Journal of Hematology Oncology Pharmacy by The Oncology Pharmacist

1-Cover_Layout 1 6/7/11 3:59 PM Page Cov1

JUNE 2011

JOURNAL OF

VOL 1 I NO 2

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

PERSPECTIVE Ipilimumab: A New Era in Metastatic Melanoma Management

Timothy G. Tyler, PharmD, FCSHP CASE REPORT Reversible Posterior Leukoencephalopathy Syndrome Secondary to Bevacizumab

Diana Pinto, PharmD; William Kernan, PharmD, BCPS; James Hoffman, MD; Mohammed Ibrahim, PharmD, CRPH, BCOP, BCPS; Bruno Bastos, MD ORIGINAL RESEARCH The Risk of Neurotoxicity with Concomitant Use of Aprepitant and Ifosfamide

Anthony Jarkowski III, PharmD, BCOP; Austin Miller, PhD; Tammy A. Hecke, RN, BSN; Leona Blustein, PharmD; Michael K.K. Wong, MD, PhD, FRCPC PRACTICAL ISSUES IN PHARMACY MANAGEMENT Implementation of a Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program in a Community Cancer Center

Robert Mancini, PharmD; Lindsay M. Kaster, PharmD; Brian Vu, PharmD; Jessie Modlin, PharmD; David B. Wilson, RPh

From the Literature Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

2-EditBoard_Cover 6/7/11 4:00 PM Page 1

Nplate® (romiplostim) Brief Summary WARNINGS AND PRECAUTIONS Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis Nplate® administration increases the risk for development or progression of reticulin fiber deposition within the bone marrow. In clinical studies, Nplate® was discontinued in four of the 271 patients because of bone marrow reticulin deposition. Six additional patients had reticulin observed upon bone marrow biopsy. All 10 patients with bone marrow reticulin deposition had received Nplate® doses ≥ 5 mcg/kg and six received doses ≥ 10 mcg/kg. Progression to marrow fibrosis with cytopenias was not reported in the controlled clinical studies. In the extension study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias. Prior to initiation of Nplate®, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable Nplate® dose, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate® and consider a bone marrow biopsy, including staining for fibrosis [see Adverse Reactions (6.1)]. Worsened Thrombocytopenia After Cessation of Nplate® Discontinuation of Nplate® may result in thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia may increase the patient’s risk of bleeding, particularly if Nplate® is discontinued while the patient is on anticoagulants or antiplatelet agents. In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions (6.1)]. Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from excessive increases in platelet counts. Excessive doses of Nplate® or medication errors that result in excessive Nplate® doses may increase platelet counts to a level that produces thrombotic/ thromboembolic complications. In controlled clinical studies, the incidence of thrombotic/thromboembolic complications was similar between Nplate® and placebo. To minimize the risk for thrombotic/ thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines 9 to achieve and maintain a platelet count of ≥ 50 x 10 /L [see Dosage and Administration (2.1)]. Lack or Loss of Response to Nplate® Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate® or bone marrow fibrosis [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO). Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg. Malignancies and Progression of Malignancies Nplate® stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. In controlled clinical studies among patients with chronic ITP, the incidence of hematologic malignancy was low and similar between Nplate® and placebo. In a separate single-arm clinical study of 44 patients with myelodysplastic syndrome (MDS), 11 patients were reported as having possible disease progression, among whom four patients had confirmation of acute myelogenous leukemia (AML) during follow-up. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Laboratory Monitoring Monitor CBCs, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate® therapy. Prior to the initiation of Nplate®, examine the peripheral blood differential to establish the baseline extent of red and white blood cell abnormalities. Obtain CBCs, including platelet counts and peripheral blood smears, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate® [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.2)]. Nplate® Distribution Program Nplate® is available only through a restricted distribution program called Nplate® NEXUS (Network of Experts Understanding and

Supporting Nplate® and Patients) Program. Under the Nplate® NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive Nplate®. This program provides educational materials and a mechanism for the proper use of Nplate®. To enroll in the Nplate® NEXUS Program, call 1-877-Nplate1 (1-877-675-2831). Prescribers and patients are required to understand the risks of Nplate® therapy. Prescribers are required to understand the information in the prescribing information and be able to: B Educate patients on the benefits and risks of treatment with Nplate®, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering Nplate®. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescriber’s direction. B Review the Nplate® NEXUS Program Healthcare Provider Enrollment Form, sign the form, and return the form according to Nplate® NEXUS Program instructions. B Review the Nplate® NEXUS Program Patient Enrollment Form, answer all questions, obtain the patient’s signature on the Nplate® NEXUS Program Patient Enrollment Form, place the original signed form in the patient’s medical record, send a copy according to Nplate® NEXUS Program instructions, and give a copy to the patient. B Report any serious adverse events associated with the use of Nplate® to the Nplate® NEXUS Program Call Center at 1-877-Nplate1 (1-877-675-2831) or to the FDA’s MedWatch Program at 1-800FDA-1088. B Report serious adverse events observed in patients receiving Nplate®, including events actively solicited at 6-month intervals. ADVERSE REACTIONS Clinical Studies Experience Serious adverse reactions associated with Nplate® in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation [see Warnings and Precautions (5.1, 5.2)]. The data described below reflect Nplate® exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Nplate® was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Nplate® over an extended period of time. Overall, Nplate® was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks. Because clinical studies 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. In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Nplate® versus placebo. The majority of these adverse drug reactions were mild to moderate in severity. Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies Preferred Term Nplate® Placebo (n = 84) (n = 41) Arthralgia 26% 20% Dizziness 17% 0% Insomnia 16% 7% Myalgia 14% 2% Pain in Extremity 13% 5% Abdominal Pain 11% 0% Shoulder Pain 8% 0% Dyspepsia 7% 0% Paresthesia 6% 0% Among 142 patients with chronic ITP who received Nplate® in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. Immunogenicity As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay. In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (17/225) and the incidence of binding antibody development during Nplate® treatment was 10% (23/225). The incidence of preexisting antibodies to endogenous TPO was 5% (12/225) and the incidence of binding antibody development to endogenous TPO during Nplate® treatment was 5% (12/225). Of the

patients with positive antibodies to romiplostim or to TPO, one (0.4%) patient had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS No formal drug interaction studies of Nplate® have been performed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Nplate® use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Nplate® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Pregnancy Registry: A pregnancy registry has been established to collect information about the effects of Nplate® use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Nplate® pregnancy registry by calling 1-877-Nplate1 (1-877-675-2831). In rat and rabbit developmental toxicity studies no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbit) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses. Nursing Mothers It is not known whether Nplate® is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nplate®, a decision should be made whether to discontinue nursing or to discontinue Nplate®, taking into account the importance of Nplate® to the mother and the known benefits of nursing. Pediatric Use The safety and effectiveness in pediatric patients (< 18 years) have not been established. Geriatric Use Of the 271 patients who received Nplate® in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment No clinical studies were conducted in patients with renal impairment. Use Nplate® with caution in this population. Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. Use Nplate® with caution in this population. OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Nplate® and monitor platelet counts. Reinitiate treatment with Nplate® in accordance with dosing and administration recommendations [see Dosage and Administration (2.2)]. Rx Only. This brief summary is based on Nplate® prescribing information v. 1 Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,835,809 and 7,189,827, as well as other patents or patents pending. © 2008 Amgen Inc. All rights reserved. MC46933-A-1 www.Nplate.com <http://www.Nplate.com> 1-877-Nplate1 (1-877-675-2831) v1

2-EditBoard_Cover 6/7/11 4:00 PM Page 2

Live rep support. E-learning. Patient resources.

