Special Issue May 2012, Vol 5, No 2 by The Oncology Pharmacist

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MAY 2012

www.TheOncologyPharmacist.com

VOL 5, NO 3

ANNUAL REVIEW ISSUE

A Look at Recent Advances in Cancer Care

Cancer Cells Image:National Cancer Institute, Dr. Cecil Fox (Photographer)

Supportive Care Prevention and Treatment of Thromboembolism in Patients With Cancer Aaron D. Dush, PharmD, CACP

Use of Bone-Modifying Agents in Oncology Patients Raj Duggal, PharmD

Hematologic Malignancies Myelofibrosis—A Myeloproliferative Neoplasm Catherine Bishop, DNP, NP, AOCNP

Melanoma Melanoma Image:Dr. Lance Liotta Laboratory

Recent Advances in the Treatment of Metastatic Melanoma Megan Hagerty, PharmD, BCOP

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NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE 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. Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

†

VELCADE IMPORTANT SAFETY INFORMATION 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

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IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. 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. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. 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(5):431-440.

2:35 PM

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Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection 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.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 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 (bortezomib) 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.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). 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. 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 V-12-0017a 03/12

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Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK

ASSOCIATE EDITOR-IN-CHIEF

Steve Stricker, PharmD, MS, BCOP

Samford University McWhorter School of Pharmacy Birmingham, AL

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

David Baribeault, RPh, BCOP Boston Medical Center Boston, MA

Betty M. Chan, PharmD, BCOP USC/Norris Cancer Hospital Los Angeles, CA

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Indiana University Simon Cancer Center Indianapolis, IN

Rebecca S. Finley, PharmD, MS Jefferson School of Pharmacy Philadelphia, PA

David C. Gammon, BSPh OncologyPharmacist.net Warwick, RI

Indiana University Hospital Indianapolis, IN

Emily Mackler, PharmD, BCOP University of Michigan Health System & College of Pharmacy Ann Arbor, MI

Laura Boehnke Michaud, PharmD, BCOP, FASHP The University of Texas MD Anderson Cancer Center Houston, TX

Desert Regional Medical Center Palm Springs, CA

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Burt Zweigenhaft, BS

BioPharma Partners LLC New York, NY

Marlo Blazer, PharmD, BCOP James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Maine Center for Cancer Medicine Scarborough, ME

www.TheOncologyPharmacist.com

Lew Iacovelli, BS, PharmD, BCOP, CPP Moses H. Cone Health System Greensboro, NC

LeAnn Best Norris, PharmD, BCPS, BCOP South Carolina College of Pharmacy Columbia, SC

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

MAY 2012 I VOL 5, NO 3

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From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Joe Chanley joe@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Managing Editor Kristen Olafson kristen@greenhillhc.com

his month’s Fourth Annual Review Issue of The Oncology Pharmacist (TOP) highlights some of the advances in cancer care over the past year. While this issue presents several of the most noteworthy developments, we could only scratch the surface of all that has happened in the world of oncology. One needs only to look at the total number of abstracts presented at the American Society of Hematology and the American Society of Clinical Oncology annual meetings to know how much potentially practice-changing research is in the pipeline. Some of these developments have been presented in previous issues, while others will be featured in upcoming issues as researchers release updated data from ongoing studies. Although each issue of TOP features articles that illustrate

Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Jackie Luma Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® 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 Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® 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 Pharmacist® 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.

MAY 2012 I VOL 5, NO 3

how rapidly practices are changing—everything from the expanding use of oral oncolytics to the increasing role of personalized medicine in oncology—this issue in particular points out how important it is for oncology pharmacists to be aware of all these advances both for themselves and for their patients. Newer therapies bring about changes to daily practice, and informed pharmacists can better help their patients understand these treatments. Visit our Web site, www.TheOncologyPharmacist. com, and tell us how you feel about what you see in TOP—in print and online. We want to know the positive and the negative. Let us know what topics you want us to cover. Is there a specific issue you would like us to examine? We want to hear from you and we appreciate your feedback. ●

Noteworthy Numbers

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

™

Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

The leading cause of cancer death among men and women is lung cancer. According to the American Cancer Society (ACS), more people die of lung cancer than of breast, colon, and prostate cancers combined. Because this deadly disease affects so many Americans, lets delve into these lung cancer–related statistics.

Lung cancer (both small cell and non–small cell) is the second most common cancer in both men (after prostate cancer) and women (after breast cancer). Approximately 14% of all new cancers are lung cancers. The ACS’s most recent estimates for lung cancer in the United States for 2012 include: • New diagnoses totaling 226,160 ■ 116,470 in men ■ 109,690 in women • An estimated 160,340 deaths ■ 87,750 in men ■ 72,590 in women

• Deaths will account for

approximately 27% of all cancer deaths Lung cancer occurs more often in older people. From 2004-2008, the average age at the time of lung cancer diagnosis was approximately 71 years; the percentage of patients diagnosed according to age was approximately: • 0.2% between 20 and 34 • 1.6% between 35 and 44 • 8.8% between 45 and 54 • 20.9% between 55 and 64 • 31.1% between 65 and 74 • 29.0% between 75 and 84 • 8.3% for 85+ years of age Since 1994, death rates have declined consistently for

men at a rate of about 3% each year. Currently, the risk of developing lung cancer during a man’s lifetime is about 1 in 13. After increasing for several decades, the death rates for women with lung cancer have stabilized since 2003. Currently, the possibility of developing lung cancer is lower for women than men—about 1 in 16. The 1-year survival rate for all people diagnosed with lung cancer is 43%. Sources: www.cancer.org/Cancer/Lung Cancer-Non-SmallCell/DetailedGuide/ non-small-cell-lung-cancer-key-statis tics; www.cancer.net/patient/Cancer+ Types/Lung+Cancer?sectionTitle=Statisti cs; http://seer.cancer.gov/statfacts/html/ lungb.html.

www.TheOncologyPharmacist.com

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Supportive Care

Prevention and Treatment of Thromboembolism in Patients With Cancer By Aaron D. Dush, PharmD, CACP The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University

he link between cancer and thrombosis has been known for many years. Recently this connection has come to the forefront with increased recognition by healthcare providers and mandates by governing bodies. The results of a thromboembolic event can be catastrophic in a patient with cancer. Malignant neoplasms alone are associated with a 4-fold increased risk of a venous thromboembolic event (VTE), and cytotoxic or immunosuppressive chemotherapy increases the malignant neoplasm–associated risk to more than 6-fold.1,2 VTE leads to a significant reduction in survival3-5 and is the second-leading cause of death in patients with cancer.6 Patients with cancer who have a VTE are also at increased risk of recurrence, bleeding complications, and morbidity.7 Patients with cancer have multiple factors that increase their risk of VTE. First, the cancer itself produces a hypercoaguable state for these patients. Certain cancers appear to carry a higher risk than others (malignant brain tumors; adenocarcinoma of the lung, ovary, pancreas, colon, stomach, prostate, and kidney; and hematologic malignancies),8 but all cancers will increase the patient’s overall VTE risk. The patient’s therapy also plays a major role in the risk of VTE. Many newer chemotherapeutic agents, such as bevacizumab, carry an increased risk of thromboembolism.9 VTE risk increases 2- to 5-fold when women with breast cancer are treated with tamoxifen.10,11 Aromatase inhibitors also increase this risk, but at about half the rate of tamoxifen.12 Thalidomide or lenalidomide increases thromboembolic risk, especially when used in combination with chemotherapy or highdose dexamethasone.13 All of these are additive to the other general risk factors that these patients may already be exposed to, such as decreased mobility, surgeries or procedures, age, indwelling catheters, and other comorbidities. Due to the high risk faced by cancer patients, many guidelines have been developed to help assist in the prevention and treatment of thromboembolic events in these patients. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and the American College of Chest Physicians (CHEST)

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have issued guidelines to help practitioners prevent and treat thrombosis in patients with cancer. These guidelines have much overlap in their recommendations, and rightfully so. I will attempt to give a brief summary of some of these guidelines specific to patients with cancer (Table). For prevention of VTE, all 3 societies agree that pharmacologic prophylaxis should be initiated in hospitalized cancer patients in the absence of contraindications.14-16 Low-dose unfractionated heparin (LDUH), lowmolecular-weight heparin (LMWH), or fondaparinux should be utilized. Pharmacologic prophylaxis would be contraindicated in patients who are bleeding or have a high risk for major bleeding. In these patients, consider mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression. If the thrombotic risk persists once the bleeding risk has subsided, the use of pharmacologic prophylaxis should be reassessed and substituted for mechanical prophylaxis.

For prevention of VTE in the surgical patient with cancer, again all 3 societies agree. The guidelines recommend extended prophylaxis for surgical cancer patients for up to 4 weeks, particularly in high-risk abdominal or pelvic surgery.14,15,17 All 3 recommend LMWH. NCCN and ASCO also support unfractionated heparin as an alternative, and NCCN supports fondaparinux as well. Mechanical methods can be added to pharmacologic prophylaxis in patients at highest risk. For patients in the ambulatory setting, the societies previously agreed that routine prophylactic anticoagulation was not recommended except in patients with multiple myeloma who were receiving thalidomide- or lenalidomidebased combination regimens and in whom the risk of VTE warranted prophylaxis.14,15 The latest additions to the CHEST guidelines have extended this recommendation. These guidelines suggest that outpatients with solid tumors who have additional risk factors for VTE but who have a low risk for bleeding use

Aaron D. Dush, PharmD, CACP

prophylactic doses of LMWH or LDUH over no prophylaxis.16 The additional risk factors include previous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, and again thalidomide or lenalidomide therapy. This recommendation is based on moderate-quality evidence of reduction in mortality and high-quality evidence of reduction in VTE. These effects were larger than any plausible increase in bleeding risk. For patients with cancer who have indwelling central venous catheters (CVCs), routine prophylactic anticoagulation is not recommended.14-16 Over the next few years, more evidence may become available on the efficacy and cost-effectiveness, and specific groups of patients with CVCs that may benefit from prophylaxis, taking into consideration VTE risk versus bleeding risk. Continued on page 8

Table Recommendations for Prevention and Treatment of VTE in Patients With Cancer ASCO

CHEST

NCCN

Prevention of VTE in the Prophylactic anticoagulation hospitalized patient with considered for all in the cancer absence of contraindications

Prophylactic anticoagulation Prophylactic anticoagulation considered for all in the considered for all in the absence of contraindications absence of contraindications

Prevention of VTE in the Extended prophylaxis up to surgical patient with 4 weeks postprocedure cancer high-risk surgery

Extended prophylaxis up to 4 weeks postprocedure high-risk surgery

Prevention of VTE in the Not recommended except ambulatory patient with with thalidomide/ cancer lenalidomide-based regimens

Prophylactic anticoagulation Not recommended except with suggested in patients with thalidomide/lenalidomidesolid tumors who have addi- based regimens tional risk factors for VTE and who are at low risk of bleeding

Prevention of VTE in patients with CVC and cancer

Not recommended

Treatment of VTE in patients with cancer

LMWH preferred and treated indefinitely as long as cancer persists

LMWH preferred and treated LMWH preferred and treated indefinitely as long as cancer indefinitely as long as cancer persists persists

Treatment of catheterrelated thrombosis in patients with cancer

Extended prophylaxis up to 4 weeks postprocedure high-risk surgery

Not recommended

Anticoagulation as long as Anticoagulation as long as catheter is in place or at least catheter is in place or at least 3 months after removal 3 months after removal

Abbreviations: ASCO, American Society of Clinical Oncology; CHEST, American College of Chest Physicians; CVC, central venous catheter; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolic event.

