemotherapy alone and 18.6 months with chemotherapy plus bevacizumab, and 1-year survival rates were 69% and 71%, respectively, reported Adam M. Brufsky, MD, of the University of Pittsburgh Cancer Institute. An exploratory analysis of the triple-negative subset gave a hint of an overall survival benefit. Median survival was 17.8 months with bevacizumab vs 13.5 months with placebo, but the 15% risk reduction was not statistically significant. Updated safety results were similar to those previously reported. “As you can tell, at this point there is no statistical basis for a survival benefit with bevacizumab in RIBBON-2. We should find the phase III TANIA trial interesting. The study is evaluating second-line bevacizumab in patients pretreated with bevacizumab, with bevacizumab extended beyond progression, which may be a rational design, according to preclinical data. As of yet, however, there is no basis for using bevacizumab beyond progression,” he said.

Some Staging Evaluations Mostly Useless A systematic literature review found that staging evaluations with bone scans,

ASCOPost.com | OCTOBER 15, 2012

PAGE 27

2012 Breast Cancer Symposium liver ultrasound, and chest x-ray have a very low yield of metastatic disease.4 This raises questions as to the utility of routinely performing these studies, especially in asymptomatic patients with small tumors, the researchers suggested. The detection rates with these modalities in patients with stage I/ II tumors ranged from less than 0.5% to 3.0%. The yield was much greater in patients with stage III disease, for whom the detection rate was 12.5% with bone scans, 4.2% with liver ultrasound, and 4.6% with chest radiographs, reported Allison M. Staley, a medical student who presented the findings. Thomas A. Buchholz, MD, of The University of Texas MD Anderson Cancer Center, Houston, commented as poster discussant, “This is a nice review supporting [National Comprehensive Cancer Network] guidelines, and it further demonstrates that most breast cancer patients do not need staging imaging for metastasis.”

Fewer Young Women Being Screened with Mammography The U.S. Preventive Services Task Force recommendation that women aged 40 to 49 not undergo mammographic screening has had a strong impact on screening rates in this age group, but not in older women, according to a time-series analysis of administrative claims data from over 100 health plans.5 The analysis evaluated screening rates between January 2006 and January 2011 among 11.4 million women. The baseline mammography rate was 39.3 per 1,000 in the 40- to 49-year-old

The Gail Modela The Gail model is a statistical tool to estimate a woman’s personal risk of developing invasive breast cancer using the following criteria:

■■ Number of previous breast biopsies and presence of atypical hyperplasia in any breast biopsy specimen

■■ Age at start of menstruation ■■ Age at first live birth of child ■■ History of breast cancer in

first-degree relatives (mother, sisters, daughters)

The Gail model is named after Dr. Mitchell Gail of NCI’s Division of Cancer Epidemiology.

For more information, visit: http://www.cancer.gov/ bcrisktool/about-tool.aspx

age group, and 47.0 per 1,000 among women aged 50 to 64. The Task Force update was associated with a decrease in screening in the younger, but not the older, population. Among younger women, mammography screening rates fell by 7.59% at 2 months postupdate, by 5.33% at 1 year postupdate, and by 5.02% at 2 years postupdate. The reduc-

treatment days, improves flexibility in clinical scheduling, and enhances patient convenience, the authors maintained. “A 2-day adjuvant radiotherapy option allows us to know surgical margin status while still enabling completion of both surgery and radiotherapy in one week or less,” according to Peter Y. Chen, MD, from William Beaumont

Key Findings Presented at the 2012 Breast Cancer Symposium ■■ Time to tissue fixation during breast cancer surgery was found to vary

significantly among surgeons and to affect estrogen receptor status of the tumor; tumors were significantly more likely to be assessed as estrogen receptor–negative if time to fixation exceeded 60 minutes.

■■ Updated results of BOLERO-2 continue to show that everolimus plus

exemestane significantly delays disease progression in patients with metastatic breast cancer, possibly due in part to beneficial effects on bone.

■■ The final overall survival analysis of RIBBON-2 confirmed a lack of survival

benefit with bevacizumab added to second-line chemotherapy in patients with HER2-negative, bevacizumab-naive metastatic breast cancer.

■■ For staging in early breast cancer, a literature review found that bone

scans, liver ultrasound, and chest x-ray are essentially useless in patients with stage I or II disease but may have some benefit in stage III patients.

■■ The USPSTF recommendation that women aged 40 to 49 not undergo routine mammography screening has resulted in a 5% reduction in screening in this age group, which for a 2-year period translates into 90,000 fewer screenings.

■■ Good outcomes were reported for accelerated partial-breast irradiation

(APBI) among women deemed suitable for this modality. A 2-day version of APBI was shown to be similar to traditional 5-day APBI.

tion in screening among younger women translates into more than 90,000 fewer mammograms over the 2 years. Other investigators asked whether young women at higher risk might be identified and thus recommended for screening.6 They applied the Gail model (see sidebar) to 223,349 women from the Screening Mammography Program of British Columbia, calculating the Gail score on these individuals and comparing it to the actual incidence of breast cancer. The Gail model was not effective in personalizing screening recommendations as it significantly underpredicted cancer detection. While it provided a sufficient fit for women with a Gail risk range between 1.51% and 4%, it did not predict cancer risk accurately for low-risk and high-risk women.

Data Support Accelerated Partial-breast Irradiation In a matched-pair analysis, accelerated partial-breast irradiation (APBI) using a 2-day regimen yielded outcomes equivalent to the 5-day schema in a study of 114 patients.7 After a mean follow-up of almost 5 years, no differences were observed in disease-free survival, distant metastases, overall survival, and other endpoints. The approach reduces on-

Hospital in Royal Oak, Michigan. In another study, investigators from multiple institutions reported on a pooled analysis of 2,127 patients treated at William Beaumont Hospital as part of the American Society of Breast Surgeons MammoSite�� ®�� Registry Trial. Patients received adjuvant radiotherapy using either interstitial brachytherapy, balloon-based brachytherapy, or threedimensional conformal partial-breast irradiation after breast-conserving surgery and were followed a median of 6.6 years.8 They reported excellent outcomes, including a 5-year rate of ipsilateral breast tumor recurrence of 2.5% in “suitable” patients. The researchers further noted that current ASTRO Consensus Statement groups do not adequately differentiate patients at an increased risk of true recurrence at the lumpectomy bed following administration of APBI. “Given that APBI is increasingly offered to appropriately selected patients outside of a clinical trial as an alternative to whole-breast irradiation, it is encouraging to note that excellent outcomes were seen at 5 years in this combined cohort of patients. These findings support the use of APBI in select individuals with early-stage breast cancer and may be useful in refining the consensus

panel guidelines pending long-term follow-up results from phase III trials,” said Ben Wilkinson, MD, lead author of the study who is also from William Beaumont Hospital.

■

Disclosure: Dr. Rugo receives research support (via UCSF) for studies in which she is the principal investigator from Novartis, Pfizer, and Merck. Dr. Brufsky received consulting fees from Genentech-Roche. Drs. Buchholz, Chen, and Wilkinson reported no potential conflicts of interest.

References 1. Arena FP, Noguchi S. Pritchard KI, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2012 Breast Cancer Symposium. Abstract 99. Presented September 13, 2012. 2. Hart LL, Baselga J, Rugo HS, et al: Effects of everolimus on disease progression in bone and bone markers in patients with bone metastases. 2012 Breast Cancer Symposium. Abstract 102. Presented September 14, 2012. 3. Brufsky A, Hurvitz SA, Perez EA, et al: Final overall survival and safety analyses of RIBBON-2, a randomized phase III trial of bevacizumab vs placebo combined with second-line chemotherapy for HER2-negative bevacizumab-naive metastatic breast cancer. 2012 Breast Cancer Symposium. Abstract 100. Presented September 14, 2012. 4. Staley S-A: Staging evaluation with bone scan, liver ultrasound, and chest radiograph in patients with primary breast cancer: A systematic review. 2012 Breast Cancer Symposium. Abstract 4. Presented September 13, 2012. 5. Wang AT, Fan J, Van Houten HK, et al: Impact of the US Preventive Services task Force update for breast cancer screening on mammography utilization in women age 40 to 49. 2012 Breast Cancer Symposium. Abstract 5. Presented September 13, 2012. 6. Rajapakshe R, Parker B, Araujo C, et al: Stratification of 5-year cancer detection rate in an organized breast screening program based on Gail model risk factors. 2012 Breast Cancer Symposium. Abstract 7. Presented September 13, 2012. 7. Chen PY, Shah C, Wilkinson JB, et al: Clinical efficacy of a 2-day versus 5-day accelerated partial breast irradiation delivered via balloon-based brachytherapy: Results of a matched pair analysis. 2012 Breast Cancer Symposium. Abstract 148. Presented September 13, 2012. 8. Wilkinson JB, Beitsch PD, Arthur DW, et al: Evaluation of current consensus panel guidelines for APBI: A pooled analysis of William Beaumont Hospital and the American Society of Breast Surgeons MammoSite® Registry Trial data. 2012 Breast Cancer Symposium. Abstract 145. Presented September 13, 2012. 9. Skinner KA, Farkas RL, McCarthy K, et al: The surgeon’s impact on ER status. 2012 Breast Cancer Symposium. Abstract 153. Presented September 13, 2012.

TREANDA速 (bendamustine HCI) for Injection is his chemo.

This is his therapy.

Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001

HR†=0.27 (95% CI‡: 0.17, 0.43)

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301) • TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150) Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511b (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

ASCOPost.com | OCTOBER 15, 2012

PAGE 31

Journal Spotlight Carcinomatosis

Successful Use of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy May Hinge on Prior Experience By Charlotte Bath

review of 60 consecutive patients with peritoneal carcinomatosis who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC)—sometimes called “hot chemotherapy”—found 0% mortality and 33% morbidity, with “a significant reduction of grade III/ IV morbidity, perioperative transfusion, and reintervention rate after 20 procedures.” Reporting their results in the Archives of Surgery,1 physicians at the Institut Paoli-Calmettes and Université de la Méditerranée in Marseille, France, noted that the “introduction of the HIPEC program was successful because of the surgical team’s prior experience in cytoreductive and cancer operations.”

Learning Curve In an accompanying editorial, Nita Ahuja, MD, agreed: “The message that we can heed here is that experience matters.” In a followup interview with The ASCO Post, Dr. Ahuja said that there are cytoreduction-withHIPEC programs See Page 110 with experienced physicians at several centers in the United States (see sidebar). These centers include Johns Hopkins Medicine, where Dr. Ahuja is Director of the Peritoneal Surface Malignancies Program, Chief of the Section of Gastrointestinal Oncology, Breast, Melanoma, Sarcoma, and Endocrine Cancers, and Associate Professor of Surgery and Oncology. The Johns Hopkins Medicine program started in 2008 and has treated approximately 60 patients. The number of centers introducing such programs is “exploding,” Dr. Ahuja added. The complexity of the procedure means that these newer centers will have a learning curve as they gain experience. As Dr. Ahuja stated in her editorial, “This study again shows that complex surgery is best performed at high-volume, experienced centers, similar to what has been shown for pancreas or esophageal resections. Programs initiating HIPEC would do well to heed this advice.”

From Small Centers to Academic Centers

Nita Ahuja, MD

Perioperative Factors Compared Among the 60 patients treated in the French study, peritoneal carcinomatosis “originated from colorectal cancer in 26 patients (43%), ovarian cancer in 12 (20%), appendix cancer in 10 (17%), pseudomyxoma/mesothelioma in 10 (17%), pancreatic cancer in 1 (2%), and small-bowel cancer in 1 (2%).” The mean peritoneal cancer index (PCI) was 9.6. (Dr. Ahuja explained that the PCI is a scale to measure the extent of disease within the peritoneum, based on the distribution of tumor throughout 13 abdominopelvic regions and lesion size. The highest score possible is 39; a lower score means less disease.) Systemic chemotherapy was received by 53 patients (88%) before cytoreduction and HIPEC and by 37 patients (62%) afterwards. Perioperative factors were studied and compared for the first, second, and third groups of 20 successive patients. “Perioperative red cell transfusion (P < .01), grade III/IV morbidity (P = .02), and reintervention rate (P =. 04) significantly decreased during the three periods. No difference was observed between the three periods with regard to mean PCI, operative duration, blood loss, mortality, overall morbidity, length of hospital stay, and readmission,” the authors stated. The authors noted that even before the HIPEC program was started at their institution in 2004, surgeons had been using aggressive cytoreduction and perioperative systemic chemotherapy to treat patients with peritoneal carcinomatosis. “Because of our experience with cytoreduction, the only learning curve that we experienced was with the introduction of HIPEC itself,” they wrote.

he use of cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) to treat carcinomatosis “came from the smaller centers,” noted Nita Ahuja, MD, Director of the Peritoneal Surface Malignancies Program at Johns Hopkins Medicine. “A lot of things in medicine come from academia and move outward, but here, the technique came from smaller centers into academic centers.” Now that cytoreduction and HIPEC has arrived as a field, Dr. Ahuja advocates establishing uniform consensus guidelines for patient selection. “Patients are seeking it. They are desperate,” she said. “I think that some patients do benefit, and we don’t need to deny them that. But we need to have clear-cut guidelines and say, these are the people who will truly benefit from this aggressive therapy. That conversation needs to happen.” So far, she said, it has only been happening “in bits and pieces.”

Established Programs Along with the program she directs at Johns Hopkins, Dr. Ahuja mentioned several other cytoreduction and HIPEC programs with experienced surgeons in the United States. “Certainly Paul Sugarbaker, MD, has been doing it the longest,” she said. Dr. Sugarbaker is at Washington Hospital Center in Washington, DC. “The University of Maryland has Richard Alexander, MD. And Jesus Esquivel, MD, who was trained by Paul Sugarbaker, is at St. Agnes Health Care.” Both of these centers are in Baltimore. “The University of Pittsburgh Medical Center has David L. Bartlett, and University of California, San Diego, has Andrew M. Lowy, just to name a few,” Dr. Ahuja added. “Certainly those are the centers that have been doing it for a while.” Dr. Ahuja noted that there are also websites where physicians can list themselves as providers of cytoreduction and HIPEC, but it is not always possible to find out their level of experience.

■

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

Safety Considerations “The heat may have potentially more side effects,” Dr. Ahuja said, but for surgeons who do not have the extensive experience of those conducting the French study, the cytoreduction may be more technically challenging. The concept of “hot chemotherapy” creates interest among patients because it is something different, she noted, but “it is not going to accomplish any wonders if you didn’t achieve a complete cytoreduction for diseases such as colorectal cancer. So if you are leaving visible disease behind and just delivering chemotherapy for 30 or 90 minutes, it will not have much efficacy.” Dr. Ahuja pointed out that while the French series used oxaliplatin, most U.S. centers performing cytoreduction with HIPEC use mitomycin because the “toxicity profile seems a little bit safer.” Safety is also the reason for using a closed circuit technique for the heated chemother-

apy vs the open technique used in the French series. “Open means you leave the abdomen open when you circulate the chemotherapy, whereas closed means you close the abdomen temporarily. The Europeans are doing it open. Most of the Americans are doing it closed. There is no difference in survival,” Dr. Ahuja explained. At Johns Hopkins, “we tend to do it closed,” she said, “because it is presumed safer for our staff.” “The data are unclear” about incremental benefit of HIPEC, Dr. Ahuja said. “A lot of preclinical basic science data suggest that if you heat chemo, it penetrates better. You get better delivery of the drug.” She said that there are also good lab data with mice. “Then you go to the clinical scenario and it is harder to tease out the benefit. Is it just good surgery, that a good surgeon takes out all visible disease? Or is the chemo adding much more benefit? Because the chemo does add toxiccontinued on page 32

The ASCO Post | OCTOBER 15, 2012

PAGE 32

Journal Spotlight

Cytoreduction plus HIPEC continued from page 31

ity. The hematologic toxicity they see on the study is related to the chemo, especially oxaliplatin, and the higher risk of fistula is likely related to the chemotherapy. So it clearly has a risk profile associated with it, oxaliplatin more than mitomycin.”

Continuum of Expanding Options Cytoreduction with HIPEC “was first espoused by Paul Sugarbaker, MD, for pseudomyxoma peritonei,” Dr. Ahuja said. (For more information on Dr. Sugarbaker and his experience with this procedure, see the October 2011 issue of The ASCO Post.2) For pseudomyxoma peritonei, “you can take patients with a very high PCI and it is completely appropriate to be super-aggressive with this therapy because there is nothing else to offer. No one is debating that. Where we debate is for colorectal cancer,” Dr. Ahuja said. Cytoreduction with HIPEC can be viewed as part of the continuum of expanding options for patients with advanced colorectal cancer. “As colon cancer treatments have become better—median survival for someone who has no surgical options is now over 27 months with chemotherapy—we have started operating on cases of metastatic disease that would not have been considered for surgery in the past,” Dr. Ahuja explained. Fiveyear survival rates are now about 40% for patients who undergo resection of a solitary liver metastasis and 35% for resection of a solitary lung metastasis, Dr. Ahuja reported. “If you think of the peritoneum as an organ and you consider that cancer has only spread to that area and hasn’t spread anywhere else, you could apply the same idea of aggressive surgery with cytoreduction and HIPEC,” Dr. Ahuja said. “And you see somewhat similar results—35%

Visit

to 40% 5-year survival in very carefully selected patients.” In the French study, all patients were under 70 years old, had no symptomatic disease, and had good clinical status. Dr. Ahuja generally agrees with those criteria, while noting that the Johns Hopkins program may soon allow patients as old as 75 years. A subject of debate, according to Dr. Ahuja, is whether to include pa-

operate on someone whose PCI is greater than 20,” she added. Patients may have received previous chemotherapy, and Dr. Ahuja said, “I tend to give patients three cycles upfront, generally with FOLFOX [leucovorin, fluorouracil (5-FU), oxaliplatin] or FOLFIRI [leucovorin, 5-FU, irinotecan]. Follow-up chemotherapy is generally determined by Dr. Ahuja and

As colon cancer treatments have become better— median survival for someone who has no surgical options is now over 27 months with chemotherapy— we have started operating on cases of metastatic disease that would not have been considered for surgery in the past. —Nita Ahuja, MD

tients with synchronous metastases of the liver. Some think cytoreduction plus HIPEC should be limited to peritoneal disease, which spreads locally through a perforated or ruptured tumor, rather than liver metastases, which would have come through the blood or lymph nodes. “I don’t think there is a good answer to that,” Dr. Ahuja said. “When I started, I said absolutely no liver metastases, but now we are doing it on a case-by-case basis. It should not be an absolute contraindication; it’s a relative contraindication. Extraabdominal metastases should be an absolute contraindication.”

Not a Last-ditch Effort The option of using cytoreduction with HIPEC “should be brought up early in the treatment course rather than as a last-ditch effort. You are not going to see any benefit if the disease is everywhere,” Dr. Ahuja stated. For patients with colorectal cancer, “we say you should never

her group on a case-by-case basis, “if I am able to complete the cytoreduction and give the HIPEC and have cleared all visible disease,” she said. “This is where the multidisciplinary part comes in, in that we all discuss it at our colorectal conference,” she added. Most patients in whom complete cytoreduction is possible are managed with expectant observation and chemotherapy in the case of a recurrence. Cytoreduction’s reputation as the “Mother of All Surgeries” is “a little outdated,” Dr. Ahuja said, coming from the era when cytoreduction was a last resort. Now that patients are coming to cytoreduction earlier and with lower PCI scores, recovery is similar to that for other colorectal surgery. “I tell them they’ll need a 2-week in-hospital stay, and younger people go home in 7 days,” Dr. Ahuja said. “We’ve prepared them psychologically. There is a little bit longer recovery for most people—6 to 8 weeks—but

they are at home. They are living their life, and they are recovering.”

Ideal Treatment? The French study report begins by asserting, “peritoneal carcinomatosis originating from digestive or ovarian malignant tumors is ideally treated by cytoreduction and HIPEC.” According to Dr. Ahuja, that would be true only in cases of pseudomyxoma peritonei but should “absolutely not” be the only therapy offered to patients with peritoneal carcinomatosis originating from colorectal cancer. “You cannot deny people systemic therapy, when we have 15 years of data saying that systemic chemotherapy works.” Morbidity and the occasional need for reintervention may also make cytoreduction plus HIPEC less than ideal. The morbidity rates in the French study and at Johns Hopkins, as reported by Dr. Ahuja, are about 30%. Morbidity could range up to 40% internationally, Dr. Ahuja noted, but it is hard to compare the data internationally because of the different drugs used (oxaliplatin vs mitomycin) and different patient selection criteria. “There are real morbidities that require reintervention, like fistulas,” Dr.Ahuja said. Some patients could also require a second surgery due to a massive bleed or a perforation, which could affect long-term recovery and possibly survival.

■

Disclosure: Dr. Ahuja potential conflicts of interest.

reported

References 1. Turrini O, Lambaudie E, Faucher M, et al: Initial experience with hyperthermic intraperitoneal chemotherapy. Arch Surg. June 18, 2012 (early release online). 2. Bath C: ‘Hot chemotherapy’ generates heated debate about its use with cytoreductive surgery to manage peritoneal metastases. The ASCO Post. October 15, 2011.

website at ASCOPost.com

NOW ENROLLING TWO PHASE III STUDIES

BELLE-2 and BELLE-3 Two Phase III studies investigating the pan-PI3K inhibitor, buparlisib (BKM120), plus fulvestrant in HR+/HER2– advanced breast cancer BELLE-2 and BELLE-3 1 Postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer pretreated with aromatase inhibitor Archival tumor tissue for analysis of PI3K pathway activation No more than one prior line of chemotherapy for metastatic disease ECOG Performance Status ≤2

Randomization

BELLE-3 1

Buparlisib + fulvestrant

Evidence of progression on or after mTOR inhibitor-based treatment

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. Additional inclusion/exclusion criteria apply.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. For more information www.clinicaltrials.gov (NCT01610284 and NCT01633060) Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only) Or contact your local Novartis representative

Pioneering Research of PI3K inhibitors in Malignancies

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936

Novartis 2012

August 2012

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Novartis Pharma AG CH-4002, Basel, Switzerland

The ASCO Post | OCTOBER 15, 2012

PAGE 34

Best of ASCO® Annual Meeting ‘12 Thoracic Oncology

Progress, Slow but Sure, Seen for Current Lung Cancer Therapies By Susan London

“T

his year, we have some abstracts that help move things forward in lung cancer, maybe at a little bit slower pace than in previous years. But there are important points that we can learn from some of these abstracts,” commented Karen L. Reckamp, MD, of the City of Hope, who presented findings on improvements in current lung cancer therapy standards at the Best of ASCO San Diego meeting. Key studies in the area of current therapy standards addressed combined-modality therapy, diagnostic tools for early-stage disease, and special considerations for therapy in patients with metastatic disease. “These are all things that are ultimately going to move the field forward in small baby steps,” she said.

chemotherapy and 18.1�� months without it. In an adjusted analysis, there was no significant survival benefit of consolidation chemotherapy. Findings were the same in subgroups stratified by time period, world region, and phase of trial. “It doesn’t appear that consolidation adds a significant benefit to standard concurrent chemoradiation. But we still do it,” Dr. Reckamp noted, pointing to ongoing cooperative group trials. “And many people still believe we must do it. So there is some emotional rationale here that doesn’t necessarily fit with the data,” she added. “The question is, will we follow the data; will we change our practice based on these studies? Or will we wait for the future trials and continue to believe based on our emotions that consolidation therapy is necessary?” she asked. “I think this is enough to say that outside of a clinical trial, consolidation should not be done.”

Delaying Thoracic Radiation in Limited SCLC

Karen L. Reckamp, MD

Consolidation Chemotherapy in Locally Advanced NSCLC A pooled analysis of 45 trials with a total of 3,447 patients assessed the benefit of consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with locally advanced non–small cell lung cancer (NSCLC).1 Median overall survival was 18.5 months with consolidation

A randomized phase�� III noninferiority trial tested concurrent thoracic radiation therapy given with the first vs the third cycle of cisplatin and etoposide chemotherapy in 219 patients with limited-disease small cell lung cancer (SCLC).2 The complete response rate was 36% when thoracic radiation was given in the first cycle and 38% when it was delayed until the third cycle, meeting criteria for noninferiority. Progression-free survival and overall survival were statistically indistinguishable.

Key Lung Cancer Standard Therapy Findings Presented at Best of ASCO® ‘12 ■■ Giving consolidation chemotherapy after definitive chemoradiation

does not improve survival in locally advanced non–small cell lung cancer (NSCLC).

■■ Concurrent thoracic radiation in limited-disease small cell lung cancer can be delayed until the third cycle of chemotherapy without loss of efficacy.

■■ FDG-PET performs poorly for diagnosing stage I NSCLC, with significant variation in sensitivity across sites.

Treatment Decisions for Locally Advanced NSCLC Draw on ‘Art of Medicine’

ith treatment advances, there are now fewer absolutes in managing locally advanced NSCLC, according to Dr. Reckamp. “We are moving toward treating performance status�� 2 patients, and obviously, that is a heterogeneous group of people,” she elaborated. “For those who need a lot of care, you need to see how much of it is due to their tumor burden that you may be able to reverse with chemotherapy, vs somebody who you are just going to make sicker. And that’s still the art of medicine.” Most patients with performance status 3 will not be able to tolerate chemotherapy or radiation therapy. But those who have an adenocarcinoma should be tested for EGFR mutations and ALK translocation because they could still benefit from EGFR tyrosine kinase inhibitors or crizotinib (Xalkori). “That might be one thing that I would do for a performance status 3 patient, other than just trying to move forward with palliative care and hospice…,” she said. “Those drugs can drastically change outcomes even for patients with performance status�� 3 and potentially in performance status 4.”

Palliative Care Considerations When it comes to early integration of palliative care, Dr. Reckamp acknowledged concerns about difficulty in getting health insurers to cover chemotherapy once patients start palliative care. “ASCO is trying to find a way for the majority of practices to integrate palliative care with oncology care.” Studies like the one from the Massachusetts General Hospital showing that using palliative care while patients are receiving chemotherapy reduces costs should be helpful. “I don’t know that we are there completely, but there is a dedication to trying to move the field forward that way and educate people. And now you have some data to argue with the insurance company and say, wait a minute, I need to [involve palliative care]; look, this may save you money in the end,” she concluded.

■

Patients given delayed thoracic radiation had a higher proportion of first failures that were locoregional only (51% vs 39%) but a lower rate of grade 3/4 febrile neutropenia (10% vs 22%). “Radiation for limited-disease SCLC can be delayed until the third cycle of chemotherapy without changes in outcomes,” Dr. Reckamp commented, while adding that there may be some differences in locoregional control and toxicity. “We need to base our decisions on the patients’ characteristics, the tumor, and the need for initiating therapy quickly vs being able to delay and wait for radiation planning,” she recommended.

■■ Combination chemotherapy improves outcomes relative to monotherapy

FDG-PET to Diagnosis Stage I NSCLC

■■ Early integration of palliative care with oncology care for metastatic NSCLC

The American College of Surgeons Oncology Group (ACOSOG) Z4031 study assessed the accuracy

in patients with advanced NSCLC and a performance status of 2. reduces total health-care costs in the last month of life.

of fluorodeoxyglucose positronemission tomography (FDG-PET) for diagnosis of early lung cancer.3 Participants were 682 patients with a lung lesion clinically suspected to be stage I NSCLC. Final pathology showed cancer in See Page 110 83%. FDG-PET had a sensitivity of 82% and a specificity of 31% for identifying cancer, with an overall accuracy of 73%. The majority of false-positive were granulomas, and the majority of false-negatives were adenocarcinomas. The sensitivity of FDG-PET differed significantly across the eight enrolling study sites. The accuracy increased with lesion size (P < .001). “We need to question our reliance on FDG-PET, especially in early-stage and stage�� I disease,” Dr. Reckamp comcontinued on page 38

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis. Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60

Not reached

7.9

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

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PAGE 38

Best of ASCO® Annual Meeting ‘12 Lung Cancer Therapies continued from page 34

Combination Chemotherapy in Advanced NSCLC

mented, noting that the ordering of this test is “pervasive.” “When you have somebody with a potential early-stage lung cancer and are asking is this lung cancer or not…, PET scan is still not as good as having a biopsy,” she maintained.

A randomized phase�� III�� trial compared pemetrexed (Alimta) alone vs combined with carboplatin in 217 patients with stage IIIB/IV NSCLC and an ECOG performance status of 2.4 Patients in the combination therapy group tended to have higher rates of

ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

grade 3/4 anemia (12% vs 4%, P = .066) and grade 5 adverse events (4% vs 0%, P = .121). However, the combination therapy group still had better progression-free survival (5.9 vs 3.0 months, HR = 0.46, P < .001) and overall survival (9.1 vs 5.6 months, HR = 0.57, P = .001). The subset of patients aged 70 years

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

disorders Cough Injury, poisoning and procedural complications Sunburn

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

or older also derived survival benefit from the combination therapy vs the monotherapy (8.3 vs 6.1 months, HR = 0.49, P < .015). “This definitely shows that in selected patients, we can use combination chemotherapy even in performance status 2 patients,” Dr. Reckamp said, noting that this is in fact a heterogeneous group. “We need studies to investigate the best regimen and understand toxicities better,” she said, recommending that for now, regimens be based on comorbidities. “Further trials are obviously needed to include these populations [performance status 2 patients and older adults] into our studies so that we can understand how best to treat [them], because clearly they are very underrepresented … and these are the majority of our patients,” she added.

Early Palliative Care Reduces Health-care Costs A randomized trial conducted at the Massachusetts General Hospital Cancer Center assessed the effect of early palliative care on health-care costs in 151 patients with newly diagnosed metastatic NSCLC.5 Patients were assigned to early palliative care integrated with oncology care (meeting with a palliative care clinician within 3 weeks and at least monthly thereafter) or to standard care (meeting with a palliative care clinician only when requested by patient, family, or oncology clinician). On average, total health-care cost per patient (for inpatient and outpatient visits, chemotherapy, and hospice services) in the final month of life was $2,282 less in the early palliative care group vs the standard care group. The biggest driver was the difference in cost for inpatient visits. “We don’t know how well this will generalize to the general population and to populations outside of a large comprehensive cancer center with a very well established palliative care team,” Dr. Reckamp commented. Moreover, some end-of-life costs were not evaluated. “Clearly, early palliative care integration is associated with better outcomes—improved quality of life, decreased chemotherapy—and this may also lead to decreased health-care costs at the end of life,” she said. Ideally, oncology care and palliative care are envisioned as integrated and coexisting along a continuum, Dr. Reckamp noted. “I would argue with lung

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Best of ASCO® Annual Meeting ‘12 cancer that there is an accelerated course through this diagram, and often we end up near the end part of it even from the beginning. So symptom control and palliative care are incredibly important from the early stages because we are not talking about curative or even much lifeprolonging treatment for most of our patients.”

■

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

References 1. Yamamoto S, Tsujino K, Ando M, et al: Is consolidation chemotherapy after concurrent chemoradiotherapy beneficial for locally advanced non-small cell lung cancer? A pooled analysis of the literature. 2012 ASCO Annual Meeting. Abstract 7000. Presented June 4, 2012. 2. Park K, Sun J-M, Kim S-W, et al: Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first cycle or the third cycle of cisplatin and etoposide chemotherapy to determine the optimal timing of TRT for limited-disease small cell lung cancer. 2012 ASCO Annual Meeting. Abstract 7004. Presented June 4, 2012. 3. Grogan EL, Deppen SA, Ballman KV, et al: Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial. 2012 ASCO Annual Meeting. Abstract 7008. Presented June 4, 2012. 4. Lilenbaum R, Zukin M, Pereira JR, et al: A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2. 2012 ASCO Annual Meeting. Abstract 7506. Presented June 4, 2012. 5. Greer JA, McMahon PM, Tramontano A, et al: Effect of early palliative care on health care costs in patients with metastatic NSCLC. 2012 ASCO Annual Meeting. Abstract 6004. Presented June 2, 2012.