Visit www.NplateHCP.com/Bvisit

Outpacing platelet destruction. Sustained response over time. 1-3 Individual results will vary Nplate® is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts. IMPORTANT SAFETY INFORMATION ■ Serious adverse reactions associated with Nplate® in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation. Additional risks include Bone Marrow Fibrosis, Thrombotic/ Thromboembolic Complications, Lack or Loss of Response to Nplate®, Hematological Malignancies and Progression of Malignancy in Patients with a Pre-existing Hematological Malignancy or Myelodysplastic Syndrome (MDS). ■ Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. ■ Monitor CBC’s, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate® therapy. ■ Nplate® is available only through a restricted distribution program called Nplate® NEXUS (Network of Experts Understanding and Supporting Nplate® and Patients) Program. ■ In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.

2-EditBoard_Cover 6/8/11 11:52 AM Page 4

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Dept of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

Gary C. Yee, PharmD, FCCP, BCOP Professor, Department of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, NE

FROM THE LITERATURE Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy, Touro Universityâ&#x20AC;&#x201C;California Atlanta, GA

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

REVIEW ARTICLES R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor of Hematology/Medical Oncology Dept of Hematology/Medical Oncology Director, Phase 1 Program Winship Cancer Institute Emory University Atlanta, GA

EDITORS-AT-LARGE Sandra Cueller, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

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

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

John M. Valgus, PharmD, BCOP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Scott Soefje, PharmD, BCOP Director Pharmacy Operations University of Texas Health Science Center at San Antonio, TX

Journal of Hematology Oncology Pharmacy

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

www.JHOPonline.com

June 2011

Vol 1, No 2

2-EditBoard_Cover 6/7/11 4:00 PM Page 5

3-TOC_Cover 6/8/11 11:26 AM Page 6

JUNE 2011

VOLUME 1, NUMBER 2

PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Dalia Buffery dalia@greenhillhc.com Associate Editors Brett Kaplan brett@greenhillhc.com Lara Reiman lara@greenhillhc.com

TABLE OF CONTENTS PERSPECTIVE

Ipilimumab: A New Era in Metastatic Melanoma Management Timothy G. Tyler, PharmD, FCSHP

CASE REPORT

Reversible Posterior Leukoencephalopathy Syndrome Secondary to Bevacizumab Diana Pinto, PharmD; William Kernan, PharmD, BCPS; James Hoffman, MD; Mohammed Ibrahim, PharmD, CRPH, BCOP, BCPS; Bruno Bastos, MD

ORIGINAL RESEARCH

The Risk of Neurotoxicity with Concomitant Use of Aprepitant and Ifosfamide Anthony Jarkowski III, PharmD, BCOP; Austin Miller, PhD; Tammy A. Hecke, RN, BSN; Leona Blustein, PharmD; Michael K.K. Wong, MD, PhD, FRCPC

Production Manager Stephanie Laudien Quality Control Director Barbara Marino Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Directors, Client Services Joe Chanley joe@greenhillhc.com Jack Iannaccone jack@greenhillhc.com

Implementation of a Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program in a Community Cancer Center Robert Mancini, PharmD; Lindsay M. Kaster, PharmD; Brian Vu, PharmD; Jessie Modlin, PharmD; David B. Wilson, RPh

Editorial Contact: Telephone: 732-992-1892 Fax: 732-656-7938 E-mail: JHOP@greenhillhc.com

MISSION STATEMENT FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor, Clinical Professor Emeritus, UCSF, Professor of Pharmacy, College of Pharmacy, Touro University – California, Mare Island Vallejo

The Journal of Hematology Oncology Pharmacy is an independent, peerreviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peerreviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 by Green Hill Healthcare Communications LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a 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, Journal of Hematology Oncology Pharmacy™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: JHOP@greenhillhc. com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ 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.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

June 2011

Vol 1, No 2

SW 888-2 2011-05 US

3-TOC_Cover 6/7/11 4:05 PM Page 7

4-Perspective_Cover 6/8/11 11:29 AM Page 8

PERSPECTIVE

Ipilimumab: A New Era in Metastatic Melanoma Management Timothy G. Tyler, PharmD, FCSHP, Section Editor

he development of ipilimumab (Yervoy) and its approval by the US Food and Drug Administration (FDA) in March 2011 have opened a new era in the treatment and management of patients with metastatic melanoma. The continued innovation in cancer drug development has been focused on a different mechanism of action that engages the patient’s own immune system in attacking malignancy in contrast to the more traditional myelosuppressive drugs that have been used in the past half century to kill rapidly dividing cancer cells. The hallmark of successful therapy for melanoma has always been surgical excision. Although curative, this method does not necessarily reduce the likelihood of recurrence. To minimize this potentially lethal risk, interferon therapy has historically been instituted, administered as 1 month of induction therapy, followed by 11 months of injections; however, this is an intense regimen for patients, who therefore benefit from a multidisciplinary approach to treatment that can include pharmacy management of symptoms. Even then, the disease can recur and progress. As a result, bioimmunotherapy, a rudimentary type of immunotherapy, was developed in the late 1990s.1 Like interferon therapy, however, bioimmunotherapy is intense and necessitates hospital services, sometimes including the intensive care unit. Despite these efforts, melanoma all too often still claims a large number of lives. Although the cure rate is high for patients whose disease is detected early and surgically resected, the 5-year survival rate is fairly low for those with disease that has metastasized—less than 15% according to the 2010 data from the American Cancer Society.2 In the United States alone, just under 70,000 new cases of melanoma were diagnosed in 2010, and 8700 deaths occurred, mostly from advanced or metastatic disease.3 For some time now, researchers have focused on the development of immune stimulants and vaccines designed to enlist a patient’s immune system to attack cancer cells, culminating with the March 25, 2011, FDA approval of ipilimumab—the first T-cell–mediated therDr Tyler is Director of Pharmacy Services, Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, California.