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Supportive Care Prevention and Treatment of Thromboembolism... For treatment of VTE in cancer patients, therapy is driven by the findings of the CLOT trial.18 This trial was conducted over a 6-month period. It compared the efficacy of LMWH (dalteparin) to oral anticoagulation in the

prevention of recurrent thrombosis in patients with cancer. The trial showed no significant difference in bleeding risk or 6-month mortality but did show a statistically significant difference in recurrent thromboembolism at 6

Continued from page 7

months favoring the LMWH group. When treating cancer patients who have a pulmonary embolism (PE) or deep vein thrombosis (DVT), LMWH is the preferred agent. These patients should be treated indefinitely as long

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MAY 2012 I VOL 5, NO 3

NO SHORTAGE OF COMMITMENT.

as they have active cancer or risk factors persist.14,15,19 Well-managed vitamin K antagonists, such as warfarin, may be an acceptable alternative when LMWH is not advisable. This may be true in patients who cannot afford LMWH, patients who are opposed to daily injections, or those who have renal insufficiency. As for the dose of LMWH, in the CLOT trial dalteparin was given at 200 IU/kg once daily for the first month then 150 IU/kg once daily for the remaining 5 months.18 Enoxaparin carries an indication for inpatient treatment of DVT with or without PE at a dose of 1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours. For outpatient DVT without PE, the indicated dose is 1 mg/kg every 12 hours.20 Both indications are in conjuction with the initiation/administration of warfarin. The quality of evidence comparing once-daily versus twice-daily LMWH is low because of impression and inconsistency in studies comparing the 2 types of administration. A metaanalysis of studies showed similar rates of mortality, recurrent DVT, and major bleeding.21 Keep in mind, these studies were not for long-term treatment with LMWH. LMWH was administered for a period of 5 to 10 days in conjunction with a vitamin K antagonist. The study by Merli and colleagues, published in Annals of Internal Medicine in 2001, suggested that outcomes may be inferior with once-daily versus twice-daily regimens.22 In the subset of patients with malignancy, the study showed a 12.2% rate of recurrence with the once-daily dose and only a 6.4% rate of recurrence with the twice-daily group; however, statistical significance was not achieved. This study also did not include long-term use of LMWH. These studies did lead to the latest CHEST recommendation for patients with acute DVT of the leg treated with LMWH. They suggest once-daily over twice-daily administration, but this recommendation applies only if the approved once-daily regimen uses the same total daily dose as the twice-daily regimen.19 This would be true for dalteparin using 200 IU/kg once daily but not for enoxaparin that uses 1.5 mg/kg once daily (twice-daily dose is 1 mg/ kg every 12 hours). This recommendation could then be interpreted as indicating that the preferred treatments are dalteparin 200 IU/kg every 24 hours or enoxaparin 1 mg/kg every 12 hours. The recommendation carries a 2C grade from CHEST, which is a weak recommendation with low- or very low-quality evidence. In patients with cancer, again based on the CLOT trial that did study long-term LMWH ther-

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Supportive Care apy, clinicians should utilize LMWH dosing where the full total daily dose is utilized. Dalteparin is the only LMWH to carry a treatment indication for patients with cancer at 200 IU/kg daily for the first month, then 150 IU/kg daily. If we carry this to a class indication, enoxaparin should be dosed at 1 mg/kg every 12 hours initially for treatment of VTE in patients with cancer. Also, one must remember that LMWH is eliminated renally, so dose adjustments may be necessary based on the patient’s renal function. For the treatment of catheter-related thrombosis, it is suggested that the catheter not be removed if it is still functioning. The treatment for this thrombosis is based on whether the catheter is or is not removed. If the catheter is removed, the patient should be treated for 3 months after the catheter is removed. If the catheter is not removed, the patient should be treated with anticoagulation therapy as long as the catheter remains in place.15,19 Two new oral anticoagulants have recently joined the market, and more are in the pipeline. These will most likely be approved in the next few years, as will additional indications for the oral anticoagulants already available. Two agents that have recently been approved are dabigatran (Pradaxa) and rivaroxaban (Xarelto). Dabigatran is a direct thrombin inhibitor, and rivaroxaban is a selective inhibitor of factor Xa. Currently both are approved for nonvalvular atrial fibrillation, and rivaroxaban is also approved for DVT prophylaxis post knee and hip replacement.23,24 Neither is currently approved for the treatment of VTE. The goal for any of the new anticoagulants is to develop an agent that is oral, requires minimal monitoring, has a predictable and rapid effect, has a large therapeutic index, and has minimal drug interactions. Dabigatran is a twice-daily medication, whereas rivaroxaban is given once daily. Both are eliminated by the kidneys, so are contraindicated in patients with renal impairment. They do have a rapid onset and a larger therapeutic index. There are no regular monitoring recommendations with these agents. Although these medications seem to make anticoagulation therapy simpler, there are a few things to consider in patients with cancer. There is currently no reversal agent available to completely reverse the anticoagulation effect of these agents. This plays a major role in anticoagulation therapy in patients with cancer who are already at a higher risk of bleeding. With the rapid onset and rapid clearance of these agents, a short half-life syndrome can result. If compliance is an issue, patients on these medications can return to baseline after

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missing only 1 or 2 doses, which can rapidly increase their risk of a thromboembolic event. An interesting phase 2 trial by Levine and colleagues that was recently published in the Journal of Thrombosis and Haemostasis initiated patients receiving chemotherapy on apixaban for 12 weeks.25 Apixaban is a factor Xa inhibitor that is not yet approved by the FDA. These were patients without a prior history of VTE. The outcomes were to determine major or clinically relevant nonmajor bleeding, VTE, and adverse events related to the drug. The trial did show a low bleeding risk for these patients and a decrease in VTE. The study protocol did potentially select for patients with a lower bleeding risk by not including patients with a prolonged bleeding time or patients receiving moderate to high doses of aspirin or other antiplatelet agents, and caution should be used when extrapolating these results to a less selective population. This does introduce what may be on the horizon for anticoagulation and cancer and the use of the newer agents. Further studies will need to be completed to support these findings. In cancer patients in whom bleeding risk is already elevated, a clear picture of the real-life bleeding risk associated with these agents is still not available. Lack of monitoring may actually be a negative in these patients. With the other agents, we have a standard laboratory value that can measure the extent of the patient’s anticoagulation. There is no standard laboratory value to measure the newer agents. Certain anticoagulation markers may be elevated with therapy, but there is no direct correlation to the actual level of anticoagulation. With cancer patients receiving chemotherapy and having frequent procedures or surgeries, we cannot assess their true bleeding risk. In patients with cancer, these medications should be used with extreme caution until more postmarketing data are available and analyzed. ● References

1. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815. 2. Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-722. 3. Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24:1112-1118. 4. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-464. 5. Sørensen HT, Mellemkjaer L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343: 1846-1850.

6. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-634. 7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484-3488. 8. Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol. 2001;73:137144. 9. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285. 10. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation. 2003;107(23 suppl 1):I17-I21. 11. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97:1652-1662. 12. Thürlimann B, Keshaviah A, Coates AS, et al. Breast International Group (BIG)1-98. Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747-2757. 13. El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and thrombosis. A meta-analysis. Thromb Haemost. 2007;97:1031-1036. 14. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505. 15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease. Version 1.2009. http://www. oncologycast.net/guidelinecasts/NCCN_Guidelines.pdf. Accessed April 26, 2012.

16. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e195S-e226S. 17. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e227S-e277S. 18. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. 19. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e419S-e494S. 20. Lovenox [package insert]. Bridgewater, NJ: sanofiaventis US LLC; 2011. 21. Couturaud F, Julian JA, Kearon C. Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis. Thromb Haemost. 2001;86:980-984. 22. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134:191202. 23. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2012. 24. Xarelto [package insert]. Leverkusen, Germany: Bayer HealthCare; 2011. 25. Levine MN, Gu C, Liebman HA, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807-814.

Oncology Pharmacist Winchester Hospital Reno Oncology Center Winchester MA

Full-time, Monday–Friday 8:30am–5pm, Day shift Our new comprehensive Cancer Care Center located at 620 Washington Street in Winchester, MA incorporates a coordinated team approach including radiation oncologists, medical oncologists, surgeons, pharmacists, nurses and support staff. We offer advanced radiation therapy treatment, Holistic treatment as well as integrative therapies. Our Cancer Care Center offers a comforting, healing environment for every patient’s cancer care journey — comprehensive cancer care in one place, close to home. The Oncology Pharmacist compounds and dispenses medications and other pharmaceutical supplies according to established operational procedures as prescribed by physicians and other qualified hospital personnel. This position reviews medication orders, obtains clarifications when necessary in addition to regularly consulting with Medical Staff, Nursing personnel and others to coordinate delivery of high quality pharmaceutical services to patients. Massachusetts Licensed Pharmacist required. At least 1 year of experience in an Oncology practice setting preferred. Doctor of Pharmacy

or residency training in Oncology area is a plus. Candidate must be able to effectively create, manipulate and employ common microcomputer applications including word processing, spreadsheets, pharmaceutical informational databases, and Pharmacy computerized purchasing systems. Position requires the ability to input data and maintain an Oncology EMR system (Mosaiq) and Pharmacy Meditech module. Winchester Hospital is a 229-Bed Community Hospital and the first community hospital in Massachusetts to receive Magnet Recognition for nursing excellence. We are continuously named by the Boston Business Journal and The Boston Globe as a best place to work in Massachusetts. Winchester Hospital offers a full comprehensive benefits package that includes 403(b) plan, choice of medical and dental plans, short- and long-term disability insurance, life insurance and more!

Please apply online at:

www.winchesterhospital.org For inquiries, please contact: Deb Coen-Coder, Senior HR Business Partner Winchester Hospital, 41 Highland Ave. Winchester, MA 01890 Email: dcoencoder@winhosp.org

Winchester Hospital is an Equal Opportunity Employer.

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Supportive Care

Use of Bone-Modifying Agents in Oncology Patients By Raj Duggal, PharmD Indiana University Simon Cancer Center, Indianapolis

Raj Duggal, PharmD

ith advances in the diagnosis and treatment of cancer, the estimated 5-year survival rate for cancer patients has significantly improved to approximately 67%.1 The most common malignancies in men and women in the United States—breast and prostate cancers— have 2 of the highest 5-year survival rates reported, at 90% and 99%, respectively.1 As oncology patients are living longer, bone health has become a pertinent issue in the treatment of both metastatic and nonmetastatic oncology patients.2 Bone metastases have been identified in approximately 68% of patients with metastatic prostate cancer and 73% of patients with metastatic breast cancer.2 Even though bone metastases are not typically life threatening, their complications, including severe pain, bone fractures, and spinal cord compression, can cause significant morbidity.3 Pharmacologic therapies utilized in the treatment of metastatic and nonmetastatic cancer, including hormone deprivation and corticosteroids, can stimulate osteoclast activity and result in bone demineralization. Prolonged therapy may result in significant bone loss leading to osteoporosis and bone fractures in both the metastatic and nonmetastatic populations.2 Bone Health in Metastatic Cancer In 2011, the American Society of Clinical Oncology (ASCO) published updated guidelines on the role of bonemodifying therapies in the management of metastatic breast cancer. While prior guidelines did include management of treatment-associated bone loss, ASCO limited this publication update to metastatic disease.4 Key changes in recommendations from this ASCO guideline update include4: • Bone-modifying agents are recommended for patients with metastatic disease and evidence of bone destruction; the following agents are recommended (none is recommended over another):

MAY 2012 I VOL 5, NO 3

– Denosumab 120 mg subcutaneously (SC) every 4 weeks – Zoledronic acid 4 mg intravenously (IV) over at least 15 minutes every 3 to 4 weeks – Pamidronate 90 mg IV over at least 2 hours every 3 to 4 weeks • Bone-modifying agents should be utilized as an adjunctive therapy, not as first-line treatment, for cancer-related bone pain, in addition to standard-of-care pain-management strategies (eg, nonsteroidal anti-inflammatory agents, opioid and nonopioid analgesics) This published guideline limits discussion to metastatic breast cancer with bone metastases.4 Since other solid tumors, including prostate cancer, frequently metastasize to the bone, clinicians should similarly support the implementation of bone-modifying therapies to promote bone health and decrease skeletal-related events in patients with bone metastases due to solid tumors.3

months to include the following7: • Treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer • Treatment of postmenopausal women with osteoporosis at high risk for fracture Also in 2011, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) submitted a position paper on preventing bone loss and fractures in postmenopausal women receiving aromatase inhibitors for breast cancer.8 At a minimum, the final publication recommends measuring serum concentrations of parathyroid hormone, calcium, and 25-OH vitamin D prior to initiation of an aromatase inhibitor to establish the risk for osteoporosis. Pharmacologic interventions, including vitamin D and calcium supplementation, should be considered for all

