December 2012, Vol 5, No 8 by The Oncology Pharmacist

DeCemBeR 2012

www.TheOncologyPharmacist.com

VOl 5, NO 8

SUPPORTIVE CARE

PROFILE

Catheter-Related Thrombosis Can Be Prevented

Onco360 The Changing Role of Oncology Pharmacy nco360 is an oncology pharmaceutical services company dedicated to advancing the continuum of pharmaceutical cancer care for patients. To that end, the company has developed specialized clinical and supportive care oncology pharmacy care programs and services that are managed by boardcertified oncology pharmacists (BCOPs) with the goal of providing quality services and improving outcomes for patients. Burt Zweigenhaft, CEO of Onco360 Onco360 provides services to more than 1800 oncologists; 43 major BlueCross/BlueShield programs; commercial, Medicare, and Medicaid managed care payers; hospital systems; and the National Comprehensive Cancer Network (NCCN) Centers of Excellence through its national network of certified and JCAHO-accredited OncoMed pharmacies. The Oncology Pharmacist spoke with Burt Zweigenhaft, CEO of Onco360, about the company and the future of oncology pharmacy.

What role do you see Onco360 playing in the current healthcare environment? Burt Zweigenhaft (BZ): We don’t believe the market has fully grasped the potential value of oncology pharmacists, outside of some of the better-known hospitals and NCCN centers like MD Anderson or Roswell Park. What keeps us awake at night is the ASCO-projected shortage of 4000 treating oncologists, and the corresponding aging of America fueled by 10,000 new Medicare beneficiaries a day until 2020; this will create a cancer care access crisis. Additionally, delivering cancer care will become exponentially more complex as we move to personalized medicine. Thus, the greater focus on patient care plan personalization, based on the specific tumor diagnosis using predictive sciences and targeted, evidence-based guidelines, will be the norm.

By Caroline Helwick

nticoagulation prophylaxis is effective in preventing both symptomatic and asymptomatic catheter-related deep vein thrombosis in ambulatory cancer patients with locally advanced or metastatic solid tumors, French investigators reported at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1 Among cancer patients who have catheters in place for chemotherapy,

catheter-related deep vein thrombosis causes morbidity and mortality. The incidence of symptomatic events ranges from 0.3% to 28.3%, and the incidence rises to 27% to 66% when asymptomatic episodes are included. Current guidelines from American and European societies do not recommend prophylactic anticoagulation for cancer outpatients, but symptomatic catheterrelated deep vein thrombosis is still a subject of active research, and the value of Continued on page 8

LUNG CANCER

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

n a phase 3 head-to-head comparison trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib proved more effective than standard chemotherapy with pemetrexed or docetaxel as a second-line treatment for

non–small cell lung cancer (NSCLC) patients with the ALK genetic abnormality. The results of the global PROFILE 1007 trial were reported by Alice Shaw, MD, of Massachusetts General Hospital in Boston, at the European Society for Continued on page 17

Continued on page 28

INSIDE CONFERENCE NEWS

Prostate CanCer

Highlights From ASTRO

Proton Beam Therapy ComPlimentary Ce

By Alice Goodman

he 2012 American Society for Radiation Oncology (ASTRO) Annual Meeting, held in Boston, Massachusetts, coincided with Superstorm Sandy. Despite the havoc wreaked by the storm, Boston was largely spared, although ASTRO can-

.............

celed Monday afternoon’s Plenary Session when public transportation was shut down. Below are some highlights from the meeting, including some news stories from the Plenary Session, which was available online.

Considerations in Multiple Myeloma—Ask the Experts: Retreatment Settings . . . . . . . . . . . . . .18 Considerations in Multiple Myeloma—Ask the Experts: Bone Health . . . . . . . . . . . . . . . . . . . . . . .32

Continued on page 26

neuroendoCrine tumors

Advances in the Treatment of Pancreatic Neuroendocrine Tumors ConferenCe news: esmo

...

Who’s Your T.O.P. Pharmacist Nominee? Nominate a pharmacist at www.TheOncologyPharmacist.com/award For more information, see page 7.

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on the next page of this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Noteworthy Numbers Billions of dollars are spent each year to fund research as scientists continue to identify the causes of cancer and to develop strategies for prevention, detection, treatments, and cures. The following statistics allow a glimpse into the immense field of cancer research funding. Cancer research is funded by the federal government primarily through the

National Cancer Institute (NCI), part of the National Institutes of Health (NIH).1

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE 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 (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: 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 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% 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 require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%. 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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms. 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 bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

More than $30 billion annually is invested into medical research by the NIH.1

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 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) 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 (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). 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 reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). 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 reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) 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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

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

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Greater than 80% of NIH’s funding is awarded through competitive grants to researchers at more than 3000 locations in all 50 states across the country.1 Between fiscal years 2010 and 2012, NIH federal appropriations fluctuated only slightly, with a low of $30,399 million (FY 2011) and a high of $31,010 (FY 2010).1 Over half of NCI’s budget is assigned to more than 6500 research grants funded at more than 150 research facilities located in 49 states.1 NCI federal appropriations also varied only marginally between fiscal years 2010 and 2012, with a low of $5058 million (FY 2011) and a high of $5103 (FY 2010).1 The National Cancer Society annually spends approximately $5.2 billion in its fight against cancer.2 Many times, research funding is appropriated to a specific cancer that has scientific groundwork already established. Therefore, the little known and/or less understood cancers tend to receive less funding than the more understood cancers, such as breast cancer.3 Sources 1. www.aacr.org. 2. www.StatisticBrain.com. 3. www.everydayhealth.com.

11:06 AM

DECEMBER 2012 I VOL 5, NO 8

www.TheOncologyPharmacist.com

Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Oklahoma University College of Pharmacy Tulsa, OK

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

ASSOCIATE EDITOR-IN-CHIEF

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

Jim Koeller, MS

Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Burt Zweigenhaft, BS

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

OncoMed Onco360 Great Neck, NY

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP

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

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

Marlo Blazer, PharmD, BCOP

The University of Texas MD Anderson Cancer Center Houston, TX

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

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

www.TheOncologyPharmacist.com

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

DECEMBER 2012 I VOL 5, NO 8

From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Associate Publisher Joe Chanley joe@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Associate Publisher Cris Pires cris@engagehc.com

n this month’s issue of The Oncology Pharmacist (TOP), we wrap up the year with highlights of the news from the 2012 American Society for Radiation Oncology Annual Meeting and the European Society for Medical Oncology 2012 Congress. Also, we continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology. The information we present from these professional meetings helps keep you up-to-date with the

Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien

Executive Administrator Jackie Luma Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-656-7935 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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology 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®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology 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.

DECEMBER 2012 I VOL 5, NO 8

latest research and may affect your daily practice as an oncology pharmacist. Our new TOP reader poll asks, “What inspired you to enter the oncology field?” Please go to our website, www.The OncologyPharmacist.com, and tell us what motivated you to become an oncology pharmacist. We’ll publish some of your responses in the first issue of the new year. All of us at TOP wish you the best for 2013. l

Recent FDA News

Business Manager Blanche Marchitto blanche@greenhillhc.com

™

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

Omacetaxine mepesuccinate Approved to Treat Cml The US Food and Drug Administration (FDA) has approved omacetaxine mepesuccinate subcutaneous injection (Synribo, Teva Pharmaceutical Industries) for the treatment of adult patients with chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Approval for omacetaxine mepesuccinate was granted on October 26, 2012. The FDA approval was based on the combined results of 2 open-label, single-arm trials that enrolled patients with CML in chronic phase or accelerated phase. Patients in the trials had received 2 or more prior TKIs, including imatinib. The end points for the studies were major cytogenetic response for chronic-phase CML and major hematologic response for accelerated-phase CML. For those with chronic-phase CML, major cytogenetic response was achieved in 18.4% of patients (median response duration of 12.5 months). For patients with accelerated-phase CML, 14.3% achieved major hematologic response (median response duration of 4.7 months). Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection-site reaction, pyrexia, infection, and lymphopenia were the most common (≥20%) grades 1 to 4 adverse drug reactions. Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia, and diarrhea were the most common (≥5%) grades 3 to 4 adverse drug reactions. Among the patients in the trials, 10 died within 30 days of the last omacetaxine mepesuccinate dose: 4 deaths were attributed to progressive disease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and 1 to unknown causes. Omacetaxine mepesuccinate was reviewed under the FDA’s accelerated approval review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. In addition, the FDA designated omacetaxine mepesuccinate as an orphan product because it is intended to treat a rare disease or condition. Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, stated that the approval of omacetaxine mepesuccinate “provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML.” He also noted that it “is the second drug approved to treat CML in the past two months.”

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

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

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Supportive Care Catheter-Related Thrombosis Can Be Prevented Continued from cover prophylaxis in this population is controversial, said Sandrine Lavau-Denes, MD, of the University Hospital at Limoges in France. Lavau-Denes reported the results of a phase 3 single-center prospective, randomized, open-label trial, conducted over a 10-year period (1999-2010), that compared a prophylactic strategy to no prophylaxis over 3 months of chemotherapy among 420 patients with advanced solid tumors. “We found that prophylaxis with either warfarin or low-molecular-weight heparin was effective in preventing thrombotic events, and there was no increase in bleeding with prophylaxis,” said Lavau-Denes. The study was initiated prior to the publication of the current guidelines. The primary end point was the rate of symptomatic and asymptomatic catheter-related deep vein thromboses of the ipsilateral upper limbs and cervical veins of patients who received, versus those who did not receive, thromboprophylaxis. It excluded intraluminal thrombosis. Investigators randomized 142 patients starting a first line of treatment to lowmolecular-weight heparin (at the recom-

mended dose), 138 to warfarin (1 mg/day), and 140 to a control arm. Patients were evaluated at baseline and on day 90 (sooner, in the case of symptoms), using Doppler ultrasound of the upper limbs and cervical veins, and venography.

Adverse events were not significantly increased with thromboprophylaxis.

effectiveness of Prophylaxis In 407 evaluable patients, 42 catheterrelated deep vein thromboses occurred (10.3%), 30 (15.1%) of which were asymptomatic. This included 20 of 135 (14.8%) patients in the control arm and 22 of 272 (8.1%) patients receiving either warfarin or low-molecular-weight heparin. The effect of prophylaxis amounted to a 45% reduction in risk that was statistically significant (P = .0357). Warfarin and low-molecular-weight

heparin were equally effective, LavauDenes noted. Rates of symptomatic events were 6.7% in controls, versus 1.1% after prophylaxis; asymptomatic events occurred in 8.1% and 7.0%, respectively. Unrelated deep vein thromboses also were prevented. Adverse events were not significantly increased with thromboprophylaxis. Bleeding occurred in 0.7% of controls, 2.2% of the low-molecular-weight heparin arm, and 4.5% of the warfarin arm (P = .1361). However, there was an increase in thrombopenia in patients receiving thromboprophylaxis (P <.0001), particularly with low-molecular-weight heparin. However, this was grade 3/4 in only 12 (8.8%), 4 (3.0%), and 7 (5.0%) patients, respectively, with no difference among the arms (P = .1039), she said. Prophylaxis was discontinued by 25% in the control arm, 27% in the warfarin arm, and 33% in the low-molecular-weight heparin arm. For 12.5% of patients in the control arm the reason was the occurrence of a thrombotic event, compared with 2.2% in the warfarin arm and 2.2% in the low-molecular-weight heparin arm.

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Who Should Receive Prophylaxis? Fausto Roila, MD, of Terni, Italy, who chairs ESMO’s Supportive Care Track, reiterated that routine prophylaxis for ambulatory patients with solid tumors is not recommended by any society, except when patients are considered at high risk. However, he noted, “Thrombosis is a potentially deadly complication, and it is not rare.” Therefore, Roila suggested that primary prophylaxis be considered under the following circumstances: • The incidence within one’s institution is 8% to 10% • The tip of the central venous catheter is not positioned at the junction between the atrium and the vena cava • The patient has factor V Leiden mutation or a previous venous thromboembolism • The patient has mediastinal syndrome l Reference 1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al. Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract 1546O PR.

