NOVEMBER 2012, VOL 5, NO 10 The Oncology Nurse by The Oncology Nurse

NOvEMBER 2012

www.TheOncologyNurse.com

vOL 5, NO 10

LUNG CANCER

CANCER CENTER PROFILE

John Theurer Cancer Center Gold Standard of Care By Alice Goodman

Crizotinib Superior to Chemotherapy in First Head-to-Head Comparison PROFILE 1007 Was a Headliner at ESMO By Audrey Andrews

n a phase 3 head-to-head comparison trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib proved more effective than standard chemotherapy with pemetrexed or docetaxel as a second-line treatment for non–small cell lung cancer (NSCLC) patients with the ALK genetic abnormality. The results of the global PROFILE

1007 trial were reported by Alice Shaw, MD, of Massachusetts General Hospital in Boston, at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1 Rearrangements of the ALK gene are found in about 5% of all NSCLC. In previous studies, crizotinib was shown to Continued on page 11

BREAST CANCER Left to right: Andrew Pecora, MD, FACP, CPE; Kevin Barga, RN, BSN, CCRP, clinical trial manager; Mary Ann Libby, clerical supervisor; Melinda Weber, RN, APN, advanced practice nurse manager; Eileen Beysel, RN, BSN, OCN, oncology nurse navigator; Jeannie Jones, executive administrative assistant; Joan Monaghan, RN, MS, APN, supervisor psychosocial team; William Benham, patient navigator; Bonnie LoGiudice, executive administrative secretary; Rebecca Hirsch, MS, RD, therapeutic dietitian; and James Wittig, MD, chief, Skin and Sarcoma Division—Cutaneous Malignancy Program.

Weight Gain After Breast Cancer Treatment Linked to Recurrence By Caroline Helwick

Photo from John Theurer Cancer Center.

he mission of the John Theurer Cancer Center is to deliver extraordinary care that is multidisciplinary, personalized, innovative, and at the appropriate cost with superior outcomes to the most satisfied patients. That’s a tall order, but it seems that the center is fulfilling its mission. The John Theurer Cancer Center at Hackensack University Medical Center in New Jersey was ranked as one of the top 50 Best Hospitals for cancer, according to U.S. News & World Report. It is the highest-ranked cancer center in New Jersey with this designation. Within its 14 specialized cancer divisions, world-class physicians, nurses, and scientists have harnessed the newest technologies

arly breast cancer patients who gain weight after treatment are at increased risk for breast cancer recurrence, according to an Italian study presented at the European Society for Medical Oncology 2012 Congress, held in Vienna, Austria. Saverio Cinieri, MD, of the Hospital Perrino in Brindisi, Italy, presented the results of the single-center study of 520 patients treated between 1990 and 2012

and followed for a median of 13 years.1 Being overweight at the time of early breast cancer diagnosis has been linked to poorer survival in most studies, and some evidence suggests that women who gain weight after diagnosis are at increased risk of cancer recurrence and death. “But most previous studies on this topic have relied on retrospective chart reviews,” Cinieri said. “So the aim of this Continued on page 7

Continued on page 15

INSIDE

CONFERENCE NEWS

Highlights from the European Society for Medical Oncology By Alice Goodman

ncology experts from all over the globe arrived in Vienna, Austria, to attend the European Society for Medical Oncology (ESMO) 2012 Congress. Attendance broke all records, with 16,394 delegates, many of them from outside of

Side effect ManageMent

Medical certificationS

Europe: 1116 from the United States, 539 from Japan, 479 from China, 292 from Argentina, and 258 from Brazil. Following are some highlights from the Presidential Symposia and papers proffered at the meeting.

...

Preventing Chemotherapy-Induced Peripheral Neuropathy Remains Elusive .....

Medical Certification by Healthcare Professionals for Patients With a History of Cancer caregiving . . . . . . . . . . . . . . . . . . . . . .

We Faced the Disease Together

coMpliMentary ce . . . . . . . . . . . .

Considerations in Multiple Myeloma—Ask the Experts: Retreatment Settings neuroendocrine tuMorS . . . .

Advances in the Treatment of Pancreatic Neuroendocrine Tumors noteworthy nuMberS . . . . . . . .

Family Caregivers

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Oxaliplatin safely and effectively. See full prescribing information for Oxaliplatin.

Docetaxel Injection, USP

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WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) • Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4) • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) • Severe fluid retention may occur despite dexamethasone (5.5) CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection, USP (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda. gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

Oxaliplatin Injection, solution for intravenous use Initial U.S. Approval: 2002 WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning. Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1) INDICATIONS AND USAGE Oxaliplatin is a platinum-based drug used in combination with infusional 5-fluorouracil /leucovorin, which is indicated for: • adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. • treatment of advanced colorectal cancer. (1) •

• • •

• •

CONTRAINDICATIONS Known allergy to Oxaliplatin or other platinum compounds. (4, 5.1) WARNINGS AND PRECAUTIONS Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension. (5.1) Neuropathy: Reduce the dose or discontinue Oxaliplatin if necessary. (5.2) Pulmonary Toxicity: May need to discontinue Oxaliplatin until interstitial lung disease or pulmonary fibrosis are excluded. (5.3) Hepatotoxicity: Monitor liver function tests. (5.4) Pregnancy. Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.5, 8.1)

ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling. Revised: 04/2011

ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

Manufactured by: Zydus Hospira Oncology Private Ltd. Ahmedabad 382-213, Gujarat, India. for Hospira, Inc. Lake Forest, IL 60045 USA Product of India

Manufactured by: Hospira Australia Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA

Editorial Board EDITOR-IN-CHIEF

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

MSN, CRNP

CS, FNP

Avid Education Partners, LLC Sharpsburg, MD

Mayo Clinic Rochester, MN

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Elizabeth Bilotti,

Shannon Hazen, RN, BSN, OCN

Melinda Oberleitner, RN,

Karla Wilson, RN,

RN, MSN, APRN, BC, OCN

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Beth Faiman, PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP

Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Jayshree Shah, NP

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

NP, MSN, ACNP-C

AOCN, LNC

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

MSN, NP, ANP-BC, AOCNP

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

Fox Chase Cancer Center Philadelphia, PA

BSN, OCN

PhD, RN, AOCN

MSN, FNP-C, CPON

Pharmacy John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Wendy DiSalvo,

Sandra E. Kurtin,

Lori Stover, RN,

DNP, APRN, AOCN

RN, MS, AOCN, ANP-C

BSN

Patient Advocate Peg Ford

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance Coronado, CA

Joseph D. Tariman, PhD,

Social Work Carolyn Messner,

APRN, BC

DSW, MSW, LCSW-R, BCD

Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

Arizona Cancer Center Tucson, AZ

Ann McNeill, MSN, RN, NP-C, OCN

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Northwestern University Myeloma Program Chicago, IL

Constance Engelking, RN,

Kena C. Miller, RN, MSN, FNP

Jacqueline Marie Toia, RN, MS, DNP

MS, CNS, OCN

Roswell Park Cancer Institute Buffalo, NY

Northwestern University Myeloma Program Chicago, IL

The CHE Consulting Group, Inc. Mt. Kisco, NY

CancerCare New York, NY

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY

Amy Ford, RN,

Patricia Molinelli,

BSN, OCN

MS, RN, APN-C, AOCNS

Quintiles Dallas, TX

CS, ANP, AOCN

Isabell Castellano, RN

Somerset Medical Center Somerville, NJ

Saratoga, CA

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Sharon S. Gentry,

Ellen A. Neylon,

Connie Visovsky,

Jeanne Westphal, RN

RN, MSN, AOCN

MSN, FNP-BC, CCRP, OCN

RN, PhD, APRN

Meeker County Memorial Hospital Litchfield, MN

Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

Pamela Hallquist Viale, RN, MS,

NOvEMbER 2012 I vOL 5, NO 10

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

University of South Florida College of Nursing Tampa, FL

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V-10-0196

11/10

From the Editor

n this month’s issue of The Oncology Nurse-APN/PA (TON), we bring you the news from the European Society for Medical Oncology 2012 Con gress. Some of the most exciting news came from the update of the PROFILE 1007 trial, with results showing that crizotinib was more effective than standard chemotherapy with pemetrexed or doceBeth Faiman, PhD(c), MSN, APRN-BC, AOCN taxel as a second-line treatment Editor-in-Chief for non–small cell lung cancer. We also cover the latest treatment information about pancreatic neuroendocrine tumors, which, as one presenter noted, is “not a rare disease any longer.” With all the research news, it’s important to recognize

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Eric Iannaccone eric@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien

the role oncology nurses play in direct patient care and acknowledge that this care often goes beyond the strictly medical. We present an article from the Cancer Legal Resource Center that covers the basics of how healthcare professionals can provide documentation to certify their patients’ medical conditions. Patients confront many nonmedical situations that relate to their cancer diagnosis, including how to deal with employment and public benefits issues, and we as oncology nurses are often asked to provide guidance. Please read the article by Rich Devlin, where he tells us about the journey he and his wife made after her diagnosis of breast cancer. Oncology nurses regularly interact with family caregivers and we know how central they are to the well-being of patients. Noteworthy Numbers presents some of the statistics related to family caregivers. We want to hear from you. Please tell us what you want to see in TON. Contact us at editorial@greenhillhc.com. l

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1249 South River Road, Suite 202A Cranbury, NJ 08512 The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Nurse-APN/PA® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Nurse-APN/PA®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Nurse-APN/PA® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Nurse-APN/PA® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.

NOvEMbER 2012 I vOL 5, NO 10

Omacetaxine Mepesuccinate Approved to Treat CML The US Food and Drug Administration (FDA) has approved omacetaxine mepesuccinate subcutaneous injection (Synribo, Teva Pharmaceutical Industries) for the treatment of adult patients with chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Approval for omacetaxine mepesuccinate was granted on October 26, 2012. The FDA approval was based on the combined results of 2 open-label, single-arm trials that enrolled patients with CML in chronic phase or accelerated phase. Patients in the trials had received 2 or more prior TKIs, including imatinib. The end points for the studies were major cytogenetic response for chronic-phase CML and major hematologic response for accelerated-phase CML. For those with chronic-phase CML, major cytogenetic response was achieved in 18.4% of patients (median response duration of 12.5 months). For patients with accelerated-phase CML, 14.3% achieved major hematologic response (median response duration of 4.7 months). Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection-site reaction, pyrexia, infection, and lymphopenia were the most common (≥20%) grades 1 to 4 adverse drug reactions. Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia, and diarrhea were the most common (≥5%) grades 3 to 4 adverse drug reactions. Among the patients in the trials, 10 died within 30 days of the last omacetaxine mepesuccinate dose: 4 deaths were attributed to progressive disease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and 1 to unknown causes. Omacetaxine mepesuccinate was reviewed under the FDA’s accelerated approval 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. In addition, the FDA designated omacetaxine mepesuccinate as an orphan product because it is intended to treat a rare disease or condition. Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, stated that the approval of omacetaxine mepesuccinate “provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML.” He also noted that it “is the second drug approved to treat CML in the past two months.”

Expanded Labeling for Pemetrexed The FDA expanded the labeling of pemetrexed (Alimta, Eli Lilly and Company) to include the results of an additional trial evaluating its safety and efficacy for the initial treatment of patients with locally advanced or metastatic, nonsquamous, non‒small cell lung cancer followed by pemetrexed maintenance in patients with disease that has not progressed after 4 cycles of platinum and pemetrexed as first-line chemotherapy. The approval for expanded labeling was granted on October 17, 2012. The expanded labeling describes the results of a multicenter, randomized (2:1), double-blind, placebo-controlled trial that evaluated pemetrexed maintenance in patients with stage IIIB/IV nonsquamous, non‒small cell lung cancer whose initial treatment was 4 cycles of pemetrexed plus cisplatin. There were 539 patients randomized to receive 500 mg/m2 pemetrexed intravenously on day 1 of each 21-day cycle (359 patients) or matching placebo (180 patients). All patients had an ECOG performance status of 0 or 1 and had completed 4 cycles of pemetrexed plus cisplatin with a best response of stable disease, partial response, or complete response. Investigator-assessed progression-free survival (PFS) was significantly improved in patients randomized to receive pemetrexed maintenance, compared with those who received placebo. Median PFS was 4.1 months for patients in the pemetrexed arm and 2.8 months for patients receiving placebo. Overall survival, a secondary end point, also was significantly improved for patients receiving pemetrexed maintenance, with median survival time of 13.9 months, compared with 11.0 months for patients receiving placebo. Neutropenia, anemia, fatigue, nausea, vomiting, stomatitis, and edema were the most common (>5%) adverse events for patients in the pemetrexed arm. Anemia and neutropenia were the most common severe adverse reactions. Approximately 25% of patients receiving pemetrexed maintenance had treatment reduced or delayed because of toxicity. l