Bone health has become a pertinent issue in the treatment of both metastatic and nonmetastatic oncology patients. Bone Health in Nonmetastatic Cancer Some anticancer treatments commonly seen in breast and prostate cancer, including hormone deprivation and corticosteroids, increase osteoclast activity and result in loss of bone mass.2 Bone-modifying therapy should be considered for cancer patients with 1 of the following2: • T-score below -2.0 or • 10-year Fracture Risk Assessment Tool (FRAX) score: – 3% for hip fractures – >20% for all major fractures In 2011, the US Food and Drug Administration (FDA) completed the evaluation of the two phase 3 clinical trials of denosumab 60 mg SC every 6 months to prevent bone loss. These trials included patients with prostate cancer receiving androgen-deprivation therapy and breast cancer receiving aromatase inhibitors.5,6 As a result of these studies, the FDA expanded the approved indications for denosumab 60 mg SC every 6

patients receiving aromatase inhibitors to promote bone health.8 Bone-modifying therapy with either zoledronic acid 4 mg IV over at least 15 minutes every 6 months or denosumab 60 mg SC every 6 months should be considered in patients with osteoporosis or osteopenia with risk factors for fractures and continue as long as aromatase inhibitor therapy is maintained.8 There is no clear recommendation for bisphosphonate therapy in nonmetastatic prostate cancer for patients receiving androgen-deprivation therapy. Recent evaluations have studied zoledronic acid 4 mg IV every 3 months for 1 year and found that therapy improved bone mineral density. The FDA has approved the use of alendronate, risedronate, and zoledronic acid in men to decrease fractures and increase bone density.9 Oral bisphosphonate therapy can be considered as an alternative to IV therapy, but these agents may be associated with additional adverse effects and vari-

able compliance. In an evaluation on medication adherence, preference, and satisfaction in 250 postmenopausal women with low bone-mineral density, investigators determined that patients were significantly more compliant with denosumab 60 mg SC every 6 months compared with alendronate 70 mg by mouth once weekly.10 Additionally, at 12 months’ follow-up, those receiving denosumab were more likely to report being very satisfied or quite satisfied with the dosing frequency, route of administration, convenience, and overall satisfaction with treatment.10 Nonpharmacologic interventions should also be considered to further promote bone health. Additional supportive care measures include smoking cessation, minimizing alcohol consumption, and dietary supplementation with calcium (1000-1200 mg by mouth daily) and vitamin D (approximately 10,000 IU by mouth daily).8,9 Drug Safety Monitoring Safety concerns with bone-modifying therapies include, but are not limited to, renal toxicity, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures.4,11,12 Appropriate monitoring should occur at initiation of treatment and with each dose to minimize severe toxicities.4 The ASCO guidelines recommend the following for patients receiving bone-modifying therapies4: • Serum creatinine should be monitored prior to each dose of bisphosphonates • Serum calcium, electrolytes, phosphate, magnesium, and hemoglobin/hematocrit should be monitored regularly [no specific recommendation provided on the interval] • Calcium should be followed closely during denosumab therapy if the calculated creatinine clearance is less than 30 mL/min [no specific recommendation provided on the interval] • Prior to initiation of bone-modifying therapies, all patients should undergo a dental examination and preventive dentistry to minimize osteonecrosis of the jaw Although bisphosphonates are known to strengthen bone and prevent fractures, there have been reports that long-term therapy can lead to fragile bones and atypical fractures of the subtrochanteric or diaphyseal femur after minimal or no trauma; these atypical fractures account for less than 1% of hip

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Supportive Care and femur fractures overall.11-13 A safety announcement published by the FDA as an update to the bisphosphonate drug safety review in 2010 indicated that it is yet unclear whether these atypical fractures are related to bisphosphonate therapy; this safety evaluation is ongoing.13 Since this FDA update, 2 studies evaluating the rates of atypical fractures in nononcology patients with osteoporosis have been published. As described below, the studies do not rule out a correlation between bisphosphonate therapy and atypical fractures, but they do confirm that the rates of atypical femur fractures are very low with concurrent bisphosphonate therapy.11,12 In the first study, an evaluation of 12,777 Swedish women with femur fractures identified atypical fractures in 59 patients.11 The investigators concluded that, because 46 of the 59 patients with atypical fractures were on bisphosphonate therapy, there was a 47-fold increased risk compared to nonusers. Based on these results, they estimated that it would take 2000 bisphosphonate users per year to have 1 case of atypical fracture to occur.11 In the second study, investigators compared the incidence of atypical fractures between patients receiving either bisphosphonate therapy or nonbisphosphonate therapy (raloxifene or calcitonin) in 33,815 patients.12 Over the median follow-up of 2.13 years, 104 subtrochanteric or diaphyseal femur fractures occurred. There was no significant difference in the incidence of atypical femur fractures between bisphosphonate users and nonusers, however.12 Nevertheless, the authors could not eliminate the possibility that bisphosphonate therapy could increase the risk of atypical fractures with prolonged use.12 Ongoing Clinical Evaluations Many studies investigating novel therapies in the management of bone health are currently ongoing. New promising approaches to the management of bone health include tyrosine kinase inhibitors (dasatinib, cabozantinib, and saracatinib), endothelin-A receptor antagonists (atrasentan and zibotentan), and bisphosphonates tagged with radiopharmaceuticals.4,14,15 It is to be hoped that these novel therapies will provide more options for clinicians to manage the bone health of oncology patients. ●

modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29:1221-1227. 5. Smith, MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745-755. 6. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26:4875-4882. 7. Prolia [package insert]. Thousand Oaks, CA: Amgen Inc; September 2011. 8. Rizzoli R, Body JJ, De Censi A, et al; on behalf of the European Society for Clinical and Economical Aspects of Osteoporosis and Osteoarthritis (ESCEO). Guidance ! !! fractures !! in! post!! for the prevention of bone loss and

menopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper [published online ahead of print January 24, 2012]. Osteoporos Int. doi:10.1007/s00198-011-1870-0, http://www.springer link.com/content/0754828832806p24/fulltext.pdf. Accessed April 16, 2012. 9. Adler RA. Management of osteoporosis in men on androgen deprivation therapy. Maturitas. 2011;68:143147. 10. Kendler DL, McClung MR, Freemantle N, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporosis Int. 2011;22:1725-1735. 11. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral ! shaft. N Engl J Med. 2011;364:1728-1737.

12. Kim SY, Schneeweiss S, Katz JN, et al. Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res. 2011;26:993-1001. 13. US Food and Drug Administration. FDA drug safety communication: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. http://www. fda.gov/drugs/drugsafety/ucm229009.htm. Published October 13, 2012. Accessed April 18, 2012. 14. Hannon RA, Finkelman RD, Clack G, et al. Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a phase I study. Bone. 2012;50:885-892. 15. Saylor PJ, Lee RJ, Smith MR. Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol. 2011;29:3705-3714.

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“Managing patients with myeloma means staying current.” Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

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References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 2. Gralow JR, Biermann JS, Farooki A, et al. NCCN task force report: bone health in cancer care. J Natl Compr Netw. 2009;7(suppl 3):S1-S32. 3. Coleman RE, Guise TA, Lipton A, et al. Advancing treatment for metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res. 2008;14:6387-6395. 4. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-

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www.ValueBasedMyeloma.com Value-Based Care in Myeloma $'(/(0+;#$*/-$1,(17(B,>/>"(A"/#-<*/&"(I1==+,$*/-$1,'2(/(="=;"&(17(@<"(F4,)(N&1+05(O(PQRP(9##(&$><-'(&"'"&%"!5 8UIIQRRPV8UK9'$W"B,>/>"

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Myelofibrosis

Myelofibrosis—A Myeloproliferative Neoplasm By Catherine Bishop, DNP, NP, AOCNP, Hematology/Oncology Nurse Practitioner Lansdowne, Virginia

Prognostic Factors Cytopenias

Weight loss

Constitutional symptoms

Low or high white cell count

Transformation to acute leukemia •Blast percent

Increasing bone marrow fibrosis

Catherine Bishop, DNP, NP, AOCNP

yeloproliferative neoplasms (MPNs) are somewhat rare chronic hematologic malignancies. There are no known cures, but the disease itself is treatable. According to the World Health Organization’s revised WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues, MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis (IMF), also referred to as primary myelofibrosis (Table 1).1 IMF, ET, and PV are considered Philadelphia chromosome (Ph) negative. Chronic myelogenous leukemia (CML) is considered Ph positive. This review article will focus on IMF, and the new treatment approved by the US Food and Drug Administration (FDA). In 1951, William Dameshek, a preeminent American hematologist, described the concept of myeloproliferTable 1 WHO 2008 Revised Classification of MPNs1 CML (BCR-ABL1–positive) Polycythemia Vera (PV) 1. Chronic-phase PV 2. Post-PV myelofibrosis 3. Blast-phase PV Essential Thrombocythemia (ET) 1. Chronic-phase ET 2. Post-ET myelofibrosis 3. Blast-phase ET Primary Myelofibrosis 1. Chronic-phase primary myelofibrosis 2. Blast-phase primary myelofibrosis Abbreviations: CML, chronic myelogenous leukemia; MPNs, myeloproliferative neoplasms. Adapted from Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951.

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Low total cholesterol

Progressive splenomegaly/hepatomegaly

Figure. Clinical Manifestations of Idiopathic Myelofibrosis Indicated in Worsening Prognosis9 Adapted from “Development of New Therapies for Myelofibrosis” presentation by Srdan Verstovsek, MD, PhD, Associate Professor, Department of Leukemia, University of Texas, MD Anderson Cancer Center.

ative disorders by grouping together CML, ET, PV, IMF, and erythroleukemia. He articulated that a self-perpetuating trilineage myeloproliferation underlined their pathogenesis.2 Etiology IMF is a disorder of the blood cells wherein the bone marrow reveals fibrous tissue, and lab values demonstrate varying degrees and combinations of leukopenia, anemia, and thrombocytopenia. The disease is thought to originate from the neoplastic transformation of a single hematopoietic stem cell. The disease presents either de novo or in the setting of PV or ET.3 Bone marrow morphology is critical to the diagnosis and will generally show a dramatic increase in reticulin fibers and collagen together with a loss of normal hematopoietic cells. Additionally, normocytic anemia with nucleated red blood cells and an increase in megakaryocytes is seen on histologic examination.4 The disease affects both men and women equally and is usually diagnosed in the fifth to seventh decade of life. There are no known risk factors, but there have been reports that myelofibrosis may be linked to immunologic-mediated hyperplasia of marrow suggestive of lupus erythematosus, and other connective tissue diseases.4 Additionally, exposure to benzenes or high-dose ionizing radiation has preceded the diagnosis of primary myelofibrosis.5 Prognosis varies accord-

ing to a set of clinical factors, including hemoglobin level, constitutional symptoms, circulating blasts, leukocyte count, and cytogenetics.6 Morbidity and mortality are commonly associated with leukemic transformation, infection, portal hypertension, and thrombohemorrhagic events.7

Approximately one-quarter of patients with idiopathic myelofibrosis are asymptomatic at the time of diagnosis.

Clinical Presentation and Diagnosis Approximately one-quarter of patients with IMF are asymptomatic at the time of diagnosis.8 Patients who are symptomatic may present to the primary care provider with complaints of fatigue, weakness, shortness of breath, and weight loss. Some patients may also complain of left upper quadrant pain or discomfort due to splenomegaly.8 Lab values can be very broad. Normocytic-

normochromic anemia is present in almost all patients. In 1 study the hemoglobin concentration in patients at diagnosis was 9.5 to 11.6 g/dL, with a range of 4 to 20 g/dL among a total of 539 patients in 4 studies.8 Anisocytosis (variation in size) and poikilocytosis (variation in shape) are constant findings, as are teardrop-shaped red cells.7 Prognosis worsens with increased presence of the clinical manifestations listed above and shown in the Figure.9 In 2008, WHO recommended 2 sets of specific criteria (major and minor) to help clinicians make an accurate diagnosis (Table 2).10 Role of the Janus-Associated Kinase (JAK) Pathway Advances in the understanding of the pathogenesis of Ph-negative MPNs such as IMF have led to the discovery of the JAK2V617F mutation as a prospective therapeutic target.11 The JAK pathway plays a major role in blood cell production and immune and inflammatory responses.12 Overactivity or imperfections in this pathway are thought to be responsible, in part, for many disease states, including IMF. The JAK pathway sends out signals from blood cell growth factors, cytokines, or hormones outside the bone marrow stem cell to its nucleus. Under normal functioning of the bone marrow, suitable blood cell development and utility are ensured.12 There is a strong association between abnor-

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Myelofibrosis mal cell signaling in the JAK pathway and the development of MPNs.12,13

Table 2 Diagnostic Criteria for Primary Myelofibrosis (WHO 2008)10

Treatment Allogeneic stem cell transplantation (SCT) offers the possibility of cure for some patients with IMF.14 However, the risk of graft-vs-host disease, transplantrelated death, and relapse of the myelofibrosis requires careful selection of appropriate candidates. Until recently there were few, if any, treatments that provided hope for patients ineligible for transplant. Most of the treatment options were palliative in nature, intended to minimize anemia, neutropenia, or thrombocytopenia, as well as the many constitutional symptoms experienced by the majority of IMF patients. Given the essential role of the JAK pathway in blood cell production and immune function, scientists began researching the potential of JAK inhibition for treating patients with IMF.