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For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)

PREVENTION BEGINS WHERE TRIPLE THERAPY STARTS

On Cycle 1, Day 1, start with Triple Therapy—EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid—for first-line prevention of CINV. EMEND for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information t EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. t Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. t EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant. t Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. t Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

Selected Important Safety Information (continued) t There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. t Coadministration of EMEND for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle. t The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. t Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. t In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). t In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. Please see the adjacent Brief Summary of the Prescribing Information.

An antiemetic regimen including

Brief Summary of the Prescribing Information for

INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.

Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of >1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

EMENDÂŽ (fosaprepitant dimeglumine) for Injection Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 Substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0â&#x20AC;&#x201C;24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as K, decrease as L, no change as ): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC K 1.8-fold on Day 1 and AUC on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC K 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC K 2.3-fold on Day 1 and K 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC K 25% on Day 4, AUC L 19% on Day 8, and AUC L 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC K 1.5-fold

were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.

A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant.

Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.

CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcgshr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcgshr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, 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: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcgshr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For detailed information, please read the Prescribing Information. Rx only

Prostate Cancer

Proton Beam Therapy: Similar Toxicity to Standard Radiation, at much Higher Cost By Phoebe Starr

he use of proton beam radiation therapy (PBRT) for the treatment of prostate cancer is in-

creasing across the United States, but there is no evidence from randomized controlled trials to suggest that PBRT is

more effective than intensity modulated radiation therapy (IMRT), which is the current standard of care. A study pre-

Newsletter Series

YOUR QUESTIONS ANSWERED

™

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

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

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

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

sented at the 2012 American Society for Radiation Oncology Annual Meeting found few differences in toxicity between the 2 techniques, but demonstrated that PBRT was associated with a 57% increase in median cost per patient. Similar efficacy, Double the Cost “PBRT is an emerging treatment for men with prostate cancer, yet it is much more expensive than IMRT,” said James B. Yu, MD, Assistant Professor of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. “We need a prospective large study comparing radiation techniques to justify widespread use of PBRT for prostate cancer,” he explained. The population-based, retrospective, observational study was based on 22,647 Medicare beneficiaries between the ages of 66 and 94 years who received PBRT or IMRT for prostate cancer in 2008 and 2009; 421 patients (2%) received PBRT and 27,226 patients (98%) received IMRT.

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

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

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

ALL NEW CONTENT FOR 2012

A study presented at the 2012 American Society for Radiation Oncology Annual Meeting found few differences in toxicity between the 2 techniques, but demonstrated that PBRT was associated with a 57% increase in median cost per patient.

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

COEAsize71912AskExperts

DECEMBER 2012 I VOL 5, NO 8

The median Medicare reimbursement per patient is $32,428 for PBRT and $18,575 for IMRT, which represents a 57% difference. PBRT was associated with a significant reduction in urinary toxicity at 6 months versus IMRT (6.1% vs 12%, respectively); however, by 1 year, there was no difference between groups for urinary toxicity (18.9% for PBRT vs 21.9% for IMRT). No signif-

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Prostate Cancer icant differences were observed at 6 months and at 1 year between the 2 groups in gastrointestinal (GI) or other toxicities. “The longer-term effects, costs, and other clinical and patient-reported outcomes are needed to inform the adoption of PBRT for prostate cancer,” Yu stated. The study had several limitations, he continued. It is a retrospective study that is a claims-based analysis with no staging information and with no data on the extent or field of radiation. Potential Differences in Side effects A second study found minimal differences between PBRT, IMRT, and the older 3-dimensional conformal radiation therapy (3D-CRT). The study included 153 patients treated with IMRT, 123 patients treated with 3D-CRT, and 94 patients treated with PBRT. Quality of life (QOL) was assessed by the Expanded Prostate Cancer Index Composite in the IMRT cohort and by the Prostate Cancer Symptom Index in the PBRT and 3DCRT cohorts. The main difference in QOL scores in the GI domain was found 2 to 3 months posttreatment, when 3D-CRT and IMRT—but not PBRT—were associated with a clinically meaningful decrement in QOL scores. Over 12 months, the 3 cohorts had similar QOL scores for GI effects. For urinary irritation, all 3 groups

“PBRT is an emerging treatment for men with prostate cancer, yet it is much more expensive than IMRT. The longer-term effects, costs, and other clinical and patient-reported outcomes are needed to inform the adoption of PBRT for prostate cancer.” —James B. Yu, MD

had lower QOL scores at 2 to 3 months of follow-up, but this was clinically meaningful only for IMRT. Sexual

function QOL scores were lower in all 3 groups at 24 months, but this was not clinically meaningful (defined in

this study as scores exceeding half of the standard deviation of the baseline mean score). “These findings are a unique addition to existing research in the field, and suggest that PBRT may lead to fewer immediate side effects in prostate cancer patients,” noted Phillip Gray, MD, a resident at Harvard Radiation Oncology Pro gram, Boston, Massachusetts. He suggested that a prospective, randomized controlled trial is needed to compare these technologies. l

Reader Survey

Have you had experience in determining the appropriate chemotherapy dose for patients who are obese? In the October issue, we published an article about the results of a meta-analysis reported at ASCO 2012 that supported the new guidelines that recommend weight-based chemotherapy dosing for obese cancer patients. We asked our online reading community if they had experience with dosing for obese patients. • 89% have dealt with weight-based dosing, with 1 reader commenting “every day” • 11% have not had experience with dosing for obese patients

Our sincere thanks to all who participated in this survey. If you want to participate in the new survey, see page 8 for details.

www.TheOncologyPharmacist.com

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor

May 2-5, 2013 Westin Diplomat • Hollywood, Florida

DECEMBER 2012 I VOL 5, NO 8

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

This is his therapy.

Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). EfďŹ cacy relative to ďŹ rst-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;Ą: 0.17, 0.43)

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

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

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

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naĂŻve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in â&#x2030;Ľ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2â&#x20AC;&#x201C;0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ÂŠ2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

Lung Cancer

Crizotinib Superior to Chemotherapy... Continued from cover

Doubling in PFS At 12 months’ median follow-up, crizotinib prolonged median PFS to 7.7 months, compared with 3.0 months with chemotherapy, a highly significant 51% reduction in the risk of progression (P <.0001). By type of chemotherapy, median PFS was 4.2 months with pemetrexed (P = .0004) and 2.6 months with docetaxel (P <.0001). The overall response rate was also significantly higher with crizotinib (65% vs 20%; P <.0001).

“These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC.”

Photo © ESMO 2012.

Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1 Rearrangements of the ALK gene are found in about 5% of all NSCLC. In previous studies, crizotinib was shown to induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase 3 study to directly compare the novel agent with standard chemotherapy. The study compared crizotinib with pemetrexed or docetaxel (by physician choice) in 347 patients with ALK-positive, stage IIIB/IV NSCLC who had already been treated with chemotherapy. Crizotinib was superior to standard single-agent chemotherapy in terms of response, progression-free survival (PFS), and quality of life in ALK-positive patients who progressed after firstline, platinum-based chemotherapy, Shaw reported. “These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC,” she maintained.

—Alice Shaw, MD

All subgroups experienced a PFS benefit with crizotinib, with the greatest advantages seen in patients with nonadenoma histology (hazard ratio [HR], 0.12). Survival, Tolerability At this point, overall survival (OS) differences have not been observed, but the survival analysis is immature, with only 40% of events occurring. Also, 87% of chemotherapy-treated patients have crossed over to receive crizotinib upon progression, and this would dilute any OS differences, Shaw said. Median OS at this point is approximately 22 months in each arm. When adjusted for confounding by crossovers, there was still a 17% reduced risk of dying from the disease for patients who received ALK inhibitor, she pointed out. Side effects were more frequent with crizotinib, but Shaw pointed out that crizotinib-treated patients received an average of 11 cycles, compared with 4 with pemetrexed or docetaxel, which partly explains these differences. Toxicities with crizotinib are, however,

distinct from those observed with chemotherapy, but are “generally tolerable and manageable,” she noted. The most common treatment-related adverse events with crizotinib were diarrhea (60%), vision disturbance (60%), nausea (55%), and vomiting (47%), but few grade 3 or 4 toxicities were reported, except for elevated transaminases, which occurred in 16% of this arm. Patients receiving chemotherapy had more fatigue, alopecia, dyspnea, and rash. Six percent of crizotinib patients, compared with 10% of pemetrexed/ docetaxel patients, discontinued the trial due to treatment-related adverse events. Better Quality of life With Crizotinib Patients on crizotinib also reported improved quality of life, compared with chemotherapy. “They reported greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with crizotinib,” Shaw said, “and all of these were statistically significant (P <.0001).” They also showed greater improvement from baseline in global quality of

life (P <.0001). Furthermore, “time to deterioration in lung cancer symptoms” was significantly extended with crizotinib treatment, to 5.6 months, compared with 1.4 months with chemotherapy (HR, 0.54; P <.0001). Crizotinib “Changes the Natural History” of lung Cancer Discussing the paper at the meeting, Jean-Charles Soria, MD, of the Institut Gustave Roussy in Villejuif, France, noted that 2 months’ extended survival in advanced NSCLC is essentially “unheard of ” in the general population of NSCLC patients. “Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with a median OS now of 22 months, versus 9 months in the past,” he said, “and this is accomplished with very mild toxicity.” Even patients in the trial who initially received chemotherapy had a median OS of nearly 23 months “because they received crizotinib,” he added. Soria suggested that clinicians become familiar with the toxicity profile, which is quite distinct from chemotherapy, but is generally manageable with the exception of “some rare side effects you need to be aware of,” he told attendees. l Reference 1. Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. Abstract LBA1 PR.

Crizotinib Is Just the Beginning By Audrey Andrews

If the abstracts presented at ESMO were any indication, the US Food and Drug Administration approval of crizotinib only opened the door to a virtual roomful of next-generation ALK inhibitors. While crizotinib targets only the 5% of non–small cell lung cancer (NSCLC) patients with the ALK genetic translocation, it makes a huge impact on this subset, doubling the time that patients with advanced disease spend in remission. “Crizotinib is the poster child for precision medicine,” according to Mace Rosenberg, MD, Senior Vice President of Clinical Development and Medical Affairs at Pfizer Oncology. At a press briefing, he noted that the robust responses observed in phase 1 trials of ALK-positive patients led to a “rapid reduction of our clinical development program.” At ESMO, data from phase 1 and 2 trials suggest that the following next-generation ALK inhibitors may follow in the footsteps of crizotinib: • AP26113 is an oral agent that also targets mutations in the epidermal growth factor receptor (EGFR). A study

www.TheOncologyPharmacist.com

of 29 patients with NSCLC showed activity in both the first-line and resistant cohorts. • LDK378, a potent oral small molecule ALK inhibitor, showed a high level of activity in patients who progressed after crizotinib. • CH5424802, an oral agent, produced 3 complete responses and 36 partial responses among 46 NSCLC patients with no prior ALK therapy; 40 patients remain on treatment. • AUY922, a heat shock protein 90 inhibitor that is delivered by weekly infusion, was highly active in 121 patients with previously treated NSCLC who had ALK or EGFR mutations. Responses were observed in 32% of ALK-positive patients and 20% of EGFR-mutated patients. NSCLC investigators at the meeting emphasized that new ALK inhibitors will be needed for treating patients, who inevitably become resistant to crizotinib, in spite of its initial efficacy. They also said that next-generation ALK inhibitors appear to be even better tolerated than crizotinib.

Pushing Your Limits Scan Here to Register.