In DCIS, Radiotherapy Benefits ‘Good Risk’ Patients By Caroline Helwick

adiation therapy will improve outcomes for patients with ductal carcinoma in situ (DCIS), even if they are considered at low risk for recurrence, according to the Radiation Therapy Oncology Group (RTOG) 9804 trial.1 But the follow-up time is short, and the findings still leave some wiggle room, according to Harold J. Burstein, MD, of Dana-Farber Cancer Institute, and Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital, Boston, who discussed the study at the Best of ASCO Boston meeting. RTOG 9804 was conducted among 585 patients with small, low-grade asymptomatic tumors who underwent lumpectomy with adequate margins. The patients were randomly assigned to observation or radiation therapy (42.5–50.4 Gy with no boost); 62% also received tamoxifen. Local failures (invasive or noninvasive) at 5 years occurred in 3.2% of the observation arm (primarily See Page 110 within the primary quadrant) vs 0.4% of the radiotherapy arm, for an 86% reduction in risk (P = .002). Contralateral cancers, disease-free survival, and overall survival were similar between the arms, and adverse events were comparable.

Findings Support Both Points of View Dr. Isakoff contrasted the lower local failure rate in RTOG 9804 (3.2%) with that of the similar Eastern Cooperative Oncology Group (ECOG) 5194 trial2 in low-risk patients (10.5%), sug-

gesting that shorter follow-up (5 vs 7 years) may account for the difference. “Beyond 5 years, the slope was still going up in the ECOG trial,” he noted. Therefore, longer follow-up is required before a group can be clearly identified as not requiring radiotherapy due to sufficiently low risk, both specialists agreed.

tient age. Since the study has only 5 years of follow-up, and more events are likely to emerge in years 6 to 10, younger patients may need to take these points into consideration and opt for the extra protection. For older patients who do not want radiotherapy anyway, “You can point to the data and say their changes are excellent for a very good

The question is not whether radiotherapy works, but whether there is benefit that makes sense. —Harold J. Burstein, MD

Meanwhile, Dr. Burstein said the findings will support both the pro and con radiotherapy camps. “Physicians who want to give radiotherapy can look at the 86% risk reduction and highly significant P value, and contend that they can’t tell patients that radiation won’t benefit them. Physicians who think radiotherapy is unnecessary will say that we have identified a group with less than a 5% incidence of recurrence over 5 years, and wonder if we are helping them in a way that is clinically compelling,” he said. “The question is not whether radiotherapy works, but whether there is benefit that makes sense,” Dr. Burstein concluded. “The debate will rage on and on.” The findings may be most useful when they are put into context by pa-

prognosis over the next 5 years,” he said. Dr. Isakoff added that in the future, molecular tests may guide the treatment of DCIS patients. Meanwhile, he suggested, “Discussions with patients are required.”

■

Disclosure: Drs. Burstein and Isakoff reported no potential conflicts of interest.

References 1. McCormick B: RTOG 9804: A prospective randomized trial for “good risk” ductal carcinoma in situ, comparing radiation to observation. 2012 ASCO Annual Meeting. Abstract 1004. Presented June 5, 2012. 2. Hughes LL, Wang M, Page DL, et al: Local excision alone without irradiation for ductal carcinoma in situ of the breast: A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27:5319-5324, 2009.

Don’t Miss These Important Announcements in this Issue of The ASCO Post NCCN Names Robert W. Carlson, MD, Chief Executive Officer, see page 9

Memorial Sloan-Kettering Appoints Jose Baselga, MD, PhD, New Physicianin-Chief, page 101

Visit The ASCO Post online at ASCOPost.com

Lisa Carey, MD, Named Physician-in-Chief of the N.C. Cancer Hospital, page 102

The ASCO Post | OCTOBER 15, 2012

PAGE 40

Journal Spotlight

Neuropathy Not Predictive of Outcomes with Adjuvant Taxane Therapy in Breast Cancer

Finding suggests increased utility of potential neuropathy biomarkers By Matthew Stenger

europathy is a common and potentially disabling adverse effect of taxane therapy, particularly weekly paclitaxel. A number of recent studies have identified single nucleotide polymorphisms that appear to increase risk of grade 2 to 4 neuropathy in patients with breast cancer who receive taxanes. It is thus of interest to examine whether neuropathy is predictive of taxane efficacy. If it is not, it would be more straightforward to use the potential biomarkers for neuropathy. These could be used to identify patients who might benefit from receiving adjuvant taxane regimens that pose lower risk of neuropathy and adjunctive treatment to reduce neuropathy. In a recent study reported in Journal of Clinical Oncology,1 Schneider and colleagues analyzed See Page 110 the potential relationship between grade 2 to 4 neuropathy and overall survival, disease-free survival, and recurrence-free survival among 4,554 women receiving taxane-containing adjuvant therapy in the E1199 trial. The adjuvant regimens consisted of up to 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by: paclitaxel at 175 mg/m2 every 3 weeks for 4 cycles (P3 regimen), paclitaxel at 80 mg/m2 weekly for 12 cycles (P1 regimen), docetaxel at 100 mg/ m2 every 3 weeks for 4 cycles (D3 regimen), or docetaxel at 35 mg/m2 weekly for 12 cycles (D1 regimen).

Neuropathy Risk Highest with Weekly Paclitaxel Overall, grade 2 to 4 neuropathy occurred in 16.9% of patients; 71.8% of cases were grade 2, 27.5% grade 3, and 0.7% grade 4. Neuropathy occurred in 22.0% of the P1 group, 17.5% of the P3 group, 14.7% of the D3 group, and 13.4% of the D1 group. The risk of neuropathy in the P1 group was significantly higher than that in the P3 group (odds ratio [OR]�� = �� 1.34, 95% confidence interval [CI] = 1.09–1.64, P = .006), the risk in the D1 group was significantly lower than that in the P3 group (OR =

0.73, 95% CI = 0.58–0.92, P = .008), and a reduction in risk in the D3 group compared with the P3 group approached significance (OR = 0.81, = .070). Pro95% CI = 0.65–1.02, P �� portions of patients requiring dose reduction for any reason and median relative dose intensity did not differ between patients with and patients without neuropathy in any treatment group. Among all patients, premenopausal status was associated with decreased risk of neuropathy (OR = 0.77, P = .025), with trends toward significantly increased risk being observed for black race and obesity. Age as a continuous or categoric variable was not associated with differences in risk, contrary to previously reported findings in study

Neuropathy and Survival with Adjuvant Taxane Therapy ■■ In a study of the relationship between neuropathy and survival among 4,554 women receiving taxane-containing adjuvant therapy in the E1199 trial, neuropathy rates were highest with weekly adjuvant paclitaxel.

■■ No association between neuropathy and overall, disease-free, or relapsefree survival was found among all patients or among subgroups with HER2-positive, triple-negative, or estrogen receptor–positive/HER2negative tumors.

■■ Since neuropathy is not a marker of taxane efficacy, biomarkers predictive of neuropathy may help in choosing an adjuvant taxane regimen.

cant association of neuropathy with overall, disease-free, or recurrencefree survival was found when all patients were included or in analyses limited to patients with HER2positive tumors, triple-negative tumors, or estrogen receptor–positive/

Taxane-induced peripheral neuropathy does not correlate with improved outcomes in patients with operable breast cancer treated with adjuvant taxane therapy. E5103 (in which weekly paclitaxel was the taxane backbone). A significant increase in risk of neuropathy was observed in patients with grade 2 to 4 hyperglycemia (OR = 1.47, P < .001), with significance persisting after adjustment for age, race, obesity, and menopausal status (OR = 1.42). Similar results were yielded by analysis in the P1 group alone, with the reduction in risk associated with premenopausal status approaching significance (OR = 0.70, P = .092) and hyperglycemia being associated with a significantly increased risk (OR = 1.98, P = .004). Among all patients, obesity, nodal status, and tumor size were significantly associated with overall survival. The only variables significantly associated with overall survival across all four treatment groups were having greater than three involved nodes and having a tumor greater than 2 cm in size.

Neuropathy Not Associated with Survival On univariate analysis, no signifi-

HER2-negative tumors. Multivariate analysis including adjustment for the covariates of age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, and treatment-related grade 2 to 4 hyperglycemia showed no significant association between grade 2 to 4 neuropathy and overall, disease-free, or recurrence-free survival among all patients or among subgroups of patients with HER2positive tumors, triple-negative tumors, or estrogen receptor–positive/ HER2-negative tumors. No association of neuropathy with overall survival after adjustment for covariates was observed within any individual treatment group. In E1199, the P1 arm, which had the highest risk for neuropathy, had improved disease-free and overall survival, and the D3 arm had improved disease-free but not overall survival at the time of planned analysis compared with the standard P3 arm. Given the improvement in overall and disease-free survival and the reduced overall toxicity observed

with the P1 regimen, this regimen has become commonly used in clinical practice. Docetaxel-containing regimens have been shown to have benefits in other clinical trials and are also widely used in clinical practice; these regimens are associated with greater overall grade 3 or 4 toxicity but less neuropathy than are observed with weekly paclitaxel. As noted by the investigators, if it is indeed the case that taxane-associated neuropathy is not a pharmacodynamic marker of taxane benefit, availability of biomarkers predictive of neuropathy could provide ‘an important tool for choosing an adjuvant taxane regimen and facilitate improved therapeutic individualization….” The investigators concluded: “[T]his analysis of greater than 4,500 patients demonstrates that taxaneinduced peripheral neuropathy does not correlate with improved outcomes in patients with operable breast cancer treated with adjuvant taxane therapy. This finding provides reassurance that biomarkers predictive for neuropathy will likely not enrich for patients who are more likely to benefit from taxane therapy and may also be useful for the identification of patients who are most likely to benefit from adjunctive therapies to mitigate neuropathy.”

■

Reference 1. Schneider BP, Zhao F, Wang M, et al: Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer. J Clin Oncol 30:3051-3057, 2012.

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The ASCO Post | OCTOBER 15, 2012

PAGE 42

Issues in Oncology

Chemotherapy Drug Shortage continued from page 1

leukemia (AML) in light of the cytarabine shortages. “His question shocked me, especially when one considers that using cytarabine in combination provides a 40% cure rate in AML, a disease that prior to the advent of this drug had a 0% cure rate,” said Dr. Kantarjian. He put the cytarabine shortage in human terms, mentioning that there are approximately 12,000 new AML cases per year, and that depriving those patients of this lifesaving drug would result in about 5,000 preventable deaths. “The answer to this doctor’s question is sobering: There is no alternative to cytarabine in the clinical scenario he presented,” added Dr. Kantarjian.

Root Causes Although the drug shortfall is still a major problem, since the President’s Executive Order, which energized the initiative to address the issue, the shortages have been substantially reduced.1 “However, it is important to examine and identify the root causes of these disturbing shortages in order to stave off future problems,” said Dr. Kantarjian. Dr. Kantarjian commented that the rise in drug shortages had a temporal correlation with the payment shift under the Medicare Modernization Act (MMA), moving from the average wholesale price (AWP) to the average sale price (ASP) plus 6%; the Medicare ASP reimbursement is substantially lower, especially among generic drugs. “Although this is a complex issue, the data show that as the profit margin on generic injectable sterile drugs decreased, many of the companies producing these agents left the market. This created consolidation, and now only four drug companies account for 70% of the generic market, which poses a potential drug shortage problem if a manufacturing problem should occur in just one of the limited number of producers,” said Dr. Kantarjian. There are numerous, well-documented reasons for U.S. drug short-

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ages, such as contamination or lack of raw materials, quality control issues that force FDA shutdowns, regulatory complexities, and overburdensome recertification requirements to clear the manufacture of generics.2 However, Dr. Kantarjian stressed that a growing number of experts blame the economic factor, which has limited the financial incentives to produce generics, as a leading cause of drug shortages. “I believe that economics are a root cause for our drug shortage problem. Along with the regulatory and manufacturing issues I mentioned, the decrease in financial incentives has led to a diversion of generics to foreign markets,” said Dr. Kantarjian. An inescapable narrative in the economic theory, one that has been editorialized in the mainstream press, is that because of the unique payment structure in medi-

certain problems, we should keep the current payment system in community oncology. To remove it, as some advocate, would in essence result in large hospital-based oncology conglomerates, mostly in urban rather that rural areas, which would compromise the quality and quantity of patient care for many U.S. populations,” stressed Dr. Kantarjian. Instead of putting the onus on oncologists, he offered possible solutions to stave off future drug shortages, such as mandating confidential reporting of drug shortages anticipated within 6 months and improving the FDA’s ability to locate and facilitate alternative solutions within 3 to 6 months of notification. “But I think the most important solution is to start a dialogue about establishing a pricing floor for generics, which would never fall below a level that allows physicians or the ge-

The Depth of the Drug Shortage Problem ■■ Shortages began increasing since 2007. ■■ Shortages tripled in the past 5 years. ■■ There were 70 drugs in short supply in 2007. ■■ Hundreds of drugs are in short supply in 2012; 20% are chemotherapy drugs.

■■ The drug shortage problem is more acute in the United States than in Europe.2

cal oncology, community doctors often choose brand drugs over generics, further exacerbating the shrinking generic market. “The argument is that faced with two choices of equally effective drugs, a low-cost generic or a higher-priced brand drug, oncologists may choose the latter to increase profit margin. I find this reasoning to be based on cynicism, not fact, because the data show that most shortages in generics occur when there is no alternative drug,” said Dr. Kantarjian.

Possible Solutions In the face of mounting calls for changes to the oncology payment structure—ostensibly to remove perverse incentives to prescribe higherpriced drugs—Dr. Kantarjian takes a different view on the issue. “Despite

neric drug manufacturing company to turn a reasonable profit,” Dr. Kantarjian said.

ASCO Recommendations Past ASCO President Richard L. Schilsky, MD, asserted that ASCO continues to be at the forefront of the drug shortage problem, using its lobbying and educational skills on the Hill, testifying in various subcommittee meetings and workshops, even having one-on-one meetings with Department of Health and Human Services Secretary Kathleen Sebelius. “The organization has been particularly visible in the media in order to raise awareness in the general public about the impact that drug shortages have on American cancer patients,” said Dr. Schilsky, pointing out that Charles Penley, MD, testified at the

Richard L. Schilsky, MD

House Energy and Commerce hearing and Past ASCO President Michael Link, MD, briefed Congressional staff on how the drug shortage problem affected patients with cancer. Among the recommendations that ASCO put forth to lawmakers, Dr. Schilsky singled out the recommendation on user fees. “We feel that Congress should establish generic user fees to ensure that FDA has the resources to review new and supplemental generic drug applications quickly and provide flexibility to allow the Agency to use fees as economic incentives for manufacturers,” he said. Dr. Schilsky explained the various aspects of new iterations of the Prescription Drug User Fee See Page 110 Act (PDUFA), one of which—the FDA Safety and Innovation Act (S3187)—introduces user fees for review of generic drugs and requires manufacturers to provide early notification of impending drug shortages. “While legislation is a good step, current FDA authorities in many ways enable only stopgap measures, and permanent solutions will require enhancing the business model of generic drug manufacturing,” concluded Dr. Schilsky.

■

Disclosure: Drs. Kantarjian and Schilsky reported no potential conflicts of interest.

References 1. Hamburg M: Six month check-up: FDA’s work on drug shortages. Posted May 3, 2012. Available at blogs.fda.gov. Accessed September 24, 2012. 2. Link MP, Hagerty K, Kantarjian HM: Chemotherapy drug shortages in the United States: Genesis and potential solutions. J Clin Oncol 30:692-694, 2012

website at ASCOPost.com

ASCOPost.com | OCTOBER 15, 2012

PAGE 43

Pearls in Neuro-oncology

Cognitive Impairment in Patients with Cancer By Jorg Dietrich, MD, PhD

ancer therapy, including radiation and chemotherapy, can be harmful to multiple organ systems. The central nervous system (CNS) has generally been considered less vulnerable to the toxic effects of cancer therapy. However, the use of more aggressive treatment modalities combined with prolonged patient survival have led to an increasing frequency of acute and delayed neurologic complications.

Incidence Cognitive dysfunction has emerged as one of the most puzzling and concerning adverse effects in patients with cancer who are treated with chemotherapy. In pediatric patients, neurocognitive adverse effects have long been recognized as a major problem in long-term survivors. Similarly, longitudinal studies in adult cancer survivors suggest that cognitive dysfunction is more common than previously anticipated. Reported incidences range from 15% to 80%, depending on the study design and the sensitivity of neurocognitive tests used. While some earlier studies have been criticized for their retrospective design and lack of cognitive baseline assessment in affected individuals prior to start of chemotherapy, more recent and prospective studies have confirmed that cognitive deficits occur in a substantial number of patients with cancer.1-3 The most compelling data exist in patients with breast cancer, where studies suggest that 20% to 40% of patients demonstrate cognitive deficits on post-treat-

ment evaluation. Moreover, long-term evaluation reveals cognitive impairment in 20% to 30% of patients examined 2 years after treatment with high-dose chemotherapy.

Types of Deficits The most frequently described neurocognitive problems include difficulty with memory, learning, attention, concentration, information-processing speed, organization, and executive function (Fig. 1).4 While many patients ex-

structural and functional changes occur in the brain in a significant number of patients.5-7

Etiology Despite the large number of patients with cancer who receive chemotherapy, cognitive deficits develop and manifest only in some individuals, while others appear to remain unaffected. The etiology of cognitive dysfunction secondary to anticancer therapy is likely multifactorial.8 Important variables known to in-

Long-term evaluation reveals cognitive impairment in 20% to 30% of patients examined 2 years after treatment [for breast cancer] with high-dose chemotherapy. —Jorg Dietrich, MD, PhD

perience such deficits only temporarily during or immediately after chemotherapy, symptoms may persist in others, preventing a return to previous level of academic, occupational, or social activities. Neuroimaging invariably demonstrates nonspecific abnormalities, although several systematic imaging studies with magnetic resonance imaging (MRI), functional MRI, and positronemission tomography (PET) imaging have provided further evidence that

fluence the risk of cognitive side effects include the type, dose, and combination of chemotherapeutic agents, patient age, and level of cognitive function prior to treatment. In addition, concurrent metabolic abnormalities, hormonal dysregulation, and medical comorbidities (eg, anemia, liver and renal dysfunction) have been shown to influence cognitive function. As both chemotherapy and brain radiation can be associated with significant CNS toxicity, patients treated with both modalities are at increased risk to develop neurocognitive deficits.

Mechanisms

Fig. 1: Cognitive domains commonly affected by systemic chemotherapy for cancer.

Several mechanisms have been proposed to play a role in chemotherapyinduced neurotoxicity, including the direct toxic effects of chemotherapeutic agents on various brain cells, vascular injury, and the indirect immunemediated inflammatory processes. The basic cell-biologic mechanisms of delayed neurotoxic syndromes, such as progressive cognitive decline, white matter degeneration, and brain atrophy, have long eluded clear understanding. Recent experimental studies suggest that chemotherapy-induced damage of dynamic progenitor cell populations required for ongoing neurogenesis, gliogenesis, and maintenance of white matter integrity is an

important etiologic factor in the development of neurocognitive deficits.9,10 Adverse neurologic effects have been observed with virtually all categories of chemotherapeutic agents and biologicals, including antimetabolites, DNA cross-linking agents, mitotic inhibitors, antihormonal agents, and moleculartargeted agents. Some agents, such as methotrexate and cytarabine, are well known to cause neurotoxicity and leukoencephalopathy (Fig. 2 on page 44), especially when administered at high doses, intrathecally, or in combination with cranial irradiation. Many questions remain regarding the effects of chemotherapy on the brain and potential repair mechanisms. For example, it is unknown why certain individuals are more susceptible than others to the adverse effects of cancer treatment. Distinct genetic risk factors, such as polymorphisms that influence efficiency of DNA-repair mechanisms and drug efflux pump systems, have been implicated in modulating the degree of toxicity.

Treatment There are currently no established therapies for patients with cancer who experience cognitive symptoms secondary to their chemotherapy or cranial radiation. Possible confounding factors, such as anemia, vitamin deficiencies, endocrine dysfunction, metabolic abnormalities, and medication effects (steroids, narcotics, etc) should be addressed or eliminated as important contributing factors. Improvement of treatment-related fatigue and mood disorders are also likely to influence cognitive performance. Neurostimulants, such as methylphenidate and modafinil, have proven effective in treating cognitive dysfunction in patients with underlying fatigue and reduced motivation. Other agents, such as the reversible acetylcholinesterase inhibitor donepezil, currently used to treat dementia, may have a role in improving cognitive symptoms in a subset of patients. Cognitive and behavioral treatment strategies may also be employed, focusing on compensatory strategy training, stress management, energy conservation, and psychoeducation. Other nonpharmacologic interventions include meditation, exercise, and continued on page 44

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; OCTOBER 15, 2012

PAGE 44

Pearls in Neuro-oncology

Cognitive Impairment continued from page 43

sleep regulation.

Summary With advanced and more aggressive anticancer treatment, prolonged overall survival, and an increased awareness among physicians of neurocognitive symptoms in patients with cancer, such adverse effects are increasingly reported. The underlying mechanisms of neurocognitive side effects are multifactorial. Damage on the level of neural progenitor cells with an impact on neurogenesis and white matter integrity likely explains delayed toxicities. There are currently no established therapies for patients with cancer who experience cognitive deficits. Although

some agents have shown promising results in pilot studies, larger prospective and randomized clinical trials are needed to guide patient management. Unraveling the precise mechanisms underlying chemotherapy-related cognitive side effects will enable us to identify novel treatment strategies. One of the most important goals will be the identification of neuroprotective strategies along with the development of tumor-specific therapies to avoid unnecessary toxicities, and to promote endogenous nervous system repair.

â&#x2013;

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

References 1. Wefel JS, Saleeba AK, Buzdar AU, et al: Acute and late onset cognitive dysfunction as-

Fig. 2: Chemotherapy-induced leukoencephalopathy. Confluent subcortical and periventricular T2/ Flair hyperintensities in both hemispheres consistent with chemotherapy-induced leukoencephalopathy. (A) 65-year-old patient with primary CNS lymphoma treated with high-dose intravenous methotrexate. (B) 55-year-old patient with chronic myelogenous leukemia treated with intravenous methotrexate and intrathecal cytarabine. (C) 44-year-old patient with acute myeloid leukemia treated with intrathecal cytarabine.

sociated with chemotherapy in women with breast cancer. Cancer 116:3348-3356, 2010. 2. Ahles TA, Saykin AJ, McDonald B, et al: Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: Impact of age and cognitive reserve. J Clin Oncol 28:4434-4440, 2010. 3. Koppelmans V, Breteler MM, Boogerd W, et al: Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol 30:1080-1086, 2012. 4. Dietrich J, Monje M, Wefel J, et al: Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 13:1285-1295, 2008. 5. Deprez S, Amant F, Smeets A, et al: Longitudinal assessment of chemotherapyinduced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol 30:274-281, 2012. 6. Koppelmans V, de Ruiter MB, van der Lijn F, et al: Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Res Treat 132:1099-106, 2012. 7. McDonald BC, Conroy SK, Ahles TA, et al: Alterations in brain activation during working memory processing associated with breast cancer and treatment: A prospective functional magnetic resonance imaging study. J Clin Oncol 30:2500-2508, 2012. 8. Ahles TA, Saykin AJ: Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7:192-201, 2007. 9. Dietrich J, Han R, Yang Y, et al: CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 5:22, 2006.

Pearls in Neuro-oncology is guest edited by Tracy Batchelor, MD, Director, Division of NeuroOncology, Massachusetts General Hospital Cancer Center, and Professor of Neurology, Harvard Medical School, Boston. The series is intended to provide the practicing oncologist with guidance in managing neuro-oncology issues that may present in their patients with cancer. 10. Monje M, Dietrich J: Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res 227:376-379, 2012. Dr. Dietrich is Neuro-oncologist and Director, Cancer Neurotoxicity Clinic, Massachusetts General Hospital Cancer Center, and Assistant Professor, Harvard Medical School, Boston.

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ASCOPost.com | OCTOBER 15, 2012

PAGE 45

Journal Spotlight Survivorship

Radiation to the Skin and Later Risk of Basal Cell Carcinoma Studied By Charlotte Bath

he likelihood of developing basal cell carcinoma was approximately 40 times higher among participants of the Childhood Cancer Survivor Study (CCSS) who received a dose of 35 Gy or more to the skin from radiation therapy than survivors who were not treated with radiation, according to a study published in the Journal of the National Cancer Institute.1 “This study provides new information on the role of ionizing radiation in the development of [basal cell carcinomas] by defining the dosedependent relationship between the amount of radiation to the skin and subsequent risk of developing a [basal cell carcinoma],” CCSS researchers stated. They noted that results “were consistent with a linear dose–response relationship, with an excess odds ratio per Gy of 1.09 (95% CI = 0.49–2.64).”

Study Design For the study, each of 199 CCSS participants reporting a basal cell carcinoma diagnosis were matched on age and length of follow-up with three participants who did not develop basal cell carcinoma. “The median age at [basal cell carcinoma] diagnosis was 31 years (range, 11–46 years), and 83% of case subjects were diagnosed with their first [basal cell carcinoma] between the ages of 20 and 39 years. The median time from first primary cancer diagnosis to [basal cell carcinoma] diagnosis was 18.2 years (range, 5.2–29.6 years),” the researchers reported. Multivariate analysis found that radiation therapy was the only treatment-related exposure, but markers of sensitivity to UV radiation, such as light skin and hair color, were also associated with a higher risk of basal cell carcinoma. “As the survival of those treated for childhood malignancies continues to improve, it is important to understand and eduSee Page 110 cate survivors about treatment-related late effects, such as subsequent malignancies. Fewer than 30% of childhood cancer survivors seek appropriate medical care, either because they are not aware of their initial diagnosis or, more frequently, because they do

not know the risks associated with the therapy they received,” the authors concluded. “An understanding of the radiation dose-dependent nature of [basal cell

carcinoma] risk may facilitate the development of improved surveillance and treatment guidelines for physicians who care for cancer survivors,” they added.

■

Reference 1. Watt TC, Inskip TC, Stratton K, et al: Radiation-related risk of basal cell carcinoma: A Report From the Childhood Cancer Survivor Study. J Natl Cancer Inst 104:1240-1250, 2012.

The ASCO Post | OCTOBER 15, 2012

PAGE 46

Pioneers in Oncology Pediatric Pathologist Sidney Farber, MD: The ‘Father of Modern Chemotherapy’ and Cofounder of the Jimmy Fund By Jo Cavallo

n June 3, 1948, The New England Journal of Medicine published a study by Sidney Farber, MD, showing that a synthetic compound, 4-aminopteroylglutamic acid (aminopterin), could induce remissions in seriously ill children with acute leukemia.1 Although the study was small—just 16 children—10 showed clinical, hematologic, and pathologic evidence of improvement. Even though the children’s remissions were short-lived, Dr. Farber’s findings were so groundbreaking—until then, no drug had proved effective against non–solid tumor cancers—they ushered in the era of chemotherapeutics, chemical agents that could stop cancer cells from growing and replicating, in effect killing them. Aminopterin was later replaced by methotrexate, a similar but more effective folic acid antagonist with fewer side effects, which is still used today in the treatment of leukemia and other blood and solid tumor cancers. Nevertheless, the results of Dr. Farber’s study earned him the title, the Father of Modern Chemotherapy. Leukemia was first identified in 1845 by German pathologist Rudolph Virchow; 100 years later little had changed in the grim prognosis of the disease, and many patients died within weeks of diagnosis. In 1947, with little more than blood transfusions and general nursing care to offer young leukemia patients, Dr. Farber enlisted the aid of members of the Variety Club of New England, a charitable organization formed by people in the entertainment industry who were interested in providing financial support for scientific efforts, especially those affecting children. Early the following year, Dr. Farber and the Variety Club launched the Children’s Cancer Research Fund to raise money and advocacy efforts around childhood cancers. They also established the Children’s Cancer Research Foundation, which began funding Dr. Farber’s small, outpatient clinic at Children’s Hospital in Boston, where he was a pathologist.

The Jimmy Fund To put a face on cancer, Dr. Farber and Bill Koster, a member of the Variety Club, scouted the wards of Chil-

cancer was becoming so well known, his clinic was moved to a fourstory complex called the Jimmy Fund Building to accommodate the increasing number of patients. In 1969, the Children’s Cancer Research Foundation expanded its programs to include patients of all ages and later became known as the Sidney Farber Cancer Center, eventually becoming the Dana-Farber Cancer Institute.

Advent of Total Medical Care Throughout the 1950s and 1960s, Dr. Farber continued to make advances in cancer research, including the discovery that the Sidney Farber, MD, founder of the Children’s Hospital Cancer antibiotic actinomycin Research Foundation, with a young patient. Source: National D (dactinomycin) and Cancer Institute. radiation therapy could dren’s Hospital looking for a poster produce remission in Wilms’ tumor, child who could take the fund-raising a pediatric cancer of the kidneys, and message to the public. They found that agents such as corticosteroids Einar Gustafson, a young boy being were effective in treating acute leuketreated for a rare form of lymphoma, mia. Buoyed by these discoveries, Dr. but to protect his privacy, Dr. Farber Farber told Redbook magazine in 1963, insisted that the boy be known only as “Now we are an army on the march.” “Jimmy.” And headlines in leading papers of the

Everything that can be done with the aid of medical tools now available should be carried out for the comfort, relief of pain, and prolongation of life of the patient with acute leukemia. When Jimmy was featured on the radio show Truth or Consequences in the spring of 1948, the show’s host, Ralph Edwards, asked listeners to “send in their quarters, dollars, and tens of dollars … to Jimmy for the Children’s Cancer Research Fund.” The broadcast lasted only 8 minutes but raised $231,000 for the Children’s Cancer Research Fund, later renamed the Jimmy Fund. By the beginning of the 1950s, Dr. Farber’s work in treating children with

day such as the Saturday Evening Post optimistically proclaimed, “Cancer Is Yielding Up Its Secrets.” Dr. Farber’s medical innovations during that time also included the concept of what is today called “total care,” in which a variety of services for patients with cancer and their caregivers, including clinical care, nutrition, social work, and counseling, are provided in one place. He described the idea in an article for CA: A Cancer Journal for Clinicians in 1965:

“A generalization may be formulated for guidance, even in the absence of truly curative therapy: everything that can be done with the aid of medical tools now available should be carried out for the comfort, relief of pain and prolongation of life of the patient with acute leukemia.” 2

Expectation of Progress Knowing that if cancer was to be conquered it would take a national effort and major funding commitments by the government, Dr. Farber became a frequent presenter at Congressional hearings on appropriations for cancer research, explaining that federal support was essential to reducing the death rate from cancer. Although Dr. Farber’s efforts paid off—between 1957 and 1967, the annual budget of the National Cancer Institute increased from $48 million to $176 million—he had no illusions of a quick cure for cancer. In a 1971 newspaper article, Dr. Farber wrote, “Any man who predicts a date for discovery is no longer a scientist. We have a solid basis of accomplishment in research and treatment to permit controlled optimism and expectation of rapid progress.” On March 30, 1973, at the age of 70, Sidney Farber passed away from cardiac arrest while working in his office in the Jimmy Fund Building. In a memoriam to Dr. Farber that appeared in the November 1974 edition of The American Journal of Pathology, Orville T. Bailey, MD, an associate and Assistant Professor at Harvard Medical School from 1946 to 1951, wrote, “There can be no end to the lines of endeavor which Dr. Farber initiated. They cover the whole spectrum of effort to improve the care of children. The best tribute to him is to observe how far his vision has carried this objective and to see how others have found the path he made.”

■

References 1. Farber S, Diamond LK: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 238:787-793, 1948. 2. Farber S: Management of the acute leukemia patient and family. CA Cancer J Clin 15:14-17, 1965.

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Janssen Biotech, Inc. ÂŠ Janssen Biotech, Inc. 2012 8/12 08Z12244A

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

www.zytiga.com Please see brief summary of full Prescribing Information on the following pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 8/12 08Z12244A

08Z11121R3

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. 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 clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders 6 Arrhythmia 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

5.1 4.1

0.3 0

2.3

4.6 2.8 1.0

1.0 0 0.3

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. Manufactured by: Patheon Inc. Mississauga, Canada

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

Revised: July 2012

08Z12237B

The ASCO Post | OCTOBER 15, 2012

PAGE 50

JCO Spotlight Hematology

Kinase Inhibitors Compared in First-line Treatment of CML By Matthew Stenger

osutinib (Bosulif) is an oral dual Src/Abl kinase inhibitor that is active against many Bcr-Abl mutations associated with imatinib (Gleevec) resistance and that has reduced activity against nonspecific molecular targets associated with toxicities reported for other second-generation kinase inhibitors. The drug was recently approved for treatment of Philadelphia chromosome–positive chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) in adult patients with resistance or intolerance to prior therapy. The recently reported BELA trial has shown that bosutinib did not produce a better 12-month complete cytogenetic response rate compared with imatinib as first-line treatment of chronic phase CML, despite significant improvements in major molecular response rate and time to complete cytogenetic response and major molecular response. The study also showed that bosutinib was associated with a distinct safety profile.