Sources http://www.fda.gov/Drugs/InformationOnDrugs/Approv edDrugs/ucm325990.htm http://www.fda.gov/NewsEvents/Newsroom/PressAnnou ncements/ucm325895.htm http://www.fda.gov/Drugs/InformationOnDrugs/Approved Drugs/ucm324239.htm

www.TheOncologyNurse.com

Breast Cancer Weight Gain After Breast Cancer... Continued from cover prospective observational single-center study was to determine whether weight at diagnosis and/or weight gain after early breast cancer treatment is associated with breast cancer recurrence.” Weight and body mass index (BMI) were recorded at baseline and 24 months after completion of treatment (radiotherapy and/or chemotherapy, but not endocrine therapy). Three categories of BMI were used: BMI <25 kg/m2 (lean), BMI 25-30 kg/m2 (overweight), and >30 kg/m2 (obese). Patients’ mean BMI at study entry was 26.8 and 24 months posttreatment was 27.7. Almost 60% of the patients were postmenopausal. The study documented recurrences in 194 patients. Weight at diagnosis was not associated with recurrences, the study found. In both the lean and overweight groups, 40% of patients had recurrences; in the obese group, 31% recurred. There was also no correlation between breast cancer recurrence and weight loss. This included moderate weight loss (<1 kg/m2), where 47% of women recurred, or greater weight loss (>1 kg/m2), where 31% recurred. “However, weight gain was rather significantly related to recurrences,” Cinieri reported. This was most striking for weight gain of more than 2 kg/m2, a group in which 48% of women had recurrences. In those with moderate gain (<2 kg/m2), 34% recurred. “Our findings show that early breast cancer patients do gain weight after treatment, and moderate or large weight gain postdiagnosis is significantly associated with an increased risk of breast cancer recurrence,” he said. “Medical oncologists should monitor weight carefully in their patients and offer intervention strategies to those who gain weight.” Abstract discussant Michael Baum, MD, of University College London in the United Kingdom, commented that “the weight of the evidence suggests that if you are overweight at diagnosis, the outcome is worse.” The current study did not find this, but did show that weight gain after treatment affects outcome. Therefore, the issue is not yet settled. Rowan Chlebowski, MD, of the University of California Los Angeles, who has conducted seminal studies on dietary and hormonal influences in breast cancer, added that the Women’s Intervention Nutrition Study, a randomized study he spearheaded,2 showed dietary fat to be significantly lower in a group that underwent an intervention program, and this was accompanied by an average

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6-pound weight loss. The intervention paid off in another way: relapses occurred in 9.8% of the dietary group, versus 12.4% of the control group, for a 24% statistically significant reduction in risk. Somewhat surprisingly, the result was most striking in the estrogen receptor–negative group, he said.

Baum agreed with the recommendation for intervention to prevent weight gain. “We must emphasize strongly to our patients that not gaining (or losing) weight after treatment is an important, and very resourceefficient, way to reduce the risk of recurrence, in addition to adjuvant therapy, of course,” he said. l

References 1. Fedele P, Nacci A, Lapolla A, et al. Analysis of correlation between weight at diagnosis, weight gain after breast cancer treatment and recurrence in women with early stage breast cancer (ebc). Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. Abstract 2480. 2. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst. 2006;98(24):17671776.

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NOvEMbER 2012 I vOL 5, NO 10

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). EfďŹ cacy relative to ďŹ rst-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function

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 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;Ą: 0.17, 0.43)

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC; HR=hazard ratio. â&#x20AC;Ą CI=confidence interval.

s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A RANDOMIZED OPEN LABEL PHASE TRIAL IN TREATMENT NAĂ&#x2022;VE PATIENTS WITH "INET STAGE " OR # 2AI STAGES ) )6 #,, WHO REQUIRED TREATMENT . s 42%!.$! IS ADMINISTERED WITH A CONVENIENT DOSING SCHEDULE n 4HE RECOMMENDED DOSE FOR 42%!.$! IS MG M2 ADMINISTERED INTRAVENOUSLY OVER MINUTES ON $AYS AND OF A DAY TREATMENT CYCLE UP TO CYCLES n )N THE PHASE TRIAL PATIENTS RECEIVED CHLORAMBUCIL AT A DOSE OF MG KG ORALLY ON $AYS AND N OF A DAY TREATMENT CYCLE UP TO CYCLES s )N THE PIVOTAL PHASE TRIAL THE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FREQUENCY â&#x2030;Ľ WERE PYREXIA NAUSEA AND VOMITING N 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ WERE ANEMIA THROMBOCYTOPENIA NEUTROPENIA LYMPHOPENIA AND LEUKOPENIA N Important Safety Information s 3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS TUMOR LYSIS SYNDROME SKIN REACTIONS INCLUDING 3*3 4%. OTHER MALIGNANCIES AND EXTRAVASATION HAVE BEEN ASSOCIATED WITH 42%!.$! 3OME REACTIONS SUCH AS MYELOSUPPRESSION INFECTIONS AND 3*3 4%. WHEN 42%!.$! WAS ADMINISTERED CONCOMITANTLY WITH ALLOPURINOL AND OTHER MEDICATIONS KNOWN TO CAUSE 3*3 4%. HAVE BEEN FATAL 0ATIENTS SHOULD BE MONITORED CLOSELY FOR THESE REACTIONS AND TREATED PROMPTLY IF ANY OCCUR s !DVERSE REACTIONS MAY REQUIRE INTERVENTIONS SUCH AS DECREASING THE DOSE OF 42%!.$! OR WITHHOLDING OR DELAYING TREATMENT s 42%!.$! IS CONTRAINDICATED IN PATIENTS WITH A KNOWN HYPERSENSITIVITY TO BENDAMUSTINE OR MANNITOL 7OMEN SHOULD BE ADVISED TO AVOID BECOMING PREGNANT WHILE USING 42%!.$! s 4HE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FOR #,, FREQUENCY â&#x2030;Ľ ARE PYREXIA NAUSEA AND VOMITING 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ 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.

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. 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 â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 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 naĂŻve 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 â&#x2030;Ľ 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

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 â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 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. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ 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 VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE 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 0.2â&#x20AC;&#x201C;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 BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM 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 (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°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 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°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. ÂŠ2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

Lung Cancer

induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase 3 study to directly compare the novel agent with standard chemotherapy. The study compared crizotinib with pemetrexed or docetaxel (by physician choice) in 347 patients with ALK-positive, stage IIIB/IV NSCLC who had already been treated with chemotherapy. Crizotinib was superior to standard single-agent chemotherapy in terms of response, progression-free survival (PFS), and quality of life in ALK-positive patients who progressed after firstline, platinum-based chemotherapy, Shaw reported. “These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC,” she maintained. Doubling in PFS At 12 months’ median follow-up, crizotinib prolonged median PFS to 7.7 months, compared with 3.0 months with chemotherapy, a highly significant 51% reduction in the risk of progression (P <.0001). By type of chemotherapy, median PFS was 4.2 months with pemetrexed (P = .0004) and 2.6 months with docetaxel (P <.0001). The overall response rate was also significantly higher with crizotinib (65% vs 20%; P <.0001). All subgroups experienced a PFS benefit with crizotinib, with the greatest advantages seen in patients with nonadenoma histology (hazard ratio [HR], 0.12). Survival, Tolerability At this point, overall survival (OS) differences have not been observed, but the survival analysis is immature, with only 40% of events occurring. Also, 87% of chemotherapy-treated patients have crossed over to receive crizotinib upon progression, and this would dilute any OS differences, Shaw said. Median OS at this point is approximately 22 months in each arm. When adjusted for confounding by crossovers, there was still a 17% reduced risk of dying from the disease for patients who received ALK inhibitor, she pointed out. Side effects were more frequent with crizotinib, but Shaw pointed out that crizotinib-treated patients received an average of 11 cycles, compared with 4 with pemetrexed or docetaxel, which partly explains these differences. Toxicities with crizotinib are, however, distinct from those observed with chemotherapy, but are “generally tolerable and manageable,” she noted. The most common treatment-related adverse events with crizotinib were diar-

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Crizotinib Superior to Chemotherapy... Continued from cover “These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC.” —Alice Shaw, MD

rhea (60%), vision disturbance (60%), nausea (55%), and vomiting (47%), but few grade 3 or 4 toxicities were reported, except for elevated transaminases, which occurred in 16% of this arm. Patients receiving chemotherapy had more fatigue, alopecia, dyspnea, and rash. Six percent of crizotinib patients, compared with 10% of pemetrexed/ docetaxel patients, discontinued the trial due to treatment-related adverse events. Better Quality of Life With Crizotinib Patients on crizotinib also reported improved quality of life, compared with chemotherapy. “They reported greater improvement

from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with crizotinib,” Shaw said, “and all of these were statistically significant (P <.0001).” They also showed greater improvement from baseline in global quality of life (P <.0001). Furthermore, “time to deterioration in lung cancer symptoms” was significantly extended with crizotinib treatment, to 5.6 months, compared with 1.4 months with chemotherapy (HR, 0.54; P <.0001). Crizotinib “Changes the Natural History” of Lung Cancer Discussing the paper at the meeting, Jean-Charles Soria, MD, of the Institut

Gustave Roussy in Villejuif, France, noted that 2 months’ extended survival in advanced NSCLC is essentially “unheard of ” in the general population of NSCLC patients. “Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with a median OS now of 22 months, versus 9 months in the past,” he said, “and this is accomplished with very mild toxicity.” Even patients in the trial who initially received chemotherapy had a median OS of nearly 23 months “because they received crizotinib,” he added. Soria suggested that clinicians become familiar with the toxicity profile, which is quite distinct from chemotherapy, but is generally manageable with the exception of “some rare side effects you need to be aware of,” he told attendees. l Reference 1. Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. Abstract LBA1 PR.

SAVE THE DATE SECOND ANNUAL CONFERENCE

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma NOvEMbER 2012 I vOL 5, NO 10

The median age of patients in the VISTAâ&#x20AC;Ą trial was 71 years (range: 48-91).

LEARN MORE AT THE 2012 AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING AND EXPOSITION

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months†; 60.1-month median follow-up‡)

Approved for subcutaneous and IV administration§ VELCADE (bortezomib) Indication and Important Safety Information INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. *Melphalan+prednisone. † HR=0.695 (95% CI, 0.57-0.85); p<0.05. ‡ VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. § The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL).

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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 effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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Cancer Center Profile

John Theurer Cancer Center

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to serve the patients who come through its doors. The Oncology Nurse-APN/PA spoke with Melinda Weber, RN, APN, about what it is like to work at the John Theurer Cancer Center.

What are you excited about right now in the field of oncology? MW: I am very excited about valuebased medicine. We are providing the appropriate individualized gold standard of care that meets and exceeds all national standards, whether diagnostic or therapeutic, without the need for undue diagnostic studies or redundant, unwarranted interventions. This approach is critical, not only because of our current healthcare economy, but because of quality and ethical issues as well. I am also very enthusiastic about evidence-based practice and its applicability

to oncology. We have created evidencebased guidelines for toxicities and adverse events such as nausea/vomiting, diarrhea, and mucositis. We have developed written guidelines/order sets on a single page via NCI [National Cancer Institute] standards using the Common Terminology Criteria for Adverse Events to grade toxicities; provide an immediate teaching tool for patients about that toxicity; and suggest the immediate evidence-based gold standard intervention for that toxicity. We are working on building this 1-page tool into the electronic medical record for all patients who are treated at our center and throughout the entire medical center as well. This will enable any practitioner who is seeing that patient to access the entire record of toxicities and interventions for that patient.

What is the approach to treating patients at the John Theurer Cancer Center? MW: Our goal is to provide comprehensive, individualized extraordinary care for every patient. Throughout our 14 cancer divisions, we employ a multidisciplinary approach with medical oncologists, surgeons, nurse navigators, clinical nursing staff, advanced practice nursing team, patient navigators, other specialty physicians, social workers, and support staff. We offer complimentary yoga, exercise, and cooking classes. We have a librarian who provides complimentary literature searches for patients. We are committed

What inspired you to become an oncology nurse? MW: As a junior volunteer, I worked with a very young patient who was dying of metastatic pancreatic cancer. I was deeply touched by the level of compassion and dignity provided by the oncology nurses.

Photos from John Theurer Cancer Center.

What is your role at the John Theurer Cancer Center? Melinda Weber (MW): I am the advanced practice nurse manager. I wear many hats. First and foremost, my managerial responsibilities focus on collaboration with my immediate team of advanced practice nurses, educators, and nurse navigators. I also work “in the trenches” with my administrative, financial, ancillary, legal, pharmacy, radiation, laboratory, dietary, psychosocial, and physician team to achieve the best possible outcomes for our patients and the institution. This includes maintaining compliance with JCAHO [Joint Commission on Accreditation of Healthcare Organizations], ACS [American College of Surgeons], Magnet, and all national accrediting agency mandates and licensure requirements. Additionally, I maintain all day-today activities of the all-division–specific advanced practice nursing team, with emphasis on scheduling all areas for patient safety outcomes. I also cover the solid tumor division when needed as a “float” to act in a clinician capacity to ensure patient care. I am also the clinical advanced practice nurse for the Skin and Sarcoma Division and act as a direct patient caregiver for the division.

well. We follow NCCN [National Comprehensive Cancer Network] guidelines, and patients have access to evidencebased clinical care. For example, today my physician colleague and I consulted with a new patient with breast cancer and incidentally discovered a spot on her lung. Her pathology slides from a previous institution were reviewed the same day, with additional pathology markers ordered, and she was immediately referred to our lung cancer expert and pulmonary care expert. She received individualized patient education, and, after we obtained insurance authorization, she received her diagnostic scans the same day as her consult, and her plan of care was created.

to clinical research, including phase 1 trials, working today to provide tomorrow’s cures. We also have an active tumor bank of blood and tissue samples for personalized cancer therapy development. We have one of the nation’s largest blood and bone marrow transplant programs. We offer “TrueBeam”-specific radiosurgery, and TomoTherapy radiation, as well as da Vinci surgical robots.