DECEMBER 2012 I VOL 5, NO 8

CONTINUING EDUCATION NOVEMBER 2012 • VOLUME 5 • NUMBER 4

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Retreatment Settings LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

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

Sincerely, Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

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

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

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

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

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

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

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

DECEMBER 2012 I VOL 5, NO 8

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

www.TheOncologyPharmacist.com

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

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

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

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

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

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

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

SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

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

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

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

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

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

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

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

www.TheOncologyPharmacist.com

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

DECEMBER 2012 I VOL 5, NO 8

CONTINUING EDUCATION

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

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

100 90

78%

Patients (%)

80 64%

70 60

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

50 40 25%

22%

20 10 0 CR/near CR

ORR ( MR)

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

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

15 (68%)

No response

7 (32%)

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

9 (60%)

No response

6 (40%)

Complete or partial response

2 (29%)

No response

5 (71%)

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

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

DECEMBER 2012 I VOL 5, NO 8

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

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

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

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

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CONSIDERATIONS IN MULTIPLE MYELOMA

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

Patients, n (%)

Anemia

20 (33%)

Lymphopenia

4 (7%)

Neutropenia

30 (50%)

Thrombocytopenia

6 (10%)

Leukopenia

24 (40%)

Fatigue

27 (45%)

Nausea

1 (2%)

Diarrhea

5 (8%)

Constipation

11 (18%)

Pneumonia

6 (10%)

Hyperglycemia

10 (17%)

Confusion

5 (8%)

Insomnia

7 (12%)

Agitation

7 (12%)

Peripheral neuropathy

6 (10%)

Thrombosis

1 (2%)

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

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

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

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

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CONTINUING EDUCATION

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

Introduction

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

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

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

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

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

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

Modification of Dose and Regimen

Grade 1 (mild)

No action

Grade 1 with pain or grade 2

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

Grade 3

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Grade 4 (permanent sensory loss that interferes with function)

Discontinue thalidomide

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

Modification of Dose and Regimen

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

No action

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

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

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

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

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

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CONSIDERATIONS IN MULTIPLE MYELOMA

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

Patients (%)

30 25 20 15 10 5 0

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

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

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

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

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

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

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CONTINUING EDUCATION

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

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

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

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

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

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

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

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

DECEMBER 2012 I VOL 5, NO 8

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

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

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

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CONSIDERATIONS IN MULTIPLE MYELOMA

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

P=.044

SC bortezomib

53% P=.012

IV bortezomib

Patients (%)

41% 40

38%

24%

P=.026

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

16%

Conclusion 10

0 Any grade

Grade 2

Grade 3

IV indicates intravenous; SC, subcutaneous.

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

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

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

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

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

DECEMBER 2012 I VOL 5, NO 8

Conference News: ASTRO Continued from cover

memantine Delays Cognitive Decline in Patients With Brain metastases Treated With Whole-Brain Radiation Memantine delayed cognitive decline in patients treated with whole-brain radiation therapy (WBRT) for brain metastases, according to results of a randomized phase 3 trial.1 Cognitive decline is common with WBRT, occurring in about 50% to 60% of patients by 4 months after radiation. Because the mechanism of radiationinduced cognitive decline appears to be similar to that of vascular or Alzheimer’s dementia, the researchers postulated that memantine, a drug used to treat Alzheimer’s disease, would be of benefit in patients treated with WBRT. “We are excited to see that adding memantine to the treatment plan for brain tumor patients helps preserve their cognitive function after whole-brain radiotherapy even 6 months after treatment. Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy, impacting future treatment practices for these patients, and suggest a role for further study in patients receiving radiation to the brain,” said presenter Nadia N. Laack, MD, radiation oncologist at the Mayo Clinic in Rochester, Minnesota.

Formal discussant of this trial, Vinai Gondi, MD, associate director of the Central Dupage Hospital’s Proton Center in Warrenville, Illinois, called this study “a good first step” in understanding the cognitive changes resulting from brain radiation and the role of memantine in preventing or delaying them. He said that

tion (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life) were assessed by different instruments at baseline and weeks 8, 16, 24, and 52. The primary end point was memory as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R).

“Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy.” —Nadia N. Laack, MD

the effect of memantine was modest in this trial and that other strategies to improve cognitive effects of radiation are being pursued by researchers. The study included 508 patients with brain metastases who received WBRT between March 2008 and June 2010. WBRT was delivered as 37.5 Gy in 15 daily fractions. Patients were randomized to memantine 20 mg/day or placebo within 3 days of the start of radiation therapy. Six domains of cognitive func-

Compliance with the cognitive testing protocol was suboptimal, with 32% of the patients completing drug therapy and cognitive assessments. The reasons for noncompliance appeared to be death, disease progression, and difficulty in getting patients to stay longer during a clinic visit or in physicians scheduling the extra 20 minutes to 1 hour required for cognitive testing. Of the 508 patients randomized to the 2 arms, only 149 patients were analyzable at 24 weeks.

For the primary end point of memory decline as assessed by the HVLT-R, memantine reduced the decline in HVLT-R delayed recall, with a median decline of 0 versus –2 for placebo at 24 weeks, with a statistical significance of P = .059. This result was “teetering on the edge of significance,” according to Laack, due to the small numbers of patients. At 24 weeks, memantine reduced the relative risk of cognitive decline by 17% versus placebo (P = .01), and it reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P <.01). Patients in both groups experienced similar rates of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea. The investigators plan to evaluate the effect of memantine on overall survival and progression-free survival in these patients. Also, tissue specimens will be studied to identify biomarkers of cognitive decline as well as of response to memantine. Reference 1. Brown PD, Shook S, Laack N, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiation therapy (WBRT): first report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 1.

Prophylactic Sildenafil Improves Sexual Function in Prostate Cancer Patients Undergoing Radiation Sildenafil is often used by men treated with radiation or radical prostatectomy for prostate cancer to achieve an erection sufficient for sexual intercourse, and it is effective to varying degrees when used on an as-needed basis. A randomized controlled trial has found that prophylactic daily use of sildenafil improved overall sexual function, as well as domains of sexual function, in prostate cancer patients undergoing radiation therapy.1 This is the first time a phase 3 study has demonstrated the effectiveness of prophylactic sildenafil in the setting of radiation. “Prostate cancer patients treated with sildenafil and adjuvant radiation treatment had improved overall erectile function and overall satisfaction of their sexual activity and function. The

most significant improvements were seen at 6 and 12 months after treatment, with a slight dip at the 24-month mark, suggesting that future trials need to be conducted to demonstrate if longer treatment duration can further improve outcomes,” said lead author Michael Zelefsky, MD, of Memorial Sloan-Kettering Cancer Center in New York City. No benefit for sildenafil was seen among a small group of 31 patients who were also treated with androgen deprivation therapy. The prospective, randomized, double-blind, placebo-controlled trial included 295 patients with clinically localized prostate cancer who were treated with external beam radiation therapy and/or brachytherapy (permanent interstitial implantation of radio-

active “seeds”). Patients were randomized in a 1:1 ratio to receive either daily sildenafil 50 mg or placebo. Treatment was initiated 3 days before radiation treatment and was continued daily for 6 months, when the drug was stopped. After that, sildenafil could be used as needed. Sexual function was assessed at 3-month intervals for the first year and thereafter at 18 and 24 months with the international index of erectile function (IIEF) and the international prostate symptom score (IPSS) questionnaires. At baseline, all patients had excellent erectile function, as assessed by IIEF. Among 144 patients treated with radiation only who completed IIEF and IPSS questionnaires, overall sexual function was improved with daily sildenafil versus

placebo at all time points. IIEF scores were 58.6 for sildenafil versus 49.4 for placebo at 6 months (P = .006); 56.3 versus 48.2, respectively, at 12 months (P = .02); and 54.9 versus 47.6, respectively, at 24 months (P = .04). Significant improvement in overall function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction were reported with sildenafil versus placebo. Overall IPSS was also significantly improved with sildenafil versus placebo (P <.001). Reference 1. Zelefsky MJ, Shasha D, Kollmeier M, et al. Results of a prospective randomized double-blind placebo-controlled trial evaluating the use of prophylactic sildenafil citrate during radiation therapy in the treatment of prostate cancer. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 3.

THIRD ANNUAL CONFERENCE Influencing the Patient-Impact Factor

May 2-5, 2013 Westin Diplomat Hollywood, Florida

DECEMBER 2012 I VOL 5, NO 8

www.TheOncologyPharmacist.com

Conference News: ASTRO Doxepin Rinse Improves Oral mucositis in Patients Treated With Radiation for Head and Neck Cancer

oxepin, a tricyclic antidepressant approved for the treatment of depression and anxiety, as well as moderate pruritus, significantly improved oral mucositis pain in patients treated with radiation therapy for head and neck cancer in a phase 3 trial.1 In the study, doxepin was combined with water and used as an oral rinse. Oral mucositis pain is a significant problem in patients with head and neck cancer treated with radiation, and treatments such as narcotics and mouth rinses are not particularly effective in alleviating this pain. Smaller studies have suggested that doxepin is safe and effective in reducing oral mucositis pain, and the present study establishes its effectiveness in a randomized controlled trial. “Our study validates doxepin rinse as an effective way to alleviate oral pain and sets a new standard of care,” said the lead author of the study, Robert C. Miller, MD, of the Mayo Clinic in Rochester, Minnesota.

–7.9 in the doxepin group versus –5.6 in the placebo group (P = .009). Doxepin was well tolerated, but it was associated with more stinging and burning (mean pain score of 3.7 for doxepin vs 1.1 for placebo) as well as an unpleasant taste (mean unpleasant taste at 5

minutes 2.9 for doxepin vs 1.6 for placebo), and it caused greater drowsiness (mean drowsiness score of 3.9 for doxepin vs 2.8 for placebo). During the optional continuation phase, the majority (64%) of patients elected to continue doxepin. l

—Robert C. Miller, MD

For the N09C6 study, pain was assessed on a visual analog scale and scored from 0 to 10, with a score of 10 signifying severe pain. N09C6 was a double-blind, randomized, placebo-controlled trial of 140 patients with head and neck cancer who had an oral mucositis pain score above 4 on the visual analog scale. Patients were enrolled between December 2010 and May 2012 and were treated with radiation at doses above 50 Gy involving more than onethird of the oral cavity for head and neck cancer. The dosage of the oral doxepin rinse was 25 mg dissolved in 5 mL of water and used for 1 minute. Patients were treated on day 1 with either the doxepin rinse or placebo; on day 2, patients crossed over to the other treatment arm. Patients could elect to continue treatment with the doxepin rinse on an as-needed basis. On day 1, doxepin-treated patients reported area under the curve (AUC) pain score reduction to –9.1 versus –4.7 for placebo patients (P = .0003). Crossover data from day 2 showed similar findings, with an AUC pain score of

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1. Miller RC, Leenstra J, Qun R, et al. N09C6 (Alliance) - a phase III, randomized double-blind study of doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract LBA1.

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

www.coexm.com/ace09 TARGET AUDIENCE

“Our study validates doxepin rinse as an effective way to alleviate oral pain and sets a new standard of care.”

Reference

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

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

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

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

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

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

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

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

DECEMBER 2012 I VOL 5, NO 8

Profile

Onco360...

Continued from cover

So, a stagnant supply of 12,000 oncologists will have twice as many cancer patients to manage, and, given the science, twice the evidence work components to review to develop the best plan of care. Thus, the opportunity for the oncology pharmacist; preferably, the BCOP. We predict that the only viable solution to the projected patient cancer care access crisis will be oncology pharmacists functioning as physician extenders and working in concert with treating oncologists or hematologists. This will allow experts in oncology drug care to support physicians in formulating the best treatment care planning, and, just as importantly, the ongoing management of patients to minimize side effects and adverse events to drive a desired outcome for the patients. We researched the cancer care pharmacy marketplace and thought to ourselves, why can’t the great multidisciplinary approach in an NCCN cancer center be deployed outside the 4 walls of the hospital? We decided we could provide community and smaller regional hospital systems with the same intensive oncology pharmacist clinical support and patient care infrastructure outside those 4 walls. We also recognized that the Onco360 service model was different than the traditional specialty generalist pharmacies that typically manage single, high-cost, self-injectable, and biological pharmaceuticals for patients on a predictable 30-, 60-, or 90-day therapy schedule. To create our service model we held extensive one-on-one meetings with key opinion leaders in pharmacy, pharma, and treating physicians to engineer a solution that addressed the gaps in care and service.

How do your services translate to better outcomes for patients with cancer? BZ: Our BCOPs are well trained and experienced. Their expertise helps cancer patients through the challenges of undergoing treatment.

“The depth and level of interaction between patients and oncology pharmacists will undoubtedly continue to increase over the coming years.” —Burt Zweigenhaft

OncoMTM, our Medication Therapy Management program, is built around the customized care and attention that each patient needs in order to stay compliant with his or her regimen, minimize adverse events, and improve outcomes. By marrying our just-in-time dose dispensing with our clinical expertise, we seek to minimize drug waste to manage a very dynamic disease and treatment regimen by focusing on quality measures.

The American Cancer Society estimates there will be 1.7 million new cancer cases in the United States in 2013.