Study Design As reported by Cortes and colleagues in a recent Journal of Clinical Oncology article,1 BELA was an open-label, multinational phase III trial in which 502 adults with Philadelphia chromosome–positive chronic phase CML diagnosed within the prior 6 months who had received no prior antileukemia treatment (apart from 6 months or less of anagrelide or hydroxyurea) were randomly assigned to bosutinib at 500 mg/d (n = 250) or imatinib at 400 mg/d (n = 252). An increase in dose of both agents to 600 mg/d was permitted for suboptimal response, and patients who could not tolerate a dose of 300�� mg/d of either drug were discontinued from the study. The primary endpoint was complete cytogenetic response rate at 12 months. For the bosutinib and imatinib groups, respectively, median ages were 48 and 47 years, 60% and 54% were male, 64% and 65% were white, median times since diagnosis were 23 and 22 days, and 74% and 72% had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Sokal risk was low in 35%, intermediate in 47%, and high in 18% of patients in each group. Median white blood cell counts in the bosutinib and imatinib groups were 21.7 and 23.5 × 109/L,

and median platelet counts were 386 and 451 × 109/L. Median duration of treatment for both groups was 13.8 months. A total of 4% of bosutinib patients and 12% of imatinib patients had their dose increased to 600�� mg/d due to suboptimal efficacy. As of the data cutoff, 71% of bosutinib patients and 80% of imatinib patients continued to receive study medication.

Major Endpoints At 12 months on intent-to-treat analysis, complete cytogenetic response rates were 70% in the bosutinib group and 68% in the imatinib group (P = .601). Median time to complete cytogenetic response was markedly reduced with bosutinib treatment (12.9 vs 24.6 weeks, P < .001), with the bosutinib group having significantly higher complete cytogenetic response rates at 3, 6, and 9 months.

Fewer bosutinib patients had an on-treatment event-free survival event with bosutinib (4%) than with imatinib (7%) and fewer had on-treatment progression to accelerated or blast phase CML (2% vs 4%). In an analysis of event-free survival including death at any time or on-treatment progression to accelerated or blast phase, events were less common in bosutinib patients (2% vs 6%). Estimated overall survival at 12 months was greater than 99% in the bosutinib group and 97% in the imatinib group and estimated 12-month event-free survival was 94% and 93%, respectively. The study population continues to be followed to allow long-term assessment of bosutinib efficacy.

Different Safety Profiles The most common adverse events of any grade (≥ 20%) were diarrhea,

Bosutinib vs Imatinib in Chronic Myeloid Leukemia ■■ Bosutinib did not produce a higher complete cytogenetic response rate than imatinib in first-line treatment of chronic phase CML.

■■ Major molecular response rate and times to response were significantly better with bosutinib.

■■ Bosutinib and imatinib showed different safety profiles.

Cumulative complete cytogenetic response rates by 12 months were similar in the two groups (79% vs 75%). The major molecular response rate was significantly higher with bosutinib treatment at 12 months (41% vs < .001), as was the rate of com27%, P �� plete molecular response (12% vs 3%, P < .001). The median time to major molecular response was significantly reduced with bosutinib treatment (37.1 vs 72.3 weeks, P < .001), and the cumulative rate of major molecular response was significantly increased (47% vs 32%, P < .001). There were no significant differences between the bosutinib and imatinib groups in complete cytogenetic response rates at 12 months according to low (78% vs 75%), intermediate (69% vs 67%), or high (56% vs 56%) Sokal risk group. Major molecular response rate was higher with bosutinib than imatinib in the low-risk group (53% vs < .001) and similar in the inter28%, P �� mediate- (31% vs 24%) and high-risk (33% vs 28%) groups.

vomiting, nausea, and rash in bosutinib patients and edema, nausea, diarrhea, and muscle cramps in imatinib patients. Diarrhea (68% vs 21%), vomiting (32% vs 13%), and abdominal pain (11% vs 5%) were more common with bosutinib, whereas edema (11% vs 38%), bone pain (4% vs 10%), and muscle cramps (2% vs 20%) were more common with imatinib. Grade 3 or 4 adverse events occurred in 64% of bosutinib patients and in 48% of imatinib patients (P < .001); the most common (>�� 2%) were diarrhea (11%) and vomiting (3%) in bosutinib patients. For grade 3 or 4 laboratory abnormalities, liver aminotransferase elevations were more common in bosutinib patients and neutropenia and hypophosphatemia were more common in imatinib patients. The most common grade 3 or 4 laboratory abnormalities (≥ 5%) were elevated ALT (22%), thrombocytopenia (14%), elevated AST (11%), neutropenia (11%), elevated lipase (9%), and anemia (6%) in bosutinib patients and neutropenia

(24%), hypophosphatemia (15%), thrombocytopenia (14%), anemia (7%), and elevated lipase See Page 110 (5%) in imatinib patients. Drug-related cardiac adverse events occurred in 4% of bosutinib patients and 3% of imatinib patients. Discontinuation of treatment due to adverse events occurred in 48 bosutinib patients (19%) vs 14 imatinib patients (6%), with 15 (31%) of the 48 bosutinib patients discontinuing treatment prior to the first post-baseline assessment at month 3. The investigators noted that these early discontinuations may have contributed to the lower rate of complete cytogenetic response in the intent-to-treat population, which included these patients as nonresponders. Treatment interruptions due to adverse events occurred in 61% of bosutinib patients vs 42% of imatinib patients, and dose reduction due to adverse events occurred in 39% vs 18%. Four bosutinib patients died, three from CML-related causes and one from mesenteric embolism/intestinal necrosis. Ten imatinib patients died, eight from CML-related causes, one from cardiovascular disease, and one from lung embolism. None of the deaths was considered related to study treatment. As summarized by the authors, “This ongoing trial did not meet its primary endpoint of [complete cytogenetic response] at 12 months, despite the observed higher [major molecular response] rate at 12 months, faster times to [complete cytogenetic and major molecular response], fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib…. Further follow-up is needed to provide long-term data on duration of response, transformation to accelerated/blast phase CML, and overall survival, as well as the tolerability profile of bosutinib in newly diagnosed [chronic phase] CML.” For information on second-line use of bosutinib, see page 51.

■

Reference 1. Cortes JE, Kim D-W, Kantarjian HM, et al: Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: Results from the BELA trial. J Clin Oncol. September 4, 2012 (early release online).

ASCOPost.com | OCTOBER 15, 2012

PAGE 51

In the Clinic Hematology

Bosutinib in Chronic Myelogenous Leukemia Patients with Resistance or Intolerance of Prior Therapy By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

n September 4, 2012, bosutinib (Bosulif) was approved for the treatment of chronic phase, accelerated phase, or blast phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy.1,2 (For information on investigational first-line use of bosutinib in CML, see page 50.) Approval was based on results of a single-arm, openlabel, multicenter trial in 546 patients with chronic phase (n�� = 406), accelerSee Page 110 ated phase, or blast phase CML (n = 140 for accelerated and blast phase) previously treated with at least one prior tyrosine kinase inhibitor.2 All patients had received prior imatinib (Gleevec) therapy; 73% were imatinib-resistant and 27% were imatinib-intolerant. Fifty-three percent of patients were male, 65% were Caucasian, and 20% were aged 65 years

or older. The T315I imatinib resistance mutation has also been found to confer resistance to bosutinib; after 396 patients had been enrolled in the trial, those known to harbor the T315I mutation were excluded. In total, 503 patients were evaluable for efficacy. Among evaluable patients with chronic phase CML (n�� =�� 374), 266 received prior treatment with only imatinib and 108 received prior treatment with imatinib followed by either dasatinib (Sprycel) and/or nilotinib (Tasigna). All 129 evaluable patients with advanced phase CML (accelerated phase = 69, blast phase =60) were previously treated with at least imatinib. Median durations of bosutinib treatment were 22 months in patients with chronic phase CML previously treated with one tyrosine kinase inhibitor (imatinib), 8 months in patients with chronic phase CML previously treated with imatinib and at least one additional tyrosine kinase inhibitor, 10 months in patients with accelerated phase CML previously treated with at least imatinib, and 3 months in patients with blast phase CML previously treated with at least imatinib. Among patients with chronic phase CML who received prior therapy with imatinib alone, 34% achieved a major cytogenetic response at week

Key Endpoints in the Bosutinib Trial ■■ Complete cytogenetic response: no cells are Philadelphia chromosome– positive

■■ Complete hematologic response: white blood cell count less than or

equal to institutional upper limit of normal, platelet count ≥ 100,000/mm3 and < 450,000/mm3, absolute neutrophil count ≥ 1.0 × 109 /L, no blasts or promyelocytes in peripheral blood, < 5% myelocytes + metamyelocytes in bone marrow, < 20% basophils in peripheral blood, and no extramedullary involvement

■■ Major cytogenetic response: reduction in Philadelphia chromosome– positive cells to < 35%

■■ Major hematologic response: complete hematologic response or no

evidence of leukemia in the setting of peripheral blood counts that have not normalized

■■ Overall cytogenetic response: complete, partial, plus minor cytogenetic response

■■ Overall hematologic response: major hematologic response or return

to chronic phase (disappearance of features defining accelerated or blast phases but still in chronic phase)

Bosutinib in Chronic Myelogenous Leukemia ■■ Bosutinib (Bosulif) was approved for the treatment of chronic,

accelerated, or blast phase Philadelphia chromosome–positive chronic myelogenous leukemia in adult patients with resistance or intolerance to prior therapy.

■■ Bosutinib is given at 500 mg orally once daily with food until disease

progression or intolerance. The dosage may be increased to 600 mg/d if complete hematologic response is not achieved by week 8 or complete cytogenetic response is not achieved by week 12 and no grade 3 or higher adverse reactions have occurred.

■■ Bosutinib inhibits the Bcr-Abl tyrosine kinase that promotes CML, as well as Src-family kinases that have a critical role in tumor development.

■■ Serious adverse reactions to bosutinib have included anaphylactic shock, myelosuppression, diarrhea, fluid retention, hepatotoxicity, and rash.

24; of 53% of those achieving a major cytogenetic response at any time during the trial, 53% had that response last at least 18 months. Among the chronic phase CML patients who received prior therapy with imatinib and at least one other tyrosine kinase inhibitor, 27% achieved a major cytogenetic response at week 24; of 32% who achieved a major cytogenetic response at any time, 51% of those had that response last at least 9 months. Among patients with accelerated phase CML, 30% achieved a complete hematologic response and 55% achieved an overall hematologic response by week 48. Among patients with blast phase CML, 15% achieved a complete hematologic response and 28% achieved an overall hematologic response by week 48.

How It Works Bosutinib inhibits the Bcr-Abl tyrosine kinase that promotes CML. It is also an inhibitor of Src-family kinases (including Src, Lyn, and Hck), which have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. Bosutinib has been show to inhibit 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, with no inhibition of T315I and V299L mutant cells being observed. Bosutinib treatment reduced the size of CML tumors in mice compared with controls and inhibited growth of murine myeloid tumors

expressing several imatinib-resistant forms of Bcr-Abl.

How It Is Given The recommended dose of bosutinib is 500 mg orally once daily with food, with treatment continuing until disease progression or intolerance. An increase to 600 mg/d can be considered in patients who

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www. fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

do not reach complete hematologic response by week�� 8 or complete cytogenetic response by week 12 and who have not had grade 3 or higher adverse reactions. Treatment interruption until recovery and dose reduction are recommended for elevated liver transaminases (> 5 times upper limit of normal), diarrhea of grade 3 or 4, neutropenia (< 1,000 × 106/L), and thrombocytopenia (< 50,000 × 106/L). The recommended dose of bosutinib in patients with mild, moderate, continued on page 52

The ASCO Post | OCTOBER 15, 2012

PAGE 52

In the Clinic

Bosutinib in CML continued from page 51

or severe hepatic toxicity is 200 mg/d. Strong or moderate CYP3A inhibitors (eg, thalidomide [Thalomid], itraconazole, clarithromycin) and/or P-glycoprotein inhibitors (eg, voriconazole) increase bosutinib exposure and strong or moderate CYP3A

inducers reduce bosutinib exposure; concomitant use of these agents with bosutinib should be avoided. Bosutinib doses of 300 mg/d or lower have not been evaluated.

Safety Profile Safety data are from the 546 patients enrolled in the single-arm trial. Serious

adverse reactions included anaphylactic shock, myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity, and rash. Among the 406 patients with chronic phase CML, the most common adverse events of any grade (> 20%) were diarrhea (84%), nausea (46%), abdominal pain (40%), thrombocy-

topenia (40%), vomiting (37%), rash (34%), fatigue (26%), anemia (23%), and pyrexia (22%). The most common grade 3 or 4 adverse events (> 5%) were thrombocytopenia (26%), neutropenia (11%), diarrhea (9%), anemia (9%), rash (8%), and increased ALT (7%). The most common grade 3 or 4 laboratory abnormalities (> 5%) were thrombocytopenia (25%), neutropenia (18%), anemia (13%), increased ALT (10%), increased lipase (8%), and low phosphorus. Among the 140 patients with advanced phase CML, the most common adverse events of any grade were diarrhea (76%), nausea (47%), vomiting (42%), thrombocytopenia (42%), anemia (37%), pyrexia (36%), rash (35%), abdominal pain (29%), and cough (21%). The most common grade 3 or 4 adverse events were thrombocytopenia (37%), anemia (26%), neutropenia (18%), and dyspnea (6%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (57%), neutropenia (37%), anemia (35%), low phosphorus (7%), and increased ALT (6%). Bosutinib carries warnings/precautions for gastrointestinal toxicity, myelosuppression, hepatic toxicity, fluid retention, and embryo-fetal toxicity.

Cost The cost of bosutinib is expected to be approximately $8,000 per month.

■

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives.

The ASCO Post Wants to Hear from You

We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

This is our pledge. This is GSK Oncology. Learn more at the new GSKoncology.com

References 1. U.S. Food and Drug Administration. Approved drugs. Bosutinib tablets. Available at http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm318203.htm. Accessed September 13, 2012. 2. BOSULIF® (bosutinib) tablets prescribing information. Pfizer, Inc, September 2012. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/203341lbl.pdf. Accessed September 13, 2012.

Write to The ASCO Post at editor@ASCOPost.com 04/12

ASCOPost.com | OCTOBER 15, 2012

PAGE 53

Best of ASCO® Annual Meeting ‘12 Neuro-oncology

Investigators’ Perseverance Pays Off in Treating Anaplastic Oligodendroglioma By Susan London

he theme of this year’s key abstracts on central nervous system tumors is that “perseverance and analysis of longterm outcomes lead to practice-changing results and imSee Page 110 portant insights,” according to Eric L. Chang, MD, of the USC Norris Cancer Hospital and Keck School of Medicine, Los Angeles, who reviewed the data at the Best

of ASCO San Diego meeting. At this year’s ASCO Annual Meeting, researchers reported updated results of a pair of key phase III trials testing radiation therapy alone against sequential approaches using radiation therapy plus PCV chemotherapy (procarbazine [Matulane], lomustine [CeeNu], and vincristine) for newly diagnosed anaplastic oligodendroglioma. Initial results, published in 2006, had shown a benefit only in progres-

Trials Establish New Standard of Care for Anaplastic Oligodendroglioma

“L

ong-term results of two cooperative group phase�� III�� trials have determined radiation therapy and chemotherapy is the new standard of care for newly diagnosed anaplastic oligodendroglioma with 1p19q loss,” commented Eric L. Chang, MD, of the USC Norris Cancer Hospital and Keck School of Medicine, Los Angeles. “Perseverance in data and tumor collection established 1p19q as a predictive marker (in addition to a prognostic marker) and underscores the importance of prospective tumor collection in hypothesis-based clinical trials.”

Practical Implications The trials have several implications for current practice, he maintained. “Radiation therapy alone is no longer adequate for treatment of patients with anaplastic oligodendroglioma with 1p19q codeletion: Existing data support first-line treatment with radiation therapy and chemotherapy.” However, “the optimal treatment paradigm has not been established, and the sequencing has also not been established—whether it should be chemotherapy followed by radiation therapy, radiation therapy followed by chemotherapy, or whether it should be temozolomide vs PCV.” And perhaps not surprisingly, a recent survey of specialists found wide variation in the treatment of choice for anaplastic oligodendroglioma, with no apparent consensus.1 In any case, the new trial results “emphasize the need to consider anaplastic oligodendroglioma as two distinct entities based on the 1p19q status,” Dr. Chang concluded. “What is the optimal regimen for anaplastic oligodendroglioma with 1p19q loss?... And are there unique molecular targets resulting from the translocation and chromosomal loss? These are areas for future directions and research.”

■

Reference 1. Abrey LE, Louis DN, Paleologos N, et al: Oligodendroglioma Study Group: Survey of treatment recommendations for anaplastic oligodendroglioma. Neuro Oncol 9:314-318, 2007.2. Bible KC, Suman VJ, Molina JR, et al: Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol 11:962-972, 2010.

Key Neuro-oncology Findings Presented at Best of ASCO® ‘12 ■■ Compared with radiation therapy alone, PCV (procarbazine, lomustine,

vincristine) followed by radiation therapy doubles median overall survival in patients with anaplastic oligodendroglioma having the 1p19q codeletion.

■■ Compared with radiation therapy alone, radiation therapy followed by PCV reduces the risk of death by nearly half in patients with anaplastic oligodendroglioma having the 1p19q codeletion.

sion-free survival with the combination. But the new data—obtained by dogged long-term follow-up and tracking down of additional tumor biopsy specimens—showed an overall survival benefit for patients whose tumors harbored the 1p19q codeletion, which is seen in about two-thirds of cases.

droglioma.2 With long-term follow-up, availability of tissue for 1p19q testing increased from 85% to 86%.

PCV then Radiation Bests Radiation Alone The Radiation Therapy Oncology Group (RTOG) 9402 trial compared radiation therapy alone vs four cycles of intensive PCV chemotherapy followed by radiation therapy in 291 patients with anaplastic oligodendroglioma.1 With long-term follow-up, availability of tissue for testing for 1p19q codeletion increased from 70% to 90%. In the updated results, the combination conferred no overall survival benefit vs radiation alone in the trial population as a whole. But it doubled survival duration in the subgroup of patients with 1p19q codeletion (median, 14.7 vs 7.3 years; HR = 0.59; P = .03). There was no significant benefit in the subgroup lacking the codeletion.

Radiation then PCV Bests Radiation Alone The European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial compared radiation therapy alone with radiation therapy followed by six cycles of PCV in 368 patients with anaplastic oligoden-

Eric L. Chang, MD

In the updated results, the combination conferred an overall survival advantage both among all patients (HR = 0.75, P = .018) and in the subgroup with 1p19q codeletion (HR = 0.56, P = .059). There was no significant benefit in the subgroup of patients who did not have the codeletion.

■

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

References 1. Cairncross JG, Wang M, Shaw EG, et al: Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study. 2012 ASCO Annual Meeting. Abstract 2008b. Presented June 3, 2012. 2. Van Den Bent MJ, Hoang-Xuan K, Brandes AA, et al: Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). 2012 ASCO Annual Meeting. Abstract 2. Presented June 3, 2012.

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PAGE 55

Direct from ASCO

ASCO Achieves Highest Level of Accreditation for Continuing Medical Education Program

n July, ASCO was awarded “Accreditation with Commendation” (the highest level achievable) by the Accreditation Council for Continuing Medical Education (ACCME). Fewer than 25% of continuing medical education (CME) providers carry the “Commendation” status distinction, which signifies an organization that

CME credit can be obtained through participation in or use of a number of ASCO programs and resources, including attendance at the Annual Meeting and thematic symposia; completion of ASCO University ® online-learning modules, ASCO-SEP self-assessment questions, and Maintenance of Certification Self-Assessment Modules; and

ASCO’s renewed Accreditation with Commendation solidifies our goal of providing comprehensive educational resources for oncology professionals that will ultimately lead to improved patient care and outcomes —Primo N. Lara, Jr, MD

“ACCME has rightly awarded the Commendation status to ASCO’s CME program, which is exceptional in its multidisciplinary educational offerings, understanding of the true spirit of disclosure of potential conflict of interest, and cutting-edge educational technology. The ASCO CME professionals are extremely knowledgeable and sophisticated about the trends in learning,” said Lucille A. Leong, MD, of City of Hope Comprehensive Cancer Center and a member of ASCO’s CME Subcommittee. As 2010-2011 Subcommittee Chair, Dr.

Volume 29, Issue 15

May 20, 2011

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

develops CME activities that meet the highest standards of educational quality. The Society has maintained this esteemed level of accreditation since 2006 and has been an accredited provider of CME since 1977. “ASCO’s renewed Accreditation with Commendation solidifies our goal of providing comprehensive educational resources for oncology professionals that will ultimately lead to improved patient care and outcomes,” said Primo N. Lara, Jr, MD, of the University of California Davis Comprehensive Cancer Center. Dr. Lara currently serves as Chair of ASCO’s CME Subcommittee.

CME Mission ASCO’s CME mission is to provide a comprehensive educational program and facilitate the acquisition and maintenance of attitudes, knowledge, and skills of oncology professionals that will positively affect the care of patients with cancer, patients at high risk of cancer, and cancer survivors. Activities are designed for a wide range of learning styles, with a goal to maintain a diversified portfolio of learning formats that are continually reassessed to meet professional practice gaps and educational needs. The activities meet the highest standards of balance, independence, objectivity, and scientific rigor.

participation in the Quality Oncology Practice Initiative Performance Improvement CME Activity.

Lengthy Reaccreditation Process “As Chair of the CME Subcommittee during the accreditation year, I was continually impressed by the expertise and strengths that the ASCO CME staff brought to the process. I really believe that the preparation for the reaccreditation and the materials produced for the examiners set a new standard for the ACCME, and all members of ASCO can be proud that the educational mission of our Society is supported in a professional way with innovation and better technology always in mind,” said 20112012 Subcommittee Chair Thomas J. Fahey, Jr, MD, of Memorial Sloan-Kettering Cancer Center. Volunteers on the CME Subcommittee and ASCO staff committed nearly two years to producing an innovative digital 285-page Self-Study Report, 15 CME activity files, and video-conference interview for the 2012 ACCME evaluation. The digital submission was well-received by ACCME, and subsequently ASCO will showcase the format at the 2013 Annual Conference of the Alliance for Continuing Education in the Health Professions (ACEHP).

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

Leong oversaw the development of the report outline. ASCO’s next evaluation will take place in 2018. For more information on ASCO’s CME program, visit asco.org/cme, email cme@asco.org, or call 571-4831403.

■

Originally printed in ASCO Connection. © American Society of Clinical Oncology. (“ASCO Achieves Highest Level of Accreditation for Continuing Medical Education Program.” ASCO Connection, September 2012: 23) All rights reserved.

5 most-accessed Top 10Top most-accessed articles recently in published articles published 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org How Genetic Variant Libraries Effectively Extend Gene Testing Patents: Implications for Intellectual Property and Good Clinical Care

Transplantation for Myeloma: Work in Progress

Concordance and Discordance in Tumor Genomic Profiling

Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial

Aromatase Inhibition in Obese Women: How Much Is Enough?

The ASCO Post | OCTOBER 15, 2012

PAGE 56

Direct from ASCO

CancerLinQ Addressing Institute of Medicine Core Recommendations for ‘Learning Health System’

SCO is applauding new Inobtain new insights from the vast stitute of Medicine (IOM) pool of “real-world” data on cancer recommendations for establishing care; and provide physicians with a “learning health system” in the decision support in real time. In United States, and is calling upon developing CancerLinQ, ASCO is other medical specialties to join in addressing the new IOM recomachieving this vision of high-qualimendations by: ■■ Developing a prototype for ty, high-value medical care. ASCO’s breast cancer to determine and recently launched multiphased rapovercome the technological barid-learning initiative, CancerLinQ, riers in improving the capacity to aims to achieve the IOM’s core capture clinical data; recommendations for the field of ■■ Seeking data use agreements oncology. with oncology practices and The recent IOM report, “Best other organizations to input deiCare at Lower Cost: The Path to dentified patient Continuously records into the Learning Health prototype; Care in America,” The [IOM] ■■ Utilizing describes a rapid report makes 10 a limited set of learning system recommendations for ASCO’s and other that will use realclinical practice time knowledge developing the rapid guidelines in the to improve outlearning system in prototype to demcomes, engage onstrate evidencepatients and famhealth care. ASCO is based clinical ily members, crealready working to decision support ate a new culture and quality meaof care, and form address seven of these surement; a continuous recommendations. ■■ Developcycle of learning ing a vision for and improveintegrating ASment. The report CO’s Quality Oncology Practice makes 10 recommendations for deInitiative, which measures and veloping the rapid learning system promotes improved physician/ in health care. Through its work patient communication and coon CancerLinQ, ASCO is already ordinated health services, into working to address seven of these the future development of Canrecommendations. cerLinQ. Rapid Learning System The CancerLinQ prototype will When complete, CancerLinQ be shared at ASCO’s inaugural Qualwill have the ability to assemble ity Care Symposium, taking place and analyze millions of unconnectNovember 30 to December 1, 2012, ed medical records from cancer paat the Manchester Grand Hyatt in tients in a central knowledge base, San Diego. which will grow “smarter” over For more information, go to: time. This rapid learning system www.asco.org/CancerLinQ. will harness technological advanc© 2012. American Society of Clinical es to connect oncology practices; Oncology. All Rights Reserved. measure quality and performance;

Stay Up to Date on New Patient Materials from Cancer.Net

ncourage your patients to use social media to stay up to date with the new resources available on Cancer.Net, such as the latest booklet on tobacco discussed on page 57. It is easier than ever for patients to get the latest cancer information on their computer or mobile device by subscribing to the Cancer.Net RSS feeds (www.cancer.net/feeds), or

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

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

www.jop.ascopubs.org

on Cancer.Net’s Facebook (www. facebook .com/CancerDotNet), Google+ (plus.google.com), and YouTube (www.youtube.com/CancerDotNet) pages, and at CancerDotNet on Twitter (www.twitter. com/CancerDotNet).

■

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

What’s Hot in

JOP

JCO.org

Effort Required in Eligibility Screening for Clinical Trials

Multisite Parent-Centered Risk Assessment to Reduce Pediatric Oral Chemotherapy Errors

Do High Symptom Scores Trigger Clinical Actions? An Audit After Implementing Electronic Symptom Screening

Health Care Costs for Patients With Cancer at the End of Life

■

National Practice Benchmark, 2012 Report on 2011 Data

ASCOPost.com | OCTOBER 15, 2012

PAGE 57

Direct from ASCO

New ASCO Tobacco Cessation Practice Resources Will Offer Help for Providers as Well as Patients

t is well recognized that tobacco use increases the risk of several kinds of cancer. However, it is less well recognized that quitting tobacco remains important once an individual has been diagnosed with cancer, a common misconception held by oncologists and patients alike. Patients with cancer who continue to use tobacco have poorer treatment outcomes compared to their counterparts who stop using tobacco, a finding that seems to occur in patients with many different types of cancer, regardless of whether the cancer was tobacco related. The good news is that quitting can have health benefits and evidence-based interventions to support quit efforts are available. “Many people have the idea that if you have a diagnosis of cancer, there

Tobacco Cessation Guide for Oncology Providers The Tobacco Cessation Guide for Oncology Providers is an evidence-

based tobacco cessation resource for providers to use in educating their patients about the negative effects of tobacco on cancer treatment outcomes

For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

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Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach K. Michael Cummings, PhD

are a lot more important things to be worried about than whether you smoke or not—but we need to change that,” said K. Michael Cummings, PhD, Professor in the Department of Psychiatry & Behavioral Sciences at the Medical University of South Carolina Hollings Cancer Center and longtime researcher on tobacco control, public policy, and tobacco cessation. The first step, said Dr. Cummings, is for health providers to be able to communicate effectively with patients about quitting tobacco in ways that remove the stigma that has for years been affixed to tobacco use, and then to equip providers with effective ways of helping patients quit. To this end, ASCO has created a new set of resources on tobacco cessation for patients and providers in the oncology setting. The resources, published earlier this month, are available online at asco.org as well in print format.

• In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010.

Now available for patients with ductal carcinoma in situ (DCIS) Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0712

and to help patients quit. Developed by a multidisciplinary group of cancer and tobacco cessation experts, this continued on page 58

The ASCO Post | OCTOBER 15, 2012

PAGE 58

Direct from ASCO

Conquer Cancer Foundation Honors Oncology Professionals for High-quality Research in Breast Cancer

ore than 15 leading young oncology professionals were honored this year by the Conquer Cancer Foundation of the American Society of Clinical Oncology (ASCO) with 2012 Breast Cancer Symposium Merit Awards for their work in breast cancer research. These trainees submitted high-quality abstracts selected for presentation at the 2012 Breast Cancer Symposium that took place in San Francisco on September 13-15, where they were recognized for their research in the areas of breast cancer disease management, survivorship care, healthcare disparities and more. “This year’s Merit Award recipients are helping to contribute to the growing body of clinical evidence in breast cancer that helps patients live longer and have better outcomes,” said Gary Levine, MD, Chair of the Breast Cancer Symposium Steering Committee. “We are honored to recognize the scientific advances of this

Tobacco Cessation Resources continued from page 57

guide is intended to help oncology providers integrate tobacco cessation strategies into their practices. An important goal of the provider guide is to help oncologists and other oncology providers become more comfortable in addressing the topic of tobacco use with their patients. “Physicians, including oncologists, do not know how to help their patients quit. We need to help them help their patients,” said Carolyn Dresler, MD, Associate Professor of Health Policy and Management in the Fay W. Boozman College of Public Health at the University of Arkansas, Tobacco Control Branch Chief at the Department of Health and Human Services for the state of Arkansas, and Chair of ASCO’s Tobacco Cessation and Control Subcommittee. “We need to

year’s recipients as well as their dedication to improving care for patients living with breast cancer.”

Promoting Clinical Research by Young Investigators

2012 Breast Cancer Symposium Merit Award Winners ■■ Lisa Allen, MD, University of Texas MD Anderson Cancer Center (Abstract 150)

■■ Amanda Arrington, MD, City of

■■ Shai Libson, MD, Sylvester

Cancer Center (Abstract 175)

■■ Herdee Gloriane Luna, MD,

The 2012 recipients and their abstract titles are featured on the Breast Cancer Symposium website at http://breastcasymposium.org/ Abstracts/MeritAwards.aspx. The Conquer Cancer Foundation of ASCO Merit Awards are designed to promote clinical cancer research by young oncology investigators and provide them with the opportunity to present their research at the Breast Cancer Symposium, a multidisciplinary meeting for breast cancer clinicians and other oncology team members who treat and care for patients with breast cancer. This year’s Symposium focused on taking the latest scientific results in the field and bringing them into the clinic for practical application. The 2012 Breast Cancer Symposium Merit Awards are supported by: Amgen; Astellas; AVEO Pharmaceuticals, Inc; Bristol-Myers Squibb; Celgene Corporation; Lilly USA, LLC; Millennium: The Takeda Oncology Company; Novartis Oncology; and

Onyx Pharmaceuticals. For more information about the Conquer Cancer Foundation’s Grants and Awards Program visit http://www.

conquercancerfoundation.org.

be able to treat the whole patient, not just his or her cancer.” The provider guide offers practical tips on how to incorporate tobacco assessment and treatment into the routine practice of oncol-

providers whose patients use tobacco, including medical oncologists, nurses, physician assistants, psychosocial providers, and primary care providers who see cancer patients in their practice.

tobacco use. It can be found at www. cancer.net/tobacco. The guide for patients and families emphasizes that, although it can be difficult, many people are successful at quitting tobacco use, and a variety of treatment options and resources exist to help people reach their goal. The booklet provides individuals with clear, practical information about the benefits of stopping tobacco use after a cancer diagnosis, and tips for how patients can talk with their doctors about stopping tobacco use. Both the provider guide and patient booklet will be available to order through the ASCO University Bookstore (http://store2.asco.org/) for your practice, either as a package of 10 provider guides and 115 patient booklets, or 125 patient booklets.