Major diagnostic criteria 1. Megakaryocyte proliferation and atypia* 2. Not meeting WHO criteria for PV, BCR-ABL1−positive CML, MDS, or other myeloid neoplasm 3. Presence of JAK2V617F or other clonal marker or no evidence of secondary bone marrow fibrosis in absence of clonal marker

Approval of a New Drug On November 16, 2011, the FDA approved ruxolitinib (Jakafi) for the treatment of intermediate- and highrisk myelofibrosis.15,16 The oral drug is the first in a new class of drugs known as JAK inhibitors. The drug inhibits JAK1 and JAK2 pathways. The approval was based on results from 2 randomized phase 3 trials—COMFORT-I and COMFORT-II—which tested the drug in patients with postPV myelofibrosis and post-ET myelofibrosis. Patients in both trials were resistant or refractory to available therapy. Additionally, they were ineligible for SCT. The COMFORT trials established that patients treated with ruxolitinib experienced significant reductions in splenomegaly. COMFORT-I also demonstrated improvements in symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) and the MFSAF Total Symptom Score to include abdominal discomfort, pain under left ribs, satiety, night sweats, bone and muscle pain, and itching. Most patients on placebo had worsening of these symptoms.15 At the time of approval, 75% of the patients on study 1 and 67% on study 2 who achieved at least a 35% reduction in spleen volume maintained this

Given the essential role of the JAK pathway in

3 major criteria + 2 minor criteria must be met to confirm diagnosis.

Minor diagnostic criteria 1. Leukoerythroblastosis 2. Increase in serum lactate dehydrogenase 3. Anemia 4. Splenomegaly *Accompanied by either reticulin and/or collagen fibrosis, or in the absence of significant reticulin fibrosis, a prefibrotic cellular-phase disease. Abbreviations: CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.

blood cell production and immune function, scientists began researching the potential of JAK inhibition for treating patients with IMF.

reduction. The most common adverse events in both studies were thrombocytopenia and anemia. These were manageable and rarely led to discontinuation of the drug.16 The recom-

The oral drug is the first in a new class of drugs known as JAK inhibitors.

mended starting dose of ruxolitinib is 20 mg orally twice daily for patients with a platelet count above 200 x 109/L, and 15 mg twice daily for those with a platelet count between 100 and 200 x 109/L.16

Conclusion Patients diagnosed with IMF do not comprise a great proportion of patients in the oncology setting. However, their uncommon, mostly incurable disease makes them at least as vulnerable as those with the most commonly diagnosed cancers. Science has been focusing on personalized medicine, and for the few diagnosed with IMF, the JAK inhibitors represent a new option for IMF management. Based on the data from the COMFORT studies, ruxolitinib has been approved for use in patients with intermediate/high-risk myelofibrosis, offering patients some hope now, and for the future development of other targeted therapies. ● References

1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951. 2. Tefferi A. The history of myeloproliferative disorders:

before and after Dameshek. Leukemia. 2008;22:3-13. 3. Passamonti F, Malabarba L, Orlandi E, et al. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia. Haematologica. 2003;88:13-18. 4. el Mouzan MI, Ahmad MA, al Fadel Saleh M, al Sohaibani MO, al Gindan YM. Myelofibrosis and pancytopenia in systemic lupus erythematosus. Acta Haematol. 1988;80:219-221. 5. Tondel M, Persson B, Carstensen J. Myelofibrosis and benzene exposure. Occup Med (Lond). 1995;45:51-52. 6. Arana-Yi C, Quintás-Cardama A, Giles F, et al. Advances in the therapy of chronic idiopathic myelofibrosis. Oncologist. 2006;11:929-943. 7. Thiele J, Kvasnicka HM, Steinberg T, et al. Survival in primary (idiopathic) osteomyelofibrosis, so called agnogenic myeloid metaplasia. Leuk Lymphoma. 1992;6:389. 8. Lichtman MA. Idiopathic myelofibrosis (agnogenic myeloid metaplasia). In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:chap 95. http://med textfree.wordpress.com/2012/01/23/chapter-95. Accessed April 18, 2012. 9. Verstovsek S. Development of new therapies for myelofibrosis. Presented at Mayo Clinic, Scottsdale, Arizona, February 2009. 10. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. 11. Quintás-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10:127-140. 12. The JAK/STAT pathway: fact sheet. Novartis Oncology Web site. http://www.novartisoncology.com/ files/media/research/JAK-STAT%20Pathway%20 Fact%20Sheet_FINAL.pdf. Accessed April 1, 2012. 13. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008;83:491-497. 14. Bacigalupo A, Soraru M, Dominietto A, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant. 2010;45:458-463. 15. FDA approves Incyte’s Jakafi(TM) (ruxolitinib) for patients with myelofibrosis [press release]. Wilmington, DE: Incyte Corporation; November 16, 2011. http://investor.incyte.com/phoenix.zhtml?c=69764&p= irol-newsArticle&ID=1631201&highlight=. Accessed April 18, 2012. 16. Pazdur R. FDA approval for ruxolitinib phosphate. National Cancer Institute Web site. http://www.can cer.gov/cancertopics/druginfo/fda-ruxolitinibphosphate. Accessed April 4, 2012.

Did You Know?

Prospective data from a recent study links the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) with the increased risk for renal cell carcinoma. The use of acetaminophen and aspirin was not associated with the risk for renal cell carcinoma. —Arch Intern Med. 2011;171:1487-1493.

Visit our user-friendly Web site www.TheOncologyPharmacist.com In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!

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Melanoma

Recent Advances in the Treatment of Metastatic Melanoma By Megan Hagerty, PharmD, BCOP Oncology Clinical Pharmacist, IU Simon Cancer Center, Indiana University Health Affiliate Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, Purdue University

Megan Hagerty, PharmD, BCOP

n 2010, there were an estimated 68,130 new melanoma cases in the United States,1 of which approximately 2% to 5% presented with metastatic disease.2 Advanced melanoma remains an incurable and highly treatment-refractory tumor, with treatment response rates of only 10% to 25% and a median survival of 2 to 8 months (Table 1).3-8 According to the National Comprehensive Cancer Network (NCCN), consensus is minimal regarding first- and second-line chemotherapy for patients with metastatic melanoma.2 Until the US Food and Drug Administration (FDA) approved ipilimumab and vemurafenib in 2011, dacarbazine and interleukin-2

(IL-2) were the only drugs indicated for frontline therapy. Chemotherapy can be used for the palliative treatment of metastatic melanoma. Single-agent dacarbazine is still the â&#x20AC;&#x153;gold standardâ&#x20AC;? treatment against which many newer regimens have been compared. An optimal dosing schedule has yet to be determined, however, with doses ranging from 250 mg/m2/day on days 1-5 every 21 days to 1200 mg/m2 only on day 1 of the 21-day cycle.4,9 Response rates to dacarbazine range from 5% to 15%, with an overall survival (OS) of about 7 months.4,9 Temozolomide is an oral prodrug of dacarbazine that can cross the bloodbrain barrier. Similar to dacarbazine, temozolomide provides an objective response rate of 13.5%, with an OS of 7.7 months.4 Several other chemotherapy drugs have been used as single agents for the treatment of metastatic melanoma with similarly disappointing results, including carmustine, cisplatin, carboplatin, vinblastine, and paclitaxel.3 The disappointing response rates

with single-agent chemotherapy have led to the evaluation of combination chemotherapy as well as biochemotherapy regimens.3 Combination chemotherapy such as the Dartmouth regimen (tamoxifen, carmustine, cisplatin, and

In March 2011, ipilimumab received FDA approval for the treatment of metastatic melanoma.

dacarbazine) and CVD (cisplatin, vinblastine, and dacarbazine) were created to improve outcomes and enhance response rates. Biochemotherapy added immunologic manipulation with IL-2

Table 1 Selected Treatments for Metastatic Melanoma4-8 Regimen

Dose(s)

Response Rate, n (%)

Overall Survival

Dacarbazine (DTIC)4

250 mg/m2 IV d1-5 Repeat q3wk

Complete response: 4 (2.7) Objective response: 18 (12.1)

6.4 mo

Temozolomide4

200 mg/m2 PO d1-5 Repeat q4wk

Complete response: 4 (2.6) Objective response: 21 (13.5)

7.7 mo

High-dose interleukin-25

600,000 or 720,000 IU/kg IV q8h d1-5, d15-19 Maximum: 14 doses/5 days Repeat q6-12wk

Complete response: 17 (6) Partial response: 26 (10) Overall response: 43 (16)

Response duration in complete response: not yet reached Response duration in partial response: 5.9 mo

Dartmouth regimen6

Tamoxifen 10 mg PO BID Carmustine 150 mg/m2 IV d1, every other cycle Cisplatin 25 mg/m2 IV d1-3 Dacarbazine 220 mg/m2 IV d1-3 Repeat q3wk

Response rate: 22 (18.5)

7.7 mo

CVD7

Cisplatin 20 mg/m2 IV d1-4, d22-25 Vinblastine 2 mg/m2 IV d1-4, d22-25 Dacarbazine 800 mg/m2 IV d1, d22 Repeat q6wk

Response rate: 23 (25)

9.2 mo

Paclitaxel 175-225 mg/m2 IV Carboplatin AUC 7.5 Repeat q3wk

Partial response: 3 (20) Stable disease: 7 (47) Progressive disease: 5 (33)

9 mo

Paclitaxel/carboplatin8

Abbreviations: AUC, area under the curve; BID, twice a day; d, day; IV, intravenous; mo, month; PO, orally; q, every; wk, week.

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and/or interferon alfa to chemotherapy to try to improve response rates with synergistic mechanisms of action. However, a 2001 meta-analysis comparing singleagent dacarbazine with combination chemotherapy and biochemotherapy regimens failed to provide evidence that combination treatments are superior to single-agent dacarbazine.10 Although combination regimens provide an increase in response rates over singleagent dacarbazine, their use is associated with significant increases in toxicities and no increase in OS. Immunotherapy with high-dose IL-2 has shown promise in the treatment of this disease, with a small percentage of patients achieving a durable remission.5 IL-2 is secreted by CD4+ T lymphocytes and modulates immunologic effects by activating natural killer cells, B lymphocytes, and macrophages.11 Although overall response rates (ORRs) have been low at 16%, patients who were able to achieve a response did not progress for more than 30 months. However, the risk of severe life-threatening toxicities (eg, capillary leak syndrome) associated with high-dose IL-2 therapy requires careful patient selection and inpatient administration of the drug. In March 2011, ipilimumab received FDA approval for the treatment of metastatic melanoma. Ipilimumab is a monoclonal antibody targeted against the immune checkpoint receptor cytotoxic T lymphocyte antigen-4 (CTLA4).2,12 By blocking CTLA-4, ipilimumab augments T-cell activation and proliferation, thus enhancing the patientâ&#x20AC;&#x2122;s own immune response against the tumor. A phase 3 clinical trial evaluated ipilimumab alone or in combination with the cancer vaccine gp100 versus gp100 alone.13 In this study, previously treated patients with unresectable stage III or IV melanoma were randomized 3:1:1 to receive either ipilimumab 3 mg/kg plus gp100 peptide vaccine (n = 403), ipilimumab plus placebo (n = 137), or gp100 plus placebo (n = 136) every 3 weeks for 4 cycles. Pertinent exclusion criteria included autoimmune disease, untreated central nervous system metastases, or ongoing treatment with long-term systemic corticosteroids. The primary end point, best ORR, was amended to OS to align with results from multiple ipilimumab trials. The study found that the median OS significantly increased in patients