How is the relationship between oncology pharmacists and patients changing? BZ: The major change will be that an oncology pharmacist will be much more directly involved in patient care. This reflects how the multidisciplinary teams operate at Cancer Care Centers. The American Cancer Society estimates there will be 1.7 million new cancer cases in the United States in

2013. This fact, coupled with the predicted shortage of oncologists, presents an opportunity for oncology pharmacists to be more involved with interventions and patient management. We believe that BCOPs will be well equipped to fill that clinical gap, to provide the personal attention and care that every patient not only needs, but also deserves. So clearly, the depth and level of interaction between patients and oncology pharmacists will undoubtedly continue to increase over the coming years. This multidisciplinary partnership will be a part of every accountable care organization or oncology medical home model that emerges.

How will this changing relationship affect the training needed for oncology pharmacists? BZ: We are working with several schools of pharmacy, including the University of Buffalo, to develop 1year and 2-year oncology pharmacy tracks that include hands-on residency and other programs. We expect programs like this will foster a learning environment where oncology pharmacists can be trained and integrated into the cancer care community to address the shortage of oncologists. Clearly, a higher level of education, training, and experience will be necessary to prepare pharmacists for an expanded role within the continuum of care. We feel this need will be best served by BCOPs, which is why we

support our pharmacists in their pursuit of such rigorous certification, as it will ultimately best serve our patients and physician partners.

What are the biggest challenges facing the field of oncology pharmacy? Are compounding issues and safety part of these challenges? BZ: In addition to the challenges already noted, the unknown effect of healthcare reform and the new world of accountable care will require oncology pharmacy to move beyond dispensing of medications. It’s no secret that cancer costs are out of control, and more and more focus will come from managed care and the government in terms of pharmacy partners that can help control those costs without compromising care. Expect comparative effectiveness and value-based contracting to become common. The heightened concern over compounding and pharmacy safety brought on by the unfortunate meningitis tragedy will certainly add to those challenges. We see stepped-up state and federal regulation around cancer pharmacy standards in terms of storage, dispensing, and waste. Oncology pharmacy must be prepared to not only meet but also exceed the minimum requirements for safely compounding and dispensing cancer drugs. What are you excited about right now in the field of oncology pharmacy? BZ: I am most excited about the shift toward accountable care and, as a natural extension, the increased need for meaningful cost containment. As the head of an organization, I am working with my team to build our oncology medical home model. We’ve built our company by creating a model that fits the disease of cancer and addresses the needs of oncologists by leveraging the partnership opportunities BCOPs can bring to improve quality and outcomes for patients. In doing so, we have a unique ability to define the value oncology pharmacy can contribute to the cancer care solution. l

Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for more information. 28

DECEMBER 2012 I VOL 5, NO 8

www.TheOncologyPharmacist.com

Neuroendocrine Tumors

Advances in the Treatment of Pancreatic Neuroendocrine Tumors By Caroline Helwick

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

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

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

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

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

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

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

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

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

DECEMBER 2012 I VOL 5, NO 8

Leukemia

Relapsed/Refractory All Vexing Problem By Alice Goodman

he management of relapsed/refractory acute lymphoblastic leukemia (ALL) is a vexing problem and requires extensive, aggressive

supportive care throughout the course of therapy, explained Joseph C. Alvarnas, MD, City of Hope Comprehensive Cancer Center, Duarte, California, in a

presentation at the National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies.1

www.avbcconline.org

MAY 2-5, 2013

THIRD ANNUAL CONFERENCE

Influencing the Patient-Impact Factor May 2-5, 2013 Westin Diplomat Hollywood, Florida

For more information please visit

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DECEMBER 2012 I VOL 5, NO 8

The NCCN guidelines for ALL reveal a dichotomy between Philadelphia-positive (PH+) and Philadelphia-negative (PH-) relapsed/refractory ALL. In PH+ ALL, gene mutation testing is important. Patients with PH+ disease who relapse following cessation of tyrosine kinase inhibitors (TKIs) can restart TKI-based therapy. For those who are refractory or relapse on TKI-based therapy, perform mutational analysis. If the T315I mutation is present, consider hematopoietic cell transplant (HCT) or clinical trial; for V299L, T315A, F317L/V/CI/C, consider nilotinib rather than dasatinib. For Y253H, E255K/V, or F359 V/C/I, consider dasatinib rather than nilotinib. For any other mutation, consider highdose imatinib, dasatinib, or nilotinib. PH- ALL is far more difficult to treat. Most regimens are front-loaded with the best therapeutic agents, leaving few options for second-line treatment at relapse. Patients with PHALL should be considered for clinical trial or allogeneic hematopoietic stem cell transplant if in remission or on chemotherapy.

The NCCN guidelines for acute lymphoblastic leukemia (ALL) reveal a dichotomy between Philadelphia-positive and Philadelphia-negative relapsed/refractory ALL.

Several challenges exist for salvage therapy for adults with relapsed/refractory ALL, Alvarnas continued. It may be difficult to identify a non‒cross-resistant regimen for reinduction. L-asparaginase–containing regimens may be difficult to administer to older patients. Even very intensive regimens may achieve response rates <30%. Comorbidities may limit therapeutic choices. Allogeneic HCT represents the only potentially curative option for adolescents/young adults (AYAs) and adults with ALL. Patients with significant residual disease are not candidates for allogeneic HCT. “The lessons from our experience with relapsed/refractory ALL are

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Leukemia twofold. First, we would like to avoid relapse, and we recommend strong risk stratification at the time of diagnosis. Second, move to transplant after first complete response is achieved,” he stated. Five-year overall survival was 62% at City of Hope when adults with ALL were transplanted in first remission. “Unrelated donor transplant produces similar outcomes as related donor transplant. Don’t let the lack of sibling donor keep you from moving on to transplant,” he told listeners. Alvarnas commented that transplant outcomes have not improved appreciably over the past 3 decades. “We have a long way to go,” he said. “At the same time, intensification of the transplant regimen is not feasible.” Experience with transplant raises the importance of timely transplantation and the need for better drugs that might improve outcomes, he said. Alvarnas discussed several new agents that may be useful in relapsed/refractory ALL. Two agents that have shown promising results in

small phase 2 trials are nelarabine, a prodrug of ara-G, and clofarabine, a second-generation purine nucleoside analog. Both drugs have distinct sideeffect profiles, with different toxicities. Neurologic toxicity is the key dose-limiting toxicity with nelara-

and cytomegalovirus reactivation. “The use of novel therapeutics in relapsed/refractory ALL is exciting to me. We would like to identify a parallel drug to rituximab in lymphoma. We are still early on in this process. Two drugs might be interesting in this re-

“Unrelated donor transplant produces similar outcomes as related donor transplant. Don’t let the lack of sibling donor keep you from moving on to transplant.” —Joseph C. Alvarnas, MD

bine. Other significant toxicities include cytopenia, gastrointestinal effects, and pyrexia. Toxicities of clofarabine include elevations of liver enzymes, febrile neutropenia, skin rash,

gard [blinatumomab and inotuzumab ozogamicin]. These antibodies are impressively tolerable in heavily pretreated patients, compared with chemotherapy,” Alvarnas said. l

Reference 1. Alvarnas JC. New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. Presented at: National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies; September 14, 2012; New York, NY.

Supportive Care for All Patients being treated for ALL require aggressive coordinated supportive care throughout the entire course of therapy. Alvarnas highlighted several supportive care needs: • Preemptive management of tumor lysis syndrome • Disseminated intravascular coagulation and L-asparaginase coagulopathies • Management of therapy-related cytopenia • Management of febrile neutropenia/opportunistic infection • Antiemetic therapy

On the Horizon for Relapsed/Refractory All By Alice Goodman

oseph C. Alvarnas, MD, discussed new drugs that might improve outcomes for relapsed/refractory acute lymphoblastic leukemia (ALL) at the National Comprehensive Cancer Network 7th Annual Congress on Hematologic Malignancies.1 Alvarnas is director of medical quality and clinical associate professor at City of Hope Comprehensive Cancer Center in Duarte, California. Two new investigational drugs in relapsed ALL are nelarabine and clofarabine. Nelarabine, a prodrug of 9-beta-Dara-G, is active in the management of relapsed/refractory ALL and is non–cross resistant with most other ALL drugs. Phase 2 trials included 39 pediatric patients and 28 adults with relapsed/refractory ALL.2 In pediatric patients, complete response (CR) rate was 5 of 39, and 9 of 39 patients achieved CR or CR with incomplete marrow recovery. In adults, 5 of 28 achieved CR, and 6 of 28 achieved CR or CR with incomplete marrow recovery. Nelarabine has a distinct toxicity profile. Neurotoxicity is the key dose-limiting toxicity. In phase 1 and 2 trials, 64% of patients experienced headache and seizures, and 1 case of fatal status epilepticus was reported. Additional significant toxicities included cytopenia, gastrointestinal disorders, and pyrexia. Clofarabine, a second-generation purine nucleoside analog, is active in both relapsed/refractory ALL and acute

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myeloid leukemia (AML). The drug can be used as monotherapy or as part of a preparative regimen for transplant in combination with additional chemotherapeutic agents, such as etoposide, cytarabine, and cyclophosphamide. It is more active in B-cell disease than T-cell disease. “These combination regimens [with clofarabine] are not for the faint of heart. Patients can develop mucositis and cytopenia. Be prepared for a sick patient who requires inpatient hospitalization,” Alvarnas told listeners.

“I am excited about the use of novel agents in relapsed/refractory ALL.” —Joseph C. Alvarnas, MD

In a single-agent trial of 61 pediatric patients with ALL who had failed 2 or more previous regimens, response rate was 20% (7 CR and 5 CR with incomplete marrow recovery).3 “The small percentage of response is impressive in this disease,” he said. In a trial of children with refractory AML or ALL treated with the combina-

tion of clofarabine, etoposide, and cytarabine, 19 of 24 ALL patients achieved CR or CR with incomplete recovery of bone marrow; 1 of 16 AML patients achieved CR or CR with incomplete recovery of bone marrow; 13 of 17 responders subsequently underwent allogeneic hematopoietic cell transplant; and 24-month overall survival was 25%.3 Toxicities associated with clofarabine include elevations of liver enzymes, febrile neutropenia, infections (cytomegalovirus [CMV] reactivations), and skin rash. Alvarnas noted that the rate of CMV reactivation is not high, “but it is real, and patients can develop visceral disease.” Investigators would like to discover a drug for ALL that is parallel to rituximab in lymphoma, but they are still early in this pursuit. “Two drugs might be interesting in this regard,” he said. Blinatumomab (AMG 103) brings the T-cell in opposition to the tumor cell and allows destruction of the tumor cell. In a phase 2 trial of 36 patients with relapsed/refractory ALL, 26 of 36 achieved CR or CR with incomplete bone marrow recovery, and median survival was 9 months (range, 8.2-15.8 months).4 Reversible central nervous system events were reported in 6 patients. Inotuzumab ozogamicin was the second drug he discussed. This is an antiCD22 antibody conjugated with

calicheamicin that induces doublestranded DNA breaks. In a phase 2 trial of 40 patients with relapsed/refractory ALL who received a median of 2 courses of therapy, CR was 56%; 70% of responders were alive at 6 months following therapy; and 12 patients went on to allogeneic stem cell transplant.5 Adverse events included grade 3 or 4 fever in 9 patients and grade 3 hypotension in 1 patient. “I am excited about the use of novel agents in relapsed/refractory ALL. These antibodies are impressively tolerable in heavily pretreated patients, compared with chemotherapy,” he stated. l References 1. Alvarnas JC. New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. Presented at: National Comprehensive Cancer Network 7th Annual Congress on Hematologic Malignancies; September 14, 2012; New York, NY. 2. Cohen MH, Johnson JR, Justice R, et al. FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008;13(6):709-714. 3. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24(12):1917-1923. 4. Topp M, Goekbuget N, Zugmaier G, et al. Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 2012; Chicago, IL. Abstract 6500. 5. Byrd JC, Furman RR, Coutre SE, et al. The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 2012; Chicago, IL. Abstract 6507.