Hope (Abstract 71)

■■ Conceicao Campos, MD, PhD, Escola Cearense de Oncologia (Abstract 178)

■■ Farrah Datko, MD, Memorial

Sloan-Kettering Cancer Center (Abstract 134)

■■ Rachel Farkas, MD, University of Rochester Medical Center (Abstract 180)

■■ Oluwadamilola Fayanju, MD,

MPHS, Washington University School of Medicine (Abstract 13)

■■ Bruna Jardim, MSc, Henry Ford Health System (Abstract 120)

■■ Jiali Li, MD, PhD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center (Abstract 2)

We need to be able to treat the whole patient, not just his or her cancer. —Carolyn Dresler, MD

ogy as well as how to be reimbursed for these services. It includes updated listings for state quitlines and websites such as www.smokefree. gov. In doing so, the guide does not endorse any one treatment for quitting, but rather emphasizes providing a personalized plan for individual patients. ASCO hopes that the resources contained within the guide will be used by all oncology

Guidance for Patients and Families As a complement to the provider guide, ASCO has also published a guide to help educate patients and their caregivers on the benefits of quitting tobacco use. The patient guide offers a quitting assessment tool, a place to develop a plan to quit, and a list of quitlines, websites, and mobile apps to help patients stop

National Kidney and Transplant Institute (Abstract 19)

■■ Aimee Mackey, MD, Columbia University Medical Center (Abstract 173)

■■ Jennifer Plichta, MD, Loyola University Health Systems (Abstract 60)

■■ Gregory Thompson, MD, University of Cincinnati (Abstract 200)

■■ Lori Uyeno, MD, City of Hope (Abstract 69)

■■ Barbara Wexelman, MD, MBA, St. Luke’s Roosevelt Hospital (Abstract 63)

■■ John Wilkinson, MD, Oakland

University William Beaumont School of Medicine (Abstract 145)

■

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Jakafi

Visit www.jakafi.com/regulate *Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

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• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

7/30/12 4:50 PM

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

b Symptom

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: June 2012 RUX-1040a

ASCOPost.com | OCTOBER 15, 2012

PAGE 63

JCO Spotlight Genitourinary Oncology

Hormonal Therapy with Enzalutamide Increases Survival in Castrate-resistant Prostate Cancer after Chemotherapy By Matthew Stenger

he androgen receptor–signaling inhibitor enzalutamide (Xtandi) is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment, has a greater affinity for the androgen receptor, and induces tumor shrinkage (rather than growth retardation) in xenograft models. Results of the AFFIRM study, recently reported in The New England Journal of Medicine by Howard I. Scher, MD, and colleagues,1 indicate that enzalutamide treatment significantly prolongs overall survival, radiographic progression-free survival, time to prostate-specific antigen (PSA) progression, and time to skeletal-related events in men with castration-resistant prostate cancer who have already received chemotherapy. The AFFIRM trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic casSee Page 110 tration-resistant prostate cancer who have previously received docetaxel.2

Study Design In the double-blind, multicenter AFFIRM trial,1 1,199 patients with castration-resistant prostate cancer who had received at least one chemotherapy regimen containing docetaxel were randomized (2:1) to receive oral enzalutamide at 160 mg once daily (n = 800) or placebo (n�� =�� 399). Treatment was continued until radiographic confirmation of disease progression requiring initiation of new systemic antineoplastic treatment. Since enzalutamide has been associated with a lowered seizure threshold, patients with a history of or risk factors for seizure or who were taking medications known to decrease seizure threshold were excluded from the trial. All patients continued androgen deprivation therapy, and patients were permitted to start or continue corticosteroid treatment during the study. The primary endpoint of the trial was overall survival. Patients in the enzalutamide and placebo groups were well-matched for baseline characteristics. The median age in both groups was 69 years, with 26% and 27% of patients aged 75 years or older, and similar proportions of patients had Glea-

son score >�� 7 (50% vs 52%), ECOG performance status of 0 or 1 (91% vs 92%), pain score ≥ 4 (28% vs 29%), one prior chemotherapy regimen (72% vs 74%), bisphosphonate use at baseline (43% in both groups), prior radiation therapy (71% vs 72%), bone disease (92% vs 92%, with 38% in both groups having > 20 lesions), soft-tissue disease (71% vs 69%), PSA progression at baseline (89% vs 90%), and radiographic progression at baseline (59% in both groups). The median number of prior docetaxel cycles was 8.5 in the enzalutamide group and 8.0 in the placebo group, and median PSA levels were 108 ng/mL and 128 ng/mL, respectively. In total, 48% of patients on enzalutamide recipients and 46% of those on placebo received corticosteroids during the study.2

Study Stopped Early, Benefit across Subgroups At the time of a preplanned interim analysis, median durations of treatment were 8.3 months in the enzalutamide group and 3.0 months in the placebo group. The median duration of followup to determine survival status was 14.4 months. Median overall survival was 18.4 months with enzalutamide vs 13.6 months with placebo, representing a significant 37% reduction in risk of death with enzalutamide (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.53–0.75, P < .001). The trial was thus stopped early and placebo patients were offered enzalutamide treatment. The overall survival benefit of enzalutamide was consistent across all subgroups examined, including those based on age, baseline pain intensity, geographic region, and type of disease progression at study entry. On multivariate analysis, the effect of enzalutamide on overall survival was maintained (HR = 0.58, 95% < .001) after adjustCI = 0.49–0.70, P �� ment for stratification and prognostic factors, including ECOG score, pain score, type of progression at study entry, visceral disease at entry, baseline hemoglobin, and baseline alkaline phosphatase. Systemic antineoplastic treatments were used after discontinuation of study treatment in 42% of enzalutamide patients and 61% of placebo patients. Treatments included abiraterone acetate (Zytiga) in 21% of patients on enzalutamide and 24% of patients on placebo, and cabazitaxel (Jevtana) in 14% and

AFFIRM Trial Results ■■ In the placebo-controlled AFFIRM trial, enzalutamide significantly

prolonged overall survival of men with metastatic castration-resistant prostate cancer after chemotherapy (18.4 vs 13.6 months).

■■ The overall survival benefit of enzalutamide was consistent across all

subgroups, and multivariate analysis showed that benefit to be maintained after adjustment for stratification and prognostic factors.

■■ Enzalutamide-related adverse events included fatigue, diarrhea, and hot

flashes; seizures were reported in five patients (0.6%) receiving enzalutamide.

10%, respectively; both agents have been shown to prolong survival in this setting. Significant improvements with enzalutamide treatment were shown for all secondary endpoints, including PSA response (≥�� 50% �� decrease from baseline; 54% vs 2%), soft-tissue response (29% vs 4%), Functional Assessment of Cancer Therapy–Prostate qualityof-life response (43% vs 18%), time to PSA progression (median, 8.3 vs 3.0 months), radiographic progression-free survival (median, 8.3 vs 2.9 months, HR = 0.40), and time to first skeletalrelated event (median, 16.7 vs 13.3 months)—all P < .001.

nificant adverse events, cardiac disorders occurred in 6% of both groups. Seizure occurred in five patients on enzalutamide (0.6%) and in none of those on placebo.

Safety Profile

As stated by the investigators, “Enzalutamide, a once-daily oral hormone treatment, is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signaling. This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a benefit in men with castration-resistant cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy. Clinical trials of enzalutamide in earlier-stage prostate cancer are ongoing.” For information on how to use enzalutamide in the clinic, see page 64.

Adverse events occurring in at least 10% of patients on enzalutamide and with at least a 2% greater frequency than in patients receiving placebo included fatigue (34% vs 29%), diarrhea (21% vs 18%), hot flash (20% vs 10%), musculoskeletal pain (14% vs 10%), and headache (12% vs 6%). Grade 3 or higher adverse events occurred in 45% of enzalutamide recipients and 53% of placebo recipients. The median time to any initial grade 3 or higher adverse event was 8.4 months longer in the enzalutamide group (12.6 vs 4.2 months), indicating improved long-term control of disease-related symptoms. Hypertension occurred in 6.6% of patients on enzalutamide and 3.3% of patients on placebo. However, the frequency of hyperglycemia, weight gain, hyperlipidemia, and glucose intolerance was similar in the two groups, suggesting that enzalutamide was not associated with excess risk of developing metabolic syndrome.. Serious adverse events occurred in 34% of the enzalutamide group vs 39% of the placebo group. Adverse events resulted in discontinuation of study treatment in 8% vs 10% and adverse events led to death in 3% vs 4%. Among clinically sig-

Howard I. Scher, MD

In Conclusion

■

References 1. Scher HI, Fizazi K, Saad F, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. August 15, 2012 (early release online). 2. XTANDI® (enzalutamide) capsules prescribing information. Astellas Pharma US, Inc, August 2012. Available at http:// www.accessdata.fda.gov/drugsatfda_docs/ label/2012/203415lbl.pdf. Accessed September 11, 2012.

The ASCO Post | OCTOBER 15, 2012

PAGE 64

In the Clinic

Enzalutamide for Metastatic Castrate-resistant Prostate Cancer By Matthew Stenger

Indication

n August 31, enzalutamide (Xtandi) was approved for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.1,2 Approval was based on results of the multicenter AFFIRM trial, in which 1,199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel were randomly assigned to receive enzalutamide at 160 mg orally once daily (n = 800) or placebo (n = 399).2,3 (For additional discussion of the AFFIRM trial, see page 63.) Patients with a history of or risk factors for seizure or who were taking medications known to decrease seizure threshold were excluded from the trial. All patients continued

OF NOTE Enzalutamide is an androgen receptor–signaling inhibitor that inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment. androgen deprivation therapy, and patients were permitted to start or continue corticosteroid treatment during the study. Approximately 70% of patients were aged 65 years or older, 91% had an ECOG performance status of 0 or 1, 51% had received more than two prior hormonal treatments, 27% had received two or more prior chemotherapy regimens, 38% had more than 20 bone lesions, and 77% had no visceral disease at baseline. In total, 48% of the enzalutamide group and 46% of placebo group received corticosteSee Page 110 roids during the

study. Median durations of treatment were 8.3 months with enzalutamide and 3.0 months with placebo and median follow up was 14.4 months. New systemic chemotherapy after progression was received by 42% of enzalutamide patients and 61% of placebo patients. At the prespecified interim analysis, median overall survival, the primary endpoint of the trial, was significantly prolonged in the enzalutamide group (18.4 vs 13.6 months), with risk of death reduced by 37% compared with placebo (hazard ratio = 0.63, 95% confidence interval = 0.53–0.75, P < .0001). Median times to PSA progression (8.3 vs 3.0 months), radiographic progression (8.3 vs 2.9 months), and first skeletal-related event (16.7 vs 13.3 months) were also significantly prolonged with enzalutamide (all P < .001).

How It Works Enzalutamide is an androgen receptor–signaling inhibitor that acts at several steps in the signaling pathway.2,3 It competitively inhibits androgen binding to androgen receptors and differs from currently available antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment. It has a greater affinity for the androgen receptor and has no known agonistic effects. Enzalutamide decreases proliferation and induces cell death of prostate cancer cells in vitro and induces tumor shrinkage in xenograft models (compared with growth retardation with conventional agents). A major metabolite of the drug, N-desmethyl enzalutamide, exhibits activity in vitro similar to the parent compound.

How It Is Given Enzalutamide is given at 160 mg orally once daily, with or without food. Recommended dose modifications include withholding of treatment for 1 week or until symptoms resolve to grade�� 2 or better in patients experiencing grade�� 3 or higher toxicity or an intolerable adverse reaction. Treatment can be resumed at the same dose or, if warranted, at a reduced dose of 120 mg

Enzalutamide in Metastatic Prostate Cancer ■■ Enzalutamide (Xtandi) was approved for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

■■ Enzalutamide is given at 160 mg orally once daily; concomitant use of strong CYP2C8 inhibitors should be avoided.

or 80 mg. Concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If coadministration cannot be avoided, the enzalutamide dose should be reduced to 80 mg once daily. If treatment with the CYP2C8 inhibitor is stopped, the enzalutamide dose should be returned to the dose prior to the dose reduction. Use of CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index (eg, celecoxib [Celebrex], omeprazole) should be avoided, since enzalutamide may decrease their plasma exposure; additional international normalized ratio (INR) monitoring is needed if enzalutamide is coadministered with warfarin (CYP2C9 substrate).

Safety Profile According to the drug’s approved product labeling, the most common adverse events in enzalutamide recipients (> 20%) in the AFFIRM trial were asthenic conditions (51% vs 44% in placebo recipients), back pain (26% vs 24%), diarrhea (22% vs 17%), arthralgia (20% vs 17%), and hot flushes (20% vs 10%).2 Grade 3 or 4 adverse events occurred in 47% of the enzalutamide group and in 53% of the placebo group. The most common (>�� 2%) were asthenic conditions (9.0% vs 9.3%), spinal cord

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

compression and cauda equine syndrome (6.6% vs 3.8%), back pain (5.3% vs 4.0%), arthralgia (2.5% vs 1.8%), lower respiratory tract and lung infection (2.4% vs 1.3%), and hypertension (2.1% vs 1.3%). Laboratory abnormalities were relatively uncommon; grade 3 or 4 abnormalities included neutropenia in 1% of the enzalutamide arm, thrombocytopenia in 0.5% of the enzalutamide arm and 1% of the

OF NOTE The most common adverse events in enzalutamide recipients include asthenia, back pain, diarrhea, arthralgia, and hot flushes; the drug carries warnings/precautions for seizure. placebo arm, and ALT elevation in 0.3% of the enzalutamide arm and 0.5% of the placebo arm. Discontinuation of treatment due to adverse events occurred in 16% of the enzalutamide group and 18% of the placebo group. Death from infection or sepsis occurred in 1.0% with enzalutamide and 0.3% with placebo, with infection-related serious adverse events occurring in approximately 6% of patients in both groups. Falls or injuries related to falls occurred in 4.6% of enzalutamide recipients and 1.3% of placebo recipients. The falls were not related to loss of consciousness or seizure. Fall-related injuries were more severe in the enzalutamide group and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations (visual, tactile, or undefined) occurred in 1.6% with enzalutamide and 0.3% with placebo; most patients were on opioidcontaining medications at the time of the hallucination. Seizures occurred in

ASCOPost.com | OCTOBER 15, 2012

PAGE 65

In the Clinic

0.9% of patients on the enzalutamide arm and in no patients on the placebo arm. Those with seizure were discontinued from the study, and all seizures resolved. Enzalutamide carries warnings/ precautions for seizure. The drug lowers the seizure threshold, possibly through inhibition of the γ-aminobutyric acid–gated chloride channel. There is no clinical trial experience with enzalutamide in patients with a history of seizure or predisposing factors for seizure or

in patients using concomitant medications that may lower the seizure threshold. Thus, the safety of enzalutamide in patients with predisposing factors for seizure is unknown.

Cost The estimated cost of enzalutamide is $7,450 per month.

■

References 1. U.S. Food and Drug Administration: Approved drugs. Enzalutamide (XTANDI capsules). Available at htt p://w w w.fda .gov/Dr ugs/InformationOnDr ugs/A pprovedDr ugs/ ucm317997.htm. Accessed September 11, 2012. 2. XTANDI® (enzalutamide) cap-

sules prescribing information. Astellas Pharma US, Inc, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf. Accessed September 11, 2012. 3. Scher HI, Fizazi K, Saad F, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. August 15, 2012 (early release online).

Contact

The ASCO Post

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Best of ASCO® Annual Meeting ‘12 Head and Neck Cancer

Pivotal Trials in Head and Neck Cancers Yield Mixed Results By Susan London

he latest research in head and neck cancer reported at this year’s ASCO Annual Meeting presents a mixed picture, according to George R. Blumenschein, Jr, MD, Associate Professor at The Unviersity of Texas MD Anderson Cancer Center, Houston, who presented the data at the Best of ASCO San Diego meeting. Three trials attempting to improve on concurrent chemoradiation for locally advanced squamous cell carcinoma had disappointing results, meaning that chemoradiation remains the standard. But a trial of a new multitargeted tyrosine kinase inhibitor showed impressive efficacy in medullary thyroid cancer.

George R. Blumenschein, Jr, MD

Induction Chemotherapy plus Chemoradiation In the randomized phase�� III �� DeCIDE trial, patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck were assigned to two cycles of induction chemotherapy—docetaxel, cisplatin, and fluorouracil (TPF)—followed by concurrent chemoradiation, or to chemoradiation alone.1 Although 400 patients were planned for the study, only 280 were accrued. Compared with their counterparts who did not get induction chemotherapy, those who did showed trends toward better recurrence-free survival (P = .16) and distant failure–free sur-

vival (P = .37). Overall survival was statistically indistinguishable. Induction chemotherapy was associated with a lower rate of distant recurrence without locoregional recurrence (P = .04). Hematologic toxicity during chemoradiation was higher in the group who had received induction chemotherapy. “This was a negative study, no overall survival difference with trends favoring the experimental arm in terms of disease-free survival,” Dr. Blumenschein said. He noted that a host of logistical issues, many seen in the next trial as well, may have played a role in the outcomes (see sidebar). The randomized phase�� III PARA�� DIGM trial also compared chemoradiation alone vs TPF induction chemotherapy followed by chemoradiation in patients with locally advanced stage III or IV squamous cell carcinoma of the head and neck.2 In the induction arm, the chemoradiation was tailored to the response to induction therapy. This trial also struggled with accrual, enrolling just 145 of 330 planned patients, and was stopped early, at a median follow-up of 49 months. The 3-year rate of overall survival was 73% with induction chemotherapy and 78% without it, a nonsignificant difference. The 3-year rate of progression-free survival was also similar (67% vs 69%), but tended to favor induction chemotherapy in patients with nonoropharynx tumors (66% vs 55%). Within the induction chemotherapy group, the subset of patients who had a complete response and received less-intensive chemoradiation still had better outcomes than their counterparts who had lesser responses and received more intensive chemoradiation. Overall, the induction chemotherapy group had higher

Key Head and Neck Cancer Findings Presented at Best of ASCO® ‘12 ■■ Giving induction chemotherapy before concurrent chemoradiation fails to improve outcomes in patients with locally advanced squamous cell carcinoma of the head and neck.

■■ Combining panitumumab with concurrent chemoradiation fails to improve outcomes in patients with locally advanced squamous cell carcinoma of the head and neck.

■■ Cabozantinib reduces the risk of progression or death by more than twothirds in patients with progressive medullary thyroid cancer.

Trials’ Shortcomings Leave Role of Induction Chemotherapy Unclear

iven certain shortcomings of the DeCIDE and PARADIGM trials, the true role of induction chemotherapy in head and neck cancer is still not clear, said George R. Blumenschein, Jr, MD, Associate Professor at The Unviersity of Texas MD Anderson Cancer Center, Houston, at the Best of ASCO San Diego meeting.

Studies Underpowered Both trials suffered from “lower than anticipated accrual,” he said. “These studies were both underpowered for what they were trying to achieve. They didn’t meet complete accrual, so it’s very difficult to make definitive conclusions about the presented data. Since these studies did not meet their proposed enrollment, they were ultimately underpowered to answer their proposed primary endpoints.” In addition, both were affected by better-than-expected outcomes in the control arms given chemoradiation alone. And DeCIDE used just two cycles of induction chemotherapy, when typical practice is to give three or even four. If designed today, the trials would likely have greater standardization of chemoradiation to permit fair comparisons and would take tumor HPV status into account, as it is now recognized to be a major determinant of outcome in head and neck cancer, and approximately two-thirds of oropharynx tumors today are HPV-positive, according to Dr. Blumenschein.

Concurrent Chemoradiotherapy Still Standard of Care “The role of induction chemotherapy has not been validated by these trials. When we look at these two head-to-head trials, we don’t see a clearcut improvement in terms of induction chemotherapy followed by concurrent chemoradiotherapy, vs concurrent chemoradiotherapy. So concurrent chemoradiotherapy is still the standard of care,” he concluded. However, he added, “I think induction chemotherapy may have a role, potentially in patients who have a higher risk for recurrence—N2c/N3 disease, patients who have level 4 lymph nodes.”

■

rates of grade 3/4 febrile neutropenia and early death. Dr. Blumenschein concurred with the investigators’ conclusion that both treatment approaches are effective. “I think what it’s going to boil down to is selection—identifying which patient groups are really going to benefit more” from a given approach. “And this should be answered by the next generation of trials,” he said. “Concurrent chemoradiation is still the standard of care for patients with locally advanced head and neck cancer,” he concluded. “In terms of induction chemotherapy, its role remains unclear, as these two trials failed to achieve their accrual goals to answer the question appropriately. I can tell you our preference is to give induction chemotherapy, especially for patients we feel are at higher risk for developing distant metastases.”

Panitumumab plus Chemoradiation In the phase II randomized CONCERT-1 trial, patients with unresected, locally advanced squamous cell carcinoma of the head and neck were randomly assigned 2:3 to concurrent See Page 110 chemoradiation without or with added panitumumab (Vectibix), an antibody to epidermal growth factor receptor (EGFR).3 The panitumumab and control groups had statistically indistinguishable rates of locoregional control (61% vs 68%) and progression-free survival (60% vs 65%). There was a trend toward poorer overall survival in the panitumumab group (HR = 1.63, =�� .12). Efficacy did not differ by tuP �� continued on page 68

CURRENTLY ENROLLING for RELAPSED or REFRACTORY MULTIPLE MYELOMA

A Multicenter, Single-arm, Open-label Treatment Use Program For Pomalidomide in Combination With Low-dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma Primary Objective To provide patients with relapsed or refractory multiple myeloma access to pomalidomide while the medication is not commercially available

Key Eligibility Criteria* • ≥18 years or older • Confirmed, measurable, relapsed or refractory multiple myeloma • Received ≥4 antimyeloma regimens (induction bone marrow transplant with or without maintenance therapy is considered 1 regimen)

N=350

Study Treatment† • Oral pomalidomide 4 mg on Days 1-21 of 28-day cycle • Oral dexamethasone 40 mg weekly on Days 1, 8, 15, and 22 of 28-day cycle

*Additional criteria apply. †

Patients may continue on study treatment until documented disease progression, discontinuation of study treatment for any reason, or pomalidomide becomes commercially available.

Investigational use of pomalidomide.

For more information, e-mail thepexiusstudy@celgene.com, visit www.thepexiusstudy.com, or scan the QR code to the left.

The ASCO Post | OCTOBER 15, 2012

PAGE 68

Best of ASCO® Annual Meeting ‘12 Childhood Radiation Increases Breast Cancer Risk By Caroline Helwick

he risk of developing breast cancer after receiving radiotherapy to the chest as a child are as high as those for BRCA1/2 mutation carriers, according to review of 1,268 cancer survivors and 4,570 female first-degree relatives of participants in the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study.1 Breast cancer was diagnosed by age 50 in 24% of all cancer survivors and in 30% of Hodgkin lymSee Page 110 phoma survivors. In comparison, among first-degree relatives of the probands, the cumulative incidence by age 50 was 4%; among BRCA1 mutation carriers, it was 31%, and among BRCA2 mutation carriers, the incidence was 10%. Greatly increased risks were observed among women receiving 10 to 19 Gy as well as ≥ 20 Gy. Approximately 50,000 American women received > 20 Gy as children, and another 7,000 to 9,000 were treated with lower doses, the investigators estimated.

A ‘Sobering’ Finding

had a risk of breast cancer that is comparable to carriers of a BRCA1 mutation, and survivors of other childhood cancers treated with chest radiation had a risk comparable to BRCA2 mutation carriers,” he said. “Unfortunately, the study showed that 10 to 19 Gy was associated with the same incidence of cancer. The

with breast exams, adding mammography and annual MRI at age 25 or 8 years after radiation therapy, but these guidelines are often ignored. In a 2009 study, almost 50% of childhood cancer survivors younger than age 40 had never had a mammogram,2 he pointed out. Noncompliance with guidelines appears to be

Pivotal Head and Neck Trials

ing to focus on how are we going to modify our treatment approaches and be a little bit smarter about how we design these studies, looking for predictive biomarkers of therapy benefit.”

nificantly better objective response rate with cabozantinib (28% vs 0%, P < .0001). Overall survival data are not yet mature. As expected, adverse events, particularly gastrointestinal issues and handfoot skin reaction, were more common with cabozantinib. “We now have a new drug for medullary thyroid cancer—cabozantinib is something that’s going to be a therapeutic option. It’s not yet approved, but I anticipate it will be, based on these results,” Dr. Blumenschein predicted. “It offers activity, both for patients who have had prior lines of chemotherapy and prior tyrosine kinase inhibitors, with robust and durable responses, and improvement in progression-free survival.”

continued from page 66

mor human papillomavirus status. Rates of grade 3 or worse adverse events, especially mucosal and skin toxicity, were higher with panitumumab. Dr. Blumenschein commented that the trend toward poorer survival with panitumumab may have been due in part to use of a lower dose of cisplatin in that arm’s chemoradiation regimen (75 vs 100 mg/m2). “Cisplatin is a fairy effective drug in head and neck cancer, and you want to maximize its dose, whether you are giving it every 3 weeks or weekly,” he asserted. “There were also more radiation therapy interruptions” in the panitumumab group. “There is certainly a role for EGFR inhibitors in head and neck cancer,” he concluded. However, “we are still trying to figure out the best role [for them], … when to use them to maximize patient benefit, and identify the most effective combinations. I think future directions in this particular space are go-

At the Best of ASCO Boston meeting, Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital, Boston, commented that the findings were “sobering.” “Females treated for Hodgkin lymphoma with mantle radiation

goal of preventing second malignancies may not be achieved by lowering the dose.”

Guidelines Ignored The Children’s Oncology Group has recommended that surveillance for breast cancer begin at puberty

We recommend prophylactic mastectomy for BRCA mutation carriers. Should we be thinking about that [in patients who receive radiotherapy to the chest in childhood] as well? —Steven J. Isakoff, MD, PhD

Cabozantinib in Medullary Thyroid Cancer The EXAM trial was the first randomized phase�� III �� trial of cabozantinib—a potent oral inhibitor of the MET, VEGFR2, and RET tyrosine kinases—in patients with medullary thyroid cancer.4 A total of 330 patients with progressive disease were randomly assigned 2:1 to cabozantinib or placebo. For the primary endpoint of progression-free survival, this was a positive study, Dr. Blumenschein said, with a median of 11.2 months with cabozantinib vs 4.0 months with placebo (HR = 0.28; �� .0001). �� The 1-year rate of proP <�� gression-free survival was 47% vs 7%, respectively. There was benefit in nearly all patient subgroups. There was also a sig-

■

Disclosure: Dr. Blumenschein receives research funding from Exelixis.

References 1. Cohen EEW, Karrison T, Kocherginsky M, et al: DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in pa-

due to lack of familiarity of the risk on the part of primary care providers, lack of physician recommendation for screening, and lack of awareness among survivors that they are at increased risk. Dr. Isakoff posed a provocative question that touches on prevention and protection: “We recommend prophylactic mastectomy for BRCA mutation carriers. Should we be thinking about that in this group as well?”

■

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

References 1. Moskowitz CS, Chou JF, Wolden SL, et al: New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study and the Women’s Environmental Cancer and Radiation Epidemiology Study. 2012 ASCO Annual Meeting. Abstract CRA9513. Presented June 4, 2012. 2. Oeffinger KC, Ford JS, Moskowitz CS, et al: Breast cancer surveillance practices among women previously treated with chest radiation for a childhood cancer. JAMA 301:404-414, 2009.

tients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). 2012 ASCO Annual Meeting. Abstract 550. Presented June 3, 2012. 2. Haddad RI, Rabinowits G, Tishler RB, et al: The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC). 2012 ASCO Annual Meeting. Abstract 5501. Presented June 3, 2012. 3. Giralt J, Fortin A, Mesia R, et al: A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN). 2012 ASCO Annual Meeting. Abstract 5502. Presented June 3, 2012. 4. Schoffski P, Elisei R, Müller S, et al: An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012.

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PAGE 69

FDA Update

New Drug Application Submitted for Regorafenib to Treat GIST

ayer HealthCare and Onyx Pharmaceuticals recently announced that Bayer HealthCare has submitted a New Drug Application (NDA) to the FDA for the oral multikinase inhibitor regorafenib for the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST) in patients whose disease has progressed despite prior treatment.

assigned 199 patients whose disease had progressed despite prior treatment with imatinib and sunitinib. Patients were randomized in a 2:1 ratio to receive either regorafenib plus best supportive care or placebo plus best sup-

portive care to evaluate efficacy and safety. Treatment cycles consisted of 160 mg regorafenib (or matching placebo) once Bleed:7.875” daily for three weeks on/one week off plus best supportiveTrim:7.625” care. The primary Live:7” endpoint was progression-free survival,

and secondary endpoints included overall survival, time to progression, disease control rate, tumor response rate, and duration of response. The safety and tolerability of the two treatment groups were also compared.

■

Pivotal Phase III Trial The submission is based on data from the pivotal phase III GRID trial, which showed that regorafenib plus best supportive care significantly improved progression-free survival compared to placebo plus best supportive care (HR = 0.27, 95% CI = 0.19-0.39; P < .0001) in patients with metastatic and/ or unresectable GIST who were previously treated with imatinib (Gleevec) and sunitinib (Sutent). The median progression-free survival was 4.8 months in the regorafenib arm vs 0.9 months in the placebo arm and there was a positive trend in the regorafenib group in improving overall survival (HR = 0.77, 95% CI = 0.42-1.41; P = .20). In addition, the study design allowed patients receiving placebo to cross over following disease progression. In this study, the most frequently reported drug-related adverse events (greater than or equal to 25%) in regorafenib-treated patients vs placebo-treated patients, respectively, were hand-foot skin reaction (56.1% vs 13.6%), hypertension (48.5% vs 16.7%), diarrhea (40.2% vs 4.5%), fatigue (38.6% vs 27.3%) and oral mucositis (37.9% vs 7.6%). Results from the study were presented at the ASCO Annual Meeting in June 2012. In addition, the FDA recently agreed that Bayer can proceed with its expanded access program to provide regorafenib to patients diagnosed with GIST through qualified clinical sites participating in the expanded access program. For more information on this program, visit www. clinicaltrials.gov [NCT01646593].

Study Design GRID was a randomized, doubleblind, placebo-controlled, multi-center, cross-over phase III study of regorafenib for the treatment of GIST. It randomly

NOW AVAILABLE ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen. IMPORTANT SAFETY INFORMATION FOR ZALTRAP WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS • Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events — Monitor patients for signs and symptoms of bleeding — Do not initiate ZALTRAP in patients with severe hemorrhage — Discontinue ZALTRAP in patients who develop severe hemorrhage Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Visit www.ZALTRAP.com to learn more. For more information about ZALTRAP, call 1-855-ZALTRAP (1-855-925-8727).