How does your approach improve patient outcomes? MW: All of our physicians are boardcertified oncology experts. Each division actively participates in multidisciplinary tumor boards, presenting patients to determine the best plan of care. We are certified by ACS; JCAHO, including DSC [disease-specific care] certification for our Breast, Gynecology, Gastrointestinal, and Bone Marrow Transplant programs; and are Magnet certified as

Pushing Your Limits

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What advice would you give to nurses just entering the field? MW: Select the best baccalaureate and graduate nursing program you can find, and be sure you are in an environment that fosters love of learning. After nursing school you will continue to learn, because the field of cancer is constantly evolving, and what was considered the best care management 5 years ago has changed dramatically. Be sure to network with great colleagues. The Oncology Nursing Society is a guiding light for every oncology nurse and offers a bastion of opportunity for networking and also for certification. For me, the most important principles of oncology nursing are intelligence, diligence, grace, and humility. To be kind, respectful, and approachable to patients, their significant others, and our entire team is absolute. We need to be agents of change. Remember, a genuine smile goes a long way for someone with cancer. What would you be if you were not an oncology nurse? MW: A stand-up comedian. l

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NOvEMbER 2012 I vOL 5, NO 10

Conference News: ESMO Continued from cover

Bevacizumab Plus Chemotherapy Extends Survival in Platinum-Resistant Ovarian Cancer Adding bevacizumab to chemotherapy regimens improved response rates and progression-free survival (PFS) in patients with platinum-resistant recurrent ovarian cancer, according to an exploratory analysis of the phase 3 AURELIA trial (Abstract LBA26).1 The study design allowed treatment with 1 of 3 chemotherapy regimens (weekly paclitaxel, pegylated liposomal doxorubicin [PLD], or topotecan). Bevacizumab improved PFS in the overall analysis of the trial (pooling data from the 3 different regimens). Median PFS was 10.4 months for bevacizumab plus chemotherapy versus 3.9 months for chemotherapy alone.

Overall response rates were superior with the addition of bevacizumab, with the highest response rates observed in the weekly paclitaxel cohort.

sive disease occurred. Overall response rates (ORRs) were superior with the addition of bevacizumab, with the highest response rates observed in the weekly paclitaxel

cohort: 51.7% versus 28.8% for chemotherapy alone. ORR was 18.3% and 7.9%, respectively, for the PLD cohort and 22.8% and 3.3%, respectively, for the topotecan cohort.

No significant differences in toxicity were observed, with the exception of more peripheral neuropathy in the weekly paclitaxel cohort and more hand-foot syndrome in the PLD cohort.

CD30-directed therapy

CT SCANS confirmed responses in relapsed patients

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“Bevacizumab combined with chemotherapy should be considered a new standard option for platinum-resistant recurrent ovarian cancer,” stated lead author Andres M. Poveda, MD, Fundación Instituto Valenciano de Oncología, Valencia, Spain. The exploratory analysis looked at each of the 3 regimens and found that weekly paclitaxel plus bevacizumab had superior results. As stated above, median PFS was 10.4 months when bevacizumab was added to weekly paclitaxel versus 3.9 months for weekly paclitaxel alone. In the PLD cohort, median PFS was 5.4 months versus 3.4 months, respectively. In the topotecan cohort, median PFS was 5.8 months versus 2.1 months, respectively. AURELIA randomized 361 patients with platinum-resistant recurrent ovarian cancer treated with up to 2 prior anticancer regimens to chemotherapy alone or chemotherapy plus bevacizumab. The chemotherapy regimen was the investigator’s choice among the 3 regimens. Treatment was continued until unacceptable toxicity or progres-

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855.4SEAGEN (855.473.2436) SeaGenSecure.com

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104d

www.TheOncologyNurse.com

Conference News: ESMO Standard of Care for Soft Tissue Carcinoma Single-agent doxorubicin remains the standard of care as first-line treatment for unresectable or metastatic soft tissue sarcomas, according to results of a phase 3 trial conducted by EORTC and presented at the Presidential Symposium during the ESMO 2012

Congress (Abstract LBA7).2,3 This study is the latest in a string of trials attempting to improve outcomes with doxorubicin by adding other agents. Soft-tissue sarcomas are a heterogeneous group of tumors that are relatively rare. Overall incidence is approxi-

mately 5 per 100,000, said Winette van der Graaf, MD, University of Nijmegen, the Netherlands. The complexity of the tumor types and the relative rarity of the tumors have made it challenging to conduct clinical trials, she added.

This study compared doxorubicin to doxorubicin/ifosfamide plus growth factor support in 455 patients aged 18 to 60 years with locally advanced or metastatic soft tissue sarcomas. This study used a higher dose of ifosfamide Continued on page 18

After multiple failures,

single-agent response Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

sALCL: 86% ORR (95% CI: 77%-95%)

32%

40%

57%

29%

complete remission (95% CI: 23%-42%)1

partial remission (95% CI: 32%-49%)1

complete remission (95% CI: 44%-70%)1

partial remission (95% CI: 18%-41%)1

N = 102, 15-77 years (median: 31 years)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

Important Safety Information BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions: • Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions: ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions: Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

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NOvEMbER 2012 I vOL 5, NO 10

Conference News: ESMO Standard of Care for Soft Tissue Carcinoma Continued from page 17 (10 g/m2 over 4 days with growth factor support) than previous studies that evaluated this combination. Treatment was continued every 3 weeks for a maximum of 6 cycles or until the development of progressive disease. At a median follow-up of 56

months, there was no significant difference between the 2 treatment arms in overall survival (OS). Median OS was 14.3 months with the combination of doxorubicin/ifosfamide versus 12.8 months with doxorubicin alone; OS at 1 year was 60% and 51% for the 2

arms, respectively. Doxorubicin/ifosfamide achieved a longer progressionfree survival: 7.4 months versus 4.6 months, respectively (P = .003), and higher overall response rates—26.5% versus 13.6%, respectively—but this came with a host of increased toxicity.

Based on these results, van der Graaf said that single-agent doxorubicin should remain the standard of care in the palliative setting. The combination might be useful for selected patients 60 years and younger with large tumors.

T-DM1 Survival Benefit Confirmed in Advanced HER2+ Breast Cancer Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage

Drug interactions

These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Contraindications

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

Effect of other drugs on ADCETRIS CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Use in specific populations Pregnancy Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. 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. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers It is not known whether brentuximab vedotin 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 ADCETRIS 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 effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

NOvEMbER 2012 I vOL 5, NO 10

General dosing information

Dose modification Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150b

T-DM1, an antibody-drug conjugate linking trastuzumab to potent chemotherapy, extended survival, compared with lapatinib plus capecitabine, in advanced HER2+ breast cancer in an updated analysis from the phase 3 EMILIA trial (Abstract LBA12).4 At a median follow-up of about 20 months, T-DM1 reduced the risk of dying by 32%, with a 6-month difference favoring T-DM1. Median overall survival (OS) (death from any cause) was 30.9 months for T-DM1 versus 25.1 months for lapatinib plus capecitabine (P <.0001). Lead author Sunil Verma, MD, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada, predicted that T-DM1 would be an important treatment option for unresectable locally advanced or metastatic breast cancer. EMILIA was conducted at 213 sites in 26 countries. The study randomized 991 patients with HER2+ advanced breast cancer who had been treated with trastuzumab and a taxane in a 1:1 ratio to T-DM1 or lapatinib plus capecitabine. Final progression-free survival (PFS), presented earlier at the 2012 Annual Meeting of the American Society of Clinical Oncology, showed median PFS of 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine, a 35% reduction in the risk of progression favoring T-DM1 (P <.0001). The OS data presented at ESMO were from the second interim analysis, with a data cutoff of July 31, 2012, when more than 50% of targeted survival events had occurred. Final OS data are expected in 2014. Grade 3 or higher adverse events occurred more frequently with lapatinib plus capecitabine: 57% versus 41% for T-DM1. Patients in the T-DM1 arm had a higher incidence of thrombocytopenia and increased serum aminotransferase levels, whereas those treated with lapatinib plus capecitabine had higher rates of diarrhea, nausea, vomiting, and handfoot syndrome. The rates of cardiac dysfunction were very low and similar in both treatment arms.

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Conference News: ESMO Promising New Drug for Pancreatic Cancer The addition of an investigational hypoxia-targeted agent, TH-302, to gemcitabine improved overall survival (OS) versus gemcitabine alone in patients with advanced pancreatic cancer in an open-label phase 2b trial (Abstract 6660).5 The lead author of this trial, Mitesh Borad, MD, of the Mayo Clinic in Scottsdale, Arizona, said that the difference in OS was not significant, but that the trend was toward improved OS with the addition of TH-302. The drug will enter phase 3 trials shortly. Hypoxia is due to the disordered vasculature that is a hallmark of pancreatic cancers and other solid tumors. TH-302 selectively targets levels of hypoxia common in tumors but rare in normal tissues. When the drug enters cancer cells, it is converted to an active form, dibromo isophoramide mustard, a potent DNA

alkylator. The active form of the drug diffuses into the surrounding oxygenated regions of the tumor, exerting a bystander effect and killing more of the tumor than can be accounted for by the hypoxic fraction alone. Theoretically,

pancreatic cancer in a 1:1:1 ratio to receive either TH-302 240 mg/m2 plus gemcitabine; TH-302 340 mg/m2 plus gemcitabine; or gemcitabine alone. Treatment was given on days 1, 8, and 15 of a 28-day cycle.

The most common adverse events related to TH-302 included skin and mucosal toxicity, and myelosuppression.

this drug will produce less systemic toxicity than that caused by most cytotoxic agents. The study randomized 214 previously untreated patients with locally advanced, unresectable or metastatic

Median OS was 9.2 months with TH-302 340 mg/m2 plus gemcitabine; 8.7 months with TH-302 240 mg/m2 plus gemcitabine; and 6.9 months with gemcitabine alone. Borad said that these results were

consistent with an overall improvement in progression-free survival reported earlier this year. The trial was not designed to detect a statistically significant improvement in OS, and survival was confounded by crossover allowing patients in the gemcitabinealone arm to receive TH-302 plus gemcitabine at progression. The most common adverse events related to TH-302 included skin and mucosal toxicity, and myelosuppression. At the higher dose of TH-302, the rate of rash was 47% and stomatitis was 42%, but these events were mainly mild and moderate. Hematologic toxicity on the higher dose of TH-302 was much greater than that seen with gemcitabine alone: thrombocytopenia was 63% versus 11%, respectively, and neutropenia was 60% versus 30%, respectively. The dose of 340 mg/m2 will be taken forward in the phase 3 trial.

Initiative Improves Pain Control in Several Countries The major barriers to implementing adequate pain control for cancer patients on a global scale are restrictive government regulations and lack of access to supplies of morphine. Individual countries may lack morphine suppliers, and regulations in countries where morphine is available may prevent doctors from prescribing doses strong enough to alleviate pain and suffering. Although a number of international organizations have made strong statements hoping to address the problem of inadequate pain control in cancer patients, this has not led to widespread reform in allowing access to standard care, said Kathleen Foley, MD, Memorial Sloan-Kettering Cancer Center in New York City, at the ESMO 2012 Congress.6 These organizations include the Council of Europe, International Narcotics Control Board, United Nations, World Health Organization, Commission on Narcotic Drugs, and Human Rights Watch, among others. Foley believes that the problems are solvable, but mainly on a country-bycountry basis. She reported success stories for programs funded by the International Palliative Care Initiative. The model for these programs is to identify a “national champion” for cancer pain control within a country, perform a needs assessment, hold a stakeholders meeting, develop task forces, and then formulate a palliative care concept for that country. So far, this has been done in 20 countries. “We use international documents with symbolic language to guide this policy at a country level. These passionate cham-

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pions are driving this movement within each country,” she told listeners. In 2012, the International Palliative Care Initiative funded fellowships in India, Bangladesh, Sri Lanka, Albania, Kyrgyzstan, and Ukraine. Fellows work at the University of Wisconsin in Madison to learn the model described above. Success Stories In Romania, 35-year-old restrictive policies were changed. Now there are no limits on daily morphine dose or patient diagnosis. “Past policies were burdensome for patients, and physicians, and these are new beginnings,” Foley said.

“The solution is to identify champions at a country level and work with them.” —Kathleen Foley, MD

In Colombia, a new palliative care law was passed in 2009, and as a result of that law, each district of the country has 1 pharmacy that can provide opioids 24 hours a day. In Guatemala, efforts are ongoing to bring a morphine supply from Guatemala City to rural areas and to provide further education to legislators, physicians, and patients. “It’s hard to believe, but in 2012, the first injectable morphine prescription was written in Guatemala, at a hospital

where bone marrow transplant is available,” she said. In Nigeria, the government is now supportive of getting cancer patients access to pain control. In Serbia, a pain policy fellow is working with the government, which has adopted a pain policy stating that opioids are essential for pain relief. In Armenia, a policy is in place, but a supplier still needs to be found. “Uganda is a great success story,” she continued. The initiative created a strategic health plan, added liquid morphine to the essential list, adopted new guidelines, and authorized prescription by nurses. Seventy-nine providers have been trained. “We argue that no country should be allowed to enter the EU [European Union] unless they have opioids and a pain policy for cancer care. The solution is to identify champions at a country level and work with them. We can do this,” Foley said. l

survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs. capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Presented at: European Society for Medical Oncology Congress; October 1, 2012; Vienna, Austria. Abstract LBA12. 5. Borad M, Reddy S, Bahary N, et al. TH-302 + gemcitabine (G+T) vs gemcitabine (G) in patients with previously untreated advanced pancreatic cancer (PAC). Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Abstract 6660. 6. Foley K. A global policy approach to freedom from cancer pain. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria.