DECEMBER 2012 I VOL 5, NO 8

CONTINUING EDUCATION DECEMBER 2012 • VOLUME 5 • NUMBER 5

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Bone Health LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

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

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

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

G. David Roodman, MD, PhD Director of Hematology/Oncology Department of Medicine Indiana University Indianapolis, IN

Raj Duggal, PharmD, BCOP Oncology Clinical Pharmacist IU Simon Cancer Center Indianapolis, IN

Lori Case, RN, BSN, OCN Nurse Coordinator IU Simon Cancer Center Indianapolis, IN

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

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

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

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

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-033-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the impact and consequences of bone destruction in patients with multiple myeloma (MM)

• Summarize recent evidence-based guidelines for the management of myeloma-related bone disease • Review safety and efficacy data on current and investigational therapies for preventing bone loss and skeletal-related events in patients with MM Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/ services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. She does intend to discuss either non–FDA-approved or investigational use for the following products/devices: pomalidomide and carfilzomib. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose. Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosed that her spouse is investigator on a study for Agenix, ImClone, and Lilly; on the Data Monitoring Committee for Infinity and Pfizer; on the Advisory Committee for Boehringer Ingelheim; and principal investigor on a study for Pfizer and Sinta. Faculty Disclosures Sagar Lonial, MD, is a consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. He does intend to discuss either non–FDA-approved or investigational use for the following products/devices: carfilzomib, pomalidomide, MLN9708, vorinostat, panobinostat, and elotuzumab. G. David Roodman, MD, PhD, is a consultant to Amgen Inc and

Celgene Corporation. He does not intend to discuss any non–FDAapproved or investigational uses of any products or devices. Raj Duggal, PharmD, BCOP, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational uses of any products or devices. Lori Case, RN, BSN, OCN, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational uses of any products or devices. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/ CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12029.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. Estimated time to complete activity: 1.0 hour Date of initial release: December 12, 2012 Valid for CME/CPE/CE credit through: December 12, 2013 SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Advances in the Treatment of MyelomaRelated Bone Disease G. David Roodman, MD, PhD Director of Hematology/Oncology, Department of Medicine Indiana University, Indianapolis, IN

Introduction At the time of diagnosis, two-thirds of patients with multiple myeloma (MM) experience bone pain and are very likely to sustain

an SRE at the time of enrollment still obtained clinical benefit from bisphosphonate therapy. In this trial, a 5.5-month overall survival advantage was reported among patients who received the intravenous (IV) bisphosphonate zoledronic acid compared with those who received the oral bisphosphonate clodronic acid.3 A subsequent analysis, however, revealed that only patients with evidence of bone disease achieved the survival benefit.5 Therefore, the survival advantage with bisphosphonate use among MM patients who have not exhibited lytic lesions or osteopenia at diagnosis remains unclear.

pathologic fractures. Therefore, an important goal of therapy when treating the disease is the prevention of fractures and other skeletal-related events (SREs). In this article, G. David Roodman, MD, PhD, discusses recent advances in the management of myelomarelated bone disease, and novel agents that are being investigated

New evidence is beginning to emerge, however, to suggest that earlier use of bisphosphonates may be warranted.

for their potential to improve patient outcomes.

How should bisphosphonates be used to improve outcomes in patients with myeloma-related bone disease?

Guidelines from the American Society of Clinical Oncology1 and the European Myeloma Network2 recommend bisphosphonate therapy for MM patients with either radiographic evidence of lytic bone lesions or severe osteopenia attributable to their disease. New evidence is beginning to emerge, however, to suggest that earlier use of bisphosphonates may be warranted. For example, in the Medical Research Council’s Myeloma IX trial,3,4 Morgan and colleagues showed that even patients who did not present with

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D’Arena and colleagues evaluated patients with smoldering myeloma who received IV pamidronate (60-90 mg once a month for 1 year).6 At the time of progression to symptomatic MM, SREs were reported in 72.7% of patients who were observed versus 39.2% of patients treated with pamidronate (P=.009). These results also suggest that bisphosphonates can be beneficial early in the course of myeloma. However, we cannot be 100% certain that the patients without documented bone disease really did not have bone disease. In the Myeloma IX trial, the investigators utilized skeletal survey rather than the more sensitive magnetic resonance imaging (MRI) to detect myeloma-related bone disease, because that was the modality available at the time.3 We now use MRI in clinical practice to obtain a

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Figure. Bortezomib and lenalidomide in the treatment of myeloma-related bone disease.14

Unfortunately, some patients remain permanently on dialysis despite the use of effective novel agents. Although pamidronate and zoledronic acid are not recommended for patients with creatinine clearance (CrCl) <30 mL/min, I think whenever possible, these individuals should receive bisphosphonate therapy to alleviate the pain associated with bone disease and to minimize the risk of pathologic fractures. In rare cases, in which patients have very poor performance status and rapidly progressing disease after frontline therapy, we may be unable to administer bisphosphonates for the purpose of preventing SREs. However, these agents may still be helpful in normalizing calcium levels in patients who are hypercalcemic. What is the latest evidence regarding the potential of novel agents to enhance bone health in patients with MM?

Reprinted with permission. Bzb indicates bortezomib; BMP-2, bone morphogenetic protein-2; MSCs, mesenchymal stromal cells; OAFs, osteoclast-activating factors; OCL, osteoclast; Runx2; runt-related transcription factor 2.

more accurate assessment of a patient’s condition. If individuals have any symptoms, but have a negative skeletal survey, we conduct an MRI examination, per current recommendations.7 In patients who have a solitary plasmacytoma or a single lytic lesion, we perform an MRI of the spine and pelvis to ensure that they do not have additional lytic disease. There is evidence that the presence of focal lesions on MRI may indicate a patient with MM— even one who is otherwise asymptomatic—is at risk for rapid progression and poor prognosis.8,9 Such patients probably should receive therapy. Fluorodeoxyglucose positron-emission tomography scanning combined with computed tomography (CT) is an excellent method for examining bone10; however, it can be very expensive and therefore cannot be used routinely. In Europe, clinicians are utilizing total-body CT scans with lower doses of radiation. This may eventually become a more standard practice here in the United States. What is your approach to treating bone disease in patients with severe renal dysfunction?

In patients with very severe renal failure at diagnosis, we use antimyeloma therapy to improve renal function prior to initiating a bisphosphonate. Bortezomib-based therapy has been used successfully to reverse renal failure in patients with MM; 59% of patients will exhibit an improvement in renal function within a median of 11 days (range, 8-41 days), with 2 of 9 dialysisdependent individuals becoming dialysis-independent.11 The International Myeloma Working Group recommends bortezomib plus high-dose dexamethasone to accelerate the reversal of renal impairment.12 Bortezomib may improve renal impairment by reducing inflammation through the inhibition of nuclear factor kappa B (NF- B), a transcription factor with proinflammatory effects in the compromised kidney.13

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Several antimyeloma agents may have secondary pro-bone effects, particularly proteasome inhibitors and immunomodulatory drugs (Figure).14 Mounting evidence suggests that the proteasome inhibitors bortezomib and carfilzomib have bone anabolic effects. In other words, they are able to build bone.15-18 These effects have been observed preclinically; clinically, the role of proteasome inhibition in bone formation requires further study. Proteasome inhibitors stimulate bone formation by their enhancement of osteoblast differentiation. In a clinical study, Giuliani and colleagues demonstrated that in human osteoblast progenitor cells, bortezomib stimulated bone nodule formation.16 These researchers, who administered bortezomib as monotherapy to 21 relapsed or previously treated patients with MM, reported that individuals who responded to bortezomib in terms of their myeloma also showed an increase in the number of osteoblasts per mm2 of bone tissue. Patients who responded to bortezomib also exhibited an increase in the number of Runx2/Cbfa1-positive osteoblastic cells; Runx2/Cbfa1 is an osteoblast transcription factor regulated by BMP-2. These signs of enhanced osteoblast activity were not observed in nonresponders to bortezomib.

In patients with very severe renal failure at diagnosis, we use antimyeloma therapy to improve renal function prior to initiating a bisphosphonate.

Terpos and colleagues reported that bortezomib use reduced patients’ serum levels of dickkopf-1 (DKK-1), thus countering the ability of DKK-1 to inhibit the Wnt signaling pathway to suppress osteoblast differentiation.18 Their study results also demonstrated a decrease in receptor activator of NFB ligand (RANKL) with bortezomib, indicating a reduction in osteoclast activity. Together, reduction in DKK-1 and RANKL indicates a normalization of bone remodeling with bortezomib in patients with relapsed MM. The caveat with current data is that, for the most part, patients who demonstrated an increase in bone formation markers also showed an antitumor response to bortezomib. This makes it unclear if bone formation is the result of an effect on osteoblast differentiation or is simply an added benefit of antimyeloma activity. Only one study to date has demonstrated enhanced bone formation markers regardless of whether a patient’s myeloma responded to bortezomib.19 The immunomodulatory agents lenalidomide, thalidomide, and pomalidomide also appear to have beneficial effects on bone. These drugs have been shown to inhibit osteoclast formation and bone remodeling markers in patients with MM.20-22 Breitkreutz and colleagues examined the osteoclast

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CONSIDERATIONS IN MULTIPLE MYELOMA

effects of lenalidomide compared with bortezomib, reporting that lenalidomide reduced levels of RANKL in the serum and bone marrow stromal cells of patients with MM.20 Anderson and colleagues reported that immunomodulators inhibit osteoclastogenesis by diverting osteoclast precursors away from their osteoclast cell lineage toward a granulocytic lineage—a unique mechanism of action mediated by downregulation of the PU.1 transcription factor.22 Osteoclast inhibition appears to be a class effect of immunomodulators. This seems to be more evident with lenalidomide and pomalidomide than with thalidomide.20-22

This is consistent with the suppression of bone remodeling—as less bone is resorbed during treatment, less bone needs to be made.

Denosumab, a fully humanized monoclonal antibody, is currently approved only for the prevention of SREs in patients with bone metastases from solid tumors.23 However, this novel agent is currently being evaluated for potential benefits in patients with MM in a phase 3 trial. RANKL is overexpressed in MM and triggers increased osteoclast activity.15 Denosumab inhibits RANKL, and therefore has potent inhibitory effects on the differentiation, activity, and survival of osteoclasts,24 although it has not been shown to augment bone formation. In clinical trials,25 markers of both bone resorption and bone formation are reduced with denosumab treatment in patients with metastatic bone disease, just as they are in trials of bisphosphonates.26 This is consistent with the suppression of bone remodeling—as less bone is resorbed during treatment, less bone needs to be made.26 Conclusion

Bone disease is a major morbidity factor in patients with MM, and the associated skeletal complications can result in significant morbidity. Bisphosphonates remain the standard of care for the treatment of myeloma-related bone disease, and have been shown to consistently reduce the incidence of SREs. However, new molecular targets of cell cross-talk in myeloma bone marrow are currently under investigation, and new drugs are being explored in preclinical and clinical trials. It is hoped that results from these studies will expand our armamentarium of treatment options for patients with MM. References 1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472.

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2. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009; 20:1303-1317. 3. Morgan GJ, Davies FE, Gregory WM, et al; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376:1989-1999. 4. Morgan GJ, Child JA, Gregory WM, et al; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-752. 5. Morgan GJ, Davies F, Gregory W, et al. Defining the biological subgroup of multiple myeloma patients which benefits maximally from the overall survival (OS) benefit associated with treatment with zoledronic acid (ZOL). J Clin Oncol. 2011;29(suppl). Abstract 8083. 6. D’Arena G, Gobbi PG, Broglia C, et al; Multiple Myeloma Working Group; Gisl (Gruppo Italiano Studio Linfomi) Cooperative Group. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma. 2011; 52:771-775. 7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 17, 2012. 8. Hillengass J, Fechtner K, Weber M-A, et al. Prognostic significance of focal lesions in wholebody magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610. 9. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25:1121-1128. 10. Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol. 2005;184:1199-1204. 11. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors. Clin Lymphoma Myeloma. 2009;9:302-306. 12. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 13. Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomibbased chemotherapy in patients with multiple myeloma. Haematologica. 2007;92:1411-1414. 14. Roodman GD. Bone building with bortezomib. J Clin Invest. 2008;118:462-464. 15. Roodman GD. Skeletal imaging and management of bone disease. Hematology. 2008:313-319. 16. Giuliani N, Morandi F, Tagliaferri S, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110: 334-338. 17. Hurchla MA, Garcia-Gomez A, Hornick MC, et al. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia. 2012 Jul 5. doi: 10.1038/leu.2012.183. 18. Terpos E, Heath DJ, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor- B ligand concentrations and normalizes indices of bone remodeling in patients with relapsed multiple myeloma. Br J Haematol. 2006;135:688-692. 19. Delforge M, Terpos E, Richardson PG, et al. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 2011; 86:372-384. 20. Breitkreutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia. 2008;22:1925-1932. 21. Bolzoni M, Abeltino M, Storti P, et al. The immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and RANKL/OPG ratio in myeloma microenvironment targeting the expression or adhesion molecules. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 448. 22. Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood. 2006;107:3098-3105. 23. Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc; 2010. 24. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 25. Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26:530-537. 26. Berenson JR, Lichtenstein A, Porter L, et al; Myeloma Aredia Study Group. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med. 1996;334:488-493.