FPO

The ASCO Post | OCTOBER 15, 2012

PAGE 70

FDA Update

FDA Approves New Treatment for Severe Neutropenia

he FDA recently approved Sicor Biotech’s tbo-filgrastim (Neutroval) to reduce the time certain patients receiving chemotherapy experience severe neutropenia. The new drug is a short-acting recombinant granulocyte colony-stimulating fac-

tor (G-CSF) agent. It is marketed as Tevagrastim in Europe, where tbo-filgrastim is classified as biosimilar to Amgen’s G-CSF product, Neupogen. Tbo-filgrastim was approved in the United States through the standard process for new drugs and some biological agents. The biosimilar approval

process has yet to be finalized by FDA. Tbo-filgrastim is intended for use in adults who have nonmyeloid malignancies and are taking chemotherapy drugs Bleed:7.875” that cause a substantial decrease in the Trim:7.625” production of neutrophils in the bone Live:7” marrow. This reduction in neutrophils

may lead to febrile neutropenia. Tbo-filgrastim stimulates the bone marrow to increase the production of neutrophils. It is administered as an injection beginning 24 hours after chemotherapy treatment. “Supportive care products, such as

NOW AVAILABLE

IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (cont’d) • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP — Monitor patients for signs and symptoms of GI perforation — Discontinue ZALTRAP in patients who experience GI perforation • Discontinue ZALTRAP in patients with compromised wound healing — Suspend ZALTRAP for at least 4 weeks prior to elective surgery — Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed • Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy in patients who develop ﬁstula • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP — Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP — Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles — Discontinue ZALTRAP in patients with hypertensive crisis • Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. Discontinue ZALTRAP in patients who experience an ATE • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP — Suspend ZALTRAP when proteinuria ×2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg — Discontinue ZALTRAP if nephrotic syndrome or TMA develops • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP — Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ×1.5 x 109/L • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI — The incidence of diarrhea is increased in patients ×65 years of age. Monitor closely • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome

ADVERSE REACTIONS • The most common adverse reactions (all grades, ×20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache • The most common Grade 3-4 adverse reactions (×5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia • Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection • In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNING. In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 sanoﬁ-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

US.AFL.12.07.046

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PAGE 71

FDA Update

tbo-filgrastim, reduce or allow for more rapid recovery from side effects of cancer treatments,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Study Design Tbo-filgrastim was evaluated in

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion

a clinical study of 348 adult patients with advanced breast cancer receiving treatment with doxorubicin and docetaxel. Patients were randomly assigned to receive tbo-filgrastim, a placebo, or a non–U.S.-approved Bleed:7.875” filgrastim product, a drug that also Trim:7.625” stimulates neutrophil production by Live:7” the bone marrow. The effectiveness of

Rx Only

Brief Summary of Prescribing Information WARNING:

HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

■

Trim:10.5”

Bleed:10.75”

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/ hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen and in none of the patients treated with placebo/ FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/ FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC,

cancer, or non-Hodgkin lymphoma who received high-dose myeloablative chemotherapy. The most common side effect observed in those receiving tbo-filgrastim was bone pain. The manufacturer, Teva Pharmaceuticals, Ltd, announced that it does not expect to market tbo-filgrastim until November 2013 at the earliest.

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1 INDICATIONS AND USAGE ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus.

tbo-filgrastim was determined based on study results that showed that patients receiving tbo-filgrastim recovered from severe neutropenia in 1.1 days compared with 3.8 days in those receiving the placebo. Tbo-filgrastim’s safety was evaluated in three clinical studies composed of 680 adults with breast cancer, lung

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FDA Update

FDA Approves First Ultrasound Imaging System for Dense Breast Tissue

he FDA approved somo-v Automated Breast Ultrasound System (ABUS), the first ultrasound device for use in combination with a standard mammography in women with dense breast tissue who have a negative mammogram and no symptoms of breast cancer.

The National Cancer Institute estimates that about 40% of women undergoing screening mammography have dense breasts. These women have an increased risk of breast cancer, with detection usually at a more advanced and difficult-to-treat stage.

Dense breasts have a high amount of connective and glandular tissue compared with less-dense breasts, which have a high amount of fatty tissue. Bleed:7.875” Mammograms of dense breasts can be Trim:7.625” difficult to interpret, since fibroglanduLive:7” lar breast tissue and tumors both appear

proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Obtain a 24-hour urine collection in patients with a UPCR greater than 1. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/ FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Conﬁrm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reﬂect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

as solid white areas on mammograms. As a result, dense breast tissue may obscure smaller tumors, potentially delaying detection of breast cancer. Ultrasound imaging has been shown to be capable of detecting small masses in dense breasts. During an ul-

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modiﬁcation in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI ZALTRAP/FOLFIRI (N=605) (N=611) Primary System Organ Class All grades Grades All grades Grades Preferred Term (%) 3–4 3–4 Infections and infestations Urinary Tract Infection 6% 0.8% 9% 0.8% Blood and lymphatic system disorders Leukopenia 72% 12% 78% 16% Neutropenia 57% 30% 67% 37% Thrombocytopenia 35% 2% 48% 3% Metabolism and nutrition disorders Decreased Appetite 24% 2% 32% 3% Dehydration 3% 1% 9% 4% Nervous system disorders Headache 9% 0.3% 22% 2% Vascular disorders Hypertension 11% 1.5% 41% 19% Respiratory, thoracic and mediastinal disorders Epistaxis 7% 0 28% 0.2% Dysphonia 3% 0 25% 0.5% Dyspnea 9% 0.8% 12% 0.8% Oropharyngeal Pain 3% 0 8% 0.2% Rhinorrhea 2% 0 6% 0 Gastrointestinal disorders Diarrhea 57% 8% 69% 19% Stomatitis 33% 5% 50% 13% Abdominal Pain 24% 2% 27% 4% Abdominal Pain Upper 8% 1% 11% 1% Hemorrhoids 2% 0 6% 0 Rectal Hemorrhage 2% 0.5% 5% 0.7% Proctalgia 2% 0.3% 5% 0.3% Skin and subcutaneous tissue disorders Palmar-Plantar 4% 0.5% 11% 3% Erythrodysesthesia Syndrome Skin Hyperpigmentation 3% 0 8% 0 Renal and urinary disorders Proteinuria* 41% 1% 62% 8% Serum creatinine increased 19% 0.5% 23% 0 General disorders and administration site conditions Fatigue 39% 8% 48% 13% Asthenia 13% 3% 18% 5% Investigations AST increased 54% 2% 62% 3% ALT increased 39% 2% 50% 3% Weight decreased 14% 0.8% 32% 3% Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients

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FDA Update

trasound exam, a device called a transducer directs high-frequency sounds waves at the portion of the body being examined. Software analyzes the differences in how the sound waves are reflected off different tissues and back to the transducer to create an image a physician can review for abnormalities. The specially shaped transducer of

the somo-v ABUS can automatically scan the entire breast in about one minute to produce several images for review.

Clinical Study As part of the approval process, the Bleed:7.875” FDA reviewed results from a clinical Trim:7.625” study in which board-certified radioloLive:7” gists were asked to review mammograms

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-AUG12

Revised: August 2012

with mammograms, as compared to mammograms alone. “A physician may recommend additional screening using ultrasound, for women with dense breast tissue and a negative mammogram,” said Alberto Gutierrez, PhD, Director of the Office of In Vitro Diagnostic Device Evaluation and Safety at FDA’s Center for Devices and Radiological Health. The somo-v ABUS is approved for use in women who have not had previous clinical breast intervention, such as a surgery or biopsy, since this might alter the appearance of breast tissue in an ultrasound image.

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FDA Approves Production of Imaging Agent to Detect Prostate Cancer

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he FDA approved the production and use of Choline C 11 Injection, a positron-emission tomography (PET) imaging agent used to help detect recurrent prostate cancer. Choline C 11 Injection is administered intravenously to produce an image that helps to locate specific body sites for follow-up tissue sampling and testing in men with recurrent prostate cancer. PET imaging with Choline C 11 Injection is performed in patients whose blood prostate-specific antigen (PSA) levels are increasing after earlier treatment for prostate cancer. An elevated PSA result suggests that prostate cancer may have returned, even though conventional imaging tests, such as computed tomography (CT), have not shown any signs of cancer. PET imaging is not a replacement for tissue sampling and testing.

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treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ZALTRAP, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

alone or in conjunction with somo-v ABUS images for 200 women with dense breasts and negative mammograms. Biopsies were performed on masses detected with the somo-v ABUS to determine if they were cancer. The results show a statistically significant increase in breast cancer detection when ABUS images were reviewed in conjunction

Specialized Facility Required Choline C 11 Injection must be produced in a specialized facility and administered to patients shortly after its production. The Food and Drug Administration Modernization Act directed the agency to establish appropriate approval procedures and current good manufacturing practice requirements for all PET products marketed and used in the United States. The Mayo Clinic is now the first FDAapproved facility to produce Choline C 11 Injection. “Choline C 11 Injection provides an important imaging method to help continued on page 74

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Best of ASCO® Annual Meeting ‘12 Sarcoma

For Advanced Sarcomas, New Agents Prolong Remission but Not Survival By Caroline Helwick

“W

e are beginning to understand the molecular biology underlying a portion of the 80 or so subtypes of sarcomas, and we hope this will lead to subtype-specific treatments,” said William D. Tap, MD, of Memorial SloanKettering Cancer Center, New York, at the Best of ASCO Boston meeting.

William D. Tap, MD

“And in gastrointestinal stromal tumors (GIST), we are going to move away from just using single-agent tyrosine kinase inhibitors. While it is currently hard to challenge imatinib [Gleevec] in the front-line setting, we will see breakthroughs that will reveal alternative pathways that are involved, and we will use this to create combination strategies that will make a difference to patients. Hopefully, we will be changing GIST from a controllable disease to a curable one,” he said.

Regorafenib Becomes a New Option A newsmaker at ASCO, the phase III GRID trial found the oral tyrosine kinase inhibitor regorafenib dramatically delayed disease progression in patients with treatment-refractory metastatic GIST.1 GRID was an international trial that quickly accrued 236 patients with metastatic unresectable GIST who were intolerant to or showing disease progression despite tyrosine kinase inhibitor treatment (59% received more than two lines of such therapy). Patients received daily

PET Imaging Agent continued from page 73

detect the location of prostate cancer in patients whose blood tests suggest recurrent cancer when other imaging tests are negative,” said Charles Ganley, MD, Director of the Office of Drug Evaluation IV in FDA’s Center for Drug Evaluation and Research. “The FDA’s approval of Choline C 11 Injection at the Mayo Clinic provides assurance to

regorafenib or best supportive care. Median progression-free survival reached 4.8 months with regorafenib but was only 0.9 months in the placebo arm, for a 73% reduction in risk (P < .0001). The disease control rate at 12 months was 52.6% with regorafenib and 9.1% with placebo. Overall survival was similar, presumably because 85% of placebo recipients crossed over to regorafenib. Median overall survival has not yet been reached in either arm. “Regorafenib has the potential to fulfill an unmet need for this patient population, and it is appropriate to seek FDA approval,” said Dr. Tap. Future studies of new agents, however, should probably not use placebo in the control arm, “since patients may now have options after imatinib and sunitinib (Sutent),” he added. “We have to compare novel drugs against these standards of care,” he added.

Pazopanib in Soft-tissue Sarcoma In the final analysis of the phase III PALETTE trial, involving 362 patients with metastatic soft-tissue sarcoma, treatment with pazopanib (Votrient) resulted in a median overall survival of 12.5 months, vs 10.7 months with placebo, for a 14% reduction in risk that was not statistically significant.2 The primary endpoint, median progression-free survival, was 20 vs 7 weeks, respectively, a highly significant 69% reduction in risk <�� .0001). Two-thirds of patients re(P �� ceiving pazopanib had stable disease over the 25 months of follow-up. The drug seemed particularly beneficial in leiomyosarcoma patients. “Pazopanib gives us a new drug for sarcoma, which is very difficult to treat and for which we have not had an FDA-approved drug since [doxorubicin],” Dr. Tap said. Sarcomas, he noted, are a very heterogeneous group of tumors that lack a patients and health care professionals they are using a product that is safe, effective, and produced according to current good manufacturing practices.”

Safety Measures The safety and effectiveness of Choline C 11 Injection were verified by a systematic review of published study reports. Four independent studies examined a total of 98 patients with elevated

Key Sarcoma Findings Presented at Best of ASCO® 12 ■■ Sarcomas represent approximately 80 different types of cancer; new

pathways are being recognized, and new drugs are needed to target them.

■■ In advanced GIST, regorafenib reduces progression by 73% and represents a new option for refractory disease.

■■ In metastatic soft-tissue sarcoma, pazopanib reduces progression by 69%. ■■ In liposarcoma, the oral CDK4 inhibitor PD0332991 shows promising activity. well-defined treatment strategy. What is becoming clear is that among the 80 different subtypes, genetic and molecular abnormalities vary considerably. “In the past, we treated all sarcomas as one malignancy, but we need to begin to stratify sarcomas based on their unique molecular characteristics. We are slowly doing this, and we hope to ultimately have histologyspecific treatments, as we do with GIST.”

New Target for Liposarcoma Liposarcoma is one of the most common soft-tissue sarcomas. The typical histology is well-differentiated/dedifferentiated (WD/DD), which reflects maturation arrest in adipocyte differentiation. These tumors are characterized by ring chromosomes and gene amplifications that ultimately affect cellular differentiation and proliferation. Blockade of CDK4, which is amplified in 90% of WD/DD patients, prevents binding to cyclin D1, prevents phosphorylation of the Rb gene, and forces cell-cycle arrest. The oral novel CDK4 inhibitor PD0332991 induces G1 cell-cycle arrest and inhibits the growth of liposarcoma cells in preclinical models. In a phase II trial reported at ASCO, daily PD0332991 was evaluated in 27 patients with metastatic or recurrent WD/DD liposarcoma, CDK4 amplification, Rb gene expression, and disease progression after at least one regimen.3 Based on historical data, a promising result was defined as a 12-week progression-free survival ≥ 40%. blood PSA levels but no sign of recurrent prostate cancer on conventional imaging. After PET imaging with Choline C 11, the patients underwent tissue sampling of the abnormalities detected on the PET scans. In each of the four studies, at least half the patients who had abnormalities detected on PET scans also had recurrent prostate cancer confirmed by tissue sampling of the abnormal areas.

The progression-free survival endpoint was reached by 19 patients, yielding a progression-free rate of 65.5%. At data cutoff, four patients remain on study with stable disease after 32 to 60 weeks of follow-up. “The response noted in patients with WD/DD liposarcomas, a difficult disease to treat systemically, shows that CDK4 has an active role in the pathogenesis of some of these tumors,” Dr. See Page 110 Tap said.

■

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

References 1. Demetri GD, Reichardt P, Kang Y, et al: Randomized phase III trial of regorafenib in patients with metastatic and/ or unresectable gastrointestinal stromal tumor progressing despite prior treatment with at least imatinib and sunitinib. GRID trial. 2012 ASCO Annual Meeting. Abstract LBA10008. Presented June 4, 2012. 2. Van Der Graaf W, Blay J, Chawla SP, et al: PALETTE: Final overall survival data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma patients. 2012 ASCO Annual Meeting. Abstract 10009. Presented June 2, 2012. 3. Dickson MA, Keohan M, Tap WD et al. Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma. 2012 ASCO Annual Meeting. Abstract 10002. Presented June 4, 2012.

PET scan errors also were reported. Depending on the study, falsely positive PET scans were observed in 15% to 47% of the patients. These findings underscore the need for confirmatory tissue sampling of abnormalities detected with Choline C 11 Injection PET scans. Aside from an uncommon, mild skin reaction at the injection site, no side effects to Choline C 11 Injection were reported.

■

FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more...

Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning. Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen. Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

Simulated image based on locally advanced BCC patient at Week 24. Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea,

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3

Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

43% (n=27) (30.5-56.0)

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 months (5.7-9.7)

7.6 months (5.6-NE)

ORR (95% CI)

Median response duration (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page. References: 1. Erivedge™ (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012; 366:2171-2179.

HED0001171901

See what you can offer your patients with advanced BCC at www.Erivedge.com

The ASCO Post | OCTOBER 15, 2012

PAGE 78

Journal Spotlight Survivorship

Prone Position during Radiation Therapy for Breast Cancer Is Associated with Reduced Irradiation to Lung and Heart By Charlotte Bath

reliminary data on prone positioning during whole-breast radiotherapy following breast-pres-

ervation surgery “suggest that radiation exposure to the heart and lung can be reduced compared with

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

supine positioning with similar efficacy,” according to a research letter in the Journal of the American Medical

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

Association. The letter notes that while radiation therapy to the breast contributes to imSee Page 110 proved outcomes in patients with breast cancer after breast-preservation surgery, wholebreast radiotherapy “is associated with damage to the heart and lung, increased cardiovascular mortality, and lung cancer development, with risks that remain 15 to 20 years after treatment. These consequences occur when breast cancer patients are treated supine.”

Prospective Study The authors of the letter conducted a study to test the hypothesis that prone positioning is superior to standard supine positioning, comparing the volume of heart and lung within the radiation field. The prospective study included patients with breast cancer who underwent two CT simulation scans, the first supine and the next prone. The researchers found that prone positioning was associated with a reduction in the amount of irradiated lung in all 400 patients with breast cancer enrolled in the study and in the amount of heart volume irradiated in 85% of the 200 patients with left breast cancer. “The study is limited to a single institution. A multi-institutional prospective trial with outcome measures is warranted to confirm these findings,” the investigators advised. “If prone positioning better protects normal tissue adjacent to the breast, the risks of long-term deleterious effects of radiotherapy may be reduced.”

■

Reference 1.Formenti SC, DeWyngaert JK, Jozsef G, et al: Prone vs supine positioning for breast cancer radiotherapy. JAMA 308:861-863, 2012.

The ASCO Post ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

For more reports on papers published recently in peer-reviewed journals, see pages 91 and 117.

ASCOPost.com | OCTOBER 15, 2012

PAGE 79

Expert’s Corner

The Language of Cancer

A Conversation with Don S. Dizon, MD, FACP By Jo Cavallo

Don S. Dizon, MD, FACP

or more than a year, Don S. Dizon, MD, FACP, has been blogging at ASCO Connection (connection.asco.org) about such diverse topics as cancer survivorship, the redesign of clinical studies based on patients’ molecular characteristics, and the power of laughter. Last May, Dr. Dizon tackled the impact that the use of particular words can have on patients with cancer, noting that if terms like “salvage treatment,” “treatment failure,” and “restaging” are not carefully explained, they can sometimes leave patients scared and bewildered.1 Dr. Dizon is a member of the Medical Gynecologic Oncology Service at Massachusetts General Hospital, Gillette Center for Women’s Cancers, Boston, and of ASCO’s Cancer Education Committee, and Immediate Past Chair of the Society’s Integrated Media and Technology Committee. His clinical and research focus centers on the treatment of breast and ovarian cancers, the development of novel therapies in these cancers, and survivorship issues, including the sexual health of female cancer survivors. He is also interested in the role that social media is playing in how information about cancer is disseminated, both to oncology professionals and survivors, and how critical it is for that information to be carefully communicated and monitored to avoid misinterpretation. The ASCO Post talked with Dr. Dizon about the language of cancer and how, even with the best of intentions, the words oncologists use can often confuse and hurt patients.

Heightening Awareness What do you want oncologists to keep in mind when they are talking to patients? When we are speaking among col-

leagues, we assume our lingo—the vocabulary of oncology—is universal, and we don’t give much thought to how what we’re saying can be interpreted by the layperson. The point of what I wrote [on ASCO Connection] is that the same information can be processed in very different ways, depending on the audience. What I’m hoping to do is heighten awareness that we as oncology professionals use words that can have dual meanings, and when you are dealing with a condition as serious as cancer, the dual meanings can confuse and scare patients, which is what we are trying to avoid. A woman recently wrote to me through my blog and said that after being diagnosed with metastatic breast cancer, she was told she was going to be restaged. To oncologists, this means the cancer’s response to treatment would be measured and its status re-

When oncologists are looking at second-, third-, and fourth-line therapies, they are considering drugs that perhaps aren’t as effective as our first-line choices. This forces a shift from treatment with curative intent to treatment for disease stability and palliation. We may also contemplate drugs that will provide improvements in or at least maintenance of current quality of life vs exposure to different toxicities. To me, when a colleague says a patient needs salvage therapy, it implies that we are not rendering treatment for cure or even looking for a response necessarily. Rather, we want to continue to treat and, hopefully, get the disease to stop growing and maybe make the symptoms improve or prevent new symptoms from developing. However, when we use the term “salvage therapy” with patients, we cannot assume that they understand that we

You need to be sure the patient recognizes the distinction between palliative care and hospice care.… Palliative care should be viewed as an adjunct to treatment, not a replacement for it. —Don S. Dizon, MD, FACP

those words should be avoided in direct conversations with patients.

‘Incurable’ vs ‘Terminal’

See Page 110

Should the potential conversion of cancers into chronic illnesses be emphasized more in discussions with patients? Absolutely. That’s a message we want to spread. There’s so much to be optimistic about in cancer therapy. The whole idea of cancer survivorship and the fact that the survivorship population is growing and will probably reach 18 million by 2022 means that we are making huge strides in cancer treatment. So, yes, incurable cancer is not synonymous with terminal disease. More frequently, it means chronic disease, which lends new meaning to the phrase, “living with cancer.” We also need to be careful of terms like “war on cancer” and “losing the battle with cancer.” Many survivors are unhappy with the overuse of the war analogy in connection with cancer. Hopefully, in the future we will more often be approaching cancer as a condition, not a death sentence—or a war.

‘Palliative Care’ vs ‘Hospice’ evaluated. But when this patient heard “restaged,” she had a bit of hope that the diagnosis was wrong and that her oncologist was going to do another test just to make sure that she actually had metastatic disease. Here, the word restaging connoted very different things. There are many ways we can create confusion when we discuss staging. We have to do a better job of explaining to patients that their prognosis is based on how they first presented. For example, we do not restage women who had early-stage breast cancer upon recurrence. Their original stage stays with them. To tell someone who was originally stage I at diagnosis, “You have stage IV disease,” isn’t the same as saying they were stage I but are now metastatic. Although most oncologists assume “stage IV” equals “became metastatic,” the same may not be true for the patient.

Understanding ‘Salvage’ How do patients perceive the words “salvage treatment”?

are talking about the drug. In my experience, some patients hear “salvage” and feel it is referencing them as the “thing” to be salvaged. Patients want to be cured, they want to be helped, but they do not want to, nor should they, think of themselves as being “salvaged.”

Avoiding Confusion Should oncologists avoid using that kind of potentially confusing terminology in front of patients? Not only should we avoid using that kind of terminology with patients, we should avoid using it among ourselves. We live in a tech-savvy world, and patients may see terms that can be taken curiously or offensively on Twitter, for example. Or they could be listening to a discussion on novel therapies in a lecture hall or viewing a video presentation online, and a term like salvage therapy may come up. So I don’t think that terms like salvage therapy or treatment failure should be part of the vocabulary of oncologists in general. For certain,

The term “palliative care” is also loaded language that patients often equate with imminent death. How can oncologists reassure their patients that palliative care does not mean the end of treatment? Separating palliative care from being an “either/or” to treatment or synonymous with hospice can help oncologists approach discussions with their patients when treatments have stopped working or when life expectancy is not going to be measured in years. What I have taught my fellows to do in these circumstances is to be honest. If you think a patient is not going to do well, or if you are afraid that further treatment is not going to be of much value and will expose the patient to a lot of toxicity unnecessarily, the patient has the right to know that. One of the ways you can approach that conversation is to acknowledge what has occurred as forthrightly as you can and then explain that although there are still options A, B, and C, another option exists that can complement or recontinued on page 82

In Advanced Renal Cell Carcinoma (RCC)...

INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic events were reported

in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than one week), and frequently thereafter. Treat increased blood pressure promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the

Move Forward With VOTRIENT In a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC of clear cell or predominant clear cell histology1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options

Once-daily oral dosing1

VOTRIENT: Adverse events profile included1:

• The recommended starting dose of VOTRIENT is 800 mg once daily without food (1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In RCC, initial dose reduction should be 400 mg; additional dose decrease or increase should be in 200-mg steps based on individual tolerability • Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced

randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions.

• Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, and fetal harm • Most common adverse events (>20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting • See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

• Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice.

• Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

• Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed June 1, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

VOTRIENT.com

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Expert’s Corner

Don S. Dizon, MD, FACP continued from page 79

place standard treatment. This is where palliative care comes in. Perhaps as important, you need to be sure the patient recognizes the distinction between palliative care and hospice care. Palliative care involves symptom management and is indicated

for anyone living with metastatic or incurable cancer, regardless of whether chemotherapy or other cancer treatments continue. Palliative care should be viewed as an adjunct to treatment, not a replacement for it. Introducing palliative care into the conversation might also give patients permission to ask the questions they are

afraid to ask but want answers to, including “Am I dying” or “How long do I have to live?” When you introduce the term palliative care, it segues naturally into a discussion about prognosis. Then patients have a chance to adjust to the fact that time is finite, which is true for all of us, and that while it may be likely they will die of their cancer, we can’t put a

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials

date on it.

■

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

Reference 1. Dizon DS: The power of words. ASCO Connection. May 19, 2012. Available at connection.asco.org. Accessed August 2, 2012.

of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy studies. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis

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News

States Aim to Increase Male Breast Cancer Awareness

overnor Chris Christie of New Jersey and Governor Deval Patrick of Massachusetts recently proclaiming October 21 through October 27 as Male Breast Cancer Awareness Week in their respective states. With this proclamation, New Jersey and Massachusetts become

the third and fourth states to recognize this week, joining Pennsylvania and Florida. Male breast cancer is rare, accounting for less than 1% of all breast cancers. Men with the disease are often undiagnosed and their cancer is not detected until it has progressed to a later stage.

during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4

% % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

■■ The American Cancer Society estimates that in 2012, about 2,190 new cases of male breast cancer will be diagnosed and that it will be the cause of approximately 410 deaths. ■■ About 27% of men with breast cancer will die from the disease.

■

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290)

Parameters

Placebo (N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose 41 <1 0 33 1 0 increased Total bilirubin 36 3 <1 10 1 <1 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium 26 <1 1 14 0 0 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

Some important facts about male breast cancer: ■■ Survival rates for men are about the same as for women with the same stage of cancer at the time of diagnosis. Unfortunately, male breast cancer is often undiagnosed until late stages.

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Best of ASCO® Annual Meeting ‘12 Epidemiology

New Studies Explore Exposure to Cancer-causing Agents By Caroline Helwick

ey studies on cancer epidemiology and prevention delivered both reassuring and not-so-reassuring findings on exposure to agents believed to be cancerpromoting. Kala Visvanathan, MD,

MHS, of The Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine and School of Public Health, Baltimore, put the abstracts into perspective at the Best of ASCO Boston meeting.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may

More data presented at ASCO confirmed previous findings that

impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of GlaxoSmithKline.

combined estrogen-plus-progestin use increases breast cancer risk, while another study concluded that this risk cannot be attenuated by low-dose tamoxifen.

Kala Visvanathan, MD, MHS

An observational study included a cohort of 41,449 postmenopausal women gleaned from the Women’s Health Initiative who used estrogen plus progestin (N = 16,121) or no hormone replacement therapy (N = 25,328).1 The average participant had received hormone replacement therapy for 5.3 years prior to cohort entry. Multivariate analysis showed invasive breast cancer incidence to be 55% higher in the estrogen-plus-progestin <�� .001) after �� taking into conusers (P �� sideration potential confounders. Survival following breast cancer was similar between hormone replacement therapy users and nonusers, but breast cancer mortality was increased in the hormone replacement group (P < .001).

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and preand post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

Combined Hormone Replacement Increases Breast Cancer Risk

‘Gap Time’ The findings from the Women’s Health Initiative observational study were consistent with other observational studies and the clinical trial in showing that combined hormone replacement therapy is associated with an increased risk of cancer—approximately 1.5- to 2.5-fold over 10 years. It is unclear when the risk actually begins to rise, whether upon initiation of hormone replacement therapy or several years later. The concept of “gap time” was substantiated in the observational study, which showed that the risk is higher if hormonal therapy is initiated close to the onset of menopause (HR = 1.45), but is attenuated if hormonal therapy is begun 5 years or more after menopause (HR = 1.19). The gap time effect is persisted in analyses adjusted for duration of estrogen-plus-progestin use,

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Best of ASCO® Annual Meeting ‘12 showing that initiation of the combination 15 years postmenopause still carried a risk higher than was seen with nonusers. “Further studies are needed to determine how we might exploit this gap time concept,” she said. Dr. Visvanathan reminded the audience that they need to be aware of the patient characteristics when interpreting data from the Women’s Health Initiative hormone trials evaluating hormone replacement therapy. The average age at entry was 63, indicating that women were initiated on hormone replacement therapy much later after the onset of menopause than is typically seen outside of a trial. Also, 80% were at least 10 years beyond menopause, 26% had previously taken hormone replacement therapy prior to enrolling, and treatment was discontinued early in 40% in the combinedhormone arm and in 54% of the estrogen-only arm in the initial trial.

Low-dose Tamoxifen to Oppose Hormone Therapy The phase III Italian HOT trial was a primary breast cancer prevention trial that aimed to determine if low-dose tamoxifen (5�� mg/d for 5 years, vs placebo) might mitigate the risk for breast cancer posed by hormone replacement therapy.2 The rationale was backed by data from collaborative groups, tamoxifen prevention trials, and neoadjuvant studies. “The concept was interesting. The aim was to identify an approach whereby women could have the benefits of hormone replacement therapy while minimizing breast cancer risk,” Dr. Visvanathan said. Unfortunately, accrual coincided with the announcement from the Women’s Health Initiative that implicated hormone replacement therapy in the development of breast cancer. Therefore, target enrollment was downsized from 8,500 to 4,500 subjects. The study found that the combined use of low-dose tamoxifen and hormone replacement therapy may

retain the benefit of each drug while reducing breast cancer risk. However, the 20% reduction in risk was not statistically significant. A subanalysis showed greater reduction (51%) in the cohort treated for at least 12 months, though again, this was not statistically significant. Nevertheless, significant effects were seen in protection against luminal A cancers (a 67% reduction, P = .019) and progesterone-positive tumors (a 57% reduction, P = .038). Adverse effects were those well known for tamoxifen: endometrial

risk of secondary acute myeloid leukemia (AML). The potential risk of secondary AML in children exposed to dexrazoxane during cancer treatment has limited its use in the United States. The potential for risk was evaluated in a retrospective cohort study of 15,532 children exposed to anthracyclines, with and without dexrazoxane.3 The incidence of secondary AML was only 0.52%, and was no different between those exposed to dexrazoxane or not. Mortality was also no different. The strength of the study is its use

Key Findings in Cancer Epidemiology and Prevention Presented at Best of ASCO® ‘12 ■■ Combined estrogen-plus-progestin use increased invasive breast cancer risk by 55% in an observational cohort of the Women’s Health Initiative.

■■ Initiation of combined hormone replacement therapy close to the time of menopause was associated with higher risk than later initiation.

■■ Low-dose tamoxifen does not mitigate the risk posed by hormone replacement therapy.

■■ Dexrazoxane, a cardioprotectant, does not increase the risk of acute myeloid leukemia in children treated with cancer.

■■ Thiazolidinediones for type 2 diabetes do not increase the risk of bladder cancer.

polyps, hot flashes, night sweats, vaginal discharge, and dryness. “The data overall were not statistically significant, but there were suggestive differences by subtype,” Dr. Visvanathan said. “This is an interesting result, but the size of the study was reduced. I look at this study more as promising but not definitive, and definitely not practice-changing.” There is a need, she added, for studies to identify subgroups of patients who might benefit from and safely receive hormone replacement therapy, and also to determine whether such treatment can be safely delivered to breast cancer survivors when required.

Dexrazoxane Does Not Increase Cancer Risk Reassuringly, investigators showed that the dexrazoxane, a cardioprotectant, is not associated with an increased

of a large administrative database, which enabled investigators to examine various settings and patterns of drug use. The diagnosis of AML in only 80 individuals indicates how rare the condition is, and how important it is to have access to well annotated large databases, she said.

Thiazolidinediones Do Not Increase Bladder Cancer The FDA has warned that the use of pioglitazone, a thiazolidinedione used to treat type�� 2 diabetes, may increase the risk of bladder cancer, but information about these drugs as a class has been lacking. Philadelphia investigators conducted a cohort study of patients with type 2 diabetes who initiated treatment with a thiazolidinedione (n = 18,459) or sulfonylureas (n = 41,396), a similar drug class, in The Health Improvement Network, a

October is

Breast Cancer Awareness Month

general practitioner database in the United Kingdom.4 After 2 years’ median duration of treatment, See Page 110 patients receiving thiazolidinediones had no greater incidence of bladder cancer than those on sulfonylureas. Subanalyses did show that ≥ 5 years of exposure to thiazolidinediones may be associated with an increased risk of bladder cancer, but there was no dose response and this is not consistent with prior studies and therefore should be interpreted with caution, she said. Dr. Visvanathan commented that the size of the study, and the fact that there was a reasonable comparator, gives validity to the results. Lack of details on dose and other confounders were definite limitations. In closing, she pointed out that observational studies and randomized trials both have a place in improving clinical practice. As is the case for clinical trials, clinicians need to be able to differentiate between those observational studies that are well done and those that are not, she cautioned.