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Melanoma receiving ipilimumab, either alone or in combination, compared with the peptide vaccine gp100 alone: ORR was 10 months for ipilimumab/gp100, 6.4 months for gp100/placebo (hazard ratio [HR] for death, 0.68; P <.001), and 10.1 months for ipilimumab/placebo (HR for death vs gp100/placebo, 0.66; P = .003). There was no difference in OS detected between the 2 ipilimumab groups. The 12-month OS rates in the ipilimumab/gp100 group, ipilimumab/placebo group, and gp100/placebo group were 43.6%, 45.6%, and 25.3%, respectively. The 18- and 24-month OS rates followed a similar trend (Table 2).13 Adverse events were primarily immune related and occurred in 60% of patients receiving ipilimumab and 32% of those receiving gp100 alone. Immune-related events included diarrhea, rash, and endocrine effects. Diarrhea was the most common adverse event, present in 27% to 31% of patients in the ipilimumab groups. Administration of corticosteroids resolved the symptoms in about 2 weeks. Death attributed to study drug occurred in 14 patients (2.1%), of which 7 were attributed to immunerelated events.13 In a subsequent study, Robert and colleagues evaluated ipilimumab plus dacarbazine in previously untreated patients with metastatic melanoma.14 This phase 3 clinical trial randomized patients to receive ipilimumab 10 mg/kg plus dacarbazine 850 mg/m2 (n = 250) or dacarbazine plus placebo (n = 252) at weeks 1, 4, 7, and 10, both regimens followed by dacarbazine alone every 3 weeks until week 22 for the induction phase. Patients with stable disease or an objective response rate without doselimiting toxicities at week 24 were eligible to enter a maintenance phase, during which they received ipilimumab or placebo every 12 weeks until progression, toxicity, or end of the study period. The primary end point was again changed from progression-free survival (PFS) to OS. Treatment with ipilimumab plus dacarbazine resulted in significantly longer OS compared with dacarbazine plus placebo (11.2 months vs 9.1 months, P value not provided). Ipilimumab/dacarbazine therapy reduced the risk of progression by 24% compared with dacarbazine/placebo (HR for progression, 0.76; P = .006). Interestingly, after 6 months, some patients who were receiving ipilimumab had an improvement from partial to complete response. Immune-related adverse events occurred in 77.7% of ipilimumab/dacarbazinetreated patients and 38.2% of dacarbazine/placebo patients. Adverse event rates were similar to those seen in prior trials and included diarrhea, pruritus, and rash; however, the rates of grade 3

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Table 2 OS Rates in Patients Treated With Ipilimumab/gp100, Ipilimumab/Placebo, and gp100/Placebo13 OS Rate

Ipilimumab/gp100

Ipilimumab/Placebo

gp100/Placebo

12 mo

43.6%

45.6%

25.3%

18 mo 24 mo

30.0% 21.6%

33.2% 23.5%

16.3% 13.7%

Abbreviations: mo, month; OS, overall survival.

or 4 hepatic events (ie, AST/ALT elevations) were higher than in previous trials.14 BRAF is a serine/threonine kinase that is frequently activated by mutations in cancer.15 It is estimated that about 40% to 60% of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signaling through the MAPK pathway.15,16 Vemurafenib is a BRAF kinase inhibitor that specifically targets the BRAFV600E mutation, a mutation harbored by approximately 45% of patients with metastatic melanoma.2,17 In August 2011, vemurafenib was approved for the treatment of BRAFV600E-mutated unresectable or metastatic melanoma. The FDA simultaneously approved the Cobas 4800 BRAF V600 Mutation Test to determine eligibility for treatment with vemurafenib.16 FDA approval of vemurafenib was based, in part, on a pivotal phase 3 clinical trial by Chapman and colleagues that evaluated OS and PFS in previously untreated melanoma patients randomized to vemurafenib or dacarbazine.16 Patients were required to have stage IIIC or IV melanoma that tested positive for the BRAFV600E mutation. Pertinent exclusion criteria included untreated central nervous system metastases and the need for continued glucocorticoid therapy. Patients were randomized to receive vemurafenib 960 mg

Table 3 Immune-Mediated Adverse Reactions to Ipilimumab12 System Organ Class Gastrointestinal

Diarrhea Abdominal pain Blood or mucus in the stool Bowel perforation Peritoneal signs Ileus

Liver Skin

Abnormal (elevated) liver function tests (AST, ALT, bilirubin) Pruritus Rash

Neurologic

Unilateral or bilateral weakness Sensory alterations Paresthesia

Endocrine

Fatigue Headache Mental status changes Abdominal pain Unusual bowel habits Hypotension Abnormal thyroid function tests

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

bazine (P <.001). OS was 84% (95% confidence interval [CI], 78%-89%) for the vemurafenib group and 64% (95% CI, 56%-73%) for the dacarbazine group. Vemurafenib resulted in a signif-

The year 2011 brought about 2 advances in the treatment of metastatic melanoma—ipilimumab and vemurafenib—and their approval has altered the landscape of melanoma treatment.

by mouth twice daily (n = 337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n = 338). At the time of interim analysis, the data and safety monitoring board determined that prespecified OS end points had been met for statistical significance favoring vemurafenib, and dacarbazine patients were then allowed to cross over to vemurafenib. The response rate was 48% for vemurafenib and 5% for dacar-

Signs and Symptoms

icant reduction in the risk of death (HR for death, 0.37 [95% CI, 0.26-0.55]; P <.001).16 Vemurafenib was associated with increased cutaneous events, arthralgia, fatigue, and photosensitivity skin reactions compared to dacarbazine. Among the cutaneous events, 61 patients (18%) developed cutaneous squamous cell carcinoma, keratoacanthoma, or both. The skin lesions were successfully treated by

surgical excision. Of the patients receiving vemurafenib, 38% required dose reductions due to toxicity.16 These recently approved treatments for metastatic melanoma come with advantages but also significant limitations.2 Ipilimumab is associated with serious, potentially fatal immune adverse events (Table 3), including diarrhea. Responses to ipilimumab may take months to develop and occur in less than 20% of patients; however, similar to immunotherapy with IL-2, responses are quite durable.2 In contrast, vemurafenib demonstrates high response rates that occur quickly. However, to be considered for vemurafenib therapy, a patient must test positive for the BRAFV600E mutation, and the median response duration is only about 5 to 6 weeks.2 Historically, treatment of metastatic melanoma has yielded low response rates and limited OS. The year 2011 brought about 2 advances in the treatment of metastatic melanoma—ipilimumab and vemurafenib—and their approval has altered the landscape of Continued on page 16

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Melanoma Recent Advances in the Treatment of Metastatic Melanoma

Continued from page 15

melanoma treatment. Despite these exciting advances, however, metastatic melanoma remains a universally fatal disease. Therefore, the NCCN recommends a clinical trial be considered as the first line of therapy for any patient with metastatic melanoma.2 If a patient is ineligible or unwilling to participate in a clinical trial, choice of therapy depends on patient characteristics. A BRAFV600E– positive patient who is symptomatic from his or her disease may benefit from up-front therapy with vemurafenib. Conversely, a clinician may choose ipilimumab for the patient who has lowvolume disease, a good performance status, and tests positive for the BRAF–wild type mutation. While questions remain regarding

agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res. 2001;11:75-81. 11. Feldmann M. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D, eds. Immunology. 5th ed. London: Mosby; 1998:147-155. 12. Yervoy [package insert]. Princeton, NJ: BristolMyers Squibb; March 2011. 13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723. 14. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:25172526. 15. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417:949-954. 16. Chapman PB, Hauschild A, Robert C, et al; for the BRM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 17. Zelboraf [package insert]. South San Francisco, CA: Genentech USA, Inc; August 2011.

optimal dosing of ipilimumab (3 mg/kg vs 10 mg/kg), the role of maintenance therapy, and the efficacy of combination regimens, as well as the fact that these drugs also have a significant financial impact both on the individual patient and the healthcare system as a whole, this is still an exciting new era in the treatment of metastatic melanoma. ● References

1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Melanoma. Version.3.2012. http://www. nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed May 1, 2012. 3. Mouawad R, Sebert M, Michels J, et al. Treatment for metastatic malignant melanoma: old drugs and new strategies. Crit Rev Oncol Hematol. 2010;74:27-39. 4. Middleton MR, Grob JJ, Aaronson N, et al.

Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000; 18:158-166. 5. Atkins MB, Lutze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:21052116. 6. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-2751. 7. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045-2052. 8. Hodi FS, Soiffer RJ, Clark J, et al. Phase II study of paclitaxel and carboplatin for malignant melanoma. Am J Clin Oncol. 2002;25:283-286. 9. Chiarion Sileni V, Nortilli R, Aversa SM, et al. Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients. Melanoma Res. 2001; 11:189-196. 10. Huncharek M, Caubet JR, McGarry R, et al. Single-

Lymphomas

Retreatment With Rituximab as Effective as Maintenance Rituximab but Less Costly in Indolent Follicular Lymphoma By Alice Goodman

he best strategy for management of low-tumor-burden follicular lymphoma (FL) following response to induction therapy is controversial. The phase 3 RESORT study compared maintenance rituximab therapy versus rituximab retreatment at disease progression, and results suggest that retreatment is the preferred approach. The study was presented at the 53rd Annual Meeting of the American Society of Hematology. The strategies achieved a similar time to treatment failure (TTTF) in this FL patient population, with no difference in quality of life or anxiety at 12 months. Both strategies appear to delay time to chemotherapy compared with historical controls. Although maintenance therapy prolonged the time until cytotoxic therapy was needed, almost 4 times more rituximab was used, making maintenance therapy by

far the more costly approach. “Given the excellent outcome with retreatment, the toxicity profile, the lack of quality of life difference [between the 2 approaches], and the required doses of

“The retreatment strategy is less costly, and we believe it is the preferred option to help patients with low-tumor-burden FL manage their disease.” —Brad Kahl, MD rituximab, retreatment is our recommended strategy if electing to use rituximab,” stated lead investigator Brad Kahl, MD, University of Wisconsin,

Madison. “The retreatment strategy is less costly, and we believe it is the preferred option to help patients with lowtumor-burden FL manage their disease.” Kahl said that the study did not determine which strategy is best for improving overall survival. Such a study would have to compare watch and wait versus retreatment versus maintenance therapy. RESORT enrolled 384 patients with FL histology; of these, 274 (71%) responded to induction therapy with rituximab and were randomized to retreatment (n = 134) or maintenance rituximab (n = 140). Median TTTF (primary end point) was 3.6 years with retreatment versus 3.9 years with maintenance rituximab. At 3 years of follow-up, only 5% of patients in the maintenance arm required cytotoxic chemotherapy versus 14% of patients in the retreatment arm. However, patients assigned to retreatment used a mean of

4.5 doses of rituximab over that time, while those assigned to maintenance rituximab used a mean of about 16 doses. Fewer than 5% of patients in the trial experienced severe hematologic or nonhematologic toxicities. No difference between the arms was observed in deaths and second cancers. There was 1 adverse event leading to discontinuation in the retreatment arm and 7 in the maintenance arm. At 12 months’ follow-up after randomization, no difference was found in health-related quality of life or burden of stress. Kahl said that the investigators were concerned that patients assigned to retreatment might experience more anxiety than those in the maintenance arm because they knew they had cancer and weren’t being treated, but this concern was not borne out. Commenting on this study, Jane Winter, MD, moderator of the press conference where RESORT was discussed, and Professor at Northwestern University Feinberg School of Medicine, Chicago, said: “If we can limit the frequency of treatment, or reduce the need for chemotherapy and still maintain good outcomes, we can reduce some of the burdens on both the patients and the healthcare community.” ●

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News Briefs

Oral Supplement in Malnourished Cancer Patients Does Not Improve Survival By Alice Goodman

ral nutritional interventions do increase nutritional intake and result in weight gain in some malnourished patients with cancer as well as improve some aspects of quality of life (QOL), but do not seem to increase survival, according to a systematic review and meta-analysis of the literature (Baldwin C, et al. J Natl Cancer Inst. 2012;104:371-385). Lead author Christine Baldwin, PhD, RD, School of Medicine, King’s College, London, United Kingdom, said that current international guidelines recommend oral interventions in this group of patients, assuming they are able to swallow, but this recommendation is not based on level A evidence from well-designed randomized trials. Since several studies have attempted to evaluate the effect of oral interventions in cancer patients but have reached variable conclusions, she and her colleagues wanted to revisit the question by reviewing the literature.

weight and energy intake is inconsistent, but that statistically significant improvements in some aspects of QOL may be achieved,” wrote Baldwin. She pointed

was observed in patients who received oral nutritional intervention. The systematic review and metaanalysis included 13 studies with a total of 1414 adult cancer patients with cancer of all sites and stages who were either malnourished or at risk of malnutrition and compared oral nutritional interventions versus usual care. The patient population, quality, and design of these studies were quite heterogeneous, which is a limitation of the review, Baldwin said. Seven of the studies included assessment of QOL, 5 of them using the EORTC cancer-specific questionnaire. There was a great deal of variability in the findings, but after adjusting for heterogeneity, oral nutritional interventions were associated with statistically significant improvement in “emotional functioning,” “global QOL,” and “dyspnea” and “loss of appetite” symptom scales. Changes in other QOL scales did not reach statistical significance. No effect on mortality was observed in patients who received oral nutritional intervention. “The findings suggest that oral nutritional interventions have no effect on survival and that the effect on body

oral nutritional support in cancer patients and to strengthen the evidence base for nutritional management in this group of patients. ●

Announcing: J-code for YERVOY™ (ipilimumab) J9228 Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1

No effect on mortality

out that several of the studies included in the review were of poor quality, emphasizing the need for more in-depth research to characterize the benefits of

Replaces J9999, J3490, J3590, and C9284.