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Pharmacologic Issues in the Management of Myeloma-Related Bone Disease Raj Duggal, PharmD, BCOP Oncology Clinical Pharmacist IU Simon Cancer Center Indianapolis, IN

pamidronate found in a single, prospective study, but this is not supported in the recent Cochrane review.2 Clinicians at our institution tend to select zoledronic acid as the preferred bisphosphonate, given the advantage of shorter infusion times for patients with adequate renal function. Pamidronate is typically reserved for patients with poor renal function at baseline.

Introduction Bisphosphonate therapy has become an essential component of treatment for patients with multiple myeloma (MM). Although zole-

What bisphosphonate dosing adjustments are necessary for comorbidities such as renal impairment?

dronic acid and pamidronate are highly effective for preventing and reducing skeletal-related events (SREs), these intravenously administered agents may cause adverse events (AEs) that require careful monitoring throughout the course of therapy. Consideration of patient comorbidities, such as renal dysfunction, prior to the initiation of bisphosphonate therapy is critical, as this influences the choice of agent, as well as the dose and schedule of administration. In this article, Raj Duggal, PharmD, BCOP, discusses these key pharmacologic issues related to the management of myeloma-related bone disease.

Which factors influence the choice of intravenous (IV) bisphosphonate therapy for patients with myeloma-related bone disease?

Bisphosphonate therapy has an established role in the treatment of patients with active MM and identified lytic lesions or compression fractures of the spine due to osteopenia.1,2 In the United States, both zoledronic acid and pamidronate are approved by the US Food and Drug Administration (FDA) to decrease bone destruction from osteolytic lesions and minimize SREs in these patients.1-4 In clinical practice, zoledronic acid and pamidronate, which are typically administered every 3 to 4 weeks, are considered basically equivalent in terms of skeletal protection and pain control.1,2 Therefore, drug selection is dictated by patient-specific factors and the healthcare teamâ&#x20AC;&#x2122;s preference.1,5 Infusion time and baseline renal function are 2 major considerations in the selection of bisphosphonate therapy for patients with MM.1 Zoledronic acid is often recommended for patients with a creatinine clearance (CrCl) >30 mL/min, as this drug can safely be infused over 15 minutes compared with the prolonged 2-hour infusion of pamidronate.1,3,4 For patients with an estimated CrCl <30 mL/min or serum creatinine (SCr) >3 mg/dL, shorter infusion times with zoledronic acid are not recommended, and the infusion time of pamidronate should be extended to 4 to 6 hours to minimize drug toxicity.1 There is no level of renal dysfunction resulting in absolute contraindication for pamidronate therapy.4 In a recent Cochrane review meta-analysis, no statistical difference was found regarding the incidence of AEs (including hypocalcemia and renal dysfunction) when comparing bisphosphonates.2 Both pamidronate and zoledronic acid are associated with osteonecrosis of the jaw (ONJ); the incidence of this AE rises with increased drug exposure (dose and duration).1-4 Guidelines published by the American Society of Clinical Oncology (ASCO)1 and the National Comprehensive Cancer Network6 cite a significantly higher incidence of ONJ with zoledronic acid compared with

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The primary dose adjustment for bisphosphonate therapy is based on renal function.1,3,4 Patients with MM are at risk for renal dysfunction at baseline and during treatment, due to kidney damage from monoclonal light chains, hypercalcemia, hyperuricemia, dehydration, and nephrotoxic pharmacologic agents (including bisphosphonates).2,3,7 Careful consideration of baseline renal function must occur prior to initiating bisphosphonate therapy in these patients (see Tables 1 and 2 for initial dosing recommendations).1,3,4 Once a patient is started on bisphosphonate therapy, ASCO guidelines recommend rechecking SCr levels prior to each subsequent dose.1 Treatment should be withheld for deterioration in renal function, which is defined as an increase in SCr by 0.5 mg/dL if normal at baseline, or 1 mg/dL if abnormal at baseline. Therapy may be restarted at the previously prescribed dose once the SCr has returned to within 10% of baseline.1,3,4 Another method of monitoring patients for renal dysfunction involves periodic assessments (every 3-6 months) for unexplained albumin spilling

Table 1. Suggested Initial Dosing of Zoledronic Acid Based on Renal Function1,3 Zoledronic Dose (infused over 15 minutes)

Creatinine Clearance >60 mL/min

4 mg

50-60 mL/min

3.5 mg

40-49 mL/min

3.3 mg

30-39 mL/min

3 mg

<30 mL/min

Avoid use

Table 2. Suggested Initial Dosing of Pamidronate Based on Renal Function1,4 Serum Creatinine

Creatinine Clearance

Pamidronate Dose

<3 mg/dL

>30 mL/min

90 mg over 2 hours

>3 mg/dL

<30 mL/min

90 mg over 4-6 hoursa

Albuminurea >500 mg/24 hours (unexplained)

Hold dose until returns to baseline Restart at 90 mg over 4 hours

Consider reducing initial dose of pamidronate for baseline renal impairment.

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CONSIDERATIONS IN MULTIPLE MYELOMA

into the urine. If there is >500 mg of albumin in the urine measured over 24 hours, IV bisphosphonate therapy should be withheld until the level of proteinuria returns to baseline. Pamidronate therapy may be reinstituted with a prolonged infusion time (over 4 hours).1,4 ASCO guidelines also recommend periodic monitoring of serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin, although no specific frequency is given, due to a lack of supportive evidence.1 Commonly, clinicians draw serum calcium levels prior to each dose of bisphosphonate therapy to monitor for additional drug toxicity and potentially, disease progression.2,3,6 Doses can be delayed for hypocalcemia at the discretion of the healthcare team. As long as hypercalcemia is not present, calcium and vitamin D supplementation can be instituted safely to minimize the risk of hypocalcemia.3,4

If there is >500 mg of albumin in the urine measured over 24 hours, IV bisphosphonate therapy should be withheld until the level of proteinuria returns to baseline. ONJ is a major concern for patients receiving bisphosphonate therapy, as it can cause significant morbidity.8 Prior to initiating therapy, a routine clinical dental exam is recommended, and dental procedures, including extractions, should ideally be completed prior to initiation of therapy. Once therapy has begun, regular dental exams should be scheduled depending on treatment- and patient-specific risk factors, such as oral health, bisphosphonate dose, and duration of therapy. Some clinicians may consider delaying the dose of bisphosphonate if a dental procedure is scheduled, but no clear recommendations have been established.1,3,4 How do you decide how long to keep patients on bisphosphonate therapy?

The optimal duration for bisphosphonate therapy is currently unknown. ASCO guidelines currently recommend monthly bisphosphonate therapy for 2 years for patients with active lytic lesions or spinal compression related to osteopenia.1,3,4 After the initial course of therapy, the healthcare team must decide whether therapy should be continued on an individualized basis. If therapy is stopped, it should be restarted upon relapse with development of additional SREs.1 Guidelines published by the European Myeloma Network similarly recommend monthly bisphosphonate therapy for 2 years.8 After this initial

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therapy, in those patients who have achieved remission and have stable disease, bisphosphonates can be discontinued. For some individuals, it may be beneficial to continue bisphosphonate therapy beyond 2 years, at a reduced dose and frequency. However, the panel noted that there is no hard data to support this approach. Recently, the Medical Research Council Myeloma IX trial provided evidence that suggests maintenance bisphosphonate therapy might have a more significant clinical benefit.9 In this study, subjects were randomized to IV zoledronic acid (4 mg every 3-4 weeks during induction chemotherapy, then every 4 weeks thereafter) or oral clodronate (1600 mg/day). In this population of newly diagnosed MM patients, an overall survival advantage was noted with zoledronic acid compared with clodronate. Many study participants received bisphosphonate therapy longer than the 2-year recommendation, so it is possible that this prolonged therapy may have contributed to the decreased SREs and increased survival times. Due to the studyâ&#x20AC;&#x2122;s small sample size, additional trials need to be completed to confirm this advantage.9 Conclusion

Bisphosphonate use has been shown to prevent, reduce, and delay SREs in MM. Although these agents have an established role in the management of the disease, additional evaluations are needed to clarify the optimal duration of therapy, identify candidates for maintenance therapy longer than 2 years, and observe and report on toxicities noted with this extended treatment regimen.1,2,9 The successful use of bisphosphonates requires careful assessment of patients prior to and during therapy, diligent monitoring for AEs, and a thorough understanding of dosing and administration guidelines that will promote optimal clinical outcomes. References 1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 2. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Coch Database Syst Rev. 2012;5:CD003188. 3. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 2012 4. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; May 2012. 5. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98:1735-1744. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinesâ&#x201E;˘). Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 31, 2012. 7. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 8. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20:1303-1317. 9. Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus longterm bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX trial. Blood. 2012;119:5374-5383.

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Nursing Considerations in Myeloma Patients with Skeletal Complications Lori Case, RN, BSN, OCN Nurse Coordinator IU Simon Cancer Center Indianapolis, IN

Introduction Sustaining skeletal integrity and preventing disability are essential goals of long-term multiple myeloma (MM) care. Achieving these goals requires pharmacologic therapy with intravenous (IV) bisphosphonates, along with strategies to protect mobility and decrease pain. In this article, Lori Case, RN, BSN, OCN, discusses important considerations in the administration and monitoring of bisphosphonate therapy, including the prevention and management of osteonecrosis of the jaw (ONJ) and other adverse events (AEs). She also summarizes best practices in surgical, physical, and educational interventions that can be used to support bone health in patients with myeloma.

How do you monitor and manage the renal AEs associated with IV bisphosphonate therapy?

For patients with MM, we have 2 choices for IV bisphosphonate therapy: zoledronic acid and pamidronate. Although generally well tolerated, these agents can cause kidney function to deteriorate.1,2 Therefore, one concern is the safe administration of bisphosphonate therapy in patients with renal insufficiency. In the case of zoledronic acid, dosage must be reduced from the standard dose of 4 mg for patients whose baseline creatinine clearance (CrCl) is <60 mL/min; use of this drug in patients with severe renal impairment is not recommended.1 In addition, zoledronic acid should always be administered over 15 minutes or longer, to prevent any renal issues that may arise during the infusion process.1 With pamidronate, caution is advised in patients with marked renal impairment (serum creatinine [SCr] >3.0 mg/dL).2 Treatment should be withheld in the event of renal deterioration, which can be defined as an increase in SCr of 0.5 mg/dL in patients with normal baseline creatinine or 1 mg/dL in patients with an abnormal baseline.2 Doses can generally be resumed when SCr levels return to within 10% of baseline value. Pamidronate dose can be reduced from the standard 90 mg when the SCr level is >3.0 mg/dL or the estimated CrCl is <30 mL/min.3 This drug is usually administered over 4 hours, but the infusion time can be increased to 6 hours or longer to minimize renal risk.3 A best practice before and during bisphosphonate therapy is frequent monitoring of renal function. Prior to each infusion, we check SCr in order to properly dose the bisphosphonate. We also conduct a panel of serum chemistries at least once every 3 to 4 months. This assessment evaluates potential metabolic effects of bisphosphonatesâ&#x20AC;&#x201D;hypophosphatemia, hypokalemia, and hypomagnesemia. If we do discover any abnormalities, we can replace the levels with oral supplementation.

DECEMBER 2012 I VOL 5, NO 8

How do you manage the flu-like symptoms that may occur following a bisphosphonate infusion?