Journal of Hematology Oncology Pharmacy

apy for unresectable or metastatic melaonoma.4 This drug is a monoclonal antibody that binds CTLA-4 (cytotoxic T-lymphocyte antigen 4), thereby blocking its interaction with the ligands CD80/CD86. This appears to result in T-cell overproduction, which in turn stimulates an activated immune response.4 My professional experience with 5 patients provides a unique perspective for those who have not yet treated any patient with this novel medication. My center is a multidisciplinary center involved in a robust clinical trials program that includes active pharmacist participation in symptom management. In one of these trials, 3 of our patients were treated with ipilimumab before the FDA approval of the drug; in addition, 1 patient was in the expanded access program created by Bristol-Myers Squibb (BMS), while awaiting final FDA approval for the drug, and 1 patient had just begun to receive it on April 11, 2011, the day ipilimumab became commercially available. Our experience with these 5 patients shows that the drug indeed has a novel mechanism of action and it quite simply “revs up” the immune system, and then stands back. There have been many previous attempts to develop vaccines and other products to stimulate the immune system in patients with melanoma by killing the melanoma-affected cells, but ipilimumab is the first product to receive FDA approval. Although the activity of ipilimumab is impressive, it is also associated with a wide range of potential toxicities, which can manifest in almost any system in the body, including gastrointestinal, liver, skin, neurologic, and endocrine toxicities that are highlighted in the risk evaluation and mitigation strategy (REMS) for this agent. There is currently no way to predict the focus of any of the immune system’s responses. What is predictable is the response to ipilimumab therapy, which is associated with a 34% risk of death.5 Unlike traditional chemotherapy, the goal with ipilimumab is not to deliver as much drug as possible but rather to stimulate the immune system properly—only 4 doses maximum can be given, according to the FDA approval.4 Also noteworthy is the agent’s cost, which has captured much media attention. The price is in the same range as the prostate cancer drug sipuleucel-T (Provenge). Both drugs have a limited number of cycles (3 administrations for sipuleucel-T and 4 for ipilimumab).

www.JHOPonline.com

June 2011

Vol 1, No 2

4-Perspective_Cover 6/8/11 10:34 AM Page 9

PERSPECTIVE

Ipilimumab will be distributed only through the wholesaler McKesson and the distributor Oncology Supply. Because ipilimumab is approved with a REMS program, BMS has designed a comprehensive plan that employs sales and medical science liaisons in coordinated teams to ensure clinicians are properly educated about the risks and benefits of the drug. The REMS program also includes a medication guide for patients. At its center is a wallet card that a patient carries to alert any potential urgent care and emergency department physicians to the possibility of immune-related toxicity and the resultant need for steroids. The copious and early use of steroids has been found to ameliorate many toxicityrelated problems, because the toxic effects in this case are not from myelosuppressive chemotherapy but rather from stimulated T lymphoctes. In addition, BMS has initiated a surveillance and peer-to-peer education program in which medical service liaisons will contact clinicians within a very tight window of a few days after receiving a new order for ipilimumab, to provide educational services and follow-up. As the Pharmacy Practice Editor of the Journal of Hematology Oncology Pharmacy, I urge those not experienced with this novel agent to accept any offer of education or assistance regarding its use. Despite the associated risks involved, this new therapy offers benefits beyond the standard myelosuppressive agents or monoclonal antibody drugs that we have become accustomed to in the past decade and a half, when these therapies proliferated on the oncology scene. It is certainly not my wish to deter clinicians from using this drug, but it does involve many occasions for errors, including the aggressive use of corticosteroids as the primary response to almost any toxicity—which is counterintuitive for many clinicians. Getting the appropriate education about the use of this drug is therefore crucial for preventing adverse outcomes and potentially

Vol 1, No 2

June 2011

denying other patients the opportunity for this therapeutic option. Although cost has become a major issue, nothing costs as much as a therapy that is not used successfully or safely.

Despite the associated risks involved, this new therapy offers benefits beyond the standard myelosuppressive agents or monoclonal antibody drugs that we have become accustomed to in the past decade and a half, when these therapies proliferated on the oncology scene. The FDA has been criticized for having approved the fewest number of new drugs in decades, but the approval of ipilimumab offers a novel agent with promising therapeutic outcomes in an area of oncology that has had few worthwhile choices. ■

Author Disclosure Statement Dr Tyler is on the Speakers’ Bureau of Bristol-Myers Squibb and Eisai Pharmaceuticals. References 1. Elsevier/Gold Standard Clinical Pharmacology website. Aldesleukin FDA approval date for MM. http://www.clinicalpharmacology-ip.com/Forms/Mono graph/monograph.aspx?cpnum=12&sec=mondesc. Accessed May 5, 2011. [Accessible through paid subscription.] 2. American Cancer Society. Cancer facts and figures, 2010. www.cancer.org/acs/ groups/content/@nho/documents/document/acspc-024113.pdf. Page 20. Accessed May 21, 2011. 3. National Cancer Institute. General information about melanoma. http://www. cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page1#Refer ence1.1. Accessed May 19, 2011. 4. US Food and Drug Administration. Ipilimumab. March 25, 2011. http://www. fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm. Accessed May 23, 2011. 5. Bristol-Myers Squibb. Yervoy (ipilimumab) website. Pivotal phase 3 study. Yervoy (ipilimumab) is the first and only approved therapy to demonstrate an overall survival benefit. http://www.yervoy.com/hcp/phase-3-study/efficacy-study-safe ty.aspx. Accessed June 2, 2011.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Case Study Pinto_Cover 6/7/11 4:11 PM Page 10

CASE REPORT

Reversible Posterior Leukoencephalopathy Syndrome Secondary to Bevacizumab: A Case Report Diana Pinto, PharmD; William Kernan, PharmD, BCPS; James Hoffman, MD; Mohammed Ibrahim, PharmD, CRPH, BCOP, BCPS; Bruno Bastos, MD

J Hematol Oncol Pharm. 2011;1(2):10-14 www.JHOPonline.com Disclosures are at end of text

This case report presents a case of a 77-year-old patient with stage IV non–small-cell lung carcinoma who developed reversible posterior leukoencephalopathy syndrome along with a hypertensive crisis after treatment with bevacizumab. Reversible posterior leukoencephalopathy syndrome is a clinical-radiologic syndrome rarely seen in association with bevacizumab use. The syndrome manifests with symptoms such as headache, seizures, altered consciousness, and visual disturbances. The typical imaging finding consists of subcortical white matter edema involving the posterior circulation. The patient was being treated with bevacizumab monotherapy at a dose of 15 mg/kg every 3 weeks. He presented with altered mental status and hypertension hours after the completion of a bevacizumab infusion. Proteinuria and visual disturbances were also associated with the event. The magnetic resonance imaging demonstrated widespread hyperintense signals in the occipital white matter. The patient was managed with supportive care and blood pressure control. Most of his symptoms resolved during admission, except for the visual disturbances that required longer rehabilitation. The presence of hypertension and worsening of proteinuria may suggest endothelial damage as bevacizumab’s mechanism for the neurologic toxicity. A recurrent episode occurred 14 months after the discontinuation of bevacizumab.

evacizumab is a recombinant humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF)-A, inhibiting the activation of its receptors (FLT1 and KDR) on the surface of endothelial cells.1 This inhibition prevents the initiation of angiogenesis, which contributes to tumor growth and proliferation by providing a blood supply for malignant cells.2 Bevacizumab is US Food and Drug Administration approved for colorectal cancer, non–small-cell lung cancer (NSCLC), HER-2–negative breast cancer, glioblastoma, and renal-cell cancer. Some of the common adverse reactions of bevacizumab include hypertension, epistaxis, headache, rhinitis, stomatitis, asthenia, proteinuria, taste alteration, dry skin, rectal hemorrhage, back pain, and exfoliative dermatitis.1 Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare adverse event reported with the use of bevacizumab. In clinical studies, the incidence has been less than 0.1% and the onset of symptoms has occurred

from 16 hours to 1 year after initiation.1 This clinicalradiologic syndrome is characterized by headache, seizures, altered consciousness, visual disturbances including cortical blindness, and radiographic abnormalities suggesting subcortical white matter edema of the posterior hemispheres.3-6 Some of the risk factors associated with the incidence of RPLS include acute elevations of blood pressure (such as eclampsia), fluid overload, renal failure, and exposure to immunosuppressants, colony-stimulating factors, or cytotoxic drug therapy.2-5 Because there was some disagreement on whether the syndrome always represented a leukoencephalopathy, Casey and colleagues proposed the term “posterior reversible encephalopathy syndrome” in 2000.7 The term “hyperperfusion encephalopathy” has also been suggested, because the condition is not always reversible.8 This present case describes the presence of RPLS in a patient with NSCLC who developed the symptoms hours after undergoing monotherapy with bevacizumab.