SECOND ANNUAL CONFERENCE

References 1. Poveda A, Selle F, Hilpert F, et al. Weekly paclitaxel, pegylated liposomal doxorubicin or topotecan ± bevacizumab in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort in the GCIG AURELIA randomised phase III trial. Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. Abstract LBA26. 2. van der Graaf W. Successful targeting of VEGFR in soft tissue sarcomas. Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. 3. van der Graaf WTA, Judson I, Verweij J, et al. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract LBA7. 4. Verma S, Miles D, Gianni L, et al. Updated overall

NOvEMbER 2012 I vOL 5, NO 10

Side Effect Management

Preventing Chemotherapy-Induced Peripheral Neuropathy Remains Elusive By Alice Goodman

dentifying agents that can prevent chemotherapy-induced peripheral neuropathy (CIPN) is a work in progress. Studies of some interventions

suggest modestly encouraging findings, but research on prevention has been hampered by a poor understanding of the different mechanisms of this toxic-

ity with the various chemotherapy agents that induce CIPN.1 “We still have much work to do. We are getting better at trial design, finding

“Quality care is everyone’s business.”

the best outcome measures, and including homogeneous populations in clinical trials. We need better preclinical models and better biomarkers,” stated Dawn Hershman, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center in New York City. “One problem in studying CIPN is that numerous anticancer drugs cause these symptoms, and the mechanism for each drug may be different. Our approach to treating one symptom can be problematic. We may miss signals that one drug works for one type of CIPN but not another,” she explained. Hershman reviewed completed clinical trials for the prevention of CIPN at the 2012 Multinational Association of Supportive Care in Cancer International Symposium.1 She emphasized that a drug that works for prevention may not be effective for treatment of CIPN, and vice versa.

“One problem in studying CIPN is that numerous anticancer drugs cause these symptoms, and the mechanism for each drug may be different.”

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

—Dawn Hershman, MD

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Vitamin E has been studied in neuropathic pain, based on positive pilot and phase 2 studies suggesting a neuroprotective effect when given with platinum or taxanes. However, a phase 3 placebo-controlled study found no effect of vitamin E 300 mg twice daily on any CIPN parameters in patients treated with adjuvant platinum or taxane therapy.2 “Think twice about recommending vitamin E to your patients for prevention of CIPN,” Hershman said. Calcium/magnesium has been studied in patients with colon cancer undergoing adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) therapy.3 The study of 104 patients had a primary end point of development of grade 2 or higher

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Side Effect Management

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weekly with paclitaxel chemotherapy in 50 patients with stage I to III breast cancer.7 Results of these studies are awaited, she said, but prevention of CIPN remains the ideal rather than the reality. l References 1. Hershman D. Cancer induced peripheral neuropathy: prevention. Presented at: 2012 Multinational Association of Supportive Care in Cancer International Symposium; June 28-30, 2012; New York, NY. 2. Kottschade LA, Sloan JA, Mazurczak MA, et al. The

use of vitamin E for the prevention of chemotherapyinduced peripheral neuropathy: results of a randomized phase III clinical trial. Support Cancer Care. 2011;19:1769-1777. 3. Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and magnesium for oxaliplatininduced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29:421-427. 4. Hershman DL, Unger JM, Crew KD, et al. SWOG S0715: randomized placebo-controlled trial of acetylL-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 9018.

5. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. 2007; 12:312-319. 6. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy or radiation therapy protectants. J Clin Oncol. 2009;27: 127-145. 7. Hershman DL. Acupuncture study for the prevention of taxane induced myalgias and neuropathy. Clinical Trials.gov Web site. http://clinicaltrials.gov/ct2/ show/NCT01163682?term=electroacupuncture& rank=31. Updated October 27, 2011. Accessed September 5, 2012.

INHIBIT ANDROGEN PRODUCTION

CIPN. The intervention appeared to be beneficial, but the study was closed prematurely because of concern that calcium/magnesium could decrease treatment efficacy; further analysis showed that this concern was false. “Even with a smaller sample size, there is a likely benefit of calcium/ magnesium in this setting, with a suggestion of significant improvement in objective and patient-reported outcomes,” she stated. Acetyl-L-carnitine is a supplement that improves neuropathy in patients with diabetes and HIV infection and is also reported to improve fatigue and cognition, with toxicity limited to mild nausea.1 Based on positive results of a small phase 2 trial showing improvement in sensory and motor neuropathy, the Southwest Oncology Group mounted a phase 3 trial in approximately 400 patients with breast cancer treated with taxanes.4 No effect of acetyl-L-carnitine was observed at 12 weeks, but at 24 weeks worsening neuropathy was observed in the group treated with the supplement. “This is a big surprise. After controlling for age and regimen, the odds ratio for worsening neuropathy was 1.57. This study shows that we have to be careful when we give agents to patients. Not everything we give is benign, and this is a good reason to study these agents,” Hershman said. Glutamine has also been studied in CIPN in a small trial of 86 patients with colon cancer and oxaliplatininduced peripheral neuropathy.5 The study found a reduction in grades 1 and 2 neuropathy as well as a significantly lower incidence of grades 3 and 4 neuropathy in the glutamine-treated group, according to patient-reported outcomes, but no difference in electrophysiological abnormalities with glutamine. Hershman commented that electrophysiologic exam may not be the right end point to study. With these equivocal results in a small trial, glutamine is not a strong recommendation. Although 4 clinical trials of amifostine conducted in patients treated with cisplatin found that pretreatment with amifostine reduced, prevented, or provided some protection against cumulative neurotoxicity, in the American Society of Clinical Oncology 2008 clinical practice guideline update, amifostine is not recommended for prevention of cisplatin- or paclitaxel-induced neuropathy due to insufficient data.6 Ongoing clinical trials of prevention of CIPN include phase 3, placebo-controlled trials of alpha lipoic acid and of erythropoietin. A separate 12-week, single-blind study at Hershman’s institution is looking at electroacupuncture given

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 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. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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NOvEMbER 2012 I vOL 5, NO 10

Medical Certifications

Medical Certification by Healthcare Professionals for Patients With a History of Cancer By Shawn Kravich, Esq Cancer Legal Resource Center, Los Angeles, California

ealthcare professionals (HCPs) are often asked to provide some form of documentation to help certify their patients’ medical conditions. To protect patient privacy, HIPAA (Health Insurance Portability and Accountability Act) significantly restricts both the type of information that can be disclosed and the categories of recipients that can receive it. However, there are numerous situations—in the context of employment rights or access to public benefits—in which disclosure of certain information may be necessary to help patients get access to protections and services to help them along the survivorship journey. Employment-related and public benefits–related certifications have two very different processes and potential

consequences, so it is important to keep both in mind when trying to help your patient navigate the system. Less Is More—When and How to Provide Medical Certification for Employment Matters In the context of certifying medical status for employees with cancer, there are two main occasions when an employer may request an employee’s medical information. However, even in those situations in which the employer is allowed to access certain information, the certification that you as an HCP provide can and should be limited. Under the Family and Medical Leave Act (FMLA) and the Americans with Disabilities Act (ADA), employers are allowed to get limited information about their employees’ med-

ical status when requesting leave or a reasonable accommodation, respectively. The FMLA gives certain employees working for covered employers (usually those with 50 or more employees) the right to take time off to care for themselves or family members with a serious health condition. Although the leave period is unpaid, and the law has very specific eligibility criteria, it is often very useful for people undergoing cancer treatment, because it gives 12 workweeks of job and health benefit protection. Any time an employee requests leave under the FMLA, an employer is allowed to ask for medical certification. The ADA prohibits employers (those with 15 or more employees) from discriminating against employees

Table The Differences in How and Whether to Report Information About Your Patients’ Medical Status

What documentation may an employer require a patient to get from HCPs?

FMLA

ADA

• Name, address, phone and fax numbers of the HCP • HCP’s type of practice/specialization • Approximate date the serious health condition began and how long it will probably last • Description of the serious health condition sufficient to support the need for leave (may include information on symptoms, doctor visits, medications, and other regimens of continuing treatment)

Employer may ask employee for documentation to prove that he or she has a disability under the ADA and needs the requested accommodation. The documentation is sufficient if it describes: 1) the nature, severity, and duration of the employee’s impairment; 2) the activities limited by the impairment; 3) the extent to which the employee’s ability to perform these activities is limited; and 4) why a reasonable accommodation is needed

Does the HCP have to disclose a specific diagnosis?

NO, as long as the documentation establishes a serious health condition sufficient to support the need for FMLA leave

NO, as long as documentation establishes that the employee has a “mental or physical impairment that substantially limits a major life activity” and needs a reasonable accommodation

Can an employer ask the HCP to provide complete medical records?

Is there a limitation on information YES, information in the certification YES, information must relate to the disability included in certification? must relate only to the serious health at issue and the need for accommodation condition related to the need for leave What type of HCP can provide certification?

Doctors, psychologists, dentists, optometrists, chiropractors, nurse practitioners, nurse-midwives, physician assistants, and clinical social workers

Doctors, psychologists, nurses, physical therapists, occupational therapists, speech therapists, vocational rehabilitation specialists, and licensed mental health professionals

Can the employer contact the HCP directly?

YES, but only to clarify handwriting, ensure that it is not a forgery, etc. Employers cannot ask for information beyond that on the certification form

MAYBE, but employers must have employee permission

Abbreviations: ADA, Americans with Disabilities Act; FMLA, Family and Medical Leave Act; HCP, healthcare professional.

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on the basis of disability, including cancer or a history of cancer in many cases. Under the ADA, employers are required to grant “reasonable accommodations” to qualified employees with disabilities to allow the employees to perform the essential functions of their job. Employers have to grant that accommodation unless doing so would be an undue hardship for the employer. When an employee makes a reasonable accommodation request, employers are allowed to require some kind of medical certification when the disability or need for accommodation is not known or obvious. In either case, if a patient is not able to provide this information to the employer, the employer can deny the leave or accommodation. However, where employment-related medical certifications are concerned, less is often more. Although many employers would never discriminate against an employee because of his or her medical history or cancer diagnosis, unfortunately some would. To ensure that all patients are protected against unnecessary discrimination, best practices dictate that HCPs should give just enough information to address the patients’ goals with the employer, but not give the employer too much information that may be used against the patient as an employee. The Table highlights the differences in how and whether to report information about your patients’ medical status. More Is More—When and How to Provide Medical Certification for Public Benefits Matters Whereas in the employment context HCPs need to balance the potential for discrimination by an employer against the ultimate goal of leave or accommodation for the employee, in the public benefits context, the more medical information you can provide for a patient the better. For example, public benefits–related medical certification is required under an application for Social Security Administration (SSA) benefits—including Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI)—or under Medicaid. For any of these programs, eligibility is determined using a governmental standard for “disability” that requires proof of some kind of medically determinable impairment. With that said, although more medical information

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Medical Certifications increases the chances of a benefits application going through, the governmental programs are concerned with facts, not opinion. Too often, HCPs see a patient presenting with a serious health condition and know that the patient has a disability. However, because the specific agency overseeing each application ultimately decides whether the patient is “disabled” by its own definition, HCPs should refrain from using con-

http://www.ssa.gov/disability/profession als/bluebook/AdultListings.htm) and use that language where appropriate. HCPs also should consider whether the patient has symptoms of more than one condition listed, particularly where the cancer diagnosis has had a negative effect on the patient’s mental health. For example, someone’s cancer might not be quite as advanced as the language requires for that condition, but when combined with

symptoms of depression or a mobility impairment, the person cannot work. Although a patient must be eligible under the programs’ other criteria, SSDI and SSI also offer a Compassionate Allowances program that expedites the application process for severe conditions that fall on the list (see http:// ssa.gov/compassionateallowances/con ditions.htm). Overall, the process for medical cer-

tification is relatively straightforward— just remember that keeping the patients’ best interests in mind means using discretion with the amount of information you as an HCP disclose when certifying the documents your patients provide. l For information about the Cancer Legal Resource Center, please visit www.cancerlegalresourcecenter.org.

HCPs should refrain from using conclusory language such as “the patient is disabled” in the certification and stick to providing as much supportive medical information as possible.

clusory language such as “the patient is disabled” in the certification and stick to providing as much supportive medical information as possible. HCPs should familiarize themselves with the language that the SSA uses in its listing of disabling conditions (see

Reader Poll Have you ever had to certify a patient’s medical status? r Yes r No Go to www.TheOncologyNurse.com to answer the question and add your comments. Please let us know how the process worked when you provided information about a patient’s medical status for matters involving employment or public benefits.