Product Description

50-mg/10 mL (5 mg/mL), single-use vial of YERVOY

200-mg/40 mL (5 mg/mL), single-use vial of YERVOY

NDC Number 10-digit

0003-2327-11

0003-2328-22

11-digit

00003-2327-11

00003-2328-22

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements. www.destinationaccess.com 1-800-861-0048 (phone) Monday through Friday, 8:00 1-888-776-2370 (fax)

to 8:00

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on the following pages. REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011. 2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/ HCPCSReleaseCodeSets/Downloads/12anweb.zip. Accessed November 1, 2011.

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News Briefs

Pazopanib Potential Treatment for Refractory Urothelial Cancer

azopanib, an angiogenesis inhibitor, achieved meaningful responses in about three-quarters of patients with refractory urothelial cancer in preliminary clinical trial results presented at a press briefing during the 2012 Annual Meeting of the American

Association for Cancer Research (AACR) in Chicago, Illinois. According to lead author of the study, Andrea Necchi, MD, Instituto Nazionale dei Tumori, Milan, Italy, this is the first targeted therapy to demonstrate meaningful clinical activ-

ity in patients with refractory urothelial cancer. He called the 76% rate of disease stabilization “remarkable,” noting that data on other efficacy outcomes are needed in the future. The study also provided some new information on interleukin-8 (IL-8) lev-

els as a potential biomarker for response. Elevated levels of IL-8, as well as rising IL-8 levels during the first 4 weeks of pazopanib treatment, were associated with tumor progression and shorter overall survival. These data need to be confirmed in further trials.

Important Safety Information (cont) Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: t Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day t Failure to complete full treatment course within 16 weeks from administration of first dose t Severe or life-threatening adverse reactions, including any of the following – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients t Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis t Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immunemediated enterocolitis following inadequate response to corticosteroids t Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms t Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid

tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients t Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Immune-mediated Hepatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% t 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2) t Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution t Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids t Withhold YERVOY in patients with Grade 2 hepatotoxicity Immune-mediated Dermatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis t There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis t Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated t Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms

Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.

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News Briefs “Our data indicate that pazopanib seems to be a legitimate drug in this disease. Most interestingly, our biomarker analysis clearly pointed out the role of rising levels of circulating interleukin-8 as an early and potentially practicechanging indicator of tumor resistance and poor survival,” he said, as reported in a news release from AACR. Second-line therapies thus far have

been disappointing in advanced urothelial cancer, which has a poor prognosis. Median overall survival is about 4 to 5 months. Five-year overall survival of metastatic urothelial cancer is about 10% to 15%. Although targeted therapies are theoretically attractive in bladder cancers, thus far no beneficial strategies have been identified until this trial.

The phase 2, open-label, proof-ofconcept study enrolled 41 patients with advanced or metastatic urothelial cancer. Fifty percent progressed on secondline therapy. Patients received daily pazopanib 800 mg once a day until development of disease progression or unacceptable toxicity, or withdrawal. According to RECIST criteria (for tumor shrinkage), objective responses

were seen in 7 patients and stable disease in 24 patients (total disease stabilization, 31 out of 41 patients: 76%). Median progression-free survival (PFS) was 2.6 months and median overall survival was 4.7 months. At 2 months, 61% of patients were free of progression, and durable PFS was seen in 10% of patients at a median followup of 19 months. ● —AG

Important Safety Information (cont) t Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: t In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported t Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported t Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes t Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: t In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients – All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism – 6 of the 9 patients were hospitalized for severe endocrinopathies t Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome t Median time to onset of moderate to severe immunemediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY t Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism – Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland t Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia t Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis t Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions t Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy Pregnancy & Nursing: t YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus t Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus t It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY Common Adverse Reactions: t The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)

Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.

731US11AB18314 TRIM 7.25" x 9.75"

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News Briefs

Women With Luminal A Subtype Breast Cancer May Be Able to Forgo Radiation

specific subgroup of women with early-stage breast cancer may be able to avoid adjuvant radiation, according to a presentation at the 2012 Annual Meeting of the

American Association for Cancer Research (AACR) held in Chicago, Illinois. Women with the luminal A subtype of breast cancer, particularly those older than age 60, had fewer local

recurrences at 10 years when treated with tamoxifen alone versus tamoxifen plus radiation therapy in a post hoc analysis of a randomized trial that compared these 2 forms of treatment.

YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3â&#x20AC;&#x201C;5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.

Senior author of this paper, Fei-Fei Liu, MD, radiologist at Princess Margaret Hospital, senior scientist at the Ontario Cancer Institute, and professor at the University of Toronto, Canada, cau-

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab). Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-BarrĂŠ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrĂŠ syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrĂŠ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3â&#x20AC;&#x201C;4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â&#x20AC;&#x201C;5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

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News Briefs tioned that local radiation therapy is still the standard of care for all other breast cancer subtypes. Liu commented that avoiding radiation therapy in these patients, who account for about 25% of all newly diagnosed breast cancer cases in North America, could achieve an estimated $400 million in savings for the healthcare system in the United States.

The luminal A subtype of breast cancer is defined as estrogen receptorâ&#x20AC;&#x201C; positive, progesterone receptorâ&#x20AC;&#x201C;positive, HER2-negative, and low Ki-67 (<14%), a proliferation marker. The study was based on molecular subtyping analysis of 304 tumor blocks from 769 women with early T1 or T2, nodenegative breast cancer who participated in a randomized controlled trial

comparing tamoxifen plus wholebreast radiation therapy versus tamoxifen alone. Using immunohistochemistry, the researchers classified tumors into 6 categories: luminal A, luminal B, luminal-HER2, HER2-enriched, basal-like, or triple-negative phenotype nonbasal. Overall, breast cancer recurrence at 10 years was 13.8% with tamoxifen

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â&#x20AC;&#x201C;5 events. Table 1:

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370: Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

Including fatal outcome. Including intestinal perforation. c Underlying etiology not established. b

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

1281558A2

IP-B0001A-03-11

Issued: March 2011

[

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The luminal A subtype of breast cancer is defined as estrogen receptorâ&#x20AC;&#x201C;positive, progesterone receptorâ&#x20AC;&#x201C;

Pregnancy

Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2:

DRUG INTERACTIONS

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Percentage (%) of Patientsa

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

alone compared with 5% for tamoxifen plus breast radiation. The luminal A subtype had the best outcome of any subgroup, with a 10-year risk of local relapse of 8% with tamoxifen alone versus 4.6% with tamoxifen and radiation. Luminal A patients older than age 60 had a 10-year local recurrence rate of 4.3% on tamoxifen alone versus 6% for combined modality therapy. Grade 1/2 luminal A tumors had a similar rate of recurrence regardless of treatment; 4.9% with tamoxifen versus 5.5% with tamoxifen plus radiation.

Pub:

positive, HER2-negative, and low Ki-67 (<14%).

The researchers said that these findings suggest that local breast radiation therapy did not affect the outcome of older patients with the luminal A subtype. By contrast, radiation therapy had a positive impact on other breast cancer subtypes. For example, women with luminal B tumors had a 10-year recurrence rate of 16.1% with tamoxifen alone versus 3.9% with tamoxifen plus radiation therapy. A similar trend was seen for HER2, HER2-enriched, and basal-like tumors, but the numbers in each group were small. These findings have implications for personalized cancer medicine, suggesting that Ki-67 be added to the current standard testing for hormone receptor and HER2 status in newly diagnosed patients with breast cancer. If these data on the luminal subtype A tumors are validated, that would pave the way for discussions with patients with this subtype about the need to undergo radiation therapy in addition to tamoxifen or other adjuvant therapy. In a news release from AACR, Liu was quoted as saying: â&#x20AC;&#x153;This is yet another powerful of example of â&#x20AC;&#x2DC;personalized cancer medicine.â&#x20AC;&#x2122; When this information is combined with wellconducted randomized clinical trials, significant advances can be made whereby we can truly start to tailor therapies, based on new molecular markers, which can be introduced into routine clinical practice.â&#x20AC;? â&#x2014;? â&#x20AC;&#x201D;AG MAY 2012 I VOL 5, NO 3

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News Briefs

Health Behaviors Worse Among Cancer Survivors Than Patients With No History of Cancer

large, population-based study found that a significant proportion of female cancer survivors had poor health behaviors compared with women who have not had cancer (Rausch SM, et al. Am J Clin Oncol. 2012;35:22-31). Several differences in engaging in health behaviors emerged among primary cancer types, with more cervical cancer survivors reporting being current smokers and regular alcohol users compared with other cancer types. Ovarian and uterine cancer survivors reported being obese more often than other cancer types, and the largest weight gain was observed among cervical cancer survivors. By contrast, leukemia survivors reported engaging in regular mammography more often, had a higher percentage of “never” smokers, and a higher percentage of normal-weight individuals compared with individuals with other primary cancers. Even though more than half of all cancer deaths in the United States can be attributed to health behaviors such as smoking (30%), poor dietary choices and obesity (25%-30%), and physical inactivity, very little is known about these behaviors in cancer sur-

vivors, wrote the authors of this study. “There is considerable need for additional studies to document the prevalence of cancer-related risk factors in a diverse sample of cancer survivors,” they added. The study included almost 20,000 women aged 35 and older with no prior breast cancer who presented for screen-

rating of health during the past year. Mean age was 58 years, mean body mass index (BMI) was 26 kg/m2, and 74% had education beyond high school. Compared with women who did not have cancer, cancer survivors were about 5 years older on average, had a similar BMI, and 4% more had education beyond high school.

Ovarian and uterine cancer survivors reported being obese more often than other cancer types, and the largest weight gain was observed among cervical cancer survivors. ing mammography. Participants were given a self-assessment questionnaire about their health behaviors and previous cancer history. The questionnaire was completed by 18,510 women—15,797 with no cancer history and 2713 cancer survivors. Health behaviors assessed included smoking, alcohol consumption, physical activity, weight, use of complementary and alternative medicine (CAM), mammography screening, and overall self-

Cancer survivors were less likely than women with no cancer history to report that they had “excellent” health: 13.6% versus 21.5%, respectively; that they engaged in moderate or strenuous exercise: 56.5% versus 63.3%, respectively, and to use CAM: 57.4% versus 60.2%, respectively. Cancer survivors were more likely to be current smokers (6.3% vs 5.5%) and to rate their overall health as “poor” (15.9% vs 9.1%, respectively), and to gain more weight over time.