Dr Pinto is Clinical Pharmacist, Department of Pharmacy; Dr Kernan is Critical Care Clinical Pharmacist, Residency Program Director, Department of Pharmacy; Dr Ibrahim is Oncology Clinical Pharmacist, Department of Pharmacy; Dr Hoffman is Associate Staff Physician, Department of Hematology-Oncology; and Dr Bastos is Associate Staff Physician, Department of Hematology-Oncology; all at Cleveland Clinic Florida, Weston.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Case Study Pinto_Cover 6/8/11 10:35 AM Page 11

Reversible Posterior Leukoencephalopathy Syndrome

Case Report A 77-year-old man presented to the outpatient oncology clinic to receive maintenance chemotherapy with bevacizumab for the treatment of stage IV NSCLC, which had been diagnosed 4 years prior. He had been initially treated with left upper lobe lobectomy, but because of recurrent metastatic disease found 2 years postsurgery, he received chemotherapy with bevacizumab, carboplatin, and paclitaxel for a period of 6 months. Because there was residual lung disease after chemotherapy, he was included in a phase 2 clinical trial using concurrent sunitinib and electron beam radiation therapy to the chest (5000 cGy). After completion of this protocol, he initiated bevacizumab monotherapy every 3 weeks for approximately 17 months. His medical history was also significant for hypothyroidism, dyslipidemia, hypertension, atrial fibrillation, and proteinuria secondary to the chronic use of bevacizumab. His home medications included nifedipine 25 mg daily, levothyroxine 125 mcg daily, niacin 500 mg daily, and warfarin with a total weekly dose of 25 mg. On examination at the clinic visit, his vital signs were normal (blood pressure, 122/60 mm Hg; pulse, 50 bpm; temperature, 97.3°F [36.3°C]) and his only complaint was fatigue. The laboratory examinations were normal, except for an increase in his liver enzymes compared with our laboratory tests taken 7 days earlier (alkaline phosphatase increased from 88 U/L to 325 U/L, alanine aminotransferase [ALT] increased from 13 U/L to 93 U/L, and aspartate aminotransferase [AST] increased from 21 U/L to 45 U/L). The patient received 1165 mg (15 mg/kg, patient’s weight, 77.7 kg) of bevacizumab in 100 mL of normal saline which was infused over a period of 30 minutes. Before the infusion, he received 25 mg of diphenhydramine intravenously as premedication and 1000 mL of normal saline for hydration. Twenty-four hours after the infusion of bevacizumab, the patient presented with disorientation along with difficulty of ambulation. The movement of all 4 extremities was not affected and no acute changes in vision, speech, facial expressions, or facial symmetry were noted. He was brought to the emergency department, where he was found to be hypertensive (221/73 mm Hg), his mental status was altered, and he was experiencing lightheadedness and decreased responsiveness. His first electrocardiogram showed marked sinus bradycardia, with a ventricular rate of 44 bpm. The results of the laboratory tests conducted on admission were within normal limits, except for the consistent elevation of alkaline phosphatase and ALT (290 U/L and 69 U/L, respectively). His blood pressure was initially managed with hydralazine 10 mg intravenous (IV) and subsequently with a nitroglycerin drip.

Vol 1, No 2

June 2011

Fluid-Attenuated Inversion Recovery Magnetic Figure Resonance Image Showing Bilateral Hyperintense Signals in Occipital White Matter

A computed tomography scan of the brain was performed, revealing cerebral atrophy and attenuation zones in the parietal lobes, temporal occipital lobes, and the right cerebellum, without significant masses. The differential diagnosis included underlying edema from metastatic disease (although the absence of a mass made this possibility unlikely), periventricular leukomalacia from underlying small vessel disease, or hypertensive encephalopathy. However, the brain magnetic resonance imaging (MRI) obtained after admission demonstrated radiologic findings suggestive of RPLS. There were large areas of abnormal fluid-attenuated inversion recovery (FLAIR) signals involving the bilateral posterior parietal, occipital, and cerebellar hemispheres primarily involving the white matter. Some gray matter involvement was also identified. Cerebellar hemisphere lesions and areas of cortical enhancement seen within the left posterior parietal lobe and right occipital lobe were found suspicious for acute infarct, and no evidence of metastatic disease was observed (Figure). A neurologic examination during the patient’s second day of admission revealed diplopia, presence of bilateral

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Case Study Pinto_Cover 6/7/11 4:11 PM Page 12

CASE REPORT

Babinskiâ&#x20AC;&#x2122;s reflex, and possible right pronator drift. A urinalysis revealed worsening of proteinuria (500 mg/dL from a baseline of 182 mg/dL 1 month prior). His blood pressure remained controlled with amlodipine 10 mg daily, oral hydralazine 10 mg twice daily, and metoprolol 5 mg IV as needed. His mental status improved slightly, but he still appeared confused. Examination on day 5 of hospitalization showed that his mental status had significantly improved, and he was awake and interactive. However, his vision was diffusely blurred on both eyes, and his reflexes were diminished bilaterally. His laboratory values remained stable during his hospital stay. The changes in his liver function tests improved. An abdominal ultrasound revealed that these changes were secondary to cholelithiasis. After discharge, the patient had gradual improvement of diplopia but continued to have difficulty reading words. Bevacizumabâ&#x20AC;&#x2122;s treatment was discontinued, and maintenance therapy was initiated with pemetrexed every 21 days. Fourteen months after the initial episode, the patient presented with similar symptoms, including altered mental status, left-sided flank pain, lethargy, visual hallucinations, bilateral blindness, and hypertension (218/95 mm Hg). His only new medication besides pemetrexed was metoprolol 12.5 mg daily in place of nifedipine, and according to his family, his systolic home blood pressure readings were usually between 100 mm Hg and 110 mm Hg. Neurologic examination on admission was remarkable for altered mental status consistent with encephalopathy and bilateral cortical blindness.

Different explanations have been proposed to understand the pathophysiology of RPLS. One theory associates RPLS with a failure in the cerebral autoregulation to maintain a constant cerebral blood flow, regardless of changes in systemic blood pressure through the constriction and dilation of the arterioles. A repeat MRI was performed showing areas of abnormal white matter FLAIR signals in the bilateral posterior parietal, occipital, and cerebellar hemispheres that were slightly improved when compared with the MRI performed during the first episode. Encephalomalacia involving the bilateral occipital lobes that were thought to represent laminar necrosis from remote infarcts were observed. No evidence of acute infarct, mass, or hemorrhage was identified.