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Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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NOvEMbER 2012 I vOL 5, NO 10

Breast Cancer

Some Staging Studies Offer No Benefit in Early Breast Cancer Workup By Caroline Helwick

hree commonly used radiological tests rarely detect metastases in newly diagnosed breast cancer patients and should not be routinely performed, according to a comprehensive literature review presented at the American Society of Clinical Oncology (ASCO) 2012 Breast Cancer Symposium, held in San Francisco, California.1 Bone scan, liver ultrasound, and chest x-ray are often used as first-line screening for potential metastases. However, there is no established protocol for this costly screening—which is often accompanied now by advanced imaging such as CT, PET, and MRI— and there is no solid evidence to justify its use, said Allison M. Staley, MPH, a medical student at the University of North Carolina School of Medicine in Chapel Hill. “Our literature analysis suggests that these 3 tests are of little use in screening women for metastases, and likely result in a lot of false negatives in early-stage disease,” Staley said at a press briefing. “The relevant topic is cost containment. When you look at the cost of these 3 tests, they are significantly less expensive than other more advanced imaging options; however, when they are used routinely in thousands of new breast cancer patients annually, collec-

tively they become costly to the healthcare system,” she said. Staley noted that as a tertiary care center, her institution receives many referrals from community oncologists. “Many patients do come in having had staging evaluations, and physicians are using chest x-ray and liver ultrasound in many cases,” she said.

Bone scan, liver ultrasound, and chest x-ray are often used as first-line screening for potential metastases.

Literature Review Examined Tests’ Utility The study asked whether bone scans, chest x-rays, and liver ultrasounds help to determine the extent of metastatic disease among newly diagnosed asymptomatic breast cancer patients. The researchers searched publications from 1990 to the present for articles that used detection rate—defined as the number of patients with an abnormal test result divided by the total number of patients tested—as their primary outcome of interest. Eight studies of

232 met the investigator’s criteria. The primary outcome measure, pooled detection rates, ranged from <0.5% to approximately 4%. As expected, they were highest for patients with stage III disease. Per modality and by stage, the detection rates were as follows: • Bone scan: stage I (1.29%), stage II (3.09%), stage III (12.5%), for an average of 4.18% • Liver ultrasound: stage I (0.47%), stage II (1.0%), stage III (4.2%), for an average of 1.34% • Chest x-ray: stage I (0%), stage II (0.42%), stage III (4.57%), for an average of 0.87% “These very low detection rates, particularly in stage I and II disease, make us question the utility of these 3 modalities for an adequate staging evaluation,” she said. Rates of metastases were higher for women with stage III disease than for those with stage I or II breast cancer, particularly as detected by bone scans (12.5%), suggesting this modality may still have a role in this subgroup. However, the authors suggested that these 3 particular imaging tests may be unnecessary even in these women, when the patients are also assessed with more sensitive imaging. Andrew Seidman, MD, of Memorial Sloan-Kettering Cancer Center, New

York, commented on the findings. “It strikes me that we are living in a time when we move quickly to embrace new, more sensitive technologies, but the elephant in the room are the false-positives. The ‘Choosing Wisely’ campaign, which ASCO participates in, recommends that we back off from examinations that are really not evidence based and which, in many cases, do more harm than good.” This study is consistent with other findings suggesting that extensive testing is futile in patients with a very low risk of distant metastases, he said. “Doing extensive imaging, looking for something that has a very low yield and little impact on health, can lead to unnecessary procedures, biopsies, complications, and costs,” he noted. The higher yield in stage III patients probably exempts this group from such restrictions, he added. Seidman said for patients with stage I and II cancer, he does not order these imaging tests, nor does he order PET scans. “I reserve these for patients at high risk, which includes stage III breast cancer,” he said. l Reference 1. Moffat Staley A-S. Staging evaluation with bone scan, liver ultrasound, and chest radiograph in patients with primary breast cancer: a systematic review. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 4.

21-Gene Recurrence Score Predicts for Residual Disease After Chemotherapy By Audrey Andrews

xpanded utility of the 21-gene recurrence score (RS) (Oncotype DX) was shown in a retrospective analysis reported at the American Society of Clinical Oncology 2012 Breast Cancer Symposium by investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP).1

The RS can help identify estrogen receptor (ER)-positive patients with any number of positive lymph nodes who will have residual disease after adjuvant chemotherapy, who might benefit from additional treatment, reported Eleftherios P. Mamounas, MD, of the Aultman Cancer Center in Canton, Ohio.

As such, the RS can help in making treatment decisions, Mamounas maintained. “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 a clinical trial. On the other hand, patients with low residual

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NOvEMbER 2012 I vOL 5, NO 10

risk may do well with less treatment,” he said. Such patients might be sufficiently treated with only 4 cycles of chemotherapy, rather than a full course of 8 cycles, including a taxane, he said. The NSABP B-28 analysis indicates that the extent of chemotherapy might be

October 4-6, 2013 The Seaport Boston Hotel 1 Seaport Lane Boston, MA 02210

www.TheOncologyNurse.com

Breast Cancer

21-Gene Recurrence Score Predicts.... Continued tailored according to the estimation of residual risk, he said. Oncotype DX is currently approved for use in patients with ER-positive, node-negative breast cancer to estimate whether the addition of chemotherapy to endocrine therapy would be beneficial. The current study shows that the RS can also be applied to ER-positive patients with any number of positive nodes, treated with chemotherapy as well as endocrine therapy. In this population, the RS was prognostic across the spectrum of subgroups. NSABP B-28 included 1065 patients treated with adjuvant endocrine therapy and anthracycline/cyclophosphamide with or without paclitaxel in the randomized NSABP B-28 trial. Researchers calculated RS using tissue specimens from past breast surgeries and then correlated the RS with outcomes. Median follow-up was 11.2 years.

benefit of paclitaxel seen mainly in the intermediate and high RS groups. Andrew Seidman, MD, of Memorial Sloan-Kettering Cancer Center, New York, said at a press briefing that 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 can be improved.” l

Reference 1. Mamounas EP, Tang G, Paik S, et al. Prognostic impact of the 21-gene recurrence score (RS) on diseasefree and overall survival of node-positive, ER-positive breast cancer patients treated with adjuvant chemotherapy: results from NSABP B-28. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 1.

Researchers calculated RS using tissue specimens from past breast surgeries and then correlated the RS with outcomes.

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Recurrence Score a Robust Independent Predictor of Outcomes The RS was low (<18) in 36% of patients, intermediate (18-30) in 34%, and high (≥31%) in 30% of patients. In the univariate analysis, the RS was a significant predictor of disease-free survival, distant recurrence-free interval, breast cancer–specific survival, and overall survival. In multivariate analysis, the RS provided independent prognostic information for all 4 end points beyond clinical and pathologic factors, including treatment, age, tumor size, tumor grade, number of positive nodes, and type of surgery (P <.001), Mamounas reported. For patients with a low RS, diseasefree survival was close to 76%, while it dropped to 48% for those with a high RS. Overall survival was 90% for the low RS group, versus 63% for the high RS patients, he reported. The RS was strongly related to a 10year risk of recurrence, with events occurring in 54% of patients in the high RS group versus 17% of those with low RS. Breast cancer–specific deaths occurred in 33% and 2%, respectively. By treatment assignment, outcomes were very similar between treatment arms in patients with low RS, with the

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 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. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 K08Z12236AR1

NOvEMbER 2012 I vOL 5, NO 10

Caregiving

We Faced the Disease Together By Rich Devlin

ancer has long been a part of my life. My grandmother was diagnosed with late-stage breast cancer when I was 12. My mother lived with the diagnosis, radical surgery, and post-op radiation treatment for 10 years. She succumbed to the ravages of breast cancer at 69 when I was 37 years old.

Seven years later, my father died of bladder cancer at 77. My wife of 38 years died of breast cancer on Dec. 27, 2008. She was 59. Kathy, first diagnosed with a Stage 3 lobular carcinoma in November 2001, experienced a recurrence in 2006. Her long, arduous course of treatment

included two individual mastectomies (one prophylactic), localized radiation, several courses of chemotherapy, and finally stereotactic brain radiation as a result of further metastasis. All along I knew I’d married an incredibly strong woman and was blessed with wonderful daughters,

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients

Release Date: May 8, 2012 Expiration Date: May 7, 2013

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.

NOvEMbER 2012 I vOL 5, NO 10

In the beginning it was difficult for us to become dependent on other people, but cancer forced us to reach out to each other and those around us.

Kathy D. Miller, MD

ACCREDITATION

now 28 and 32. Throughout the course of Kathy’s illness we experienced an extraordinary closeness as a couple. Early on we realized that we couldn’t fight cancer alone. So we faced the disease together. In the beginning it was difficult for us to become dependent on other people, but cancer forced us to reach out to each other and those around us. We needed help with transportation to and from treatment and routine chores. We needed flexibility in work scheduling. At the same time we received our share of unsolicited advice from well-meaning people and sorted through their conflicting recommendations for kernels of usable information. Some friends drifted away while others acted like nothing had happened or expected that everything would remain unchanged.

But Kathy’s breast cancer diagnosis was a sea change in our lives. It stopped the clock and undermined all our distant hopes and dreams. Kathy had just completed a master’s degree in social work a year before her diagnosis. Her achievement fulfilled a lifelong dream to help others overcome the effects of personal trauma, especially childhood incest survivors like herself. Cancer treatment delayed her plans to begin a private counseling practice. Then the disease cut it short after only four years when it became impossible for her to carry on. Two months before we found out Kathy had cancer I had accepted an early retirement buyout from a telecommunications firm. So I had to scramble to find a new job to help meet our escalating medical bills. All our plans were replaced by what

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Caregiving was happening at the present moment — waiting nervously for biopsy and scan reports, holding back Kathy’s hair while she got sick from chemotherapy, cradling each other in bed on Christmas Eve and still counting our blessings days before she died. One particular eerie moment occurred on Sept. 11, 2001. Kathy was scheduled for an MRI in the afternoon to confirm her diagnosis but when we arrived at the hospital we found it under shutdown. All appointments had been canceled in anticipation of an influx of injured from the World Trade Center. The place was a ghost town. We just sat on the curb and cried. For a long time I was angry that Kathy had to endure such things. The emotion receded very slowly. Here was a woman who did all the right things because she knew she was at high risk for the disease. Her grandmother succumbed to ovarian cancer in her early 50s. Kathy’s mother, diagnosed with breast cancer 20 years ago, had a mastectomy and is alive today at 84. So Kathy had had regular mammographies and annual checkups. She did self-exams religiously. But her cancer defied early detection. Lobular breast cancer can be particularly difficult to catch in its early stages of development. According to a recent study by the National Cancer Institute, mammography — our first line of defense against breast cancer — still misses about 20 percent of breast cancers present at the time of screening. Sadly, Kathy was part of that 20 percent. Her breast cancer turned out to be elusive and particularly aggressive. Throughout the journey I learned that Kathy’s love for me and our daughters knew no bounds because she fought so hard to stay alive for us. One particular grueling procedure involved screwing a metal halo into her skull in preparation for stereotactic brain radiation treatment. She was fully awake. She never whimpered. She never cried. Everyone in the room was in awe of her courage. That spirit was her gift to her family and friends. We were fortunate to have been allowed time for intimacy and closure and for that I am very thankful. But there is never, ever, ever enough time. Make no mistake about it: people are living longer with a cancer diagnosis. But the price of survivorship is heavy and unacceptable. In exchange for more time breast cancer survivors frequently endure a slash-and-burn treatment plan offered as a cure. Too often they become case studies shuttled from one specialist to another as they get lost in a sea of symptom management and diagnostic testing. All the while

www.TheOncologyNurse.com

Throughout the journey I learned that Kathy’s love for me and our daughters knew no bounds because she fought so hard to stay alive for us. the actual disease consumes the person within the body that is being treated. Today I fear for my own daughters

and for any women, or men, faced with this dreaded disease. Forty years have elapsed since President Richard Nixon

signed the National Cancer Act declaring a war on cancer that, in effect, harnessed the nation’s resources with the “… same kind of concentrated effort that split the atom and took man to the moon.” How far we have come. How very far we have yet to go. l Reprinted with permission from New Jersey Press Media.

THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Chief Medical Officer Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Roy A. Beveridge, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much? John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future? Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery. • Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered. • Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively. • Examine the current trends in personalized care and companion diagnostics. • Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015? Linda Bosserman, MD, FACP; John D. Sprandio, MD

LEARNING OBJECTIVES 3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

TARGET AUDIENCE

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD Thomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

COMMERCIAL SUPPORT ACKNOWLEDGMENT

10:00 am - 10:15 am

Break

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, the Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Large Oncology Group Practices—Successes, Issues, and Challenges

11:45 am - 12:00 pm

Summary and Conclusion of Conference

CONFERENCE REGISTRATION Discounted Pricing Available!

$375.00 until January 15, 2013 $475.00 until March 15, 2013 $675.00 after March 15, 2013

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

*Agenda is subject to change.

www.regonline.com/avbcc2013

NOvEMbER 2012 I vOL 5, NO 10

CONTINUING EDUCATION NOVEMBER 2012 • VOLUME 5 • NUMBER 4

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Retreatment Settings LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the application and interpretation of recent clinical advances. In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, and professional experience regarding evidence-based care. In this fourth issue, experts from the University of California, San Francisco answer questions pertaining to the management of patients in the retreatment setting.