Cancer survivors reported more regular participation in mammography screening than women with no cancer: 91.1% versus 86.3%, respectively; the difference was more marked in patients younger than age 40: 80.2% versus 74.3%, respectively. Cancer survivors were more likely to have had a smoking history; 59% versus 63.7%, respectively, reported being “never” smokers; 34.6% versus 30%, respectively, reported being “former” smokers; and 6.3% versus 5.9% said they were current smokers. The smoking rates were similar between cancer survivors and those without cancer for women older than age 65, whereas cancer survivors aged 30 to 49 years were more likely to be current smokers than women of the same age group who were not cancer survivors: 13% versus 8.5%, respectively. The authors state that presenting for screening mammography is “a teachable moment” when healthcare providers can educate cancer survivors and discuss risky behaviors. Studies such as this one suggest that there is much room for improvement in areas such as smoking, alcohol consumption, exercise, and weight gain. ● —AG

Acute Lymphoblastic Leukemia: RemissionInduction Failure Can Be Treated

ailure of remission-induction therapy in pediatric acute lymphoblastic leukemia (ALL), although rare, can lead to highly adverse outcomes, but outcomes differ according to type of ALL: B-cell or T-cell, as well as other characteristics (Schrapps M, et al. N Engl J Med. 2012;366:1371-1381). The study showed that patients with childhood ALL who fail on induction therapy are highly heterogeneous. T-cell leukemia appears to be associated with improved outcomes if treated with allogeneic stem-cell transplant, while precursor B-cell

leukemia with no adverse features appears to be better treated with chemotherapy. According to the authors, “These findings have considerable implications, since transplantation is generally considered to be standard of care for such patients.” The study was based on 1041 children and adolescents (aged 0-18 years) with newly diagnosed ALL who experienced failure after 4 to 6 weeks of remission-induction therapy; these children were culled from 44,017 patients with childhood ALL treated

by 14 cooperative study groups between 1985 and 2000. Patients with induction failure tended to have high-risk features that included older age, high leukocyte count, T-cell leukemia phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up of 8.3 years, the 10-year survival rate was 32%. Characteristics associated with a particularly poor outcome included age of 10 years or more, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more

blasts in the bone marrow at the end of induction therapy. Improved outcomes in precursor B-cell ALL were associated with high hyperdiploidy (a modal chromosome number >50) and age of 1 to 5 years; these patients composed about 25% of the sample. Improved outcomes in T-cell ALL were seen with allogeneic stem-cell transplant from matched, related donors. Children younger than 6 years with precursor B-cell ALL and no adverse genetic features had a 10-year survival rate of 72% when treated with chemotherapy only. ● —AG

MAY 2012 I VOL 5, NO 3

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Conference News:



   



Global Biomarkers Consortium—Implementing the Promise of Personalized Cancer Care

he inaugural annual conference of the Global Biomarkers Consortium brought together an international panel of oncology experts to explore the rapidly evolving field of biomarker research. Cochairs of the event were Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, and Rüdiger Hehlmann, MD, PhD, professor of medicine at the University of Heidelberg. Michael Kattan, PhD, Vincent Miller, MD, Edith Perez, MD, and Charles Bennett, MD, PhD, served as session chairs. At the conference, held March 9-11, 2012, in Orlando, Florida, a diverse field of experts addressed oncologists, hematologists, oncology nurses, pharmacists, and other healthcare professionals on a wide range of topics related to the clinical application of biomarkers in the treatment of solid tumors and hematologic malignancies. Conference attendees had numerous opportunities to ask questions. In addition, an audience response system provided opportunities for interactive learning experiences.

Personalized medicine based on an understanding of predictive molecular biomarkers holds great promise.

Hehlmann opened the conference with a valuable historical overview of genetic profiling and oncologic biomarkers. In discussing development of new technologies, Miller reported, “There are an unprecedented number of targeted therapies in clinical trials—about 500 targeted therapies looking at about 140 genomic alterations.” In looking forward to next-generation sequencing, Miller concluded, “So I’m really excited about these broader technologies that may allow us to help more patients and more rationally approach treating patients in the near future.” Case studies of several types of cancer were presented by panel members. Perez presented “Evidence-Based Medicine to Translational Medicine to Personalized Medicine: A Natural Evolution,” and Beth Faiman, PhD(c), MSN, APRN-

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BC, AOCN, discussed “Roles and Responsibilities of the Interprofessional Team.” Perez and Faiman led a group composed of several doctors who had presented casestudies in a panel ques

tion-and-answer session on “Incorporating Personalized Medicine Into Practice.” Personalized medicine based on an understanding of predictive molecular

biomarkers holds great promise. Conferences such as this one help clinicians and other healthcare professionals keep up to date on developments in this challenging field. ●

The Next Generation in Oncologic Care

PM O

PERSONALIZED MEDICINE IN ONCOLOGY 

Join us on our journey to realize the tremendous possibilities of improving cancer prevention, diagnosis, and treatment through a new medical model of personalized care. Where are

you on the path?

    

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Conference News:

Payer Trends in Oncology: Challenges and Solutions Putting Patients First Remains a Key Component By Caroline Helwick

he need to optimize the treatment of patients with cancer while using healthcare resources wisely—in other words, providing “value-based cancer care”—is not a topic of debate, but how to achieve this pressing goal is far from clear. In a panel discussion during the Association for Value-Based Cancer Care’s Second Annual Conference, held in Houston, Texas, strategists from the payer side of the issue discussed the current trends and the challenges they are facing. Burt Zweigenhaft, BS, President and Chief Executive Officer of OncoMed, Great Neck, New York, who led the discussion, noted that the rising cost of cancer care is clearly the trigger point for change. “The cost curve is unsustainable. Who will win and who will lose? Clearly, there are realignments.” Ira M. Klein, MD, MBA, Chief of Staff to the Chief Medical Officer at Aetna Oncology Strategy, New York, added, “We get feedback from our different customers as to what they want, from the self-insured employers to the small businesses down to the individual in the market. And the unifying theme is that they cannot sustain any more cost.”

Employers Are Confused Employers may be steadily downsizing their benefits, but this does not mean they do so without pain, participants noted. “Employers are more paternalistic than one would think. They are concerned about the care their employees are getting,” said Klein. “They want benefit designs that do not deny patients access to essential services, but they want these to be acquired at the most favorable unit price. Cost is a very big factor to them.” Maria Lopes, MD, MS, Chief Medical Officer for AMC Health, Cresskill, New Jersey, agreed. “Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” Employers clearly do not understand why costs are so high, added Winston Wong, PharmD, Associate Vice President of Pharmacy Management with CareFirst BlueCross BlueShield in Maryland. “The employers ask their consultants. The consultants come to us because they think pharmacy is the silver bullet. When you look at it from the employer and consultant standpoints, you see there is not much

MAY 2012 I VOL 5, NO 3

understanding about what is driving the numbers,” he said. Drug Costs: The Big Bugaboo The exorbitant cost of new treatments clearly contributes to the crisis in paying for cancer care, and payers’ hands are relatively tied to do much about this, the panelists said. “We know drugs are the biggest part of the escalation,” observed Zweigenhaft, and John Fox, MD, MHA, Associate Vice President of Medical Affairs for Priority Health, Grand Rapids, Michigan, proposed 2 main reasons for this.

“Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” —Maria Lopes, MD, MS “Number one, we do not have the wherewithal or interest in the public domain to say that society will not pay for a cancer drug because it is too expensive,” Fox offered. “Number two, there are state mandates to cover expensive drugs, and the drug companies have the power to set the price of the drug. We cannot control these prices, yet that is where the greatest cost is.” Fox contrasted the system in the United States with that of the United Kingdom, which does consider the cost of a drug when deciding its fate. “In the United Kingdom, they take the 2 independent variables, which are outcomes established through clinical trials and willingness to pay, and that defines the dependent variable, which is the cost of the drug,” he said. “In this country, the manufacturer sets the cost of the drug…. The conundrum is that the pharmaceutical industry has a responsibility to its investors and the innovators have to recoup their investments, yet the people who pay for that are increasingly unable to do so.” Although discussions about reducing emergency department visits and hospi-

talizations as a cost-savings approach have merit, they stem merely from the fact that these are “things we can control,” Fox said. “The reality is that until we find a way to provide more rationality around our drug reimbursements, I do not know that there is a solution.” Keeping Oncology CommunityBased Payers indicated and studies have shown that cancer care is more affordable when delivered in the community rather than the hospital setting; however, economic factors are steadily threatening the viability of this site of care, because community practices are being sold or absorbed by hospitals, or are merely closing. This trend worries Jeffrey A. Scott, MD, Senior Vice President and General Manager for P4 Healthcare Cardinal Health Specialty Solutions. “What will it take for this to stop?” he questioned. “When will health plans incentivize doctors to stay out of the hospital? We know the lowest cost comes from treating patients in the community, but how do we drive this?” Zweigenhaft noted that the “shift to a hospital base” is a universal concern in the payer community, because this essentially doubles the cost of delivering cancer care, with little or no improvement in outcomes. Panelists agreed that site of service is an important issue. Part of the lure of hospital-based care, as Zweigenhaft put it, is the 340B Drug Pricing Program, which limits the cost of covered outpatient drugs to certain federal grantees, federally qualified health center look-alikes, and qualified hospitals. Participation in the program results in savings estimated to be 20% to 50% of the cost of pharmaceuticals, which naturally appeals to providers. According to Zweigenhaft, the pitch made by hospital representatives to physician groups is the opportunity to share in the substantial additional revenue afforded through 340B drug pricing. Scott agreed that 340B pricing is “clearly a driver for getting new doctors into the hospital,” and part of the reason why struggling community practices view the hospital system as “the savior.” What it will take to strengthen community oncology practices is not completely clear, but Mona M. Chitre, PharmD, CGP, Director of Clinical Services, Strategy and Policy for Excellus BlueCross Blue Shield, FLRx

Pharmacy Management, Rochester, New York, said helping them maintain “cost neutrality” is important. Her company’s goals are to create innovative programs to pay for patient management, help patients avoid emergency department visits, and aid clinicians in reducing other unnecessary services. Guiding Physicians to Best Practices Value in cancer care, however, is not only about cost but also about quality, and the 2 components are necessary for optimizing value while maintaining good outcomes, the panel agreed. Lopes suggested that the concept of value must be aligned with an appropriate outcome, and this can be difficult to determine. Scott added that better measures are needed to define quality outcomes, and that there is increasing recognition that it is “total cost of care” that matters most—which includes reductions in downstream costs and returning patients to work. Klein agreed that benefits programs cannot be designed simply on the basis of cost. “We want quality first, then we deliver on cost,” he said. Scott added, “There is no question that good, quality care is already being provided, but it comes down to how to maintain that quality at a lower cost. That is the big discussion we have with providers.” Standardization is an important part of this strategy, typically via guidelines and clinical pathways. “We found that by more or less standardizing treatments in the program we have with community oncologists, we take out variability and have a gross savings of about 13%,” Wong reported. “These savings will be shared with the community oncologists as an effort to maintain their margins and to be an incentive to sustain their community practices.” Moving from branded to generic products has also been a big cost-saver, and reducing emergency department visits and hospitalization rates by 4% has produced additional savings. “We know the savings are there,” he said. According to Klein, this works best when providers are in the driver’s seat. “We delegate decision-making to physician groups and allow them to choose their pathways. You get higher quality and lower costs because you give control and power to the providers to use what they are comfortable with,” he said.

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Conference News: Scott suggested that pathways work best when they are “narrow,” which is what P4 attempts to do with providers. “We try to neutralize the name of the drugs so physicians are free to choose a regimen based on what is best for the patient and separate from the economics of it. We have demonstrated in 10 different markets that you can use consensus to drive a narrow set of pathways, and it works, although it may not be the long-term answer.” Lopes added that there is a need to do more to aid physicians in decision-making. “We want to align incentives,” she said, emphasizing that healthy collaboration is critical to success. “We will not win without good partnerships with our treating providers.”

Need to Involve the Patient Central to any conversation about cancer care should be the patient. They should also become more active participants in the quest for value, and there is room for improvement in this area, the panel pointed out. “The ‘value proposition’ has to be considered at the patient level,” said Chitre. New York State now has chemotherapy parity. “Patients will not pay any differential for generic versus branded drugs, so the ‘value discussion’ with the patient is actually absent,” she noted. “If a drug is indicated or listed as 2A or 2B in the Compendia, it is covered and at a high level. There is very little patient out-of-pocket expense, and therefore very little driving our

members to ask ‘value questions’ of their providers.” She observed, however, that the trend toward high-deductible premiums is beginning to alter how patients talk about value to their providers. Wong reported that CareFirst programs are beginning to integrate oncology with primary care through the patient-centered medical home model, and this is helping to steer care in the direction of value. “These 2 specialties are collaborating. Primary care is directing patients to oncology practices they perceive will provide the best quality and value,” he said (see an interview with Wong below). Ultimately, what emerges as the picture of value-based cancer care must be

patient-centered, the panel agreed. A “fully engaged” patient is one who understands the treatment scenario and determines what is most important to him or her, said Fox. This is only done when physicians have time for it, added Klein. “If we could get physicians to spend more time talking to patients, all our costs would go down, because the patient would feel more empowered to do the right thing,” he maintained. “Comparatively speaking, physician labor time is cheap. The cost-over-quality balance must hierarchically satisfy all stakeholders as equitably as possible. We have to manage expectations. We cannot move cancer care forward until we change society’s perceptions.” ●

Site of Care Influences Value in Cancer Care Interview With Winston Wong, PharmD Associate Vice President, Pharmacy Management, CareFirst BlueCross BlueShield of Maryland

t the Association for ValueBased Cancer Care (AVBCC) second annual meeting, Winston Wong, PharmD, expressed concerns that the site of delivery of cancer care affects efforts to rein in costs and provide value in cancer care. Wong expanded on this issue in the following interview.