Some patients experience fever, chills, flushing, and body aches resulting from a bisphosphonate infusion.1,2 For instance, with zoledronic acid and pamidronate at standard doses, approximately 44% and 33% of patients, respectively, report fever.1,2 We inform our patients that they may experience these flu-like symptoms during therapy, so that they are not caught off-guard. We also encourage them to call the clinic if any of these AEs occur. Typically, we recommend acetaminophen to manage mild-to-moderate flu-like symptoms; use of this medication was reported effective for this indication in a 2012 study.4 We do not recommend nonsteroidal anti-inflammatory drugs for MM patients because of the potential for renal toxicity. For patients with severe flu-like symptoms, we have also utilized dexamethasone at very low doses. Since many patients are receiving a steroid as part of antimyeloma therapy, we will try to have them coordinate their weekly dose on the same day that they are scheduled for their bisphosphonate treatment, which may prevent or minimize flu-like symptoms. What strategies do you use to reduce the risk of ONJ related to IV bisphosphonate therapy?

At baseline and at every visit, we look inside the mouth for ulcers, bumps, or protrusions. If individuals wear dentures, we ask them to remove these appliances so we can closely examine the gums; we also try to ascertain whether dentures are fitting well. Poorly fitting dentures are a risk factor for ONJ, as are invasive dental procedures such as extractions.5 Evidence also suggests that periodontal disease may increase the risk of ONJ.6 These potential risk factors can be addressed by ensuring that all patients receive a thorough dental checkup and cleaning, and take care of any extractions, dental implants, or other invasive procedures before they start bisphosphonate therapy.3,7

Poorly fitting dentures are a risk factor for ONJ, as are invasive dental procedures such as extractions.

We educate our patients to continue twice-yearly checkups and cleanings, and to inform their dentists of any and all treatments they are receiving. If an invasive dental procedure is recommended during bisphosphonate therapy, we ask that the dentist call our office before scheduling the procedure, to discuss risks and benefits. We encourage our patients to call us every time they are planning to go to the dentist, to reiterate the importance of avoiding specific procedures. Prevention of ONJ is critical, because once it occurs, healingâ&#x20AC;&#x201D;if it happens at allâ&#x20AC;&#x201D;is a slow process.8,9 We send some patients with ONJ to our oral surgeon for assessment. The surgeon may be able to smooth jagged bone edges and make the area more comfortable. We prescribe chlorhexidine

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CONSIDERATIONS IN MULTIPLE MYELOMA

Figure 1a and b. Efficacy of treatments for ONJ (N=53).9 a. Antibiotics vs antibiotics + oral surgery

b. Concomitant O2 hyperbaric/ozonotherapy* vs no concomitant O2 hyperbaric/ozonotherapy 80

Resolution of ONJ Improvement in ONJ

66.6%

No change/progression in ONJ

Patients (%)

52.6% 50

45.5% 40.9% 36.9%

40 30 20

13.6%

48.2% 44.4% 38.4%

40 30.8% 30.8% 30 20

16.7% 16.7%

10.5% 10

7.4%

0 Antibiotics Alone (n=19)

Antibiotics + Curettage (n=22)

Antibiotics + Sequestrectomy (n=12)

With O2 Therapy (n=27)

Without O2 Therapy (n=26)

*Concomitant O2 hyperbaric/ozonotherapy was used in 16 patients who also received antibiotics and curettage and in 12 patients who also received antibiotics and sequestrectomy. This group of patients is included in the data in Figure 1a. ONJ indicates osteonecrosis of the jaw.

mouthwash to keep the area clean, and we use antibiotics for infection.7 Data suggest that combining antibiotic therapy with oral surgery (eg, curettage, sequestrectomy) may be the most effective approach to ONJ, especially if augmented with a novel treatment called O2 hyperbaric/ozonotherapy, which locally increases the oxygen content of blood (Figure 1a and 1b). However, even the best available interventions fail to resolve ONJ fully in a significant proportion of patients.9 In addition to bisphosphonate therapy, what strategies can be used to prevent or minimize skeletal-related events (SREs)?

Nonpharmacologic management to prevent SREs and to minimize their pain and impact on function must be highly individualized. The first thing for nurses to do is to speak with the physicians about limitations and interventions appropriate to the patient. Taking into consideration the individualâ&#x20AC;&#x2122;s health status, level of pain, location of osteolytic lesions, and psychosocial profile, we can devise a plan that may include some or all of the following: weight-bearing exercises; strength training; kyphoplasty10,11; physical therapy; localized, palliative radiation therapy; nutritional counseling and calcium/vitamin D supplementation; reduction of alcohol and caffeine (which interfere with calcium and vitamin D absorption); elimination of contact sports; and a home-health intervention to minimize the risk of falls. We conduct yearly skeletal surveys in our patients, and will often adjust our nonpharmacologic recommendations based on the results. Patients need to be educated about their bone health. An annual skeletal survey can help illustrate any skeletal changes that have occurred. If there are no changes, it can help them to see that therapy is working to prevent further bone damage.

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Conclusion

Whole-patient care in MM requires a commitment to bone health. Nurses play a pivotal role in supportive therapy, including careful administration of bisphosphonates, prevention and control of treatment-related AEs, and individualized nonpharmacologic regimens to protect against SREs, reduce pain, and maintain function. All of these work together to provide the best possible quality of life for patients. References 1. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; February 2011. 2. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; April 2011. 3. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 4. Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int. 2012;23:503-512. 5. Kyrgidis A, Arora A, Lyroudia K, Antoniades K. Root canal therapy for the prevention of osteonecrosis of the jaws: an evidence-based clinical update. Aust Endod J. 2010;36:130-136. 6. American Association of Oral and Maxillofacial Surgeons Position Paper on BisphosphonateRelated Osteonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons; 2006. http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf. Accessed December 4, 2012. 7. Shannon J, Shannon J, Modelevsky S, Grippo AA. Bisphosphonates and osteonecrosis of the jaw. J Am Geriatr Soc. 2011;59:2350-2355. 8. Badros A, Terpos E, Katodritou E, et al. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol. 2008;26:5904-5909. 9. Andriani A, Petrucci MT, Caravita T, et al; on behalf of GIMEMA. Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstromâ&#x20AC;&#x2122;s macroglobulinema: a retrospective multicentric study [published online ahead of print March 23, 2012]. Blood Cancer J. doi:10.1038/bcj.2012.9. 10. Berenson J, Pflugmacher R, Jarzem P, et al; for the Cancer Patient Fracture Evaluation (CAFE) Investigators. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235. 11. Kristinsson SY, Minter AR, Korde N, Tan E, Landgren O. Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management. Expert Rev Mol Diagn. 2011;11:593-603.

DECEMBER 2012 I VOL 5, NO 8

Conference News: ESMO

Highlights From the european Society for medical Oncology 2012 Congress By Alice Goodman

Oncology experts from all over the globe arrived in Vienna, Austria, to attend the European Society for Medical Oncology (ESMO) 2012 Congress. Attendance broke all records, with 16,394 delegates, many of them from outside of Europe: 1116 from the United States, 539 from Japan, 479 from China, 292 from Argentina, and 258 from Brazil. Following are some highlights from the Presidential Symposia and papers proffered at the meeting.

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

recurrent ovarian cancer,” stated lead author Andres M. Poveda, MD, Fundación Instituto Valenciano de Oncología, Valencia, Spain. The exploratory analysis looked at each of the 3 regimens and found that

versus 3.9 months for weekly paclitaxel alone. In the PLD cohort, median PFS was 5.4 months versus 3.4 months, respectively. In the topotecan cohort, median PFS was 5.8 months versus 2.1 months, respectively.

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

weekly paclitaxel plus bevacizumab had superior results. As stated above, median PFS was 10.4 months when bevacizumab was added to weekly paclitaxel

AURELIA randomized 361 patients with platinum-resistant recurrent ovarian cancer treated with up to 2 prior anticancer regimens to chemotherapy

alone or chemotherapy plus bevacizumab. The chemotherapy regimen was the investigator’s choice among the 3 regimens. Treatment was continued until unacceptable toxicity or progressive disease occurred. Overall response rates (ORRs) were superior with the addition of bevacizumab, with the highest response rates observed in the weekly paclitaxel cohort: 51.7% versus 28.8% for chemotherapy alone. ORR was 18.3% and 7.9%, respectively, for the PLD cohort and 22.8% and 3.3%, respectively, for the topotecan cohort. No significant differences in toxicity were observed, with the exception of more peripheral neuropathy in the weekly paclitaxel cohort and more hand-foot syndrome in the PLD cohort.

Standard of Care for Soft Tissue Carcinoma Single-agent doxorubicin remains the standard of care as first-line treatment for unresectable or metastatic soft tissue sarcomas, according to results of a phase 3 trial conducted by EORTC and presented at the Presidential Symposium during the ESMO 2012 Congress (Abstract LBA7).2,3 This study is the latest in a string of trials at-

tempting to improve outcomes with doxorubicin by adding other agents. Soft-tissue sarcomas are a heterogeneous group of tumors that are relatively rare. Overall incidence is approximately 5 per 100,000, said Winette van der Graaf, MD, University of Nijmegen, the Netherlands. The complexity of the tumor types and the rela-

SECOND ANNUAL CONFERENCE

tive rarity of the tumors have made it challenging to conduct clinical trials, she added. This study compared doxorubicin to doxorubicin/ifosfamide plus growth factor support in 455 patients aged 18 to 60 years with locally advanced or metastatic soft tissue sarcomas. This study used a higher dose of ifosfamide

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013 Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California

DECEMBER 2012 I VOL 5, NO 8

(10 g/m2 over 4 days with growth factor support) than previous studies that evaluated this combination. Treatment was continued every 3 weeks for a maximum of 6 cycles or until the development of progressive disease. At a median follow-up of 56 months, there was no significant difference between the 2 treatment arms in overall survival (OS). Median OS was 14.3 months with the combination of doxorubicin/ifosfamide versus 12.8 months with doxorubicin alone; OS at 1 year was 60% and 51% for the 2 arms, respectively. Doxorubicin/ifosfamide achieved a longer progression-free survival: 7.4 months versus 4.6 months, respectively (P = .003), and higher overall response rates—26.5% versus 13.6%, respectively—but this came with a host of increased toxicity. Based on these results, van der Graaf said that single-agent doxorubicin should remain the standard of care in the palliative setting. The combination might be useful for selected patients 60 years and younger with large tumors.

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Conference News: ESMO T-Dm1 Survival Benefit Confirmed in Advanced HeR2+ Breast Cancer T-DM1, an antibody-drug conjugate linking trastuzumab to potent chemotherapy, extended survival, compared with lapatinib plus capecitabine, in advanced HER2+ breast cancer in an updated analysis from the phase 3 EMILIA trial (Abstract LBA12).4 At a median follow-up of about 20 months, T-DM1 reduced the risk of dying by 32%, with a 6-month difference favoring T-DM1. Median overall survival (OS) (death from any cause) was 30.9 months for T-DM1 versus 25.1 months for lapatinib plus capecitabine (P <.0001).

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

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Initiative Improves Pain Control in Several Countries The major barriers to implementing adequate pain control for cancer patients on a global scale are restrictive government regulations and lack of access to supplies of morphine. Individual countries may lack morphine suppliers, and regulations in countries where morphine is available may prevent doctors from prescribing doses strong enough to alleviate pain and suffering.