Sincerely, Director, Production and Manufacturing Alaina Pede

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Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

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Web Coordinator Jose Valentin

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Jeffrey Wolf, MD Clinical Professor Department of Medicine, UCSF Director, Myeloma Program UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Jennifer Knoche, RN, BSN Lead Practice Nurse UCSF Hematology/BMT Ambulatory Care Center San Francisco, CA

Helen T. Wu, PharmD, BCOP Clinical Pharmacist Adult Hematology/Oncology and Health Sciences Associate Clinical Professor School of Pharmacy, UCSF San Francisco, CA

Supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company.

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 1249 South River Road Suite 202B Cranbury, NJ 08512

NOvEMbER 2012 I vOL 5, NO 10

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

www.TheOncologyNurse.com

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours.

in the relapsed/refractory setting • Apply evidence-based retreatment strategies for MM, taking into consideration patient- and disease-related factors • Describe appropriate prophylactic measures for managing adverse events to optimize treatment efficacy Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/ services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose. Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosed that her spouse is investigator on a study for Agenix, ImClone, and Lilly; on the data monitoring committee for Infinity; on the Advisory Committee for Boehringer Ingelheim; and on the data monitoring committee and principal investigator on a study for Pfizer.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-030-H01-P.

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. *Jeffrey Wolf, MD, is on the speakers’ bureau for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals, Inc. Helen T. Wu, PharmD, BCOP, has nothing to disclose. Jennifer Knoche, RN, BSN, is on the speakers’ bureau for Celgene Corporation.

Learning Objectives Upon completion of this activity, the participant will be able to: • Review data from recent clinical trials evaluating novel agents for MM

*Content will include non–FDA-approved uses. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any

financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/ CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12028.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. Estimated time to complete activity: 1.25 hours Date of initial release: November 13, 2012 Valid for CME/CPE/CE credit through: November 13, 2013

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Making Treatment Decisions in Relapsed and Refractory Multiple Myeloma Jeffrey Wolf, MD Clinical Professor, Department of Medicine, UCSF Director, Myeloma Program UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Eligible patients advance to autologous stem cell transplantation (ASCT) following this therapy. More and more patients receive maintenance therapy, either with lenalidomide or bortezomib. Therefore, when patients relapse, they have already received quite a bit of therapy. The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

Introduction Novel agents and regimens have greatly improved the management of multiple myeloma (MM). However, the retreatment setting remains complex, since many patients have already received numerous therapies at the time of disease progression. The result can

The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

be resistance to specific agents and/or cumulative toxicities, which may influence the choice of therapy. In this article, Jeffrey Wolf, MD, discusses therapeutic decision-making in relapsed and refractory MM and the latest evidence on investigational drugs that may expand treatment options for the disease.

When a patient experiences a first relapse, what factors do you consider in choosing retreatment with previously used therapy versus treatment with different agents?

Because first-line therapy for MM often involves several different combinations,1 choosing second-line therapy can be a challenge. In the setting of initial treatment, we are using doublet and triplet combinations that may include bortezomib, lenalidomide, cyclophosphamide, or dexamethasone.

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For example, if a patient has progressed on lenalidomide maintenance, we would not choose lenalidomide as part of second-line therapy. However, if that same patient achieved a very good partial response (VGPR) or a complete response during induction with a bortezomib-based regimen, we might utilize bortezomib at relapse, provided that the patient did not have significant peripheral neuropathy (PN) or other adverse events (AEs) associated with treatment. Bortezomib-related AEs might suggest the use of an alkylator alone at the time of relapse in such a patient. Another example is a patient who relapses after initial therapy with a combination of lenalidomide, bortezomib, and dexamethasone (RVD)2 but who has not undergone transplant or maintenance therapy. We could go back to RVD, which has been shown to be effective (Figure),3 or we may switch the patient to a regimen of cyclophosphamide, bortezomib, and dexametha-

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CONTINUING EDUCATION

who exhibited resistance earlier in the clinical course of the disease. In other words, â&#x20AC;&#x153;once resistant, always resistantâ&#x20AC;? may not be true. Of course, one could argue that the best option for a patient resistant to bortezomib would be treatment with carfilzomib. That is an argument that will play out now that both agents are available. My point is that going back to a proteasome inhibitor makes sense, even if a patient had only a modest prior response to bortezomib.

Figure. Response rates with RVD in a phase 2 trial of relapsed/refractory MM (N=64).3

100 90

78%

Patients (%)

80 64%

70 60

Has the approval of carfilzomib impacted treatment approaches in the retreatment setting?

50 40 25%

22%

20 10 0 CR/near CR

ORR ( MR)

CR indicates complete response; MR, minimal response; NR, no response; ORR, overall response rate; PR, partial response; RVD, lenalidomide, bortezomib, and dexamethasone.

Table 1. Response to Bortezomib-Based Retreatment Following Response to Initial Bortezomib-Based Therapy (N=22)8 Response to Initial Therapy, n (%) Complete or partial response

No response

15 (68%)

7 (32%)

Response to Retreatment, n (%) Complete or partial response

9 (60%)

No response

6 (40%)

Complete or partial response

2 (29%)

No response

5 (71%)

sone.4,5 Both of these regimens yield a response rate of about 75% in the relapsed setting.3-5 We could consider ASCT as part of second-line therapy, usually with some initial therapy to get better control pretransplant. If the myeloma is particularly aggressive at relapse, we may use a combination such as bortezomib and dexamethasone with cisplatin, doxorubicin, cyclophosphamide, and etoposide (VD-PACE) and then go to transplant.6 If the patient has renal insufficiency, we will use modified HyperCVAD (cyclophosphamide, bortezomib, doxorubicin, and dexamethasone; with bortezomib in place of vincristine) instead of VD-PACE.7 How would you choose therapy for a patient who is resistant to initial treatment?

Drug resistance is a topic of ongoing investigation, and therapeutic choices in this setting require careful consideration. Recently, we had a patient who was treated with a 2-drug regimen of bortezomib and dexamethasone and attained only a partial response. We added lenalidomide, and his response improved to a VGPR. At the time of relapse, we might be disinclined to use bortezomib for such a patient, because of the modest initial response. There is a caveat here, however. Evidence suggests that, if you wait long enough, you can often go back to a drug such as bortezomib despite initial resistance (Table 1).8,9 We now believe that myeloma is made up of various clones with multiple sensitivity and resistance patterns to different drugs. Sometimes, if a patient has not received a drug for a period of time, the clone that may be relapsing most recently may be one that is sensitive to bortezomib. Therefore, it may be worth retrying this agent. Often we do see a response in patients

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The next-generation proteasome inhibitor carfilzomib is now available for use in the relapsed/refractory setting for MM, but it is approved by the US Food and Drug Administration only for patients who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent.10 Clinical trials have shown the efficacy of carfilzomib in this setting and have also indicated that carfilzomib is less likely than bortezomib to cause PN.11,12 Because we see many patients who have run through all of the other treatment options and have progressed on bortezomib-based therapies, our team has used carfilzomib frequently since its approval. However, in patients who received bortezomib with good response a long time ago, or in patients who progressed on bortezomib 2 to 5 years ago, retreatment with bortezomib could be considered at relapse. In such cases, the decision of which drug to use may be influenced by possible prior toxicities.

Drug resistance is a topic of ongoing investigation, and therapeutic choices in this setting require careful consideration.

For instance, in a patient who still has PN that developed during prior treatment with bortezomib, I would probably lean toward using carfilzomib. Even though you can give bortezomib subcutaneously (SC) and possibly avoid making neuropathy worse,13 it may not be worth taking that chance. In contrast, if there is no neuropathy and the patient did not progress on bortezomib initially, I would lean toward bortezomib retreatment. Convenience is a consideration here. At the present time, carfilzomib is cumbersome to administer. It is given intravenously over 2 to 10 minutes 2 days in a row, weekly for 3 weeks followed by a 12-day rest period.10 Bortezomib, which can now be given SC twice a week,13 is more convenient. For the patient with relapsed or refractory MM, what investigational therapies show the most promise?

The immunomodulator pomalidomide is the first agent that comes to mind, as it may be approved in the next 6 months. Clinical data support the efficacy of this agent when combined with weekly dexamethasone in the relapsed/refractory setting for MM, and it is fairly well tolerated. In 2 phase 2 trials of pomalidomide plus dexamethasone in patients refractory to bortezomib and lenalidomide, overall response rates were 43% to 49%.14 In an earlier report, this combination showed a 63% response rate in patients receiving 1 to 3 prior therapies; however, the incidence of grade 2 toxicities was high, including neutropenia, fatigue, leukopenia, and anemia (Table 2).15 Elotuzumab is an antibody that does not have a lot of activity on its own, but looks good when combined with lenalidomide and dexamethasone.16

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CONSIDERATIONS IN MULTIPLE MYELOMA

References Table 2. Toxicities Grade 2 with Pomalidomide Plus Dexamethasonea in a Phase 2 Trial (N=60)15 Toxicity

Patients, n (%)

Anemia

20 (33%)

Lymphopenia

4 (7%)

Neutropenia

30 (50%)

Thrombocytopenia

6 (10%)

Leukopenia

24 (40%)

Fatigue

27 (45%)

Nausea

1 (2%)

Diarrhea

5 (8%)

Constipation

11 (18%)

Pneumonia

6 (10%)

Hyperglycemia

10 (17%)

Confusion

5 (8%)

Insomnia

7 (12%)

Agitation

7 (12%)

Peripheral neuropathy

6 (10%)

Thrombosis

1 (2%)

a Patients also received aspirin 325 mg once daily for thromboprophylaxis. Patients were allowed to substitute full-dose anticoagulation with either low-molecular-weight heparin or warfarin at physician discretion.

There are also CD38 antibodies—daratumumab and SAR650984—in phase 1/2 trials that look promising.17,18 Additional drugs that are progressing through clinical trials include the Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765)19 and the mammalian target of rapamycin inhibitor MLN0128.20 The histone deacetylase inhibitor vorinostat and the pan-deacetylase inhibitor panobinostat do not seem to have very good antimyeloma activity on their own. Vorinostat has provided a slight advantage in combination with bortezomib, but it appears to add quite a bit of toxicity.21 Panobinostat is in trials in combination with a proteasome inhibitor,22-24 but it is not yet clear if this drug will perform better than vorinostat. Conclusion

Over the past decade, we have witnessed spectacular progress in the area of treating myeloma. Today, a majority of patients are alive and doing well at 5 years following initial treatment. It is becoming apparent that many patients can hope for very extended survival because of novel drugs and our ability to treat relapsed and refractory disease.

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1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 12, 2012. 2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 3. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3049. 4. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, Velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92: 1149-1150. 5. Fu W, Delasalle K, Wang J, et al. Bortezomib-cyclophosphamide-dexamethasone for relapsing multiple myeloma [published online ahead of print June 18, 2011]. Am J Clin Oncol. doi:10.1097/COC.0b013e31822043f6. 6. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185. 7. Pegylated liposomal doxorubicin hydrochloride, bortezomib, cyclophosphamide, and dexamethasone in treating patients with multiple myeloma (NCT00849251). http://www.clinical trials.gov. Accessed October 22, 2012. 8. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol. 2008;6:755-760. 9. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol. 2009;84:657-660. 10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 11. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825. 12. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739-748. 13. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 14. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dualrefractory disease. Blood. 2011;118:2970-2975. 15. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-5014. 16. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012; 30:1953-1959. 17. Gimsing P, Plesner T, Nahi H, et al. A phase I/II, dose-escalation study of daratumumab, a CD38 Mab in patients with multiple myeloma—preliminary safety data. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 1873. 18. Dose escalation study of anti-CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies (NCT01084252). http://www.clinicaltrials.gov. Accessed October 22, 2012. 19. Study of the Bruton’s tyrosine kinase inhibitor in subjects with relapsed or relapsed and refractory multiple myeloma (NCT01478581). http://www.clinicaltrials.gov. Accessed October 22, 2012. 20. Dose escalation study of MLN0128 in relapsed or refractory multiple myeloma or Waldenstrom macroglobulinemia (NCT01118689). http://www.clinicaltrials.gov. Accessed October 28, 2012. 21. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: vorinostat in combination with bortezomib in patients with relapsed/refractory multiple myeloma: results of a global, randomized phase 3 trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 811. 22. San Miguel JF, Hungria VTM, Yoon S-S, et al. Update on a phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3976. 23. Richardson PG, Alsina M, Weber DM, et al. Phase II study if the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomibrefractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011; 118:Abstract 814. 24. Carfilzomib plus panobinostat in relapsed/refractory multiple myeloma (MM) (NCT01301807). http://www.clinicaltrials.gov. Accessed October 22, 2012.

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Nursing Interventions in the Relapsed and Refractory Settings for Myeloma Jennifer Knoche, RN, BSN Lead Practice Nurse UCSF Hematology/BMT Ambulatory Care Center San Francisco, CA

Introduction

laxation become important components of therapy, in addition to dose reduction. Fortunately, we now have the option of administering bortezomib subcutaneously (SC), which has been shown to help reduce the incidence and severity of PN.5 How has the recent approval of carfilzomib affected your approach to treating relapsed and/or refractory disease?