■

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

References 1. Chlebowski RT, Anderson GL, Kuller LH, et al: Estrogen plus progestin and breast cancer incidence and mortality. 2012 ASCO Annual Meeting. Abstract 1501. Presented June 3, 2012. 2. Bonanni B, Maisonneuve P, Serrano D, et al: A phase III prevention trial of lowdose tamoxifen in HRT users: The HOT trial. 2012 ASCO Annual Meeting. Abstract 1500. Presented June 3, 2012. 3. Walker DM, Li Y, Huang Y-S, et al: Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric cancer patients. 2012 ASCO Annual Meeting. Abstract 1504. Presented June 3, 2012. 4. Mamtani R, Haynes K, Bilker WB, et al: Long-term therapy with thiazolidinediones and risk of bladder cancer: A cohort study. 2012 ASCO Annual Meeting. Abstract 1503. Presented June 3, 2012.

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2012-2013 Oncology Meetings October 2012 14th Biennial Meeting of the International Gynecologic Cancer Society October 13-16 • Vancouver, Canada For more information: www2.kenes.com/igcs2012/Pages/ home.aspx 13th World Congress of the International Society for Diseases of the Esophagus October 15-17 • Venice, Italy For more information: www.isde2012.org

Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com Society for Immunotherapy of Cancer Workshop—Focus on the Target: The Tumor Microenvironment October 24-25 • North Bethesda, Maryland For more information: www.sitcancer.org/meetings/am12/ workshop12

2nd Annual Oncology Market Access Forum October 16-17 • Barcelona, Spain For more information: pharma.flemingeurope.com/ oncology-market-access/

Society for Immunotherapy of Cancer: Primer on Tumor Immunology and Cancer Immunotherapy October 25 • North Bethesda, Maryland For more information: www.sitcancer.org/2012/primer

7th European Scientific Oncology Conference October 17-19 • Marbella, Spain For more information: www.esocmarbella.com/

12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

Current Approaches to Diagnosis and Treatment of Non-Hodgkin’s Lymphoma October 18-19 • Kiev, Ukraine For more information: nbscience.com/current-approachesto-diagnosis-and-treatment-of-nonhodgkins-lymphoma

50th Annual Meeting of the Japan Society of Clinical Oncology October 25-27 • Yokohama, Japan For more information: www.congre.co.jp/jsco2012/english/

Cancer Care in the Older Population October 18-19 • Cairo, Egypt For more information: www.semco-oncology.info Medical Oncology and Hematology 2012: Clinical and Scientific Approaches that Enhance Patient Outcomes October 18-20 • Houston, Texas For more information: www.mdanderson.org/conferences Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: www.gi.org

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com 9th Oncologic Imaging: A Multidisciplinary Approach Conference October 25-28 • New York, New York For more information: www.mdanderson.org/conferences New Therapeutics in Oncology: The Road to Personalized Medicine October 26-27 • Los Angeles, California For more information: research3. csmc.edu/eventinfo_147.html Society for Immunotherapy of Cancer 27th Annual Meeting October 26-28 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/annualmeeting

Optimization Methods for Radiation Diagnosis in Oncology October 27-28 • Odessa, Ukraine For more information: nbscience. com/optimization-methods-forradiation-diagnosis-in-oncology 3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

November 2012

8th NCRI Cancer Conference November 4-7 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ 2nd International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation November 5-6 • Bethesda, Maryland For more information: http://ncifrederick.cancer.gov/events/ relapse2012/ 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu PEGS Europe – The Essential Protein & Antibody Engineering Summit November 6-9 • Vienna, Austria For more information: www.pegsummiteurope.com Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 2012 Science of Global Prostate Cancer Disparities Conference November 1-4 • Nassau, The Bahamas For more information: cancer.ufl.edu/research/symposiaand-conferences

Cancer Summit: Novel Approaches to Drug Discovery November 8-9 • Boston, Massachusetts For more information: www.gtcbio.com

7th Urologic Oncology Conference: Advances in Clinical Practice November 2-3 • Houston, Texas For more information: www.mdanderson.org/conferences

BCY1 – Breast Cancer in Young Women Conference November 8-10 • Dublin, Ireland For more information: www.eso.net/events-2.html

8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

The Second International Conference on Cancer and the Heart November 9-10 • Houston, Texas For more information: www.mdanderson.org/conferences continued on page 90

NOW

APPRO ED For Patients With Advanced HR+ BC AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

Important Safety Information

There have been reports of non-infectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR® (everolimus), some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared to patients <65 years of age. Oral ulceration is the most frequently occurring adverse event and occurred at an incidence ranging from 44% to 86% of AFINITOR-treated patients across the clinical trials experience. Most of these events were Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 4%-8% of patients. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported; monitoring of laboratory tests is recommended. The use of live vaccines and close contact with those who have received live vaccines should be avoided. AFINITOR can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Please see Brief Summary of Prescribing Information on adjacent pages. For more information, please visit www.AFINITOR.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

7/12

AFB-1039129

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

T:14”

B:14.25”

S:13”

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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. Pediatric Use AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years. A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITORtreated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-132 July 2012

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2012-2013 Oncology Meetings continued from page 86

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

Current Concepts in Head and Neck Surgery November 10-11 • Houston, Texas For more information: www.mdanderson.org/conferences

2nd Annual Best of Oncology Conference November 30 • Toronto, Ontario For more information: www.oncologyeducation.com/ conferences/best-of-oncology-2012.html

Joint Meeting of IPOS 14th World Congress and COSA’s 39th Annual Scientific Meeting November 11-15 • Brisbane, Australia For more information: www.ipos-cosa.org

ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org

World Circulating Tumor Cells Summit November 12-15 • Boston, Massachusetts For more information: www.ctc-summit.com

Global Conference on Perioperative Medicine: Care of the Elderly and the Cancer Patient November 28-December 2 • Houston, Texas For more information: www.mdanderson.org/conferences

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Connective Tissue Oncology Society 17th Annual Meeting November 14-17 • Prague, Czech Republic For more information: www.ctos.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com 2nd Symposium Targeted Cancer Therapy November 19-20 • Heidelberg, Germany For more information: www.dfkz.de/en/symposiumTCT/ RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/

December 2012 35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

2013 Gastrointestinal Cancers Symposium January 24-26 • San Francisco, California For more information: www.gicasymposium.org

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

January 2013 Breast-Gynecological International Cancer Congress January 17-18 • Cairo, Egypt For more information: www.bgicc.eg.net/

NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org

April 2013

T-cell Lymphoma Forum January 24-26 • San Francisco, California For more information: www.tcellforum.com The 15th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research January 31-February 2 • San Diego, California For more information: www.mdanderson.org/conferences

February 2013 ASCO-MECC Palliative Care Workshop February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare

The Second Montréal Conference on Focal Therapy for Prostate Cancer December 7-8 • Montreal, Canada For more information: www.focaltherapymontreal.com

March 2013

3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org

May 2013 European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

American Psychosocial Oncology Society 10th Annual Conference February 14-16 • Huntington Beach, California For more information: www.apossociety.org 2013 Genitourinary Cancers Symposium February 14-16 • Orlando, Florida For more information: www.gucasymposium.org North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Conference February 14-16 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com

June 2013 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

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JOP Spotlight

Tweeting at ASCO Annual Meetings Can Enhance the Experience By Charlotte Bath

weeting at concerts or plays may earn you scornful looks or even stern warnings from ushers, but tweeting at the ASCO Annual Meeting may enhance the meeting experience for you and others. In a study comparing trends in Twitter use by physicians during the 2010 and 2011 ASCO Annual Meetings, some Twitter users reported that tweeting “improved their meeting experience, increasing understanding of the data through following others,” the study’s authors reported in the Journal of Oncology Practice.1 Twitter also provided instant accessibility for those unable to attend the meeting.

much more than saying, here is our hashtag, it took on a life of its own between 2010 and 2011.” The three physician authors of the paper reviewed the tweeted messages

and assigned them to one of four subjective categories: clinical management discussion, clinical news or trial outcome, promotional tweet, and social comment or other tweet (includ-

ing personal or humorous tweets). “We intentionally did not discuss our methodology for categorization so that the independence of the physician continued on page 92

CARIS TARGET NOW ™ JUST GOT SMARTER

Virtual Connection “Not only was knowledge being advanced, but those who were participating in the Twitter experience felt a connection to each other,” Robert S. Miller, MD, senior author of the article and Oncology Medical Information Officer at Johns Hopkins Medicine, Baltimore, told The ASCO Post. “Some of them may or may not have known each other. Some of them weren’t even on-site,” he said.

Decode each patient’s tumor— individualize cancer treatment. DNA mutations. Gene copy number variations and rearrangements. RNA. Protein expression. Each part of cancer biology reveals relevant biomarker information. Caris Target Now™ examines them all to illuminate a clearer path through your patients’ treatment options.

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Robert S. Miller, MD

“Physicians used Twitter for reporting clinical news from scientific sessions, for discussions of treatment issues, for promotion, and to provide social commentary,” the authors reported. “The tangible impact of Twitter discussions on clinical practice remains unclear,” they added.

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Volume Grew Significantly The authors analyzed a combined total of 12,644 tweets that incorporated the official ASCO Annual Meeting hashtags (#ASCO10 and #ASCO11). The final data set included 979 tweets collectively generated by 14 physicians in 2010 and 1,477 tweets collectively generated by 34 physicians in 2011. The volume “grew significantly,” Dr. Miller said. “Without ASCO doing

ON-COMPENDIUM DRUG ASSOCIATIONS AND CLINICAL TRIALS

ON- AND OFF-COMPENDIUM DRUG ASSOCIATIONS AND CLINICAL TRIALS

The use of the Caris Target Now service, the use or interpretation of any information prov ro ided d as a part art of su such ch ser servic vice, e, and and/or /or th the e sele selecti ction on of any dr drug ug age agents nts is so solel lelyy at at and and wit within hin th the e discretion of the treating physician’s independent medical judgment. The Caris Target Now w services are perf erform ormed ed by Car Caris is Lif Life e Scie Science ncess, a C CLIA LIA-ce -certi rtifi fied ed llabo aborat ratory ory op opera eratin ting g unde underr the U.S. Clinical Laboratory Amendment Act of 1988 and in compliance with all releva v nt U.S. state and n fed f eral rregu ulations. s None of the e Caris r Targe rget Now services have e been n re evie i wed w by the United States Food and Drug Administration. Persons depicted are models and used for illustrative purposes only. y ©201 2 2 Cari r s Life Scien i ces an a d affi ffiliaates. All right h s rese erved. CTN051512AP

The ASCO Post | OCTOBER 15, 2012

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JOP Spotlight

Tweeting at ASCO Annual Meetings continued from page 91

authors could potentially represent a larger point of view,” the authors explained. “We acknowledge there was a tremendous amount of subjectivity,” Dr. Miller said. Among physician-generated tweets analyzed from the 2010 meeting, the highest average percentage (34.5%) was assigned to the social comment or other category, followed by clinical news or trial outcome (28.6%), clinical management discussion (25.9%), and promotional (11.1%). Average category rankings for tweets from the 2011 meeting were led by clinical news or trial outcome (41.5%), followed by social comment or other (29.8%), clinical management discussion (18.9%), and promotional (9.9%) (see Table 1).

Perspective of Colleagues Twitter can provide “up-to-thesecond colleague-generated commentary and perspective on breaking data ahead of traditional online or print media and formal peer-reviewed publication,” according to the study authors. “Increasingly, conferences are promoting or otherwise enabling the use of these types of social media during their meetings for this very purpose,” Dr. Miller said. “Meeting organizers need to expect it, prepare for it, and understand that this is the way many people will be experiencing meetings and reporting the results. A paper gets reported at a meeting and the presenters should now expect that as they are talking, people are going to be tweeting what they are saying and people are going to be commenting on that.” There is some concern that social media leads to premature release of data, even though major media have been reporting meetings for years, perhaps not instantaneously but within hours or a day. “I have heard anecdotes about some organizations actively discouraging tweeting of results, which I frankly don’t understand, because the information is out there. ASCO releases all of its abstracts at the same time every year, and it is very appropriate to have that notification, so there is no question of impropriety of timing,” Dr. Miller said. While he had heard that some professional societies have specifically warned meeting attendees

Table 1: Tweet Content Assignment by Blinded Rater 2010 Tweets (N = 979)

2011 Tweets (N = 1,477)

Tweet type

Rater 1

Rater 2

Rater 3

Average

Rater 1

Rater 2

Rater 3

Average

Clinical management discussion

31.4%

25.3%

20.9%

25.9%

15.2%

24%

17.6%

18.9%

Clinical news or trial outcome

23.2%

27.2%

35.3%

28.6%

38.9%

39%

46.5%

41.5%

Promotional

16.3%

10.9%

11.1%

5.5%

15.2%

9.9%

Social comment or other

39.4%

31.3%

32.8%

34.5%

40.4%

21.8%

27.3%

29.8%

not to tweet, “I don’t know how they would enforce that, frankly. People are sitting there with their phones.”

Possible Commercial Interests The 2011 tweets included mention of “more than 100 unique drugs or drug-drug combinations,” compared to 82 mentions in the 2010 tweets. “The frequency of drug mentions loosely correlated with abstracts featured in the plenary session,” the authors reported. “Our analysis does not exclude the possibility that some of those tweeting about specific agents had a commercial interest in the products being discussed,” they stated.

formation is contingent on knowing the people that you follow and maintaining transparency regarding the nature of any commercial interests tweet authors may have.” Three of those responding to the survey reported tweeting for reasons that were categorized as self-promotion and included “promoting a poster presentation, sharing results of a clinical trial in order to recruit more patients, and generating traffic to a personal blog.” Other promotional tweets, which increased from 2010 to 2011, were for hotels, restaurants, and other commercial and tourist-related businesses in Chicago, the site of the ASCO meetings, according to Dr. Miller. “Most of the promotional stuff

Increasingly, conferences are promoting or otherwise enabling the use of these types of social media during their meetings for this very purpose. —Robert S. Miller, MD

Dr. Miller said that he did not know if Twitter followers in the study were generally aware of this potential for promoting specific drugs. Those tweeting about specific agents “certainly could have conflicts of interest that they are not obligated to report,” he stated. “It is not like when you’re presenting a paper at the ASCO meeting, you’re absolutely obligated, under threat of scientific disrepute, to reveal your conflicts. There is no obligation at all to do that on Twitter. So I think that someone other than the most savvy of social media users could be hoodwinked by a clever individual who has an agenda. I don’t suspect that happens very often, but there really are no safeguards.” Among 14 physicians responding to a follow-up survey of Twitter users at the 2011 ASCO meeting, “the majority stated that the quality of in-

was innocuous and helpful and otherwise of interest,” he said. Overall, “there was more good than bad” resulting from the 2010 and 2011 tweets, Dr. Miller stated, with the valuable outcomes, such as improved understanding and accessibility to data, outweighing the detriments, such as unwelcome promotions and time spent tweeting.

Encouraging Tweeting at Meetings The use of Twitter at mainstream scientific meetings like the ASCO conference is still relatively limited, Dr. Miller said, mainly appealing to a group of early adopters, but it is growing. He acknowledged that “certainly there will be many who have reservations about this,” particularly those who feel that we already spend too much time looking at electronic screens and too

little time in actual human interactions. An e-mail survey conducted in 20112 revealed that there See Page 110 was a significant minority of “adamant nonadopters,” Dr. Miller said. Professional organizations that want to “promote Twitter as a legitimate medium to communicate meeting proceedings and enhance attendee experience should encourage participation through the development and advance distribution of official hashtags posted on their official Web sites and their own Twitter accounts,” the authors advised. “I think you lead by example,” Dr. Miller added, “by having an appropriate volume of Twitter usage and content links. If an organization like ASCO sends out messages that drive members to specific content— for example, come to this meeting, or read this latest journal article, or we just released some guidelines, or here’s a press release related to an important regulatory issue you ought to know about—I think that gets people’s attention.”

■

Disclosure: Dr. Miller reported no potential conflict of interest.

References 1. Chaudhry A, Glodé M, Gillman M, et al: Trends in Twitter use by physicians at the American Society of Clinical Oncology Annual Meeting, 2010 and 2011. J Oncol Pract 8:173-178, 2012. 2. McGowan B, Vartabedian B, Miller R, et al: The “meaningful use” of social media by physicians for learning. Medicine 2.0: 4th World Congress on Social Media and Web 2.0 in Medicine, Health, and Biomedical Research. Presented September 17, 2011. Available at www.medicine20congress.com/ ocs/index.php/med/med2011/paper/ view/764. Accessed September 11, 2012.

ASCOPost.com | OCTOBER 15, 2012

PAGE 93

Psychosocial Oncology

American Psychosocial Oncology Society Provides Helpline for Counseling Services he American Psychosocial Oncology Society (APOS) offers a toll-free national Helpline as a resource to help people with cancer and their caregivers find counseling services in their own communities. Patients with cancer, caregivers, and advocacy organizations may obtain referrals for local counseling services throughout the United States by contacting the Helpline at 1-866-2767443. This referral program aims to connect cancer patients and their caregivers to psychiatrists, psychologists, nurses, social workers, and counselors skilled in the management of cancerrelated distress. If the Helpline staff cannot find local support services and there is an immediate need for help, an APOS mental health counselor from the Helpline will continue to support them by phone while they seek professional help with coping in their community. Counseling sessions will be scheduled at the discretion of the Helpline counselor according to patient need.

Confidential Referral To request a confidential referral, interested persons may call: toll free 1-866-276-7443 (1-866-APOS-4-HELP) or send an email to info@apos-society.org The following information is requested: ■■ Caller’s name (spelling of the last name) ■■ Contact phone number(s), including area code ■■ Patient’s city/town and state of

residence ■■ Zip code of the location where you are searching for a referral Calls are accepted 24 hours a day

through a voicemail system and then handled by trained staff members who have access to a national directory of community mental health resources.

Helpline inquiries will normally be returned within 24 to 48 hours. For additional information, visit http://www.apos-society.org/

■

InsIght

NEw iN EVERy iSSUE Of

JnCCn

NEW

Read the October Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non–Small Cell Lung Cancer and Palliative Care NEW

NCCN Guidelines® insights: waldenström’s Macroglobulinemia/ Lymphoplasmacytic Lymphoma, Version 2.2012 In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Short-Course Radiation Versus Long-Course Chemoradiation for Rectal Cancer • Use of Endobronchial Ultrasound and Endoscopic Ultrasound to Stage the Mediastinum in Early-Stage Lung Cancer • Progressive Chronic Lymphocytic Leukemia After Allogeneic Hematopoietic Cell Transplantation

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

DOwNLOaD the JNCCN aPP Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

The ASCO Post | OCTOBER 15, 2012

PAGE 94

Book Review

Cancer Memoir Provides Inspiration for Those with Terminal Illness and Their Caregivers By Ronald Piana

“I

t almost always begins in darkness, my memory’s trip back to China where Terrence and I meet.” So begins Amanda Bennett’s moving new memoir, The Cost of Hope, the story of an intensely devoted marriage, cruelly shortened by the cancer that killed her husband. The word “darkness” in Ms. Bennett’s opening sentence implicitly foreshadows her husband’s death. After all, cancer is not only a disease, but also a very personalized destination, sometimes to a dark and isolated place. However, it is the words in the title, cost and hope, that immediately resonate with the oncology community at large—patients with cancer hang on the hope of a cure, and doctors increasingly worry about how the rising cost of care might hamper their ability to treat patients.

Roller Coaster Ride of a Marriage Ms. Bennett, a Pulitzer Prize–winning journalist, uses the short, punchy syntax of her trade to propel the story along. The memoir opens in Peking (it was still Peking in those days), China, in 1983. Ms. Bennett, then a foreign correspondent for the Wall Street Journal, meets her future husband, one Terrence B. Foley, at a raucous, late-night cocktail party. Foley, working as envoy for the American Soybean Association, is a bow tie–wearing, multilingual, polymath, curmudgeon—he knows how to say ‘artificial insemination’ and ‘ribonucleic acid’ in Chinese—who both dazzles and

infuriates Ms. Bennett all the way to the alter and beyond. During their peripatetic marriage they have two children, as Ms. Bennett slugs away at her writing career and her husband “reinvents himself once, twice, three times.” It’s an interesting roller coaster ride of a marriage that, despite constant friction, never seems in peril of collapsing. Then it happens: Acute intestinal pain drives Foley to an emergency room visit during which he is diagnosed with severe ulcerative colitis; the attending doctor mentions, almost as an aside, that on the scan a “shadow” appeared on Foley’s kidney, which turns out to be cancer. Remarkably, the couple views the cancer as “a nuisance, a distraction from another more demanding illness and everything else going on in our lives.” After weeks of unremitting pain, Foley has a total colectomy.

Battleground of Illness Shortly after, the shadow on Foley’s kidney assumes a leading role in the narrative as Ms. Bennett and her husband are summoned by a phone call to Dr. Turner’s office, where he uses the words “very concerning” and “worrisome” to describe the lesion. Dr. Turner recommends that the kidney be removed. It is just 3 weeks since Foley’s colectomy, and from this point, the reader is pulled into the battleground of illness. Three days after the operation, Ms. Bennett and her husband see Dr. Turner,

who tells them that the kidney cancer is an odd type, “of unknown origin,” (later referred to as “collecting duct” by one doctor, and “papillary” by another, though ultimately the type of kidney cancer was not confirmed), reassuring them that he’ll call as soon as he knows more. Her husband tears up and thanks the doctor for saving his life. They shake hands. Foley never sees the doctor again. At this point in the book, Ms. Bennett weaves back and forth in time, using her husband’s illness and subsequent death as the fulcrum. Some of the more interesting sections deal with Ms. Bennett’s transformation from wife to that of caregiver/advocate. “What makes me think curing Terrence’s cancer is my responsibility?” she asks, at the opening of chapter 12. In search of an answer, she states, “I become part of a cancer community.” She investigates cancer on the Internet, keeps voluminous notes, and barrages the doctors with questions, as the couple navigates a maze of diagnoses and treatments. Anyone who has been a caregiver will embrace these sections, as Ms. Bennett champions her husband’s battle with cancer.

Immeasurable Rewards Through it all, her husband serves as

Title: The Cost of Hope: A Memoir Author: Amanda Bennett Publisher: Random House, New York Publication date: June 5, 2012 Price: $26.00 (hardcover, 240 pages) an inspiration for anyone facing serious illness. “Terrence never does stop doing what he loves. Even during his treatment, even on the hardest days, Terrence’s life is full,” she writes as they carry on with their life together, despite his declining health and imminent death. Most patients with cancer want therapy, even if it only gives them limited time. Ms. Bennett says, “The medicine buys him time with our children. Time with me. It buys him music and study and Sunday afternoons with his friends.” This is an important observation. Ms. Bennett understands that small parcels of time have immeasurable rewards for patients staring mortality in the face, and for their loved ones. The Cost of Hope is a personal and insightful glimpse into how highpriced medicines and expensive technologies burden this nation’s healthcare system but at the same time afford patients and their families precious added time together.

■

Contact The ASCO Post Advertising

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Rates, reprints, or supplements

James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

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Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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NOW ENROLLING ASCOPost.com | OCTOBER 15, 2012

PAGE 95

XXXX

ACUTE LYMPHOBLASTIC LEUKEMIA

INO-VATE ALL INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy A randomized, phase 3 trial in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) This is a 2-armed, randomized, open-label, phase 3 study designed to evaluate the hematologic remission rate (CR + CRi) with inotuzumab ozogamicin compared with investigators’ choice of FLAG, cytarabine combined with mitoxantrone, or HIDAC.

Selected inclusion criteria • Relapsed or refractory CD22-positive ALL due to receive salvage 1 or salvage 2 therapy • Ph+ ALL patients must have failed treatment with at least 1 second-generation tyrosine kinase inhibitor • Bone marrow involvement with ≥5% lymphoblasts • Aged 18 years or older • ECOG performance status 0-2 • Adequate liver function

Selected exclusion criteria • Isolated extramedullary relapse, Burkitt’s lymphoma or mixed-lineage leukemia, or active central nervous system leukemia • Active heart disease • Prior chemotherapy ≤2 weeks prior to randomization and/or patients not recovered from acute toxicity • Prior treatment with monoclonal antibodies ≤6 weeks before randomization • Prior allogeneic hematopoietic stem cell transplant ≤4 months before randomization • Peripheral lymphoblasts >10,000/µL

Reference: ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01564784. Accessed April 3, 2012.

Inotuzumab ozogamicin is an investigational compound. This information is current as of August 14, 2012.

STW00067B

April 2012

Learn more about INO-VATE (B1931022) For more information about this trial, please visit www.clinicaltrials.gov (NCT01564784) or call: 1-877-369-9753 in the United States and Canada (toll-free) or +1-646-277-4066 outside the United States

The ASCO Post | OCTOBER 15, 2012

PAGE 96

Integrative Oncology Antioxidant Supplementation in Patients with Cancer: Is It Safe and Effective? By Barrie Cassileth, PhD, and Ian Yarett Integrative Medicine Service Memorial Sloan-Kettering Cancer Center, New York

ntioxidant supplements are widely used by healthy individuals as a preventive measure against cancer and heart disease and by patients with cancer to promote healing and prevent recurrence. Studies suggest that dietary supplements are used by up to 81% of cancer survivors, and that 14% to 32% begin using supplements following diagnosis.1 Increasing one’s intake of antioxidants, which are involved in repairing cellular oxidative damage, theoretically should lower cancer risk, but there is little evidence to suggest that supplementation is efficacious, or even safe.2,3 Although increased consumption of antioxidant-rich fruits and vegetables may reduce the risk of certain cancers, studies of isolated antioxidants in supplement form have not been equally promising. Of particular concern to clinicians and patients is the use of antioxidant supplements during the course of chemotherapy and/or radiation therapy, as antioxidants consumed at doses common in nutritional supplements could potentially interfere with the effectiveness of these treatments.4 Here we provide an overview of relevant findings and existing recommendations on antioxidant supplementation that may be useful to clinicians.

Can Antioxidants Help Prevent Cancer? Antioxidants comprise a broad class of compounds that counteract free radicals, thus inhibiting oxidative chain reactions that can react with DNA and damage cells. Their chemical structures and particular mechanisms, however, vary widely. While studies have described an inverse relationship between consumption

of antioxidant-rich foods and cancer risk, there is no definitive evidence that dietary supplements containing high levels of antioxidants can reduce cancer incidence. Antioxidant supplementation has been studied in randomized clinical trials, most of which found no decrease in cancer risk or, in some cases, an increased risk. The SELECT trial, for instance, investigated the effects of supplemental selenium and vitamin E on the incidence of prostate cancer in 34,887 healthy men and found that vitamin E supplementation significantly increased cancer risk.5 Similarly, highdose supplementation with beta-carotene in several clinical trials showed no benefit in preventing lung and other

ntegrative Oncology is guest edited by Barrie R. Cassileth, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan-Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 260 and growing number of entries offers health-care professional and patient versions, and entries are regularly updated with the latest research findings. consume at least 2.5 cups of a variety of colorful fruits and vegetables each day.”3

Although it is not yet clear whether or in which specific cases antioxidant consumption may interfere with chemotherapy or radiation treatment, it is advisable to apply the cautionary principle and advise patients to avoid antioxidant dietary supplements during treatment, until further study brings greater clarity. cancers. Two of these studies found that the supplements increased the risk of lung cancer in cigarette smok �� C supplemeners.6,7 Studies of vitamin�� tation have had null results as well; the Physicians’ Health Study II found no significant effect of vitamin�� C supplementation (500 mg/d) on prostate or total cancer incidence.8 To reduce cancer risk, the American Cancer Society (ACS) recommends that antioxidants be consumed through food sources rather than as dietary supplements. “The best advice,” the ACS guidelines state, “is to

Can Antioxidants Interfere with Chemotherapy and/or Radiotherapy? The safety and efficacy of antioxidant supplements taken during the course of treatment is particularly controversial. Many clinicians are concerned that high-dose antioxidant supplements could decrease the effectiveness of chemotherapy or radiation by protecting cancer cells as well as healthy cells from oxidative damage associated with these treatments. Others argue that antioxidant supplementation could selectively protect

Visit the About Herbs website at

www.mskcc.org/aboutherbs

healthy cells from such damage, thus minimizing toxicity and adverse side effects of the treatment regimen.4 Although findings vary among existing randomized controlled trials of antioxidant use during cancer treatment, many are of relatively low quality and/or limited statistical power. Moreover, it is difficult to draw conclusions due to variations in malignancy type, antioxidant type and dose, and treatment regimen, among other factors.4 One of the best designed studies involved 540 patients with head and neck cancer undergoing radiation treatment. It found significantly higher mortality among those prescribed 400�� IU of daily vitamin E supplementation compared to placebo.9 In the absence of definitive evidence, the American Cancer Society and most other national nutrition guidelines advise caution, suggesting that patients with cancer “obtain antioxidants through food or beverage sources rather than dietary supplements.” The ACS further states that “it is prudent for cancer survivors currently receiving chemotherapy or

ASCOPost.com | OCTOBER 15, 2012

PAGE 97

Integrative Oncology radiation therapy to limit the usage of supplements to nutrients for which a deficiency has been demonstrated, and avoid dietary supplements exceeding 100% of the Daily Value for antioxidant vitamins.”2

Can Antioxidants Help Prevent Recurrence and/or Reduce Mortality? Cancer survivors are at an increased risk of secondary cancers, and the ACS advises that such patients “should be encouraged to consume a variety of … antioxidant-rich foods each day.”2 Clinical studies, however, suggest that consumption of antioxidant supplements after diagnosis is not likely to improve prognosis or long-term survival in patients with cancer. A 2006 systematic review of randomized controlled trials in patients with cancer or preinvasive lesions found no relationship between antioxidant supplementation and all-cause mortality.10 Another study followed 77,719 residents of Washington State over 10�� years and found no association between supplementation with vitamin E or C and cancer mortality.11 Additionally, a randomized trial found that beta-carotene supplements raised the risk of recurrence in colorectal

adenoma patients who smoke and/or consume alcohol (but decreased it in nonsmokers/nondrinkers).12

no way compensate for consumption of healthful foods.

■

Disclosure: Dr. Cassileth and Mr. Yarett reported no potential conflicts of interest.

Concluding Thoughts Based on existing evidence, patients with cancer should minimize supplement use, especially in doses higher than the recommended daily value, except to meet nutritional needs or as evidence-based therapy for a chronic condition such as osteoporosis.2,3 Very few antioxidant dietary supplements have been studied for their safety and effectiveness, and results from many clinical studies conducted to date have not shown benefits—and in some cases have suggested harm. Although it is not yet clear whether or in which specific cases antioxidant consumption may interfere with chemotherapy or radiation treatment, it is advisable to apply the cautionary principle and advise patients to avoid antioxidant dietary supplements during treatment, until further study brings greater clarity. Moderate consumption of antioxidant-containing foods such as vegetables and fruits, however, may be beneficial in reducing cancer risk and in maintaining health postdiagnosis. Vitamin pills in

References 1. Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: A systematic review. J Clin Oncol 26:665-673, 2008. 2. Rock CL, Doyle C, Demark-Wahnefried W, et al: Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 62:243-274, 2012. 3. Kushi LH, Doyle C, McCullough M, et al: American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: Reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 62:30-67, 2012. 4. Lawenda BD, Kelly KM, Ladas EJ, et al: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 100:773-783, 2008. 5. Klein EA, Thompson IM, Jr., Tangen CM, et al: Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306:1549-1556, 2011. 6. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The

Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330:1029-1035, 1994. 7. Omenn GS, Goodman GE, Thornquist MD, et al: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334:1150-1155, 1996. 8. Gaziano JM, Glynn RJ, Christen WG, et al: Vitamins E and C in the prevention of prostate and total cancer in men: The Physicians’ Health Study II randomized controlled trial. JAMA 301:52-62, 2009. 9. Bairati I, Meyer F, Jobin E, et al: Antioxidant vitamins supplementation and mortality: A randomized trial in head and neck cancer patients. Int J Cancer 119:2221-2224, 2006. 10. Davies AA, Davey Smith G, Harbord R, et al: Nutritional interventions and outcome in patients with cancer or preinvasive lesions: systematic review. J Natl Cancer Inst 98:961-973, 2006. 11. Pocobelli G, Peters U, Kristal AR, et al: Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality. Am J Epidemiol 170:472-483, 2009. 12. Baron JA, Cole BF, Mott L, et al: Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: Results of a randomized trial. J Natl Cancer Inst 95:717-722, 2003.