Journal of Hematology Oncology Pharmacy

The patientâ&#x20AC;&#x2122;s laboratory tests were significant for elevated liver and pancreatic enzymes (alkaline phosphatase, 262 U/L; total bilirubin, 10.7 mg/dL; AST, 176 U/L; ALT, 222 U/L; amylase, 242; lipase, 205), and his urinalysis was negative for proteinuria. The results of an endoscopic retrograde cholangiopancreatography were normal. The management consisted of IV and oral antihypertensive medications, as well as broad-spectrum antibiotics because of the presence of bacteremia.

Discussion This report describes a case of possible RPLS in a patient receiving maintenance therapy with bevacizumab. He developed some of the typical manifestations, including decreased levels of consciousness, confusion, and visual disturbances.4 The findings in his MRI were consistent with the characteristic radiographic changes of RPLS described in previous reports, indicating white matter involvement and bilateral abnormal FLAIR signals in the posterior circulation areas, especially the parietal and occipital lobes.4,7 The observed gray matter involvement and cerebellar neuroimaging abnormalities have also been reported but are considered atypical features of RPLS.3,4,9 Resolution of the clinical symptoms was observed within the 6 days of hospitalization, except for the visual disturbances, which required longer rehabilitation. This is consistent with the time to recovery previously published, which suggests a range of several days to weeks for the resolution of both clinical and MRI manifestations.3-5,9 The intracranial findings in the repeated neuroimaging study revealed that the radiologic lesions were not fully reversible. Other RPLS cases have reported the presence of irreversible damage and the need of extended periods of time (up to 17 months) for a complete resolution of the initial findings.3,4,7-9 Residual infarcts have also been previously observed, but the improvement or resolution during follow-up studies suggested that the abnormalities were secondary to edema, and for other cases it was unknown whether the findings represented preexisting ischemia.4,9 Different explanations have been proposed to understand the pathophysiology of RPLS. One theory associates RPLS with a failure in the cerebral autoregulation to maintain a constant cerebral blood flow, regardless of changes in systemic blood pressure through the constriction and dilation of the arterioles. According to this hypothesis, spontaneous and severe elevations in blood pressure are not compensated, and the constricted arterioles dilate leading to brain hyperperfusion. The increased perfusion can result in the breakdown of the blood-brain barrier, which leads to extravasation of fluid,

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Case Study Pinto_Cover 6/7/11 4:11 PM Page 13

Reversible Posterior Leukoencephalopathy Syndrome

macromolecules, and red blood cells into the brain parenchyma.4,5,7 A second theory involving endothelial damage is often associated with drug-induced RPLS. This mechanism, although not clearly understood, can alter the vascular permeability of the blood-brain barrier and the systemic blood pressure, decreasing the threshold for the development of RPLS.3,5 The pathogenesis of RPLS secondary to bevacizumab appears to be related to those 2 theories, because bevacizumab not only has the ability to cause rapid elevations of blood pressure, but also causes VEGF alterations that may increase cerebral vascular permeability.2,3,5 Vascular endothelial dysfunction also appears to be the mechanism by which bevacizumab causes proteinuria and hypertension. A study comparing the amniotic fluid of healthy, diabetic, and preeclamptic women concluded that preeclampsia, a condition characterized by hypertension and proteinuria, was associated with increased levels of soluble FLT1 suggesting endothelial cell alterations.10 A different study conducted in mice indicated that IV infusion of anti-VEGF–neutralizing antibodies caused rapid glomerular endothelial cell detachment and hypertrophy, inducing the development of proteinuria.11 Similarly, 2 articles describing the management of bevacizumab’s toxicities affirmed that the binding inhibition of VEGF-A to VEGF-R impairs protein homeostasis by altering the permeability, development, and function of the glomerular vascular endothelium and the renal filtration system.2,6 After a review of current evidence, the Cardiovascular Toxicities Panel from the National Cancer Institute (NCI) concluded that the elevations in blood pressure caused by VEGF signaling pathway inhibitors were a result of increased peripheral resistance secondary to endothelial damage and decreased nitric oxide production.12 Using the Naranjo algorithm, the likelihood that the RPLS in the patient described in this report was caused by bevacizumab was estimated as probable, because the calculated score was 6. The acute elevation of blood pressure (221/73 mm Hg in the emergency department from 122/60 mm Hg before bevacizumab’s infusion) and the worsening of proteinuria (500 mg/dL from a baseline of 182 mg/dL 1 month earlier) suggest the incidence of endothelial cell dysfunction secondary to bevacizumab’s anti-VEGF activity, which, as described, may explain the development of RPLS. Hypertension and proteinuria were present in another case of RPLS in a patient receiving chemotherapy with FOLFIRI (leucovorin, fluorouracil, irinotecan) plus bevacizumab, in which systemic endothelial cell dysfunction was also suspected.13 This case was included

Vol 1, No 2

June 2011

in a MEDLINE search that identified 24 cases of RPLS in patients treated with anticancer drugs. Five of these cases (21%) were associated with the use of bevacizumab and similar to our patient; all these patients receiving bevacizumab presented with elevations of blood pressure (systolic blood pressure range, 140-190 mm Hg), and the majority of them were managed with either oral or IV antihypertensive medications.3,13-17 Because systemic hypertension predisposes to the development of RPLS, Tam and colleagues have concluded that patients with cancer who have significant fluid overload, mean blood pressure more than 25% of baseline, and/or creatinine greater than 0.16 mmol/L are at high risk for the development of this syndrome.18 Similarly, Koopman and colleagues have recommended strict blood pressure control to prevent RPLS in patients undergoing therapy with bevacizumab and have suggested to withhold treatment when blood pressure reaches grade 2 severity or more based on the NCI Common Toxicity Criteria.19

Vascular endothelial dysfunction also appears to be the mechanism by which bevacizumab causes proteinuria and hypertension. In fact, the association between unmanaged hypertension and serious adverse events from endothelial growth factor signaling pathway inhibitors was one of the reasons the Investigational Drug Steering Committee of the NCI recently published the following recommendations for the management of blood pressure in patients receiving this type of chemotherapy agent12: • Assess for potential cardiovascular complications before initiation of treatment, identify and address preexisting hypertension before initiation of therapy • Monitor blood pressure weekly during the first cycle and at least every 2 to 3 weeks throughout treatment, set a blood pressure goal of <140/90 mm Hg or lower based on patients’ comorbidities • Aggressively manage emergent hypertension to prevent the development of complications. In addition to hypertension, different reviews of cases have identified other common features that may explain the increased incidence of RPLS. It appears to develop more often in females, and it has been found in patients as young as 12 years of age.3,9,20 The most common associated malignancies identified by Marinella and Market include lymphoma, colorectal cancer, and lung cancer.3 However, the authors conclude that because of the diversity of underlying malignancies, it is uncertain whether the biology of the tumor has a causal rela-

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Case Study Pinto_Cover 6/7/11 4:11 PM Page 14

CASE REPORT

tionship; they have found a better correlation with the use of polychemotherapy and the emergence of new cytotoxic agents.3 Similarly, Vaughn and colleagues have suggested that the increased incidence of RPLS cases in patients with cancer was probably secondary to the toxic effects of most major classes of chemotherapy in the vascular endothelium.5 It is undetermined whether the use of the other chemotherapy agents might have put our patient at an increased risk for the development of this adverse event. Sunitinib has demonstrated anti-VEGF activity, it can cause hypertension similar to bevacizumab, and it has been previously related to this syndrome.21 Another case also reported the development of RPLS in a patient receiving chemotherapy with pemetrexed and cisplatin, but the authors hypothesized that it was not related to pemetrexed but rather to the extended use of dexamethasone and cisplatin.22 Cases of recurrent RPLS have been previously reported and include acute blood pressure elevations as a common finding.9,18,23