For patients with multiple myeloma (MM), prompt and effective nursing interventions can make a significant difference in care—from minimizing adverse events (AEs) to protecting bone health and alleviating pain. In this article, Jennifer Knoche, RN, BSN, examines key strategies for improving outcomes in the relapsed/refractory setting for myeloma, and discusses best practices for whole-patient care.

When patients are retreated with agents such as bortezomib or thalidomide, what strategies are effective for minimizing the risk of peripheral neuropathy (PN)?

The main strategy for minimizing this risk remains dose adjustment or treatment interruption. With thalidomide, which is administered orally, PN can be an especially challenging toxicity to manage. We often use thalidomide at a low dose in the relapsed/refractory setting; therefore, to reduce the amount even further may require patients to cut their pills in half or take their medication every other day—neither of which are ideal options. With intravenous (IV) bortezomib, reducing or holding the dose is easier. Recommended dose reductions for thalidomide- and bortezomib-based PN are shown in Tables 1 and 2.1,2 Of course, we cannot make an informed decision regarding dose adjustment without an accurate assessment of a patient’s condition. In the relapsed/refractory setting, we must look at current symptoms as well as treatment history. What drugs have been administered previously? Did the patient experience neuropathy with prior treatment, and if so, did dose reduction or discontinuation provide relief? Did supportive therapies help to reduce symptoms? Are there comorbid conditions associated with the existing PN? Is the patient taking any medications for comorbidities that may contribute to neuropathy? Answers to these questions help us to plan the schedule and dose of agents at the time of relapse. Complementary therapies, such as alpha lipoic acid, L-carnitine, and vitamin B6 may be helpful.3 At our institution, we begin patients on these therapies prior to antimyeloma treatment to prevent or minimize PN. In those who already exhibit symptoms, we may add these therapies as supplements, to keep neuropathy from progressing. Some patients need a more robust medical intervention, in which case we may prescribe gabapentin, pregabalin, tricyclic antidepressants, or even nonopioid analgesics.3 Our goal is to do whatever works to manage pain, tingling, burning, and functional impairment to keep the patient on therapy. PN may cause the nerves that control intestinal muscle contractions to malfunction, leading to gastrointestinal problems, including constipation.4 If this occurs, a good bowel regimen, proper diet, hydration, and exercise, and

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With the approval of carfilzomib, we now have another treatment option at our disposal, which is extremely important. Given the challenges patients face in the relapsed/refractory setting, including the fact that they have already been treated with so many therapies, it matters greatly to have one more way to attack the disease. In addition to demonstrating good efficacy, carfilzomib has been associated with low rates of PN (Figure).6 Anecdotally, we are not seeing this toxicity among patients receiving carfilzomib. However, since these individuals are on so many drugs, sequenced over time, it can be hard to determine whether AEs are related to past or current regimens. For instance, an agent may cause some degree of neu-

Table 1. Thalidomide Dose Modifications Based on Severity of Peripheral Neuropathy1 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

Grade 1 (mild)

No action

Grade 1 with pain or grade 2

Intermittent symptoms: Continue therapy Continuous symptoms: Withhold thalidomide until toxicity resolves, then reduce dose

Grade 3

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Grade 4 (permanent sensory loss that interferes with function)

Discontinue thalidomide

Table 2. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy2 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

No action

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

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CONSIDERATIONS IN MULTIPLE MYELOMA

Figure. Carfilzomib-related, nonhematologic adverse events with an incidence 5% in a single-agent study of relapsed/refractory MM patients (N=266).6 40 35

Patients (%)

30 25 20 15 10 5 0

e igu Fat

a use Na

ea rrh Dia

ea spn Dy

e um ach ser ine ad He sed atin rea cre Inc

g tin mi Vo

y a ia mi ath rex ate Py rop eu sph ln ho op era p h Hy rip Pe

ropathy, but symptoms do not appear until later, after another therapy is given. Administration of carfilzomibâ&#x20AC;&#x201D;2 days in a row intravenously, weekly for 3 weeks7â&#x20AC;&#x201D;is not as simple as administration of bortezomib, especially bortezomib SC. Some patients, depending on how far they live from the cancer center, may have to spend the night once a week to receive carfilzomib. The infusion time for this drug is longer than it is for IV bortezomib. Additionally, if you compare IV carfilzomib administration to the use of bortezomib SC,

Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy.

there is a big difference in convenience favoring bortezomib. Dose adjustment schedules for carfilzomib-related PN are available, along with those for hematologic, cardiac, pulmonary, and hepatic toxicities. In some patients, we have noticed a decline in red blood cells with carfilzomib use, typically during the first cycle. As with any agent, careful monitoring of blood counts and vital organ functions are an essential part of nursing care. How do you support bone health and manage skeletal-related events over the course of care in the relapsed/refractory setting?

Supporting bone health in this setting is essential but can be complex. Many myeloma patients are older, with comorbidities such as osteoarthritis

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and osteoporosis. When treating a patient for osteoporosis, we need to assess his or her current bisphosphonate regimen and see how it dovetails with the need for myeloma bone support. In a patient who has experienced a long clinical course and relapsed, prior bisphosphonate treatment is a given. Currently, the American Society of Clinical Oncology recommends 2 years of bisphosphonate therapy for myelomarelated bone disease. After that, treatment is at the discretion of the physician.8 Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy. Our biggest concern is the risk for osteonecrosis of the jaw, which increases with prolonged time on bisphosphonate therapy.9 As the myeloma disease process continues, and as patients age, they may need supportive devices, surgical care, and pain management strategies. Functional limitations and pain can be improved with antimyeloma therapy and bisphosphonates, but for some individuals, canes, walkers, wheelchairs, or braces may be necessary. We may also refer patients with spine involvement for vertebroplasty or kyphoplasty, which can be very effective.10 Local irradiation is occasionally used for supportive care, especially if there is a plastocytoma. Bone pain often requires opioid analgesics, and we encourage our patients to accept such medications when necessary.11 Pain can delay healing and diminish quality of life and must therefore be minimized whenever possible. Conclusion

Nurses need to carefully monitor relapsed and refractory MM patients, and be ready to intervene to ensure the continuation of treatment and the ability to perform activities of daily living. The detection and effective management of AEs, skeletal-related complications, and pain are essential components of evidence-based care, which will lead to better clinical outcomes. References 1. Thalomid [package insert]. Summit, NJ: Celgene Corporation; 2012. 2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012. 3. Tariman JD, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12:29-36. 4. National Institute of Neurological Disorders and Stroke. Peripheral neuropathy fact sheet. http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm. Accessed October 27, 2012. 5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825. 7. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals Inc.; July 2012. 8. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 9. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945-952. 10. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;13:225-235. 11. Definitions related to the use of opioids for the treatment of pain: Consensus statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. www.asam.org. Accessed October 30, 2012.

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Pharmacologic Considerations in the Retreatment Setting for Multiple Myeloma Helen T. Wu, PharmD, BCOP Clinical Pharmacist Adult Hematology/Oncology and Health Sciences Associate Clinical Professor, School of Pharmacy, UCSF San Francisco, CA

Introduction In patients with relapsed/refractory multiple myeloma (MM), retreatment can contribute to longer survival and better quality of life,

mended in the NCCN guidelines for this indication.6 In the salvage setting, choosing therapies that are least likely to be toxic to the kidneys is a must. It is also important to remember that myeloma patients with renal dysfunction often have other comorbidities and poor performance status.7 Therefore, therapeutic benefit must be balanced with drug-related toxicities. Although lenalidomide can be effective in the retreatment setting, this agent needs to be dose-adjusted for patients with varying degrees of renal dysfunction.8 Bortezomib and carfilzomib, which have also demonstrated efficacy as second-line therapies, do not require dosing adjustments in renally impaired patients.9,10

but can also pose a number of clinical challenges. When choosing therapies for this indication, it is necessary to consider numerous factors, including preexisting toxicities, patient preferences and perfor-

How has the approval of subcutaneous (SC) bortezomib impacted your approach to retreatment?

mance status, and agents used during initial therapy. In this article, Helen T. Wu, PharmD, BCOP, shares her perspective on these issues in both the transplant and nontransplant settings and discusses recent advances that may promote better patient outcomes.

How do comorbidities and other patient factors affect selection and administration of therapy in the retreatment setting?

An important issue to consider is how well a patient has tolerated a specific agent or regimen in the frontline setting, as this may affect administration and dosing at the time of retreatment. For example, if a patient did not experience serious adverse events (AEs) with frontline therapy, we can typically start retreatment at the standard, recommended dose of the same agent. Conversely, if a patient did suffer significant toxicities, we may choose to retreat with an agent from a different class. However, studies have shown a therapeutic benefit when patients are retreated with agents they have received previously.1-5 Therefore, if a patient has achieved a good response to a specific agent as induction, we may try using dose modifications to reduce the incidence of AEs. For example, we can consider a patient with preexisting peripheral neuropathy (PN) who relapses after being treated with lenalidomide, bortezomib, and dexamethasone (RVD) and autologous stem cell transplantation (ASCT). According to the most recent National Comprehensive Cancer Network (NCCN) guidelines for the treatment of MM, RVD is a recommended primary therapy (category 2A) for transplant candidates.6 If relapse occurs at >6 months, the same primary regimen may be repeated. However, in a patient who has residual PN, clinicians may consider avoiding bortezomib and instead select a regimen that has less potential for neurotoxicity. In addition, because of previous ASCT and lenalidomide treatment, a regimen that has the least hematologic toxicity would be preferred. It would be necessary to look at which agents are available for salvage therapy, based on these factors. In a different type of scenario, you may be treating a relapsing patient who is not eligible for transplant and who has renal impairment. Such a patient may have been treated initially with bortezomib, melphalan, and prednisone or lenalidomide plus low-dose dexamethasoneâ&#x20AC;&#x201D;regimens that are recom-

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In January 2012, the US Food and Drug Administration (FDA) approved SC administration of bortezomib for the treatment of MM. This mode of delivery has several advantages, as shown in a recent multicenter trial by Moreau and colleagues.11 These investigators compared the efficacy and safety of SC versus intravenous (IV) bortezomib in patients with relapsed MM who had received 3 previous lines of therapy. The end point was to show noninferiority of SC versus IV bortezomib in terms of overall response rate (ORR) following 4 treatment cycles. After these cycles, ORR was 42% in both groups, showing noninferiority (P=.002). After a median follow-up of 11.8 months in the SC group and 12.0 months in the IV group, there were no significant between-group differences in time to progression and 1-year overall survival. PN of any grade was significantly reduced with SC versus IV bortezomib (Figure). Grade 3 or higher AEs were reported in 57% of patients in the SC group versus 70% in the IV group; the most common were thrombocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12% vs 8%), respectively.11

if a patient has achieved a good response to a specific agent as induction, we may try using dose modifications to reduce the incidence of AEs.

It is important for pharmacists to be aware of how to prepare SC bortezomib for administration. The concentration for IV infusion of bortezomib is 1 mg/mL, which is significantly different from the concentration for SC injection, which is 2.5 mg/mL.9 Pharmacists should be cautious when reconstituting this medication and calculating the volume to be administered. However, the amount of work involved in preparing bortezomib for SC versus IV administration is really no different, and SC bortezomib appears to be a much-preferred route of administration for several reasons. For nurses, it simplifies care, since there is no need to obtain IV access, and the potential risks and complications of inserting IV lines are eliminated. In addition, it reduces chair time, allowing for a much quicker turnaround time for appointments. For patients, it is easier and generally less stressful to receive an SC injection compared with IV administration. Since there is no need

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CONSIDERATIONS IN MULTIPLE MYELOMA

Figure. Incidence of peripheral neuropathy in a phase 3 trial comparing SC versus IV bortezomib dosing in relapsed myeloma (N=222).11

P=.044

SC bortezomib

53% P=.012

IV bortezomib

Patients (%)

41% 40

38%

24%

P=.026

fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). The rate of treatment-related PN was 12.4%. Our institution was one of the participating centers for clinical trials of carfilzomib prior to its FDA approval. Now, we are able to offer this agent to patients off study, and we make sure to follow the recommended dosing, reconstitution, and administration guidelines to ensure maximum benefit and safety. Although we rarely use carfilzomib in the inpatient setting, we do utilize it in patients who come in for emergent plasmapheresis after failing transplant, administering concomitant IV hydration to prevent tumor lysis syndrome. I think this agent is becoming an important retreatment option in MM.

16%

Conclusion 10

0 Any grade

Grade 2

Grade 3

IV indicates intravenous; SC, subcutaneous.

to insert an IV line, wait time is much shorter, which can potentially improve quality of life.

Although MM remains an incurable disease, retreatment with novel agents is leading to higher response rates, prolonged survival, and better quality of life. An important goal in this setting is the prevention and management of AEs, which allows the cancer care team to maximize dose intensity and provide continuation of therapy. This requires careful consideration of comorbidities and other patient factors, as well as a thorough understanding of the doses, schedules, and modes of administration recommended for available agents. References

How is the recently approved agent carfilzomib being used at your center in the retreatment setting?