Don’t Miss These Important Reports Inside this Issue of The ASCO Post John D. Groopman, PhD, on Viral Infection and Liver Cancer, page 11

Katherine M. Serrurier, on Anthracycline use in Early Breast Cancer, page 20

Nita Ahuja, MD, on Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy, page 31

Jorg Dietrich, MD, PhD, on Cognitive Impairment in Patients with Cancer, page 43

Howard I. Scher, MD, on Enzalutamide in Prostate Cancer, page 63

Don S. Dizon, MD, FACP, on The Language of Cancer, page 79

Mario E. Lacouture, MD, on vandetinib-induced photosensitivity, page 100

Stanley L. Liauw, MD, on Aspirin an Reduced Risk of Death Due to Prostate Cancer page 106

Deborah L. Barton, RN, PhD, on Symptom Management, page 111

Visit The ASCO Post online at ASCOPost.com

THORACIC ONCOLOGY UPDATE:

Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients During the past decade the identification of molecular biomarkers for clinically relevant mutations or other genetic abnormalities in non-small cell lung cancer (NSCLC) has improved the understanding of lung cancer pathogenesis, and of the proliferation and survival of cancer cells.1 This significant development is setting the stage for a paradigm shift toward the adoption of treatments directed to the particular genetic makeup of the tumor.1,2

Over 50% of NSCLC Cases Are Linked to Known Molecular Biomarkers

At Least 10 Known Molecular Biomarkers in NSCLC3

with similar clinical stage and tumor histology can have dramatically different

50% of NSCLC cases are linked to one of

clinical outcomes.4

KRAS

at least 10 currently known biomarkers

Indeed, biomarkers may give clinicians

for NSCLC — and many of these patients genetic abnormalities that are “drivers” for their cancers and are treatable with approved biomarker-driven therapies or

Unknown EGFR

as well as the treatment sensitivity/

ALK

resistance of the tumor to specific agents.4,5

TP53

Moreover, as genomic and mutational PIK3CA

1DH1

CTTNB1

HER2 NRAS

BRAF

research continues, more biomarkers will inevitably be discovered, so that the proportion of NSCLC cases with unknown drivers will continue its decline. The

Now that more than half of NSCLC cases

ultimate goal of this approach to

can be linked to one or more of these

treatment is to identify every driver

biomarkers, it is possible to subdivide

mutation for non-small cell lung cancer,

the histological subtypes of NSCLC

and design a corresponding treatment

— adenocarcinoma, squamous cell

for each of these oncogenes.1,2,4

carcinoma, and large cell carcinoma — into clinically relevant molecular subsets.1

In partnership with:

an indication of the patient’s prognosis (outcome independent of treatment),

investigational agents in clinical trials.2,3

Sponsored by:

considerable heterogeneity of non-small cell tumors and suggest why patients

According to recent studies, more than

may test positive for mutations or other

These molecular subsets show the

Curbside Consult New Diagnostic Paradigm: Histology + Molecular Profile

For patients whose tumors test positive

David R. Gandara, MD Director, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

for a biomarker that is treatable with approved or investigational agents, the

Recently it has been proposed that

benefits of testing are self-evident.1,5,6

lung cancer treatment be based on the histology of the tumor. But there is

But in the future, molecular profiling

a growing consensus that molecular

will help an increasing proportion

profiling — testing the tumor at biopsy

of patients with NSCLC because the

for all appropriate biomarkers — should

additional information it reveals about

be part of the clinician’s standard

their tumor has the potential to guide

approach to pathologic evaluation.1,2

clinical management.2,7

And this is supported by the National Comprehensive Cancer Network (NCCN®)

Molecular Profiling Is Key in NSCLC

Clinical Practice Guidelines in Oncology

The discovery of biomarkers has

(NCCN Guidelines®) for all non-squamous

demonstrated the molecular complexity

non-small cell lung cancer (NSCLC)

of NSCLC, and it highlights the need

histologies, which state :

to move toward molecularly based

classification and treatment of these tumors.1,4 But only if patients are tested is it possible for them to potentially benefit

of “ Determination the specific molecular

from these developments. As additional mutations are discovered

abnormalities of the tumor is critical for predicting sensitivity or resistance to a growing number of targeted therapies.

through efforts such as the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) and the Cancer Genome Atlas — and as new agents are

”

developed to address these abnormalities — the hope for the over 215,000 people

– NCCN Guidelines® Version 3.2012, for Non-Small Cell Lung Cancer 5

diagnosed with lung cancer each year is that these advances will lead to more treatment options.1,8-10 In the words of Dr. David Gandara, Director of Thoracic

The NCCN® recommends EGFR and ALK

Oncology at UC Davis Comprehensive

testing for all advanced non-squamous

Cancer Center, “Our goal is to learn the

NSCLC, in order to guide treatment

‘molecular fingerprint’ of each person’s

decisions. Multiplex molecular profiling

lung cancer, and to personalize their

assays may make the prospective

therapy based on this information. The

discoveries that could make this possible

genotyping of tumors possible, to aid clinical decision making and management.

What is the most significant development you’ve seen in the treatment of lung cancer today? DG Knowing what is driving the cancer! We have recently been using histology to treat cancer based on the appearance of the cells. But cells that look identical under the microscope can have dramatically different clinical outcomes because of what is driving them at the molecular level. And that is leading us to molecularly based treatment options.

Can many NSCLC patients benefit from this testing? Who should be tested? DG When you consider both approved and investigational agents, yes, a considerable proportion of NSCLC patients can receive therapy based on molecular testing. But at present I believe that all patients with NSCLC of the adenocarcinoma subtype should be tested.

That seems like a lot of testing. Wouldn’t that require a re-biopsy for many patients? DG These tests do require adequate tumor tissue. Some patients will need to be re-biopsied — some for lack of sample tissue, but also to look for changes that have occurred over time and as a result of therapy. Other patients may not have to be re-biopsied. To do the testing that reveals the “molecular fingerprint” of each person’s lung cancer, we have to get sufficient tumor tissue at biopsy.

Visit www.lungcancerprofiles.com for the patient perspective on molecular profiling.

are being made at a rapid pace.”

References: 1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. 2. Gandara DR, Li T, Lara PR Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5):321-325. 3. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. 4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med. 2008;359(13):1367-1380. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-small Cell Lung Cancer V.3.2012. ©National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed August 20, 2012. To view the most recent and complete version of the guideline, go online to http://www.nccn.org/. NATIONAL COMPREHENSIVE CANCER NETWORK,® NCCN,® NCCN GUIDELINES,® and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Carr LL, Finigan JH, Kern JH. Evaluation and treatment of patients with non-small cell lung cancer. Med Clin N Am. 2011;95:1041-1054. 7. Goetsch CM. Genetic tumor profiling and genetically targeted cancer therapy. Semin Oncol Nurs. 2011;27(1):34-44. 8. National Institutes of Health. Lung cancer mutation consortium protocol. http://clinicaltrials.gov/ct2/show/NCT01014286. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. http://cancergenome.nih.gov/abouttcga/overview. Accessed January 19, 2012. 10. Boland JM, Erdogan S, Vasmatazis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152-1158. © 2012 Pfizer Inc.

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The ASCO Post | OCTOBER 15, 2012

PAGE 100

Dermatologic Events in Oncology How to Recognize and Manage Vandetanib-induced Photosensitivity By Mario E. Lacouture, MD

andetanib (Caprelsa) is an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinase receptors. It has been approved by regulatory agencies for the treatment of unresectable or metastatic medullary thyroid cancer. Although vandetanib therapy

is devoid of significant hematopoietic or gastrointestinal adverse events, skin toxicity with the drug is common. An acneiform rash affects 46% of patients, mostly grade 1/2 as per Common Terminology Criteria for Adverse Events (CTCAE). Less commonly, phototosensitive (11%–23%) reactions have been reported (Fig. 1).

Photosensitive reactions induced by vandetanib are usually characterized by effects on exposed areas of the body, such as the face, ears, upper chest, and dorsal distal extremities, while sparing areas behind the ears, under the chin, or on the hair-bearing scalp. These reactions can appear after a short period of exposure to the sun, and the rash may progress rapidly, over hours to days, to painful, pruritic papules, plaques, or blisters. Skin biopsies demonstrate edema with a mixed inflammatory infiltrate and, in some cases, necrosis.

Treatment Recommendations

Fig 1: Typical photosensitivity reaction, on the arm (left) and chest (right), associated with vandetanib therapy.

Treatment for vandetanib-induced photosensitive reactions includes topical corticosteroids (for grades 1/2) or oral corticosteroids (for grade 3). Oral antihistamines can also be employed to control pruritus, as well as analgesics and oatmeal baths to mitigate skin pain. In addition, holding vandetanib for grade 3 events may be necessary. Reports of recurrence of photosensitive reactions have been reported when patients are treated with docetaxel after experiencing vandetanib-induced photosensitivity. Therefore, sun protective clothing, glasses, and avoidance of direct sun exposure between 10:00 AM and 4:00 PM is recommended for all patients on vandetanib. In addition, the liberal appli-

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, a  board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. He is an Associate Member at Memorial Sloan-Kettering Cancer Center, New York. The series is intended to offer oncologists guidance in recognizing and treating the skin toxicities associated with anticancer agents. cation of a broad-spectrum sunscreen with an SPF of at least 15, applied every 2 hours to exposed areas of the body, is always recommended. Prevention of photosensitive reactions for patients on vandetanib is critical in order to minimize disabling events and to maintain dose intensity. Disclosure: Dr. Lacouture is a consultant for AstraZeneca.

Download The ASCO Post iPad App FREE from iTunes today!

ASCOPost.com | OCTOBER 15, 2012

PAGE 101

Announcements

Memorial Sloan-Kettering Cancer Center Appoints José Baselga, MD, PhD, New Physician-in-Chief

emorial Sloan-Kettering Cancer Center announced that José Baselga, MD, PhD, has been named Physician-in-Chief of Memorial Hospital. Currently, Dr. Baselga is Chief of the Division of Hematology/Oncology at Massachusetts General Hospital (MGH) and Associate Director of the MGH Cancer Center.

identification of novel mechanisms of resistance to current cancer therapies. His laboratory investigations have focused primarily on breast cancer, in particular in the area of growth factor

receptors as targets for breast cancer therapy. He has also been involved in the preclinical and clinical development of several molecularly targeted agents in-

FREE CME-ACCREDITED INTERACTIVE CASE SCENARIOS

cluding trastuzumab (Herceptin) and lapatinib (Tykerb), and insulin-like growth factor receptor inhibitors. More recently, he led the early continued on page 102

ON ASCO UNIVERSITY

>>UNIVERSITY.ASCO.ORG/FOCUS-UNDER-FORTY

THE NEEDS OF THE

José Baselga, MD, PhD

“Memorial Sloan-Kettering is embarking on a new period of growth and development across our range of clinical programs, and in José Baselga we are fortunate to have recruited a leader with the vision, skill, and experience to work with me during this exciting time,” said Memorial SloanKettering President and CEO Craig B. Thompson, MD. “Dr. Baselga is a dedicated clinician and a distinguished researcher. I know he will collaborate energetically and enthusiastically with his colleagues throughout this great institution to accelerate cancer discovery and help bring new and more-effective treatments to the clinic, while ensuring the highest and most humane standards in patient care.” More than 123,000 patients are seen annually at Memorial SloanKettering. As Physician-in-Chief, Dr. Baselga will direct the clinical component of Memorial Sloan-Kettering, leading a staff of approximately 834 attending physicians. His responsibilities will include the management of patient care delivery in Memorial Hospital as well as at Memorial SloanKettering’s clinics and regional sites. He will also focus on clinical strategic planning and will oversee clinical and translational research.

Translational Research Specialist Dr. Baselga is an internationally recognized physician-scientist with a special interest in translational and early clinical research as well as the

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The ASCO Post | OCTOBER 15, 2012

PAGE 102

Announcements

Lisa Carey, MD, Named Division Chief of Hematology-Oncology, UNC School of Medicine, and Physician-in-Chief of the N.C. Cancer Hospital

ationally recognized clinical researcher and physician Lisa A. Carey, MD, has been appointed Chief of the Division of Hematology and Oncology at the University of North Carolina School of Medicine and Physician-in-Chief of the N.C. Cancer Hospital.

the UNC Breast Center, and Associate Director for Clinical Research at UNC Lineberger Comprehensive Cancer Center. “Dr. Carey is exactly the right leader for these key roles,” said William L. Roper, MD, MPH, Dean of the UNC School of Medicine and CEO of UNC Health Care. “This is an area of great importance to our health-care system, and to the people of North Carolina.”

New Responsibilities

Lisa A. Carey, MD

Dr. Carey, a member of the UNC faculty for more than 10 years, is Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, Professor of Medicine, Medical Director of

New Physician-in-Chief at MSKCC continued from page 101

clinical development and the pivotal clinical studies that resulted in approval by the FDA of two drugs for the treatment of breast cancer— pertuzumab (Perjeta) for the treatment of patients with HER2-positive metastatic disease, and everolimus (Afinitor) for the treatment of advanced hormone receptor–positive, HER2-negative breast cancer. His current work focuses on the development of PI3K inhibitors in patients with tumors that have PI3K mutations. “One of today’s major challenges in clinical oncology is translating as rapidly as possible findings made in the laboratory into effective therapies for patients,” said Dr. Baselga. “Memorial Sloan-Kettering is uniquely positioned to do this—and at a time when the opportunities in cancer research and treatment have never been greater. I am delighted, and feel privileged, to be rejoining the Memorial Sloan-Kettering family.”

Career Overview Dr. Baselga completed a medical oncology fellowship at Memorial

In her role as Division Chief, Dr. Carey will be responsible for the overall administration of the division, including clinical practice, educational activities, research programs, fiscal management, and meeting the missions of patient care, research, and education. This includes leading a diverse group of more than 50 clinicians, investigators, physician extenders and fellows, which has grown substantially. Hospital and remained as a faculty member on the Breast/Gynecological Oncology Service from 1994 through 1996, when he returned to Spain. He received his MD and PhD degrees from the Universitat Autònoma de Barcelona, in Spain, and did residencies at Vall d’Hebron University Hospital in Barcelona and the State University of New York Health Science Center at Brooklyn. Dr. Baselga is a Past President of the European Society for Medical Oncology, has served on the Board of Directors of ASCO and the American Association for Cancer Research (AACR), and is the author or coauthor of more than 300 peer-reviewed articles and publications. He is also a founding Editor-in-Chief (with Lewis C. Cantley) of the AACR’s new journal, Cancer Discovery. He has received numerous awards and honors, among them ASCO’s Young Investigator and Career Development Awards and the Rosenthal Family Award from the AACR. He succeeds Robert E. Wittes, MD, who announced in August 2011 his intention to step down at the end of this year, after serving for a decade as Physician-in-Chief.

■

As Physician-in-Chief, Dr. Carey is responsible for the clinical operations of the N.C. Cancer Hospital and will work with Shelley Earp, MD, Director of UNC Lineberger and UNC Cancer Care to coordinate care of cancer patients throughout the UNC Health Care System. More than 135,000 patients with cancer are served each year by UNC Health Care through inpatient and outpatient clinics. “Dr. Carey is recognized internationally as one of the world’s most thoughtful clinician investigators. Her mastery of cancer biology and genetics and their application to improving patients’ lives sets her apart. This type of interdisciplinary leadership combined with her consummate clinical skills, will provide remarkable direction as the division prepares for the new era of cancer care,” said Dr. Earp.

Career Background Dr. Carey is the principal investi-

gator on multiple clinical trials conducted at UNC and across the nation. She co-leads the UNC Breast Cancer SPORE (Special Programs of Research Excellence) grant and is a nationally respected breast cancer expert who has been appointed to the National Cancer Institute (NCI) Committee that reviews and approves all of the NCI breast cancer trials. UNC Lineberger currently offers more than 225 clinical trials of the latest treatments developed at UNC or available through affiliation with national clinical trials groups. Dr. Carey earned her undergraduate degree in Biology and Art History from Wellesley College. She completed her medical degree at Johns Hopkins University, was a resident on the Hopkins Osler service in Internal Medicine, then a fellow in Medical Oncology. She earned an advanced degree in Clinical Investigations at the Johns Hopkins School of Public Health in 1998.

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Levine Cancer Institute Opens New Research and Administrative Headquarters

arolinas HealthCare System's Levine Cancer Institute recently announced the opening of its research and administrative headquarters on the campus of CHS's Carolinas Medical Center in Charlotte, North Carolina. The development of the Institute and the building was made possible by a $20 million gift from the Leon Levine Foundation. The building features six stories with more than 171,000 square feet of space. It also houses nine cancer clinics, teleconference space, infusion therapy, palliative care and a phase I clinical trials unit which will support the administration of novel therapies. "The opening of the building is symbolic of the entire Levine Cancer Institute network being fully functioning, for the advancement of patient care across the Carolinas," said Institute President Derek Raghavan, MD, PhD. For more information, visit www.levinecancerinstitute.org.

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ASCOPost.com | OCTOBER 15, 2012

PAGE 103

Announcements

Einstein-Montefiore Scientists Awarded NCI Grants to Study ‘Provocative Questions’ in Cancer Research

wo research teams at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, the University Hospital for Einstein, have each been awarded grants from the National Cancer Institute (NCI) as part of their “Provocative Questions” program. The innovative effort is designed to ignite investigations into 24 promising but neglected or unexplored areas of research. Answering the questions would dramatically enhance ongoing efforts to prevent, treat and cure the disease.

phenomenon, which they call “tissueselective tumorigenesis.” The model they’ll be using in their study is a rare condition that results in human cancer called multiple endocrine

neoplasia type 1 (MEN1). This inherited cancer results from a mutation in the MEN1 gene. Since MEN1 is a tumorsuppressor gene, mutations in this gene permit tumors to occur. People with this

cancer have a mutated MEN1 gene in every cell of their body, yet their tumors occur only in their endocrine glands (most often the parathyroid glands, the pancontinued on page 104

All of your

Oncology News...

Shared Resources The Einstein-Montefiore grants—2 of only 57 given nationwide and only five in New York City, and totaling more than $3 million over the next 5 years— are aimed at determining why cancer arises in certain tissues and how the disease spreads. Grant recipients are Steven Libutti, MD, Richard Kitsis, MD, John Condeelis, PhD, Sumanta Goswami, PhD, and Maja Oktay, MD, PhD. Both research teams will leverage the shared resources and unique assets of the two institutions to tackle their research projects, tapping into the clinical opportunities at Montefiore Einstein Center for Cancer Care and the advanced technical resources at the Albert Einstein Cancer Center and the Gruss Lipper Biophotonics Center.

Steven Libutti, MD

...at your

Fingertips Now Available: The ASCO Post iPad App

Richard Kitsis, MD

‘Tissue-selective Tumorigenesis’ The first grant, awarded to Drs. Libutti and Kitsis, will investigate why certain mutations promote cancer in some tissues of the body but not in others. The researchers will try to identify the factors responsible for this

• Complete issues of The ASCO Post • Oncology News Feed – updated throughout the day • Analysis and opinions from the experts you trust

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The ASCO Post | OCTOBER 15, 2012

PAGE 104

Patient’s Corner

Starting Over after Cancer Treatment

Having breast cancer has affected my health and cost me my job, but I’m still optimistic about my future. By Paula Tamboli, as told to Jo Cavallo

hen bloody discharge started oozing from the nipple on my left breast, I knew instinctively that it was serious. Although I was just 43, having lost two aunts to breast cancer, I knew my family history increased my risk for developing the disease. So when I saw my gynecologist for an exam, I was shocked that he dismissed my symptoms and family history and said I was too young to have breast cancer. I don’t know if the fact that I didn’t have health insurance played a role in his decision not to order a diagnostic test, but I left his office feeling truly frightened and confused about what to do next. A friend suggested that I try Planned Parenthood, and a doctor there immediately sent me for a mammogram and a tissue biopsy. The initial diagnosis was stage II invasive ductal carcinoma. Planned Parenthood helped me get into Social Security’s Supplemental Security Income Program and Medicaid, and I was able to get treatment. My oncologist recommended a lumpectomy, followed by chemotherapy and radiation therapy, but I wanted a mastectomy to get rid of my cancerous breast. My cancer was so aggressive, by the time I had the surgery in August 2010, just 1 month after my di-

Einstein-Montefiore Awarded NCI Grants continued from page 103

creas, and the pituitary gland) and their duodenum (small intestine). The goal of this study is to discover why. The researchers will take advantage of unique mouse models they developed and the fact that MEN1 tumors form only in the portion of the pancreas that produces insulin and other hormones and never in the “nonendocrine” part of the organ. Therefore, part of their research will involve comparing the two types of pancreatic tissue, looking for differences in gene expression. Dr. Libutti is Director of the Montefiore Einstein Center for Cancer Care, Associate Director of Clinical Services at Albert Einstein Cancer Center, Professor of Surgery and of Genetics at Einstein, and Vice Chair of Surgery at Einstein and Montefiore. Dr. Kitsis holds

agnosis, the pathology report showed that the tumor had grown to more than 5 cm and that the cancer had spread to six lymph nodes under my arm. I was reclassified at stage III.

Combatting Treatment Side Effects After a 12-week regimen of docetaxel, doxorubicin, and cyclo-

surgery, I had to quit my job as a home health aide, and I’m still so fatigued, some days it’s difficult for me to get out of bed. Despite these issues, I’ve gone back to school to get training in medical coding and billing and, hopefully, I’ll be able to get back into the workforce soon. I’m looking forward to being a member of the working public again,

My cancer is incurable, and I know that I’ll probably need additional therapy at some point. The thought of having to once again navigate through a complicated health-care system as well as deal with physicians who are not always helpful is daunting. —Paula Tamboli

phosphamide and 25 rounds of adjuvant radiation therapy, the side effects have taken their toll. I was thrown into early menopause, and I have severe neuropathy in my hands and feet. I lost my hair, and the radiation therapy has left my skin burned and in constant pain. My left arm is so weak from the

but I worry that companies will be reluctant to hire someone with my health history. Maintaining insurance coverage is also a concern. Once I start earning a salary again and can get off Medicaid, I don’t know if I’ll be able to get private insurance either through my employ-

the Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease and is Professor of Medicine and of Cell Biology and the Director of the Wilf Family Cardiovascular Research Institute at Einstein.

invading blood vessels and that these “intravasation-competent” cancer cells have distinct gene expression profiles. The proportion of such tumor cells and the genes they express would determine whether a breast tumor metastasizes or not. The goal of the research is to develop a human intravasation “signature” that will predict whether a breast cancer tumor is destined to metastasize. Identifying this signature will help to reveal targets for antimetastatic therapies. Such therapies are urgently needed to decrease the morbidity and mortality associated with breast cancer. Dr. Condeelis is Professor and Cochair of Anatomy and Structural Biology, Co-director of the Gruss Lipper Biophotonics Center, leader of the program in tumor microenvironment and metastasis in the Albert Einstein Cancer Center, and holder of the Ju-

Biology of Metastasis The second team of grant recipients, consisting of Drs. Condeelis, Goswami, and Oktay, will focus on developing new approaches to investigating the biology of metastasis. Using human breast cancer cells obtained from tumors of patients treated at Montefiore Einstein Center for Cancer Care, the scientists will focus on intravasation—the crucial step in which tumor cells invade blood vessels and are then carried to distant sites where they become seeded in new tissues. The researchers have hypothesized that different breast tumors contain varying proportions of cells capable of

er or on the open market. I’ve been warned that health insurance can cost between $900 and $1,000 a month, and that’s if I could even find a company to insure me.

Looking toward the Future My cancer is incurable, and I know that I’ll probably need additional therapy at some point. The thought of having to once again navigate through a complicated health-care system as well as deal with physicians who are not always helpful is daunting. Having cancer is scary. I wish more of my doctors could have shown me compassion and answered my questions instead of telling me that they knew what was best for me and ignoring or discounting my complaints about treatment side effects. I wish I could have felt in partnership with my medical team instead of feeling like a burden. And I wish I could be cured of my breast cancer or at least have it turned into a chronic disease that I can live with for many years. Maybe that will be possible. For now, I’m not looking too far into the future. I just take life 1 day at a time.

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Paula Tamboli lives in Montvale, New Jersey.

dith and Burton P. Resnick Chair in Translational Research at Einstein. Dr. Goswami is Assistant Professor of Anatomy and Structural Biology at Einstein and Associate Professor of Biology at Yeshiva University. Dr. Oktay is Associate Professor of Pathology (Clinical) at Einstein and Attending Physician, Pathology at Montefiore.

Grant Details The MEN1 grant (CA170911) is for $1.7 million over 5 years; the metastasis grant (CA170507) totals $1.4�� million over 4 years. The preliminary work for the MEN1 grant was funded by a gift from Linda and Earle Altman to Dr. Libutti. The preliminary data that made the metastasis grant possible were obtained from a gift from the Dempsey Family to the Albert Einstein Cancer Center that was awarded to Dr. Oktay in the fall of 2011.

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Announcing ASCO’s

SympoSium

November 30-December 1, 2012 Manchester Grand Hyatt San Diego, California

rs october 24, 2012 11:59 pm EDT Housing & Early Registration Deadline

lity Ma t t e

Quality Care

This new ASCO Symposium will bring together top leaders in the field to share strategies and methods for measuring and improving the quality of cancer care. Through a dynamic program featuring didactic lectures, panel discussions, and abstract presentations, the Symposium will promote innovation and strategic planning in the expanding fields of oncology outcomes and health services research. Educational Sessions • Payer Perspectives: Does Value Mean Quality? • Models that Work across the Spectrum • IT Interventions to Improve Quality • Reengineering Your Practice to Deliver Quality and Value • Much more!

Register by October 24 for best rates. Visit quality2012.asco.org This live activity has been approved for AMA PRA Category 1 Credit™.

The ASCO Post | OCTOBER 15, 2012

PAGE 106

In the News Genitourinary Oncology

Link Found between Aspirin and Reduced Risk of Death Due to Prostate Cancer 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.

ver the past few weeks, Stanley L. Liauw, MD, Associate Professor, Department of Radiation and Cellular Oncology at the University of Chicago, has received a lot of emails from men with prostate cancer “who are wondering whether they should take aspirin,” Dr. Liauw said. These men are contacting Dr. Liauw because he is the corresponding author of a study finding a “very strong association” between use of aspirin and reduced risk of death due to prostate cancer. The study was published in the Journal of Clinical Oncology ( JCO).1

tegic Urologic Research Endeavor (CaPSURE) database was used to investigate whether anticoagulant therapy was associated with prostate cancer–specific mortality among men with localized adenocarcinoma of the prostate treated with radical prostatectomy or radiotherapy (brachytherapy, external-beam radiation, or a combination of the two). Among 5,955 men meeting these criteria, 2,175 (37%) were receiving anticoagulants (warfarin, clopidogrel [Plavix], enoxaparin, and/or aspirin). “After a median follow-up of 70 months, risk of prostate cancer–specific mortality was significantly lower in the anticoagulant group compared with the non-anticoagulant group (3% vs 8% at 10 years, P < .01),” according to the study report. “Analysis by type of anticoagulant medication suggested that the prostate cancer–specific mortality reduction was primarily associated with aspirin,” the authors added. “In multivariable analysis, use of aspirin was significantly associated with improved prostate cancer–specific mortality, independently of other prognostic factors.”

Subgroup Findings

Stanley L. Liauw, MD

Risk-Benefit Considerations “The study did find a very strong association in aspirin users having a reduced chance of prostate cancer failure, but the type of the analysis done probably isn’t strong enough to make a recommendation formally for men with prostate cancer to start taking aspirin,” Dr. Liauw said in an interview with The ASCO Post. “What we found was as association in looking at a large registry of men in a database, but this doesn’t really speak to the balance of the risks and benefits and it also doesn’t imply causality,” he continued. “We really need a trial to answer whether the benefits outweigh the risks.” Those risks include hemorrhagic stroke and gastrointestinal bleed. (For more information on risks, see sidebar, “Expect Questions from Your Patients.”) The Cancer of the Prostate Stra-

A subgroup analysis by clinical risk category found “the reduction in prostate cancer–specific mortality was most prominent among patients with high-risk disease who have the highest risk of developing metastases.” In this subgroup, the 10-year prostate cancer–specific mortality was 4% for men taking anticoagulants vs 19% for those not taking anticoagulants (P < .01). High-risk disease was defined using National Comprehensive Cancer Network (NCCN) guidelines. “That means men who had clinical T3 disease, or Gleason 8 to 10 cancers cancers, or a prostate-specific antigen level of 20 ng/mL or higher,” Dr. Liauw explained. “Men with intermediate-risk disease had a modest difference in prostate cancer–specific mortality with anticoagulant use (3% vs 6%, P = .01). The difference was not statistically significant in low-risk patients (10-year prostate cancer–specific mortality of 2% vs 4%, P = .12),” the authors reported.

Expect Questions from Patients

recently reported study finding that anticoagulants and particularly aspirin were associated with a reduced risk of prostate cancer–specific mortality1 has the potential to generate a lot of questions because of the large number of patients potentially affected. As the study’s corresponding author, Stanley L. Liauw, MD, noted, “Prostate cancer is the most common cancer among men in the United States, and aspirin is one of the most commonly used medicines, especially in an elderly population, which is predisposed toward having prostate cancer.” Dr. Liauw is Associate Professor, Department of Radiation and Cellular Oncology at the University of Chicago “We are excited about the outcome and the possibilities, but we can’t really say that the evidence is strong enough to say that men with prostate cancer should start taking aspirin,” Dr. Liauw told The ASCO Post. “You worry about people overinterpreting the strength of the data,” and based on that, start taking aspirin. “We know that aspirin is pretty safe—it’s used by so many people,” Dr. Liauw said, but there are risks of bleeding, including hemorrhagic stroke and gastrointestinal bleed. He cited a meta-analysis published in The Lancet in 2009 that showed that low-dose aspirin taken for primary or secondary prevention of vascular disease increased the risk of major gastrointestinal and extracranial bleeds from 0.07% to 0.10% per year.2 “So, overall, although risk is pretty low, it is still elevated with low-dose aspirin,” Dr. Liauw stated.

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

References 1. Choe KS, Cowan JE, Chan JM, et al: Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol. August 27, 2012 (early release online). 2. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, et al: Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual data from randomized trials. Lancet 373:18491860, 2009.

Men who took anticoagulants also had a significantly lower risk of disease recurrence and bone metastases. The benefit from anticoagulants extended to patients in both the radical prostatectomy and radiotherapy groups.

Conflicting Results “Our findings corroborate and strengthen the hypothesis that aspirin may have chemopreventive and antineoplastic effects,” the authors concluded. They also acknowledged, however, that findings from other studies of aspirin and other anticoagulants have been conflicting and inconclusive, possibly due to the heterogeneity in cancer types and stages. Another study released early online by JCO at the same time as the aspirin and prostate cancer study “suggests that use of aspirin, other NSAIDs, and acetaminophen is not importantly as-

sociated with the risk of postmenopausal breast cancer, either overall or by specific subtype.”2 A recently published analysis of daily aspirin use and overall cancer mortality See Page 110 among 100,139 men and women with no history of cancer in the Cancer Prevention Study II Nutrition Cohort found that current daily aspirin use “was associated with modestly lower overall cancer mortality.3

Dose and Duration Not Addressed The prostate cancer study did not address in detail the dosage, duration, and timing of aspirin or other anticoagulants. Patients reported their use of medications at study entry and at apcontinued on page 109

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS.

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib

Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7

months (95% CI: 6.3, 8.6) [43% longer median PFS]

0.8 0.7

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.4, 3.0) All responses were partial responses per RECIST criteria INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3, in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

0.6 0.5 0.4 0.3

sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers. The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST. Please see brief summary on the following pages.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU471611

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS 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 clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, 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. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

June 2012

ASCOPost.com | OCTOBER 15, 2012

PAGE 109

In the News

Aspirin and Prostate Cancer Death continued from page 106

proximately 1-year intervals and were classified as “ever users” or “never users.” Users likely included those who took adult doses of aspirin occasionally or frequently for pain reduction as well as those who took smaller doses for primary prevention of cardiovascular disease. “So it is probably a heterogeneous group,” Dr. Liauw said. “Despite the fact that people may have taken aspirin ever single day or more sporadically after they were treated for prostate cancer, it is interesting to note that there was still a strong association with prostate cancer mortality,” he commented. “The optimal usage of aspirin as well as the potential toxicity should be addressed in a prospective study,” the authors noted in their report. “We are exploring the feasibility of doing such a trial,” Dr. Liauw said. “It will take a lot of work and patience. There are many details to be ironed out, and there are challenges to doing a randomized study. For example, in this group you can see that a lot of men were already on aspirin. We would only be able to recruit patients who are not on aspirin. Then we would probably have to double-blind the

study and apply a placebo, and that might impose challenges on men who want to go on aspirin later for cardiovascular reasons. I think it could probably be worked out, but the discussion is very preliminary right now.”