Conclusion In this report we describe a case of a patient with NSCLC who presented with clinical features and neuroimaging findings suggestive of RPLS after the infusion of bevacizumab. Although resolution of most of the clinical symptoms was observed within days, a repeat episode occurred 14 months later. The presence of hypertensive crisis and worsening of proteinuria on the first presentation suggests anti-VEGF–mediated endothelial dysfunction as the mechanism for the development of RPLS. Strict blood pressure control appears to be essential for the prevention of this syndrome, but sudden elevations may be difficult to anticipate. Further research for understanding the mechanism for bevacizumab’s neurologic toxicity and potential prevention measures for its development and recurrence is warranted. ■ Author Disclosure Statement Drs Pinto, Kernan, Hoffman, Ibrahim, and Bastos have reported no actual or potential conflicts of interest.

Journal of Hematology Oncology Pharmacy

References 1. Avastin (bevacizumab) [package insert]. San Francisco, CA: Genentech, Inc; 2010. 2. Shord SS, Bressler LR, Tierney LA, et al. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm. 2009;66:999-1013. 3. Marinella MA, Markert RJ. Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs. Int Med J. 2009;39:826-834. 4. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494-500. 5. Vaughn C, Zhang L, Schiff D. Reversible posterior leukoencephalopathy syndrome in cancer. Curr Oncol Rep. 2008;10:86-91. 6. Gressett SM, Shah SR. Intricacies of bevacizumab induced toxicities and their management. Ann Pharmacother. 2009;43:490-501. 7. Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions. AJNR Am J Neuroradiol. 2000;21: 1199-1206. 8. Schwartz RB. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:1743. 9. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65:205-210. 10. Vuorela P, Helske S, Hornig C, et al. Amniotic fluid—soluble vascular endothelial growth factor receptor-1 in preeclampsia. Obstet Gynecol. 2000;95:353-357. 11. Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278:12605-12608. 12. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102:596-604. 13. Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch Neurol. 2006;63:1475-1478. 14. Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006;354:981-982. 15. El Maalouf G, Mitry E, Lacout A, et al. Isolated brainstem involvement in posterior leukoencephalopathy induced by bevacizumab. J Neurol. 2008;255:295-296. 16. Peter S, Hausmann N, Schuster A, Bohem HF. Reversible posterior leukoencephalopathy syndrome and intravenous bevacizumab. Clin Experiment Ophthalmol. 2008;36:94-96. 17. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006;354:980-981. 18. Tam CS, Galanos J, Seymour JF, et al. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol. 2004;77:72-76. 19. Koopman M, Muller EW, Punt CJ. Reversible posterior leukoencephalopathy syndrome caused by bevacizumab: report of a case. Dis Colon Rectum. 2008;51: 1425-1426. 20. Baytan B, Ozdemir O, Demirkaya M, et al. Reversible posterior leukoencephalopathy induced by cancer chemotherapy. Pediatr Neurol. 2010;43:197-201. 21. Martin G, Bellido L, Cruz JJ. Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol. 2007;25:3559. 22. Nguyen MT, Virk IY, Villano JL. Extended use of dexamethasone-associated posterior reversible encephalopathy syndrome with cisplatin-based chemotherapy. J Clin Neurosci. 2009;16:1688-1690. 23. Hagemann G, Ugur T, Witte OW, Fitzek C. Recurrent posterior reversible encephalopathy syndrome (PRES). J Hum Hypertens. 2004;18:287-289.

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Case Study Pinto_Cover 6/7/11 4:11 PM Page 15

6-Jarkowski_Cover 6/7/11 4:06 PM Page 16

ORIGINAL RESEARCH

J Hematol Oncol Pharm. 2011;1(2):16-21 www.JHOPonline.com Disclosures are at end of text

Background: Ifosfamide-based chemotherapy is the standard of care for treatment of softtissue sarcomas. Previous studies have shown an increased risk for ifosfamide neurotoxicity among patients with low albumin levels, but the association between aprepitant use and the risk of neurotoxicity in patients receiving ifosfamide-based chemotherapy is still unknown and controversial. Objective: The primary objective was to determine whether concomitant aprepitant was associated with an increased risk of neurotoxicity in patients with sarcoma receiving high-dose ifosfamide-based chemotherapy. Other variables associated with ifosfamide-induced neurotoxicity were also assessed. Method: This retrospective cohort analysis was conducted over a 54-month period between January 2005 and July 2009 in 65 patients with sarcoma receiving ifosfamide-based chemotherapy. Wilcoxon rank sum and Pearson chi square tests were used to assess statistical significance in univariate associations with aprepitant use. The probability of aprepitant use or neurotoxicity was assessed using multivariable logistic regression analyses. Results: Sixty-five patients (mean age, 41.6 years; standard deviation, 2.5) received a total of 308 cycles of ifosfamide-based chemotherapy. Twenty-nine (45%) patients received aprepitant during ifosfamide-based chemotherapy. Sixteen (25%) patients had a documented neurotoxic event during ifosfamide chemotherapy, as documented by the attending physician. Of the 222 cycles without aprepitant, 7.6% (n = 17) of patients had neurotoxicity. Of the 86 cycles with aprepitant, 5 (5.8%) patients had neurotoxicity. This difference was not significant (P = .57). In univariate analyses, an increased risk of neurotoxicity was associated with gender (women more likely, P = .012), low albumin (P = .007), or ideal body weight (P = .038). Univariate (P = .94) and multivariate analyses (P = .86) failed to detect a significant association between aprepitant use and neurotoxicity. Low albumin was the only significant variable associated with neurotoxicity in the multivariate model (P = .025). Conclusion: We found no association between aprepitant use and the risk of neurotoxicity in patients receiving ifosfamide-based chemotherapy. The increased risk for ifosfamide neurotoxicity among patients with low albumin levels is consistent with previously published studies and may help identify patients at risk for neurotoxicity.

tructurally related to cyclophosphamide, ifosfamide is an alkylating chemotherapeutic agent used to treat a variety of solid tumors and hematologic malignancies.1 Ifosfamide is a prodrug that is metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme to its active (ifosfamide mustard and 4-hydroxy-ifosfamide)

and neurotoxic metabolites. Neurotoxicity is a wellknown adverse effect of ifosfamide occurring in up to 60% of patients.2 The signs and symptoms of neurotoxicity may include confusion, drowsiness, seizures, blurred vision, auditory or visual paranoid hallucinations, extrapyramidal symp-

Dr Jarkowski is Clinical Pharmacy Specialist, Department of Pharmacy; Dr Miller is Assistant Professor of Biostatistics and Oncology, Senior Biostatistician, Department of Biostatistics; Ms Hecke is Oncology Nurse, Roswell Park Cancer Institute, Roswell Park Cancer Institute, Buffalo, NY. Dr Blustein is Adjunct Clinical Faculty, University of the Sciences in Philadelphia, PA. Dr Wong is Professor of Medicine, University of Southern California, USC/Norris Comprehensive Cancer Center, Los Angeles, Cailfornia. This manuscript was presented as an oral abstract presentation in Salt Lake City, UT, at the 7th Hematology/Oncology Pharmacy Association 2011 Annual Conference.