On July 20, 2012, the FDA approved carfilzomib, a next-generation proteasome inhibitor, for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of therapy completion. Many patients who have relapsed/refractory MM are being treated with carfilzomib at our institution, given its proven efficacy and good safety profile. In a phase 2 study conducted by Siegel and colleagues, patients received single-agent IV carfilzomib for relapsed/refractory MM; all of these individuals were heavily pretreated.12 Of the evaluable patients in this study, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. The treatment regimen was designed as IV carfilzomib 20 mg/m2 (cycle 1) followed by 27 mg/m2 (cycle 2), on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The ORR was 23.7%, median duration of response was 7.8 months, and median overall survival was 15.6 months. Reported AEs included

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1. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol. 2009;84:657-660. 2. Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer. 2005;104:2141-2148. 3. Hrusovsky I, Emmerich B, von Rohr A, et al. Bortezomib retreatment in relapsed multiple myelomaâ&#x20AC;&#x201D;results from a retrospective multicentre survey in Germany and Switzerland. Oncology. 2010;79:247-254. 4. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;27:5713-5719. 5. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood. 2011;118:1763-1765. 6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncologyâ&#x201E;˘: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 24, 2012. 7. Glade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma presenting features and predictors of outcome in a series of 94 patients from a single institution. Arch Intern Med. 1998;158:1889-1893. 8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012. 9. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012. 10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

NOvEMbER 2012 I vOL 5, NO 10

Neuroendocrine Tumors

Advances in the Treatment of Pancreatic Neuroendocrine Tumors By Caroline Helwick

nterest in pancreatic neuroendocrine tumors (pNETs) has grown since the recent approval of targeted agents for advanced disease, as was evident by the attendance at several sessions during the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, Austria.1 Kjell Öberg, MD, of Uppsala University in Sweden, noted, “These tumors are steadily increasing, compared with other malignant neoplasms. It’s not a rare disease any longer, and we don’t know why. Partly, it’s better awareness among physicians. This room at ESMO is filled. And also, better diagnostic methods and treatment opportunities.” “Still, there is usually a delay of 4 to 5 years from first symptom to diagnosis, and 50% of patients present with metastatic disease. They have an indolent course, but median overall survival [OS] is only 33 months, and that is not very impressive,” he said. The good news, added Tim Meyer, MD, of University College London in the United Kingdom, “is that with pNETs we are now in the luxurious position of having lots of treatments. The question now is, which is best?”

Treatment Options Prior to May 2011, options were limited. For patient with hormonal symptoms, octreotide LAR could be beneficial, and for oncologic control streptozocin-based chemotherapy was indicated. Upon disease progression, patients went on to investigational agents or regional therapy; no approved therapies were available.

alone to 11.0 months with everolimus, representing a 65% reduction in risk (P <.0001). An understanding of the role of the angiogenesis pathway in pNETs also led to the development of sunitinib for this malignancy. The phase 3 trial showed median PFS increased from 5.5 months with placebo to 11.4 months with sunitinib, which was a 58% reduction in

“These tumors are steadily increasing, compared with other malignant neoplasms. It’s not a rare disease any longer, and we don’t know why.” —Kjell Öberg, MD

But identification of somatic mutations in the mTOR pathway in pNET formed the scientific rationale for testing mTOR inhibitors in this disease. The 410-patient RADIANT-3 trial demonstrated that everolimus could effectively prolong remission, from a median progression-free survival (PFS) of 4.6 months with best supportive care

risk; this did not reach statistical significance due to early termination of the study and truncated enrollment. “We have clear and convincing evidence that everolimus and sunitinib are effective in improving PFS,” Meyer told attendees. James C. Yao, MD, of the University of Texas MD Anderson Cancer Center,

New Data Presented at ESMO Neuroendocrine tumors are highly vascular, expressing vascular endothelial growth factor (VEGF) and demonstrating angiogenesis. Since the mTOR inhibitor everolimus has antiangiogenic activity, RADIANT-3 investigators evaluated several VEGF pathway tumor markers for their prognostic and predictive potential. The results were presented by James C. Yao, MD, in an abstract presentation at ESMO.1 Yao and colleagues evaluated pretreatment plasma samples for levels of the angiogenic cytokines VEGF-A, soluble VEGF receptors (sVEGFR1 and sVEGFR2), and placental growth factor (PlGF). The multivariate analysis showed that sVEGFR1 and PlGF were significant prognostic markers, with lower baseline levels associated with longer progressionfree survival (PFS). This means that patients with high sVEGFR1 and high PlGF are likely to have a worse prognosis. None of the markers, however, proved predictive of a benefit with everolimus, he reported. “PFS was significantly improved to a similar extent in patients receiving everolimus, compared with patients who received placebo, regardless of baseline levels of these markers,” he said, “suggesting that none of these markers are associated with the efficacy of everolimus in patients with pNET. The markers are prognostic but not predictive.” An updated overall survival (OS) analysis of the phase 3 sunitinib trial was also reported at ESMO by Sandrine Faivre, MD, of Clichy, France.2 “At trial closure, there was an advantage for sunitinib

NOvEMbER 2012 I vOL 5, NO 10

over placebo in OS, a secondary end point. At that time 69% of patients on placebo crossed over to sunitinib upon disease progression or trial closure, potentially confounding the OS analysis. We now present OS data 2 years after study closure and after adjusting for crossover,” she said. The intent-to-treat analysis without adjustment for crossover showed OS to be 33 months with sunitinib and 26.7 months with placebo (hazard ratio [HR], 0.71). The investigators then adjusted for crossover using 4 different statistical methods, which showed median OS with sunitinib to range from 16.4 months (HR, 0.43) to 26.7 months (HR, 0.49), depending on the model employed. This yielded an OS benefit that ranges from 6.3 to 16.7 months. “Four methods of adjusting for crossover suggested that the effect of sunitinib on OS may have been more pronounced had no crossover occurred,” she said. “These analyses demonstrate a survival advantage and further support the clinical benefit of sunitinib for patients with advanced, progressive pNET.” References 1. Yao JC, Shah M, Panneerselvam A, et al. The VEGF pathway in patients with pancreatic neuroendocrine tumors: efficacy of everolimus by baseline marker level, and prognostic and predictive effect analyses from RADIANT-3. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Abstract 11540. 2. Niccoli P, Faivre S, Raoul J, et al. Updated overall survival (OS) analysis from a phase III study of sunitinib vs. placebo in patients (Pts) with advanced, unresectable pancreatic neuroendocrine tumor (NET). Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Abstract 11550.

Houston, added, “Both everolimus and sunitinib result in about 6 months of PFS benefit, but neither study was designed to evaluate overall survival.” He explained that because these tumors are rare, and patients live for years, clinical trials with an OS end point are not feasible, and an OS might not be formally demonstrated. “Nonetheless, we actually do have improved survival,” he suggested. “When we only had streptozocin, median OS was 16 to 24 months. With the newer drugs, we are pushing OS to 3 years and beyond.” He added that while the drugs have almost equivalent PFS benefit, everolimus has activity in controlling hormonal output from pNETs. “It is the most active agent I have seen for controlling hypoglycemia in patients with insulinoma,” he noted, “and it may reduce gastrin and glucagon as well.” Algorithm for Managing Patients Yao said he approaches the initial management of pNETs by considering the disease burden (ie, the percentage of liver involvement), the aggressiveness of the tumor (ie, Ki67 levels, tumor grade), and the primary site of the tumor. “If I have a patient with low-volume, very low-grade disease, I think that surveillance or a somatostatin analogue is reasonable. For the opposite, a patient with 50% liver involvement and a high Ki67, chemotherapy may be the best starting point. For the intermediate patient, targeted therapy is a good choice,” he maintained. To decide whether to treat with everolimus or sunitinib, Yao said, “There has been no head-to-head comparison. Practically speaking, most pNET patients will receive both agents at some time, but there are some factors to help you decide.” He believes that everolimus is the preferred choice for the patient with a functional tumor or a high risk of bleeding, such as patients with a primary tumor at the tail of the pancreas and those with gastric varices. Everolimus also is preferred for patients with coronary artery disease, congestive heart failure, or uncontrolled hypertension. Sunitinib would be favored for patients with severe lung disease and uncontrolled diabetes, he said. l Reference 1. Öberg K, Meyer T. NETs and endocrine tumors. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Proffered paper session.

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Noteworthy Numbers In 2012, approximately 1.6 million new cases of cancer will be diagnosed in the United States.1 A family caregiver, or informal caregiver, will become a necessity for many of the newly diagnosed patients. A family caregiver provides emotional, physical, psychological, and spiritual support to the patient. This, in turn, can take a toll on a caregiver’s own physical, emotional, and even financial health as well. The following statistics provide a glimpse into the characteristics of these unique care providers. The majority of caregivers are female (82%), and 71% are married. Almost half (47%) are over 50 years old.2

accepting the caregiving duties themselves.2

Sources 1. www.cancer.org/cancer/news/news/ann ualreport.

2. http://www.strengthforcaring.com/man ual/about-you-you-are-not-alone/cancercaregivers/.

Six of 10 caregivers (61%) have been providing support for less than 6 months.2

Newsletter Series

YOUR QUESTIONS ANSWERED In 54% of cases, caregivers live with the patient for whom they are caring.2 ™

Health concerns resulting from providing care are an issue for 62% of caregivers. In fact, 70% of caregivers report taking between 1 and 10 medications per day.2 Often, caregivers miss as many workdays as those patients for whom they care, and almost half (46%) of caregivers report insufficient financial resources. The weekly time required is greater than 40 hours per week for 36% of caregivers.2 A feeling of resentment for having to provide care is felt by 85% of caregivers, and 70% claim their families do not work well together.2

™

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

Topics include: • Newly Diagnosed Patients • Maintenance Settings • Transplant-Eligible and -Ineligible Patients • Retreatment Settings • Bone Health

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

ALL NEW CONTENT FOR 2012 Accreditation

Although 97% of caregivers say their roles are important, 35% are overwhelmed by their caregiving responsibilities.2 However, 81% want to provide care and insist on www.TheOncologyNurse.com

These activities will be accredited for physicians, nurses, and pharmacists. For complete accreditation information, please refer to each activity. This activity is jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC.

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NOvEMbER 2012 I vOL 5, NO 10

Breast Cancer

No Increase in Leukemia or Myelodysplastic Syndrome With Adjuvant Chemotherapy for Breast Cancer By Audrey Andrews

Photo by ÂŠ ASCO/Todd Buchanan 2012.

ccording to a study from the US Oncology Network, breast cancer patients treated with adjuvant chemotherapy have no increased risk for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), at least within the first 3 years of treatment. The study was presented at the American Society of Clinical Oncology 2012 Breast Cancer Symposium by Neelima Denduluri, MD, of Virginia Cancer Specialists.1 â&#x20AC;&#x153;The rates of AML/MDS were found to be low after adjuvant chemotherapy, and similar to those noted in nonâ&#x20AC;&#x201C;chemotherapy-treated patients,â&#x20AC;? Denduluri reported.

â&#x20AC;&#x153;This study can reassure patients who receive adjuvant chemotherapy that their risk of a secondary AML/MDS is very low within the first 3 years.â&#x20AC;? â&#x20AC;&#x201D;Neelima Denduluri, MD

Previous estimates have placed the risk of developing AML/MDS after breast cancer therapy at around 1%, with the greatest risk seen among older patients and those who receive anthracyclines, higher cumulative doses of cyclophosphamide, and radiotherapy. It has not been established whether granulocyte colony-stimulating factors are correlated with increased risk, nor are incidence rates with taxane combinations well characterized. Denduluri and colleagues explored the oncology-specific electronic health record, iKnowMed, which contains nearly 1.3 million patient records. The

NOvEMbER 2012 I vOL 5, NO 10

base population included 20,900 breast cancer patients, of whom 11,295 received chemotherapy.

At a median follow-up time of about 3 years, 12 cases were identified among chemotherapy recipients (0.106%),

including 1 case among 2466 patients receiving pegfilgrastim and 11 cases among 8829 patients not receiving peg-

(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 Asthenic Conditionsa 9.0 44.4 9.3 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 c Disorders 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 e Infection Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.3 4.0 0.0 Anxiety 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

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Breast Cancer filgrastim. Among breast cancer patients not receiving chemotherapy, there were 16 cases (0.167%). The median time to onset of AML/MDS was 22 months. Risk was increased 7-fold among patients aged â&#x2030;Ľ70 years and nearly 4-fold among those who received anthracyclines. These were statistically significant effects, whereas the almost 3-fold increase with pegfilgrastim use was

Risk was increased 7-fold among patients aged â&#x2030;Ľ70 years and nearly 4-fold among those who received anthracyclines. numerically higher but not statistically significant, she said. â&#x20AC;&#x153;With the recent news that Robin Roberts with Good Morning America

----------------------------------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\@

www.TheOncologyNurse.com

developed MDS after beating breast cancer, many of my patients were concerned about the risk,â&#x20AC;? Denduluri said. â&#x20AC;&#x153;This study can reassure patients who receive

adjuvant chemotherapy that their risk of a secondary AML/MDS is very low within the first 3 years.â&#x20AC;? l Reference 1. Denduluri N, Espirito JL, Turnwald B, et al. Risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after adjuvant chemotherapy (CT) for early breast cancer (BC) in the community setting. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 62.

-------------------------------------- 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. ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV Â&#x2021; treatment during the course of treatment with XTANDI. ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG Â&#x2021; 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. ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW Â&#x2021; 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.

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

NOvEMbER 2012 I vOL 5, NO 10

NOW APPROVED for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previouslyy received docetaxel

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

• Seven patients (0.9%) out of 800 treated AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information 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. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients 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. Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

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 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

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. © 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.