Why do you believe that the site of delivery of cancer care can impact the attempt to rein in costs of cancer care and provide value? Wong: Here is why. When chemotherapy is delivered to a patient in the physician’s office, there are the cost of the drug, administrative costs, and the cost of ancillary services. Let’s say the total office visit, including the cost of chemotherapy, is $4000. You can take that exact same service and drug and deliver it at a large center, such as, in our area, Johns Hopkins, and the cost could be $6000 or even up to $8000. Essentially, it may double or even triple in cost, depending on the procedure, the service, and the drug that is prescribed. Why is there such a large differential in cost? Wong: It is basically because the healthcare system cannot function without the large hospitals. They have market power and can negotiate better deals. At the end of the day, hospital billing will be at least twice that of a community practice, across the board. Do large hospitals and cancer centers acknowledge this? Wong: Their comment to payers would be that they are tertiary care hospitals, www.TheOncologyPharmacist.com

and that their patient population is sicker, and to some degree that is true. Large hospitals may get more difficult cases, administer more expensive third-line therapies, and so forth. But comparing apples to apples, their costs are much higher than in community practices.

What can be done to bring more equity? Wong: On the oncology side, we have not been able to achieve more equity yet. The strategy that we at CareFirst are trying to employ initially with our Pathways Program is to reimburse at a higher rate to community practices. We may not necessarily be directing patients away from hospitals, but we are doing something to help maintain community oncology practices so that they are available to treat these patients. If there are fewer community practices, patients with cancer have less choices. The site-of-care issue will be driven by the viability of community practices. If we cannot help community oncologists stay in business, the site of care will not be an issue. You have talked about the need to integrate primary care and to bring more value to oncology. Could you elaborate on this? Wong: Here is an example of the current state of things. My mother passed away in 2007. When she was diagnosed with cancer and was being treated with chemotherapy, she became neutropenic and ended up in the emergency department. The hospital contacted the primary care physician (PCP) on record, but he had no clue about her condition. Once an oncologist was taking care of

her, there had been no communication with the PCP. And let’s look at survivorship. She may have to go back to the oncologist for some routine tests, but she may have an annual check-up the following week with her PCP, and he may order the same laboratory tests. This kind of overlap and duplication should be eliminated from the system.

How is CareFirst BlueCross BlueShield advancing this concept of more integrated care? Wong: With the primary care patientcentered medical home, we are trying to involve the PCP as the “quarterback of care,” as we say. Currently, when an individual is diagnosed with cancer and referred by his or her PCP to a specialist, the PCP usually severs ties with the patient. We are asking our PCPs to be more accountable and to follow these patients while they are under the care of specialists—oncologists or others—and maintain primary care as the patient’s home, but within an integrated process. Maybe 5 of 10 patients with cancer will ask their PCP to refer them to an oncologist, but the other 50% will choose an oncologist on the basis of favorable word of mouth. Or, they may want to go, for example, to MD Anderson, because of its reputation and not because they have seen scientific evidence that their care will be better or that community care is worse. We all pay more for that patient, with very little difference in quality of care or in outcomes compared with care in the community setting. We believe that the PCP can direct the patient more toward value-based cancer care. PCPs can help guide these referrals, and they can take

Winston Wong, PharmD

care of the non–cancer-related conditions that patients with cancer will have. We want this care to be under the PCP, not the oncologist.

How are PCPs and oncologists accepting this model? Wong: We do not know yet—our program just started—but this is something we are interested in learning. We believe that it is in everyone’s best interest for patients to have a coordinator of care, and we think that the most important provider in this regard is the PCP. We think that PCPs and oncologists working together will become inevitable with the changing time. As the PCP becomes more involved, there will have to be more communication between them. What progress is being made to bring this concept to fruition? Wong: There are many groups with their own small projects like ours, and none is known to be the best way to do this. I think that these will eventually merge into something that we will all use; however, we are still trying to get some accountability around these programs, and we are still very early in that game. ● MAY 2012 I VOL 5, NO 3

TOP_May 2012_v4_TOP 5/22/12 10:44 AM Page 26

Emerging Agents

What Pharmacists Need to Know About 7 New Agents By Caroline Helwick

ncology pharmacists should understand the characteristics of 7 emerging drugs and biologics. At the 2012 Pharmacy Program held during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida, Van Anh Trinh, PharmD, of the University of Texas MD Anderson Cancer Center, Houston, and Robert Ignoffo, PharmD, of the University of California San Francisco and the Touro University College of Pharmacy in Vallejo, described the appropriate use of axitinib, crizotinib, ipilimumab, and vemurafenib, and previewed carfilzomib, regorafenib, and vosaroxin. New Tyrosine Kinase Inhibitors Axitinib was recently approved for, and carries an NCCN category 1 recommendation for, advanced renal cell carcinoma after failure of 1 prior systemic therapy, joining everolimus and sorafenib in this setting. “It’s hard to say which to use first. Selection can be guided by the toxicity profile,” Trinh suggested. In the pivotal phase 3 trial comparing axitinib with sorafenib, the most potency was seen in cytokine-refractory patients, while in patients with prior sunitinib treatment the delay in progression was a modest 1.4 months, she noted. The approved dosing schedule is 5 mg orally twice a day (PO BID), with titration (after 2 weeks) to 7 mg BID, then (after 2 more weeks) to 10 mg BID. Axitinib should not be used concurrently with CYP3A4/5 inducers. Crizotinib is indicated for, and carries an NCCN category 1 recommendation for, locally advanced or metastatic non–small cell lung cancer with the ALK translocation. Off-label use is anticipated for anaplastic large cell lymphoma, Trinh said. The approved dose is 250 mg PO BID, with adjustments recommended for patients with hepatic impairment or

severe renal insufficiency but not for creatinine clearance 30 mL/min. Drug interactions can occur with potent CYP3A inducers or CYP3A substrates with a narrow therapeutic index. Complete blood count, liver function tests, and EKG are recommended for monitoring. Novel Melanoma Agents “Ipilimumab and vemurafenib are longawaited treatments for melanoma,” Trinh said. “Ipilimumab was the first drug to provide a survival improvement in a randomized phase 3 trial in melanoma.” The approved dosing schedule for ipilimumab is 3 mg/kg intravenously every 3 weeks for 4 doses, by 90-minute infusion. Premedication and prophylactic antiemetics are not needed, nor are adjustments necessary for patients with hepatic or renal dysfunction. It is unclear whether “reinduction” is effective upon progression, but ipilimumab has been shown to restore disease control in twothirds of patients and is an option in the NCCN Guidelines, although whether it will be reimbursed beyond 4 doses is an open question, according to Trinh. Since the drug works via the immune system, the unique clinical features of ipilimumab are a delayed onset of response and immune-related adverse effects. Inflammatory T-cell infiltrates can produce tissue necrosis within 12 weeks, which is mostly mild to moderate and reversible but can be life-threatening. The skin, gastrointestinal tract, liver, and endocrine system can be affected (Table). Patients should be instructed to report side effects promptly; clinicians should monitor for these closely and treat them immediately with steroids (1-2 mg/kg prednisone or equivalent, then tapered). Ipilimumab can be restarted when grade 1 or 2 toxicity resolves but should be stopped in the case of grade 3+ toxicity. Vemurafenib is a kinase inhibitor of

mutant BRAF (with activity against several other mutations) and is approved, with an NCCN category 1 recommendation, for unresectable or metastatic melanoma with the BRAFV600E mutation. Vemurafenib led to a 67% reduction in risk of death in the phase 3 trial. The approved dosing schedule is 960 mg PO BID; adjustments are not needed for patients with mild to moderate liver or kidney dysfunction, although vemurafenib should be used with caution in patients with severe impairment. Drug interactions are possible when used along with CYP3A4 inducers and with CYP1A2, CYP2D6, and CYP3A4 substrates with a narrow therapeutic index. Adverse events are largely dermatologic, and more than one-third of patients may need dose modifications because of them. Clinicians should also watch for changes in liver function tests and for QT prolongation. “There is no consensus yet about how to integrate these agents into the treatment schema for advanced melanoma,” Trinh said. A reasonable approach is to use vemurafenib first in patients with mutant BRAF and rapidly growing disease or a need for immediate relief of symptoms, since patients respond rapidly, although drug resistance also emerges soon. Ipilimumab may be a good first choice for patients with limited tumor burden who “can afford to wait 3 or 4 months for clinical benefit.” Emerging Drugs Ignoffo described 3 agents on the horizon that could also be game-changers. Carfilzomib is a novel irreversible proteasome inhibitor that is mechanistically distinct from, more potent than, and a more selective inhibitor of the proteasome and immunoproteasome than bortezomib. In the PX-171-004 study, in bortezomib-naïve patients with relapsed/ refractory disease, median progressionfree survival (PFS) was 8 months and

median overall survival (OS) was not reached in myeloma patients receiving carfilzomib. (Vij R et al. Blood. Published online ahead of print May 3, 2012). Carfilzomib is dosed on 2 consecutive days, 1 week apart, in 28-day cycles. Its rapid plasma clearance is not affected by renal dysfunction. Proteosome inhibition occurs after 1 dose and is prolonged, due to inhibition of proteasome recovery between doses. In striking contrast to bortezomib, peripheral neuropathy grade 2-3 occurs in <1% of patients. Fatigue is the dose-limiting toxicity. Approval from the FDA is “highly probable,” he predicted. Regorafenib is an oral multikinase inhibitor against several endothelial receptor tyrosine kinases that is active in colorectal cancer. In the phase 3 CORRECT trial, median OS was significantly improved, although the difference was only 1.4 months (P = .005) (Grothey A et al. J Clin Oncol. 2012;30[suppl 4]. Abstract LBA385). Median PFS was improved by 1.2 months, a 51% reduction in risk (P <.000001). “Clinically, it’s an exciting drug based on the PFS curve,” Ignoffo said. “It seems regorafenib does not so much produce tumor shrinkage as prevent progression, leading to a high disease control rate.” Vosaroxin is a first-in-class anticancer quinolone derivative that induces site-selective DNA damage by intercalating DNA and inhibiting topoisomerase II, leading to apoptosis. Vosaroxin combined with cytarabine showed favorable clinical activity and tolerability in patients with relapsed or refractory acute myeloid leukemia, with a median OS of 7.1 months, a 29% complete remission rate, and a median leukemia-free survival of 14.4 months. (Stuart RK. Presented at: Chemotherapy Foundation Symposium XXVII, New York, November 10, 2012). Pharmacist’s Role Trinh concluded the session, “These are new and exciting drugs with efficacious and unique safety profiles. Pharmacists need to ensure their appropriate use, educate patients, monitor for and manage adverse events, guide patients to drug assistance programs, and stay updated with emerging information.” ●

Table Ipilimumab Immune-Related Adverse Events Incidence (%) Any Grade (grade 3+)

Median Onset (weeks)

Rash, pruritus, vitiligo, Stevens-Johnson syndrome, toxic epidermal necrolysis

40 (2)

3-4

Antihistamine, topical corticosteroid, high-dose corticosteroid

Diarrhea, colitis, toxic megacolon, bowel perforation

30 (7.6)

6-7

Antidiarrheal, budesonide, high-dose corticosteroid, infliximab

Right upper quadrant pain, transaminitis, hepatic failure

4 (<2)

6-7

High-dose corticosteroid, mycophenolate, other immunosuppressants

Fatigue, headache, visual changes, altered mental status, hypotension, decreased libido

4 (<2)

9-11

High-dose corticosteroid and hormone replacement

Toxicity Dermatologic Gastrointestinal Hepatic Endocrine

Presentation

MAY 2012 I VOL 5, NO 3

Management

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