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Jarkowski_Cover 6/7/11 4:06 PM Page 17

The Risk of Neurotoxicity with Aprepitant and Ifosfamide

toms, and urinary incontinence. Female sex, hepatic or renal dysfunction, and low albumin have been associated with increased ifosfamide neurotoxicity. The risk of neurotoxicity may also increase when ifosfamide is administered with other drugs metabolized through the CYP3A4. Dechloroethylation via CYP3A4 results in the release of potential neurotoxic metabolites. Thus CYP3A4 inducers have the potential to increase formation of both active and neurotoxic metabolites. Conversely, CYP3A4 inhibitors may impede with the activation of ifosfamide. Ifosfamide-based chemotherapy is the standard of care for treatment of soft-tissue sarcomas. It is one of the most active single agents used to treat sarcoma, usually given in conjunction with doxorubicin and occasionally a platinum analog.3 Ifosfamide is a key component in the treatment for metastatic sarcoma and as adjuvant therapy in surgically resected soft-tissue sarcomas. These regimens, including mesna, doxorubicin, and ifosfamide (MAI), can be very emetogenic. The National Comprehensive Cancer Network guidelines identify ifosfamide-based chemotherapy combinations used to treat sarcoma as moderate to high in emetogenic potential.4 Dose-limiting nausea and vomiting are common, adversely affecting patientsâ&#x20AC;&#x2122; ability to tolerate further chemotherapy and overall quality of life. Dexamethasone and a 5-hydroxytryptamine-3 (5-HT3) antagonist are considered standard of care for nausea and vomiting prevention in moderatehigh regimens, with a strong consideration given for the addition of aprepitant.4 Aprepitant is approved by the US Food and Drug Administration for use in combination with corticosteroids and 5-HT3 receptor antagonists in moderately to highly emetogenic chemotherapy regimens. In clinical practice and clinical trials, aprepitant has proved to benefit patients by preventing acute and delayed nausea and vomiting.5 Concomitant use of aprepitant with ifosfamide is controversial because of a perceived potential drug interaction. Aprepitant is known to inhibit and induce CYP3A4, making it a potentially significant problem in patients receiving medications metabolized by CYP3A4.6 Dexamethasone can also induce CYP3A4. In combination, these 2 agents contribute to the pharmacokinetic variability of ifosfamide and its active metabolites. A 2007 case report first reported increases of 66.7% and 37.3% in the neurotoxic 2 and 3 dechloroethylifosfamide metabolites 2 hours after aprepitant administration.7 Another recent case report described a patient receiving ifosfamide-based chemotherapy who exhibited symptoms of neurotoxicity after adding aprepitant to the

Vol 1, No 2

June 2011

antiemetic regimen.6 Howell and colleagues noted an increased trend of neurotoxicity with the addition of aprepitant to ifosfamide-containing regimens in sarcoma,8 whereas a subsequent letter to the editor reported no change in neurotoxicity rates with the combination.9 The debate about the significance of the drug interaction between aprepitant and ifosfamide is important, because nausea/vomiting and neurotoxicity directly impact patientsâ&#x20AC;&#x2122; tolerance of the therapy designed to improve their prognosis. The primary objective of this study was to determine whether concomitant aprepitant was associated with an increased risk of neurotoxicity in patients with sarcoma receiving high-dose ifosfamidebased chemotherapy. In addition, we considered other patient and treatment factors that may influence ifosfamide-induced neurotoxicity.

Methods A retrospective study was conducted on all patients (the total number by the end of the study was 65) diagnosed with any histologic subtype of sarcoma who received ifosfamide-based chemotherapy at Roswell Park Cancer Institute (RPCI) between January 2005 and July 2009. Patients were identified through the RPCI pharmacy system. Patients could receive any number of chemotherapy regimens, as long as the treatment included ifosfamide. The treatment regimens had various schedules of 5-HT3 antagonists based on physician preference and the drug formulary at the time of treatment. All patients were assessed on whether they received a concomitant corticosteroid (ie, dexamethasone) or aprepitant for nausea and vomiting prophylaxis. Data on ifosfamide dose, regimen, cycle number, infusion length (hours), and cumulative dose at the time of the cycle were collected. Demographics including age, sex, chemotherapy regimen received, diagnosis, height, actual body weight, ideal body weight, body surface area, albumin, aspartate aminotransferase, alanine aminotransferase (ALT), total bilirubin, hemoglobin, serum creatinine, and calculated creatinine clearance based on ideal body weight at time of admission were collected. The written notes from nurses, mid-level practitioners, and physicians in each patient case report form were reviewed to identify neurotoxic events. There had to be clear documentation by the provider that neurotoxicity was suspected or probable, but other potential confounding variables could not be ruled out. Treatment of neurotoxicity with methylene blue or by discontinuing ifosfamide was also recorded. Our primary research concern was the effect of aprepitant use on the incidence of neurotoxicity. All 65 patients in this study received a high dose of ifosfamide.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Jarkowski_Cover 6/7/11 4:06 PM Page 18

ORIGINAL RESEARCH

Other independent variables of interest included body weight, infusion schedule (continuous vs 5 hours or less), ideal body weight, and baseline measures of albumin, liver function tests, and hemoglobin. Preliminary analysis showed the natural log transformation of ALT to be better suited for statistical modeling. The primary neurotoxicity model was fit, using multivariable logistic regression to control for potential confounding variables. The full model was specified to include the independent variables discussed above and the plausible interaction of infusion schedule. The full model was reduced using manual backward select with a P value threshold of .05, starting with the interaction term, and constrained to retain the aprepitant main effect. For the final model, goodness of fit was assessed using the Hosmer-Lemeshow test. Similar methods were used to investigate the probability of receiving aprepitant. In our sample, all 65 patients received high doses of ifosfamide. Approximately 25% of the patients experienced neurotoxicity. The primary null hypothesis assumed no association between aprepitant use and toxicity rate. If the true neurotoxicity rate among aprepitant users in this population is 42% (corresponding to an odds ratio of 2.2), logistic regression modeling with a 2-sided significance level of 0.05 would correctly reject the null hypothesis in 80% of similarly conducted experiments. When the variability in the toxicity rate explained by additional covariates offsets the incremental loss in degree(s) of freedom, a lower minimum detectable odds ratio would be obtained. Some power is lost if other covariates in the model are correlated with aprepitant use. To be useful, predictions for the probability of neurotoxicity generated from the final model should accurately separate patients who experienced neurotoxicity from those who did not. A statistically significant factor in a logistic regression model may not be useful in predicting neurotoxicity in an individual patient. The predictive ability of the final logistic regression model was assessed in 2 ways. First, the receiver operating characteristic (ROC) curve plots the sensitivity as a function of (1 â&#x20AC;&#x201C; specificity) for all possible predicted probabilities estimated from the final model.10 This plot summarizes the predictive power of the model, with larger gaps between the ROC curve and the 45-degree reference line indicating greater predictive power. Second, the concordance index estimates the probability of concordance between the predicted probability and the observed neurotoxicity outcomes. The concordance index is the area under the ROC curve (AUC). An AUC of 0.5 suggests the model predictions are no better than random guessing. AUC values >0.8 are generally considered useful for predicting neurotoxicity in individual patients.