Looking for the ‘Next Big Sensitizer’ Dr. Liauw explained that the recently reported study was conducted “as

“Once we had those data collected, we decided to look at the disease outcomes because of the evidence suggesting that anticoagulants may have an anticancer effect. In doing that, we found an association. We were pretty surprised at the magnitude of the benefit, which is similar to what is shown in this paper.” Following the initial study with anticoagulants, Kevin S. Choe, MD, of

The optimal usage of aspirin as well as the potential toxicity should be addressed in a prospective study… We are exploring the feasibility of doing such a trial — Stanley L. Liauw, MD

an offshoot” of a study to determine the risk of bleeding in patients who received radiation treatment for prostate cancer. “One of the issues with radiation for prostate cancer is that it can damage the bladder and rectal tissue around the prostate. We try to use planning parameters to spare those tissues, but in people who are on anticoagulants, the risks of bleeding are higher,” Dr. Liauw noted. “Therefore, we initially conducted a study to try to quantify the elevated risk of bleeding,” he continued.

The University of Texas Southwestern Medical Center in Dallas and the lead author of the current study, expanded the analysis, using the CaPSURE database to include a larger number of men, and not only men treated with radiation, but also men treated with surgery. “In doing the analysis with the CaPSURE database, we tried to separate out the nonaspirin anticoagulants and then compared them to the aspirin anticoagulants. It seemed then that the benefit came from aspirin use rather than from warfarin and clopidogrel

and other anticoagulants,” Dr. Liauw said. “When we did the analysis as a radiation-only group, we didn’t know whether this effect was related to radiation sensitization or something else. As radiation oncologists, we are always interested in finding the next big sensitizer,” Dr. Liauw said. “If it were the case that this was a sensitizer, we might have seen an effect in the radiation group, but not in the surgery group. Our findings suggest that there is another mechanism of action, or at least it is a sensitizer plus it has other effects.”

■

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

References 1. Choe KS, Cowan JE, Chan JM, et al: Aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol. August 27, 2012 (early release online). 2. Zhang X, Smith-Warner SA, Collins LC, et al: Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. J Clin Oncol. August 27, 2012 (early release online). 3. Jacobs EJ, Newton CC, Gapstur SM, et al: Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst 104:1208-1217, 2012.

The ASCO Post Wants to Hear from You 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

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The ASCO Post | OCTOBER 15, 2012

PAGE 110

Journal Spotlight

Radiotherapy Not Helpful in Early-stage Parotid Acinic Cell Cancer By Charlotte Bath

djuvant radiotherapy for patients with parotid acinic cell carcinoma “does not confer a therapeutic advantage in low-grade and early-stage tumors if resection is complete,” but the benefit for patients with higher-grade or higherstage disease is uncertain because there were few of these patients included in the retrospective database review, the reviewers reported in the Archives of Otolaryngology Head and Neck Surgery. 1 The authors noted that acinic cell carcinoma is a rare parotid gland See Page 110 tumor accounting for approximately 10% of salivary gland tumors. “Given this tumor’s rare incidence, treatment paradigms used for other tumors have been applied to [acinic cell carcinoma]. These recommendations include the use of radiotherapy because parotid cancers overall demonstrate a potential survival advantage with adjuvant radiotherapy, despite studies of this particular tumor showing a lack of radiosensitivity,” the investigators stated. Using the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, the researchers identified all cases of acinic cell carcinoma of the parotid gland from 1998 to 2007. This totaled 1,241 patients, including 969 patients that had sufficient data for inclusion. “To our knowledge, this retrospective study of

20 years of SEER data is the largest analysis of this type of tumor,” the investigators reported.

Key Results Comparing surgery alone to surgery plus radiotherapy, the researchers found “no statistical difference in overall survival” when stratifying for stage. There were, however, few stage

enough patients who were treated with and without [radiotherapy] to distinguish a difference, we cannot definitively determine whether adjuvant external beam [radiotherapy] for these uncommon high-stage or high-grade variants holds clinical utility,” the authors wrote. However, they continued, this study shows that adjuvant radiotherapy offers

Reducing the number of treatment modalities would reduce patient inconvenience, risk of posttherapy complications, and treatment cost. IV tumors (occurring among 21 patients receiving surgery only and 58 patients receiving surgery plus radiation). When data were stratified by tumor grade, surgery alone demonstrated a survival advantage over surgery plus radiotherapy for grade 1 tumors, the researchers reported, “but this survival difference disappeared when further stratifying for tumor stage.” There was no statistical difference in overall survival between the surgery alone and surgery plus radiotherapy for patients with grade 2 and 3 tumors. “However, there were only 35 grade 3 tumors with sufficient data for survival analysis,” the investigators noted.

no survival advantage in acinic cell carcinoma for tumor stage I/II and tumor grade 1/2, despite widespread use of this approach. “These results should be considered during

■

Reference 1. Andreoli MT, Andreoli SM, Shrime MG, et al: Radiotherapy in parotid acinic cell carcinoma: Does it have an impact on survival? Arch Otolaryngol Head Neck Surg 138:463-466, 2012.

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.

Study Implications “Owing to the more aggressive course of these stage III, stage IV, and grade 3 tumors, and the lack of

patient counseling and treatment planning and may spare these patients unnecessary radiation,” the authors wrote. “Considering the potentially serious complications of parotid [radiotherapy], … recognizing tumors that lack sensitivity to [radiotherapy] may reduce the need for ineffective adjuvant therapy,” the researchers commented. “Reducing the number of treatment modalities would reduce patient inconvenience, risk of posttherapy complications, and treatment cost.”

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PAGE 111

Best of ASCO® Annual Meeting ‘12 Supportive Care

2012 Is ‘Banner Year’ for Research on Symptom Management By Susan London

he year 2012 was “a banner year for symptom management,” according to Debra L. Barton, RN, PhD, of the Mayo Clinic, Rochester, Minnesota, who presented data on patient and survivor care at the Best of ASCO San Diego meeting. “I have been doing symptom management for about 20 years, and it seems like way too often we have way too many negative studies, and I’d be saying, here is a litany of things that don’t help patients,” she said. “However, this year, we actually have positive studies.”

Agents for Managing Peripheral Neuropathy The Cancer and Leukemia Group B (CALGB) 170601 phase III trial tested duloxetine (Cymbalta)—an antidepressant that blocks serotonin and norepinephrine reuptake—for treatment of painful chemotherapy-induced peripheral neurop-

Key Patient and Survivor Care Findings Presented at Best of ASCO® ’12 ■■ Duloxetine reduces pain in patients with chemotherapy-induced

peripheral neuropathy. Acetyl-L-carnitine is ineffective for prevention and potentially harmful.

■■ Ginseng reduces cancer-related fatigue and appears safe. ■■ Women starting letrozole might be less likely to have worsening Debra L. Barton, RN, PhD

athy.1 In a randomized, crossover design, 220 patients with painful neuropathy from paclitaxel or oxaliplatin were given duloxetine with the dose gradually titrated upward or placebo for 5 weeks, and then switched to the alternative treatment. Mean scores were lower with duloxetine vs placebo for both pain (P = .003; effect size, 0.513) and its interference with daily activities = .015). Patients were more like(P �� ly to have any pain reduction and at

Is Vitamin D Supplementation Ready for Prime Time?

he VITAL study generated a host of questions about vitamin D among ASCO Annual Meeting attendees, including whether the study’s findings are ready for clinical application, according to Debra L. Barton, RN, PhD, of the Mayo Clinic, Rochester, Minnesota, speaking at the Best of ASCO San Diego meeting. There are reasons to think about vitamin D beyond preventing musculoskeletal pain, such as maintaining bone health and preventing falls, she contended. “We already know that a lot of patients treated for breast cancer are deficient in vitamin D based on other, descriptive studies.… And we know that older folks are at risk for decreases in vitamin D anyway. So you put all those things together … and it is worth taking a look at.” Additionally, it is imperative that women be able to stay on aromatase inhibitors to minimize their risk of breast cancer recurrence. “If you have a patient who is just not getting good enough relief from her symptoms, and she is thinking about quitting her letrozole or whatever aromatase inhibitor she’s on, it’s certainly worth it, based on this study” to consider supplementation.

Dosage Considerations “I was extremely disappointed when the Institute of Medicine revisited the vitamin D supplementation data and didn’t really change their recommendation,” Dr. Barton commented. “Now, 400 IU of vitamin D per day only changes vitamin D levels by 2 to 3 ng/mL, so if somebody is deficient, it’s not going to do much. It really takes about a 1,000 IU per day to change the level by about 10 ng/mL, which is getting somewhere.” Clearly, the 30,000 IU weekly used in the trial was a very large dose, she acknowledged. “That’s why it would be really nice for the VITAL investigators to repeat that study in a cooperative group setting and give us some very good, clear guidelines on when that’s necessary, or when we should be doing that,” she concluded. “We are obviously not going to do that for everybody right now. But I will say, I encourage everybody I speak with to take 1,000 IU a day.”

■

musculoskeletal symptoms if given vitamin D3.

■■ Compared with standard care, early palliative care is associated with better outcomes.

least a 30% reduction on duloxetine. Rates of adverse events were generally similar with the drug and placebo, although dropouts were more common with the former. Duloxetine is “the very first pharmacologic agent found effective for reducing pain from peripheral neuropathy,” Dr. Barton noted. “Is this practice-changing? You betcha!” she commented. “It is important to titrate dose up for tolerability, beginning at 30 mg and then going up to 60�� mg,” she recommended. Two weeks at that target dose should be sufficient to tell if the drug is working. The randomized Southwest Oncology Group (SWOG) S0715 trial tested use of acetyl-L-carnitine—a derivative of endogenous L-carnitine marketed as a weight loss product— for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy in 409 patients.2 Relative to the placebo group, acetyl-Lcarnitine recipients were more likely to have a worsening of neurologic symptoms from baseline at 24 weeks (38% vs 28%, HR = 1.50, P = .05) and to develop grade 3/4 peripheral neuropathy (4% vs < 1%). “It’s very important to inform patients to avoid acetyl carnitine for prevention of chemotherapy-induced neuropathy,” Dr. Barton contended. “Granted, you could say you can’t necessarily apply these results to other neurotoxic agents. But given that in every single outcome, neuropathy got worse, I sure wouldn’t encourage patients to take this for non–paclitaxelinduced neuropathy.”

Ginseng for Cancer-related Fatigue The North Central Cancer Treatment Group (NCCTG) phase III

N07C2 trial assessed use of ginseng, which has anti-inflammatory and cortisol-regulating properties, to improve cancer-related fatigue in 339 oncology patients.3 Patients were randomized to Wisconsin ginseng (Panax quinquefolius) in ground root form or placebo for 8 weeks. The ginseng group had a greater change in the 100-point Multidimensional Fatigue Symptom Inventory from baseline at 4 weeks (14.4 vs 8.2 points, P = .07) and 8 weeks (20.0 vs 10.3, P = .003). Rates of toxicity due to any cause did not differ. The fatiguereducing benefit of ginseng was greater among the 49% of patients still in active cancer treatment. “Admittedly, the impact on fatigue was not large,” Dr. Barton commented. “Since ginseng is not an FDA-regulated product, there is a lot of variability in over-the-counter products, and patients need to be counseled about this,” she said. “I do think it is reasonable to try ginseng for fatigue, particularly since there are no other pharmacologic agents that are helpful for this,” she continued. “It’s important not to use extracts, because extracts can be made with methanol, which actually causes characteristics of the ginseng to be estrogenic.”

Aromatase Inhibitor–related Musculoskeletal Events The randomized VITAL trial assessed use of vitamin D3 to prevent worsening of musculoskeletal symptoms in 160 women with breast cancer starting adjuvant therapy with the aromatase inhibitor letrozole who had suboptimal levels of 25-hydroxyvitamin D (≤ 40 ng/mL).4 They were assigned to vitamin D3 at 30,000 IU weekly or placebo weekly, each added continued on page 115

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

736 355

657 306

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufficiency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. 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 clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 Muscle discomfort3 26.2 3.0 General disorders 4 26.7 1.9 Edema Vascular disorders Hot flush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5 5.9 1.4 Fractures Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3

Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1

4.1 2.3

18.3

0.8

16.8 6.9

0.3 0.3

13.5 3.3

1.3 0

7.1 2.5

0.5 0

7.6

5.1 4.1

0.3 0

2.3

4.6 2.8 1.0

1.0 0 0.3

ZYTIGA® (abiraterone acetate) Tablets 4 5 6

Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044

Issued: May 2012

08Z12155B

ASCOPost.com | OCTOBER 15, 2012

PAGE 115

Best of ASCO® Annual Meeting ‘12 Symptom Management continued from page 111

to the recommended dietary allowances of calcium and vitamin D. Patients in the vitamin D group had a lower incidence of any musculoskeletal event defined as worsening pain, worsening disability, and/or discontinuation of letrozole. The benefit differed when worsening pain was assessed with a simple descriptive pain scale (37% vs 51%, P = .069) or with the Brief Pain Inventory (38% vs 61%, P = .008). “I think their biggest limitation was their primary endpoint. It’s really hard for me to get See Page 110 my arms around what benefit or lack of benefit women receive in either of those two groups, especially when you consider those three criteria—they are very different in my mind,” Dr. Barton commented. “It’s also a little concerning to me that the significance of the primary endpoint changed according to what measure was used,” she added. “Is this practice-changing? Not quite yet,” she said (see sidebar on page 111, “Is Vitamin D Supplementation Ready for Prime Time?”). “The main reason why it wouldn’t universally be practice-changing is because of that outcome weakness.”

Early Palliative Care Improves Outcomes In a cluster-randomized trial at a tertiary center, investigators assigned oncology clinics to use standard care (patients seen by palliative care team on request with follow-up as required) or early palliative care (patients seen by palliative care team within a month

with monthly follow-up) for adults with metastatic cancer.5 Analyses were based on 233 patients receiving standard care and 228 patients in the intervention group, most of whom were getting active chemotherapy. Relative to patients in the standard care group, patients in the palliative care group had more favorable mean changes at 4 months in scores for quality of life (P = .007), symptom control (P = .05), and satisfaction with care (P < .001). “It’s important that the extra clinic visits from the palliative care team were not overly burdensome. A vast

Comprehensive Centers and Racial Disparities A cross-sectional study in Los Angeles compared outcomes between adolescents and young adults treated at three National Cancer Institute– designated Comprehensive Cancer Centers (NCICCCs) with those of their counterparts treated at all other centers.7 Among the 10,602 patients studied, just 9% received care at an NCICCC. The 10-year rate of overall survival was better for patients treated in these centers than for their peers treated at others (83% vs 81%, P = .02). “Although it’s statistically

It’s important to think about what [palliative care] characteristics you can provide or integrate into your care for your patients to improve upon outcomes. — Debra L. Barton, RN, PhD

majority of patients got four palliative care visits or less, so we aren’t talking about a whole bunch of extra work,” Dr. Barton maintained. This study “further supports the mounting data out there on the benefits of early palliative care,” she contended. “So if your institution has a palliative care team, refer. If your institution is thinking about creating a palliative care team, help. And if you don’t have a palliative care team or palliative care providers, it’s important to think about what characteristics you can provide or integrate into your care for your patients to improve upon outcomes such as we have seen in these early palliative care studies,” she recommended, pointing to ASCO’s provisional clinical opinion endorsing early palliative care and outlining its key elements.6

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“Case Studies in Rare Lymphomas” moderated by James O. Armitage, MD, and featuring the following experts: Joseph M. Connors, MD, on Hodgkin lymphoma following failure of autologous stem cell transplant Andreas Engert, MD, on relapsed and refractory Hodgkin lymphoma Steven M. Horwitz, MD, on systemic anaplastic large cell lymphoma following failure of one or more combination regimens View this special webcast at

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significant because there were more than 10,000 people, it’s a difference of only 2% to 3%,” Dr. Barton noted. Compared with white youth, black and Hispanic youth fared significantly more poorly at non-NCICCCs, but not at NCICCCs. Race/ethnicity, socioeconomic status, and health insurance status all influenced access to care at NCICCCs (P < .001 for each), with higher proportions of white, better-off, and privately insured youth obtaining care in these centers. “The investigators say future directions [in research] are to understand the barriers to care at a Comprehensive Cancer Center,” Dr. Barton said. “I actually would like to know what characteristics account for better survival at Comprehensive Cancer Centers so that we can spread them around to all cancer centers, so that

everybody everywhere has good outcomes.”

■

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

References 1. Lavoie Smith EM, Pang H, Cirrincione C, et al: CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN). 2012 ASCO Annual Meeting. Abstract CRA9013. Presented June 5, 2012. 2. Hershman DL, Unger JM, Crew KD, et al: SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy. 2012 ASCO Annual Meeting. Abstract 9018. Presented June 4, 2012. 3. Barton DL, Liu H, Dakhil SR, et al: Phase III evaluation of American ginseng (Panax quinquefolius) to improve cancerrelated fatigue: NCCTG trial N07C2. 2012 ASCO Annual Meeting. Abstract 9001. Presented June 4, 2012. 4. Khan QJ, Kimler BF, Reddy PS, et al: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial. 2012 ASCO Annual Meeting. Abstract 9000. Presented June 4, 2012. 5. Zimmermann C, Swami N, Rodin G, et al: Cluster-randomized trial of early palliative care for patients with metastatic cancer. 2012 ASCO Annual Meeting. Abstract 9003. Presented June 4, 2012. 6. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012. 7. Wolfson JA, Sun C-L, Kim H, et al: Evaluation of the effect of care at NCI comprehensive cancer centers (NCICCCs) on disparities in outcome within adolescents and young adults (AYAs) with cancer. 2012 ASCO Annual Meeting. Abstract 9512. Presented June 4, 2012.

No Availaw ble

The ASCO Post | OCTOBER 15, 2012

PAGE 116

FDA Update

Paclitaxel Poliglumex Gets Orphan Drug Designation for Glioblastoma Multiforme

ell Therapeutics, Inc, recently announced that paclitaxel poliglumex (OPAXIO) has been granted orphan drug designation by the FDA for the treatment of glioblastoma

multiforme. Orphan designation was granted based on preliminary activity seen from phase II results of paclitaxel poliglumex when added to standard therapy (temozolomide

plus radiation). In this study, progression-free and overall survival was encouraging among patients with glioblastoma multiforme, including patients

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

whose tumors expressed unmethylated MGMT (O[6]-methylguanineDNA methyltransferase). Current standard therapy is less effective in patients with tumors that have unmethylated MGMT, an important DNA repair enzyme. A randomized trial is now underway for patients with glioblastoma multiforme with unmethylated MGMT, comparing standard temozolomide and radiation to OPAXIO and radiation.

Randomized Trial “The current randomized trial is based on the encouraging results previously demonstrated with OPAXIO and radiation in patients with newly diagnosed malignant brain cancer and specifically targets GBM patients with a genomic marker, unmethylated MGMT, who are less likely to benefit from the current standard of care TMZ and radiation,” stated Howard Safran, MD, Medical Director of the Brown University Oncology Group, Providence, Rhode Island.

Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

About the Author

The study is expected to enroll up to 120 patients. Patients in the OPAXIO arm will receive OPAXIO once every week plus radiotherapy for 6 weeks. Patients in the temozolomide arm will receive daily oral temozolomide plus radiotherapy for 6 weeks. After completion of initial therapy, both arms will receive maintenance temozolomide on days 1 to 5 and then every 28 days for up to 12 cycles for a total of 48 weeks.

■

Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

FDA Update For more on newly approved drugs and indications, see pages 2 and 69-73 in this issue of The ASCO Post

ASCOPost.com | OCTOBER 15, 2012

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Anthracycline/Trastuzumab Treatment Linked to Increased Risk of Heart Failure, Cardiomyopathy A population-based, retrospective cohort study of 12,500 women diagnosed with incident, invasive breast cancer found that anthracycline and trastuzumab (Herceptin) were associated with increased risk of heart failure and/or cardiomyopathy. “Compared with women who received no chemotherapy, our hazard ratios suggest a fourfold increase in the risk of [heart failure/cardiomyopathy] among women who received trastuzumab alone and a sevenfold increase in the risk of [heart failure/cardiomyopathy] for those who received anthracycline plus trastuzumab,” the researchers reported in the Journal of the National Cancer Institute. The women, who ranged in age from 22 to 99, had been enrolled at least 12 months before diagnosis in one of See Page 110 eight Cancer Research Network health systems. Most (46.5%) received no chemotherapy, 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Study Data The cumulative incidence of heart failure/cardiomyopathy increased over 5 years, rising from 1.2% in year 1 to 4.3% at 5 years in women receiving anthracycline only, from 3.6% to 12.1% in women receiving trastuzumab only, from 6.2% to 20.1% in women receiving anthracycline plus trastuzumab, from 1.3% to 4.5%% in women receiving other chemotherapy, and from 0.9% to 3.1% in women who received no chemotherapy. “The risk of incident [heart failure/cardiomyopathy] among all women was statistically significantly increased for anthracycline alone [adjusted HR = 1.40, 95% CI = 1.11–1.76], trastuzumab without anthracycline [HR = 4.12, 95% CI = 2.30–7.42], anthracycline plus

trastuzumab [HR = 7.19, 95% CI = 5.00–10.35], and other chemotherapy [HR = 1.49, 95% CI = 1.25–1.77], compared with no chemotherapy,” the authors reported. The women who received anthracycline alone or anthracycline plus trastuzumab were younger and had fewer comorbidities. “These results suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice,” the investigators noted. “Consistent with previous studies, the majority of women 65 years or older in our population received no chemotherapy. Among older women who did receive chemotherapy, most received agents other than anthracycline or trastuzumab,” the researchers continued. “This population-based observational study complements findings from clinical trials on cancer treatment safety,” the authors concluded.

tinib were well tolerated with no unexpected adverse events,” researchers reported in the Journal of Clinical Oncology. “Both maintenance strategies resulted in a nonsignificant improvement in overall survival,” the investigators stated. Patients who received the predefined second-line therapy with pemetrexed or who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 “appeared to derive greater benefit,” the authors added. Exploratory subgroup analysis suggested gemcitabine maintenance therapy might have an overall survival benefit for patients with an objective response to induction chemotherapy, but not those who had stable disease.

LUNG CANCER

A “new finding” that long-term survivors of childhood Hodgkin lymphoma may be at risk for neurocognitive impairment and central nervous system (CNS) pathology arose from a study among 62 patients treated with either high-dose (≥ 30 Gy) thoracic radiation or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline therapy. “Compared with national ageadjusted norms, [Hodgkin lymphoma] survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007),” the researchers reported in the Journal of Clinical Oncology. Previous research had shown that Hodgkin lymphoma survivors treated with radiation were at risk for cardiac and pulmonary morbidity related to dose of mantle-field radiation exposure. Patients were randomly selected from a cohort of more than 400 adult survivors of childhood Hodgkin lymphoma in the St. Jude Lifetime Cohort Study. Mean age of the study

Bowles EJ, et al: J Natl Cancer Inst 104:1293-1305, 2012.

Reduced Disease Progression in Patients with Continued Gemcitabine Maintenance or Erlotinib Switch Maintenance A phase III study showed that progression-free survival was significantly prolonged with continuation maintenance with gemcitabine or switch maintenance with erlotinib (Tarceva) compared with observation in patients with advanced non– small cell lung cancer (NSCLC) who received first-line treatment with cisplatin/gemcitabine. Median progression-free survival was 1.9 months for observation patients vs 3.8 months for patients receiving gemcitabine and 2.9 months for those receiving erlotinib. The improved duration in disease control was consistent irrespective of gender, smoking status, and response to induction therapy.

Trial Design The study involved 464 patients with stage IIIB/IV NSCLC who were enrolled in 73 centers in France and did not have tumor progression after four cycles of cisplatin-gemcitabine. “Maintenance gemcitabine and erlo-

Pérol M, et al: J Clin Oncol. September 4, 2012 (early release online).

SURVIVORSHIP Long-term Survivors of Hodgkin Lymphoma May Have Increased Risk of Neurocognitive Impairment

participants was 42.2 years, and the mean age at diagnosis was 15.1 years. As part of the study, the patients had neurocognitive evaluations, brain MRI, echocardiograms, pulmonary function tests, and physical examinations. “Survivors demonstrated high rates of neuropathology on structural brain imaging, with leukoencephalopathy identified in 53% of survivors,” the investigators noted. “CNS pathology was associated with neurocognitive impairment.”

Study Implications Compared to survivors of CNS tumors and acute lymphoblastic leukemia, Hodgkin lymphoma survivors are more likely to experience neurocognitive impairment at a later stage of development, “a factor that will reduce the impact on core academic skills because most survivors will have completed their primary and secondary education before the delayed onset of cardiac and pulmonary morbidity. Thus, neurocognitive impairment in [Hodgkin lymphoma] is likely to have a negative impact during postsecondary education and employment, as was demonstrated in this study. This pattern may account for the fact that the neurocognitive deficits in long-term survivors of [Hodgkin lymphoma] have gone unreported before this study.” The authors noted that “given the delayed onset, preventive interventions should be considered. Primary prevention has begun with the transition from mantle-field radiation to modern protocols that incorporate combined-modality therapy with reduced dose, limited-volume radiation, and polychemotherapy (eg, anthracyclines and bleomycin). Although this approach may reduce long-term morbidity, significant risk is likely to remain, given the known associations between anthracyclines and cardiac toxicity and bleomycin and pulmonary toxicity. Longitudinal follow-up of such cohorts will be important to fully evaluate long-term neurocognitive and CNS pathology outcomes.”

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Krull KR, et al: J Clin Oncol. September 4, 2012 (early release online). In the Literature is compiled and written for The ASCO Post by Charlotte Bath

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The ASCO Post | OCTOBER 15, 2012

Letters to the Editor

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004

compared to 0.8% 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).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Individualism in Clinical Decision-making

found a statement by Dr. Peter Bach in the August 15, 2012, issue of The ASCO Post (in the article, “As Conflicting Guidelines Evolve, Experts Continue to Debate the Merits of Cancer Screening”) very troubling. To wit: There’s a cognitive dissonance between the practice of evidence-based medicine and how we train doctors to make clinical decisions. And they are fundamentally different. I think that this is going to be a generational change. As we shift to doctors who are brought up more on the ability to evaluate and utilize comparative effectiveness research when making clinical decisions, rather than relying on personal experience or intuition, the use of cancer screening tests will become more strategic.

In my opinion, this is an example of utopian statism, as it assumes that all cancer-screening issues will be solved through centralized research and that there will be no outliers who require an individualized approach to their problem. Not only is this statement chilling coming from someone who helps set national policy, it is an insult to all us “old and in the way guys” who work hard to critically evaluate data and do the best thing for our patients on an individual basis. This statement is anti-doctor (let’s be honest, anti–profit-making doctor), and it is anti-individual, which by definition is against the Hippocratic oath. Furthermore, we have instituted these sorts of solutions over the past 45 years (diagnosis-related groups, current readmission policies, etc), and they have led to a dysfunctional system with high demand, high costs, clinician shortages, and generalized dysfunction, where the individual can get lost if not for doctors with “personal

experience” and “intuition.” I would like Dr. Bach and his colleagues to at least consider that not all patients fit nicely into a bell-shaped curve and that experience and acumen (the so-called art of medicine) is what keeps our current system from being a topSee Page 110 down bureaucracy. While I applaud attempts to standardize decision-making in oncology (I use NCCN guidelines frequently), I do not feel that patients should be put through a cookbook approach to their care. In my opinion, a true patient’s bill of rights would state that guidelines, best practices, evidence-based medicine, pathways, etc, can only be used by doctors and patients to make complex medical decisions and cannot be used by the government and the insurance industry to ration care. I can assure you that no member of Congress nor Dr. Bach would want to be treated in such a sterile one-size-fits-all manner. We need new and innovative ideas that empower patients and doctors, and not policymakers in Washington, DC (or even from Memorial SloanKettering). Costs cannot be restrained nor compassion maintained through centralized planning that further insulates individual patients from their care. The 20th century was proof enough of the failure of collectivism. Why are physicians like Dr. Bach attempting to reinvent what has already bankrupted the system both financially and morally while claiming to be saving it? —Jonathan Schwartz, MD Oncologist Tucson, Arizona

Statement of Ownership, Management and Circulation

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1. Publication Title: The ASCO Post. 2. ISSN 2154-3283; Publication Number 6885. 3. Filing Date: 9/25/12. 4. Issue Frequency: Semi-Monthly except Monthly in February, April, June, August, October and December. 5. Number of Issues Published Annually: 18. 6. Annual Subscription Price: Individual Print $235. 7. Complete Mailing Address of Known Office of Publication: Harborside Press, LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 8. Complete Mailing Address of Headquarters or General Business Office of Publisher: Harborside Press, LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 9. Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Editor: Publisher – John A. Gentile Jr, Harborside Press, LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423; Editor – James O. Armitage, MD, Harborside Press, LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423; Managing Editor – Cara Glynn, Harborside Press, LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 10. Owner: Full Name – Harborside Press, LLC; John A. Gentile, Jr. (Principal), Anthony Cutrone (Principal), Conor Lynch (Principal). Complete Mailing Address: 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 11. Known Bondholders, Mortgagees, and Other Security Holders Owning or Holding 1 Percent or More of Total Amount of Bonds, Mortgages or Other Securities: None. 13. Publication Title: The ASCO Post. 14. Issue Date for Circulation Data Below: September 15, 2012. 15. Extent and Nature of Circulation. Average No Copies Each Issue During Preceding 12 Months: a) Total Number of Copies 27,490. b) Legitimate Paid and/or Requested Distribtuion (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541 14,224. c) Total Paid and/or Requested Circulation 14,224. d) Nonrequested Distribtuion (By Mail and Outside the Mail) (1) 13,075. (4) Nonrequested Copies Distributed Outside the Mail 49. e) Total Nonrequested Distribution 13,124. f) Total Distribution 27,348. g) Copies not Distributed 142. h) Total 27,490. i) Percent Paid and/ or Requested Circulation 52%. 15. Extent and Nature of Circulation. No Copies of Single Issue Published Nearest to Filing Date: a) Total Number of Copies 27,576. b) Legitimate Paid and/or Requested Distribtuion (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541 14,504. c) Total Paid and/or Requested Circulation 14,504. d) Nonrequested Distribution (By Mail and Outside the Mail) (1) 12,863. e) Total Nonrequested Distribution 12,863. f) Total Distribution 27,367. g) Copies not Distributed 209. h) Total 27,576. i) Percent Paid and/or Requested Circulation 53%. 16. Publication of Statement of Ownership for a Requester Publication is required and will be printed in the October 15 2012 issue of this publication. 17. Signature of Publisher: John A. Gentile, Jr. Date 9/25/12.

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), 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), Adverse Reactions (6.1).] 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 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 (14.3).] 1.4 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 2.6%

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%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of 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 encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. 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 dipstick reading should undergo further assessment with a 24‑hour urine collection. 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).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 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).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] 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 4198 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who 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. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. 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,

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AVASTIN® (bevacizumab)

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 5, 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).]

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. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control))

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

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 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, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. 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 (VTE). 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. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] 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

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central 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.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring 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 (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%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1– 4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 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 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); 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) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any 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 cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with 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 (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

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Congestive Heart Failure (CHF) 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 metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 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. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

7% 5% 5%

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Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, 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 7). [See Warnings and Precautions (5.8).]

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Arm 2 IFL+ + Avastin (n = 392) 87%

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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 5, 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%.

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Arm 1 IFL+ + Placebo (n = 396) 74%

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. 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 Precautions (5.8).]

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3). Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for 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 (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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. 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.

Most common adverse events

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm 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 mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage 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%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) 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%)

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious 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, 2.6%) — Proteinuria (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%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is not approved for use in combination with irinotecan.

†

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.