Although a number of international organizations have made strong statements hoping to address the problem of inadequate pain control in cancer patients, this has not led to widespread reform in allowing access to standard care, said Kathleen Foley, MD, Memorial Sloan-Kettering Cancer Center in New York City, at the ESMO 2012 Congress.5 These organizations include the Council

of Europe, International Narcotics Control Board, United Nations, World Health Organization, Commission on Narcotic Drugs, and Human Rights Watch, among others. Foley believes that the problems are solvable, but mainly on a country-bycountry basis. She reported success stories for programs funded by the International Continued on page 42

ANNUAL CONFERENCE

! *

Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:00 am - 11:45 am

General Session I • Welcome to the Second Annual Conference of the Global Biomarkers Consortium—Setting the Stage for the Meeting • Personalized Medicine in Oncology: The Future Is Now • Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies • Biomarker-Defined Populations • Taking Stock of Molecular Oncology Biomarkers: Genomics, Proteomics, Imaging, Bioinformatics • Solid Tumors • Hematologic Malignancies • The Value Proposition of Real-Time Genomic Testing The Payer Perspective The Provider Perspective • Panel Discussion: The Value Proposition of Real-Time Genomic Testing • Keynote Lecture: Understanding Cancer at the Molecular Level

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

General Session II • Molecular Subtyping of Solid Tumors • Molecular Subtyping of Hematologic Malignancies • Case Studies: Optimal Value-Based Use of Molecular Biomarkers in Oncology: The Expert’s Perspective on How I Treat My Patients • NSCLC • Breast Cancer • Melanoma • Colorectal Cancer and Other GI Malignancies • Prostate Cancer • Multiple Myeloma • Leukemia • Lymphoma • MDS/Myelofibrosis • Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:00 am - 11:45 am

General Session III • Review of Saturday’s Presentations and Preview of Today • Impact of Cancer Genomics on Advances in Cancer Therapy • Recent and Late-Breaking Clinical Trial Data • Solid Tumors • Hematologic Malignancies • Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care • Tumor Board: Challenging Cases in Managing Solid Tumors (attendee-contributed cases) • Tumor Board: Challenging Cases in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV • Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine • The Future of Personalized Medicine: A Systems Biology Approach • Cost-Effective Technologies That Can Drive Therapeutic Decision Making • Panel Discussion: Can We Afford PMO? A Value-Based Analysis • Practical Considerations in Incorporating PMO into Everyday Cinical Management • Reimbursement Challenges: Guidence from a Payer • Closing Remarks

3:00 pm

Departures

Upon completion of this activity, the participant will be able to: • Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies • Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies • Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

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

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

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

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EARLY BIRD REGISTRATION NOW OPEN! $125.00 until December 31, 2012

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*Agenda is subject to change.

PMPMERSONALIZED EDICINE IN ONCOLOGY O

DECEMBER 2012 I VOL 5, NO 8

Conference News: ESMO Continued from page 41

Initiative Improves Pain Control in Several Countries

Palliative Care Initiative. The model for these programs is to identify a “national champion” for cancer pain control within a country, perform a needs assessment, hold a stakeholders meeting, develop task forces, and then formulate a palliative care concept for

that country. So far, this has been done in 20 countries. “We use international documents with symbolic language to guide this policy at a country level. These passionate champions are driving this movement within each country,” she told listeners.

In 2012, the International Palliative Care Initiative funded fellowships in India, Bangladesh, Sri Lanka, Albania, Kyrgyzstan, and Ukraine. Fellows work at the University of Wisconsin in Madison to learn the model described above.

Th eO s V nc eri ie olo es w gy on the Ph lin ar e a m t ac ist .co

2ND ANNUAL

CONQUERING THE CANCER CARE CONTINUUM

™

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CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I

A 6-part series

The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series. Upcoming topics include:

Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. 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Success Stories In Romania, 35-year-old restrictive policies were changed. Now there are no limits on daily morphine dose or patient diagnosis. “Past policies were burdensome for patients, and physicians, and these are new beginnings,” Foley said. In Colombia, a new palliative care law was passed in 2009, and as a result of that law, each district of the country has 1 pharmacy that can provide opioids 24 hours a day. In Guatemala, efforts are ongoing to bring a morphine supply from Guatemala City to rural areas and to provide further education to legislators, physicians, and patients. “It’s hard to believe, but in 2012, the first injectable morphine prescription was written in Guatemala, at a hospital where bone marrow transplant is available,” she said. In Nigeria, the government is now supportive of getting cancer patients access to pain control. In Serbia, a pain policy fellow is working with the government, which has adopted a pain policy stating that opioids are essential for pain relief. In Armenia, a policy is in place, but a supplier still needs to be found. “Uganda is a great success story,” she continued. The initiative created a strategic health plan, added liquid morphine to the essential list, adopted new guidelines, and authorized prescription by nurses. Seventy-nine providers have been trained. “We argue that no country should be allowed to enter the EU [European Union] unless they have opioids and a pain policy for cancer care. The solution is to identify champions at a country level and work with them. We can do this,” Foley said. l References 1. Poveda A, Selle F, Hilpert F, et al. Weekly paclitaxel, pegylated liposomal doxorubicin or topotecan ± bevacizumab in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort in the GCIG AURELIA randomised phase III trial. Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. Abstract LBA26. 2. van der Graaf W. Successful targeting of VEGFR in soft tissue sarcomas. Presented at: European Society for Medical Oncology 2012 Congress; September 30, 2012; Vienna, Austria. 3. van der Graaf WTA, Judson I, Verweij J, et al. Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract LBA7. 4. Verma S, Miles D, Gianni L, et al. Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs. capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Presented at: European Society for Medical Oncology Congress; October 1, 2012; Vienna, Austria. Abstract LBA12. 5. Foley K. A global policy approach to freedom from cancer pain. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria.

www.TheOncologyPharmacist.com

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

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

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

Docetaxel Injection, USP

Gemcitabine Injection

Oxaliplatin for Injection,

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Oxaliplatin Injection,

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning F & >1-@91:@ >18-@10 9;>@-85@E 5:/>1-?1? C5@4 -.:;>9-8 85B1> 2A:/@5;: -@ 45341> 0;?1? -:0 5: <-@51:@? C5@4 !% -:0 <>5;> <8-@5:A9 .-?10 @41>-<E >1/15B5:3 docetaxel at 100Â mg/m2 (5.1) F % 4;A80 :;@ .1 35B1: 52 .585>A.5: ' ! ;> 52 %& -:0 ;> & D ' ! /;:/;95@-:@ C5@4 -87-85:1 <4;?<4-@-?1 D ' ! & 181B-@5;:? 5:/>1-?1 >5?7 ;2 ?1B1>1 ;> 8521 @4>1-@1:5:3 /;9<85/-@5;:? ".@-5: &? .12;>1 1-/4 treatment cycle (8.6) F % 4;A80 :;@ .1 35B1: 52 :1A@>;<458 /;A:@? ->1 < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) F % 1B1>1 4E<1>?1:?5@5B5@E 5:/8A05:3 B1>E >->1 2-@-8 -:-<4E8-D5? 4-? .11: >1<;>@10 5: <-@51:@? C4; >1/15B10 dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4) F ;:@>-5:05/-@10 52 45?@;>E ;2 ?1B1>1 4E<1>?1:?5@5B5@E >1-/@5;:? @; 0;/1@-D18 ;> @; 0>A3? 2;>9A8-@10 C5@4 polysorbate 80 (4) F % 1B1>1 28A50 >1@1:@5;: 9-E ;//A> 01?<5@1 01D-91@4-?;:1 (5.5) CONTRAINDICATIONS H G>3@A3<A7B7D7BG B= 2=13B/F3: =@ >=:GA=@0/B3 H $3CB@=>67: 1=C<BA =4 13::A ;;3 WARNINGS AND PRECAUTIONS H 1CB3 ;G3:=72 :3C93;7/ < >/B73<BA E6= @3137D32 2=13B/F3: 2=F=@C0717< /<2 1G1:=>6=A>6/;723 ;=<7B=@ 4=@ 23:/G32 ;G3:=2GA>:/A7/ =@ ;G3:=72 :3C93;7/ H CB/<3=CA @3/1B7=<A '3/1B7=<A 7<1:C27<5 3@GB63;/ =4 B63 3FB@3;7B73A E7B6 323;/ 4=::=E32 0G 23A?C/;/B7=< ;/G =11C@ (3D3@3 A97< B=F717BG ;/G @3?C7@3 2=A3 /28CAB;3/@3AB63A7/ 2GA3AB63A7/ /<2 >/7< ;/G =11C@ (3D3@3 <3C@=A3<A=@G AG;>B=;A @3?C7@3 2=A3 /28CAB;33@A7AB3@35</=B3<B7/: A6=C:2 03 /2D7A32 <=B B= 031=;3 >@35</3<7/ /<3;7/ 430@7:3 <3CB@=>3<7/ 6G>3@A3<A7B7D7BG B6@=;0=1GB=>3<7/ <3C@=>/B6G 2GA53CA7/ 2GA><3/ 1=<AB7>/B7=< /<=@3F7/ </7: 27A=@23@A 4:C72 @3B3<B7=< /AB63<7/ >/7< </CA3/ 27/@@63/ D=;7B7<5 ;C1=A7B7A /:=>317/ A97< @3/1B7=<A ;G/:57/ To report SUSPECTED ADVERSE REACTIONS, contact Hospira, :/ -@

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<;C01> 2;> ?;8A@5;: 2;> 5:@>-B1:;A? A?1 solution for intravenous use Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning. Anaphylactic reactions to Oxaliplatin have been >1<;>@10 -:0 9-E ;//A> C5@45: 95:A@1? ;2 "D-85<8-@5: administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1) INDICATIONS AND USAGE %F/:7>:/B7< 7A / >:/B7<C; 0/A32 2@C5 CA32 7< 1=;07</B7=< E7B6 7<4CA7=</: 4:C=@=C@/17: :3C1=D=@7< E6716 7A 7<271/B32 4=@ H /28CD//B73<BA E6= 6/D3 C<23@5=<3 1=;>:3B3 @3A31B7=< =4 B63 >@7;/@G BC;=@ H B@3/B;3<B =4 /2D/<132 1=:=@31B/: 1/<13@ H

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ADVERSE REACTIONS #=AB 1=;;=< /2D3@A3 @3/1B7=<A 7<1723<13 I E3@3 >3@7>63@/: A3<A=@G <3C@=>/B6G <3CB@=>3<7/ B6@=;0=1GB=>3<7/ /<3;7/ </CA3/ 7<1@3/A3 7< B@/<A/;7</A3A /<2 /:9/:7<3 >6=A>6/B/A3 27/@@63/ 3;3A7A 4/B75C3 /<2 AB=;/B7B7A %B63@ /2D3@A3 @3/1B7=<A 7<1:C27<5 A3@7=CA /2D3@A3 @3/1B7=<A 6/D3 033< @3>=@B32 To report SUSPECTED ADVERSE REACTIONS, contact Hospira :/ -@

;> -@ ;> CCC 20- 3;B 910C-@/4 See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling. Revised: 04/2011

ADVERSE REACTIONS )63 ;=AB 1=;;=< /2D3@A3 @3/1B7=<A 4=@ B63 A7<5:3 /533<7/ :3C9=>3<7/ /:9/:7<3 >6=A>6/B/A3 >@=B37<C@7/ 43D3@ 63;/BC@7/ @/A6 B6@=;0=1GB=>3<7/ 2GA><3/ To report SUSPECTED ADVERSE REACTIONS, contact ;?<5>- :/ -@

;> 181/@>;:5/-88E at ProductComplaintsPP@hospira.com, or FDA at ;> www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2011

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#/<C4/1BC@32 0G Zydus Hospira %<1=:=5G &@7D/B3 "B2 6;32/0/2

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#/<C4/1BC@32 0G =A>7@/ CAB@/:7/ "B2 #C:5@/D3 +

CAB@/:7/ Manufactured for: Hospira, Inc. "/93 =@3AB " *(

AVAILABLE FROM HOSPIRA

OXA L I PL ATI N I N JE C TI ON ( 5 mg /mL )

50 mg/10 mL single-dose vial 100 mg/20 mL single-dose vial

As the complexity of healthcare evolves,

See Black Box Warning Below

we’re doing our part to improve cost savings, optimize workflow and enhance patient care. With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR CLINICIANS—UNIQUE ONCO-TAIN ™ VIALS REINFORCE SAFETY 1

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST D OC E TA XE L I N JE C TI ON ( 1 0 mg /mL )

U N I Q U E O N C O - TA I N S A F E T Y F E AT U R E S 1

PVC BOTTOM offers shatter resistance.

SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

GLASS CLARITY allows for easy inspection of the vial as a final safety check before administration.

PREWASHED VIALS reduce cytotoxic residue.

160 mg/16 mL multiple-dose vial 80 mg/8 mL multiple-dose vial 20 mg/2 mL single-dose vial See Black Box Warning Below

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com. Docetaxel: WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION Oxaliplatin: WARNING: ANAPHYLACTIC REACTIONS

GE MC I TA B I N E I N JE C TI ON ( 3 8 mg /mL )

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

2 g/52.6 mL single-dose vial Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

1 g/26.3 mL single-dose vial P12-3707-11.125x14.125-Jul., 12

200 mg/5.26 mL single-dose vial