Journal of Hematology Oncology Pharmacy

These primary results were supplemented with univariate descriptions of associations between baseline patient or disease characteristics and aprepitant use or presence of neurotoxicity. Statistical significance of these associations were assessed using Wilcoxon rank sum test (for continuous covariates) and the Pearson chi square test (for categorical covariates). P <.05 was deemed statistically significant. No adjustments were made to this threshold to control the effects of multiple testing on the overall type I error rate. Confidence intervals (CIs) of 95% were presented as the plausible range of values for the true (unknown) population parameter that is supported by the data. All analyses were completed with SAS version 9.2 (SAS Institute, Cary, NC).

Results The 65 patients received a total of 308 cycles of ifosfamide-based chemotherapy. The Table (page 19) shows patient characteristics. Twenty-nine (45%) patients received aprepitant during ifosfamide-based chemotherapy. Of the 65 patients, 16 (25%) had a neurotoxicity event during ifosfamide chemotherapy as documented by the attending physician. Of the 16 patients, 7 (43.8%) received aprepitant during ifosfamide-based chemotherapy. Of the 222 cycles without aprepitant, 17 (7.6%) involved documented neurotoxicity compared with 5 (5.8%) of the 86 cycles with aprepitant, a not significant difference (P = .57). Subgroup comparisons were performed on patients who experienced a neurotoxic event versus those who did not (Table). Patients with documented neurotoxicity during ifosfamide therapy tended to be female, have a lower albumin level and ideal body weight, and received ifosfamide infusions over 5 hours or less. Five of the 16 patients who had neurotoxicity were treated with methylene blue. Three patients who had previous ifosfamiderelated neurotoxicity received methylene blue as prophylaxis on the subsequent cycle. Univariate results suggest a significant association between neurotoxicity, sex (P = .01, women more likely), low albumin (P = .007), and ideal body weight (P = .038). Neither univariate analysis (P = .936) nor the multivariate model (P = .86) detected a significant association between aprepitant use and the probability of neurotoxicity. Low albumin was the only significant variable predicting for neurotoxicity in the multivariate model (P = .025). The adjusted odds ratio for neurotoxicity in patients treated with aprepitant versus those treated without it was 1.15 (95% CI, 0.2-5.5), and it was not significant

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Jarkowski_Cover 6/8/11 10:36 AM Page 19

The Risk of Neurotoxicity with Aprepitant and Ifosfamide

Table Baseline Patient Characteristics Characteristic

No aprepitant

Aprepitant

P value

No neurotoxicity

Neurotoxicity

P value

40.8 (3.4) 15 (41.7)

42.5 (3.9) 16 (55.2)

.4 .3

40.3 (3.0) 19 (38.8)

45.4 (4.9) 12 (75.0)

.39 .01

16 (44.4)

5 (17.2)

15 (30.6)

6 (37.5)

.09

MAI, N (%) Other, N (%) Mean actual body weight, kg (SE) Mean ideal body weight, kg (SE)

15 (41.7) 5 (13.9) 73.9 (3.7)

11 (37.9) 13 (44.9) 82.5 (4.2)

.19

23 (46.9) 11 (22.4) 79.1 (3.2)

3 (18.8) 7 (43.8) 73.5 (5.7)

60.4 (2.1)

63.9 (2.2)

63.5 (1.8)

57.0 (2.6)

.038

Mean albumin, g/dL (SE) Mean alanine aminotransferase, IU/L (SE) Mean aspartate aminotransferase, IU/L (SE) Mean total bilirubin, mg/dL (SE)

3.8 (0.1) 35.0 (3.7)

3.9 (0.1) 23.5 (2.3)

.7 .02

3.9 (0.1) 29.5 (2.7)

3.5 (0.2) 30.9 (5.1)

.007 .7

30.5 (2.7)

26.6 (1.5)

27.9 (2.0)

31.3 (3.0)

0.3 (0.0)

108.7 (8.4)

104.1 (8.5)

108.2 (6.3)

101.9 (14.9)

.47

0.9 (0.1)

0.8 (0.0)

0.8 (0.1)

11.3 (0.2) 12 (33.3) 9 (25) 59.2 (7.2)

12.2 (0.3) 7 (24.2) 7 (24.1) 47.8 (5.3)

.03 .4 .9 .43

11.8 (0.2) 17 (34.7)

11.2 (0.4) 2 (12.5)

.26 .09

58.1 (5.7)

41.8 (6.7)

.19

Mean age, yrs (SE) Female, N (%) Chemotherapy IE, N (%)

Mean CrCl, mL/min (SE) Mean SCr, mg/dL (SE) Mean hemoglobin, g/dL (SE) 24-hour infusion, N (%) Neurotoxicity, N (%) Total dose, g (SE)

CrCl indicates creatinine clearance; IE, ifosfamide and etoposide; MAI, mesna, doxorubicin, and ifosfamide; SCr, serum creatinine; SE, standard error.

(P = .9). This estimate was adjusted for sex, infusion schedule, and other covariates that may influence the association between aprepitant use and neurotoxicity. Albumin was the only significant predictor (odds ratio = 0.2; P = .03; 95% CI, 0.06-0.8) in the multivariable neurotoxicity model (Hosmer-Lemeshow chi square = 3.6, P = .82). The modeled association between albumin and neurotoxicity is illustrated in Figures 1 and 2 (page 20). Figure 1 shows the protective effect of higher albumin levels on the predicted probability of neurotoxicity. The ROC curve indicates how accurately albumin levels can be used to categorize patients by neurotoxicity status. The AUC of 0.73 suggests a moderate degree of accuracy for predicting neurotoxicity in individual patients (Figure 1).

Discussion Of the 65 patients in our study who received ifosfamide-based chemotherapy for sarcoma, 16 experienced (25%) a neurotoxic event. This number is within the range described in previous literature reports.2

Vol 1, No 2

June 2011

We found no evidence to show that aprepitant increased the rate of neurotoxicity with high-dose ifosfamide therapy. Less than half of the patients (7 of 16) with a neurotoxic event received aprepitant during ifosfamide-based chemotherapy. There was no significant difference in the number of cycles of chemotherapy with or without aprepitant and neurotoxicity rates (P = .57). However, consistent with previous studies,8,9,11 low albumin was a significant indicator of increased risk for neurotoxicity. Durand and colleagues were first to report a positive association between aprepitant and the development of neurotoxicity during ifosfamide treatment.7 They described a case of a 57-year-old woman who experienced neurotoxicity while receiving ifosfamide to treat osteosarcoma. Their pharmacokinetic results revealed a significant increase in the formation of neurotoxic metabolites from ifosfamide when used concomitantly with aprepitant. A subsequent case report described development of neurotoxicity when aprepitant was added to ifosfamide-based chemotherapy.6

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Jarkowski_Cover 6/7/11 4:06 PM Page 20

ORIGINAL RESEARCH

Figure 1

Association Between Baseline Albumin and Estimated Probability of Neurotoxicity

Figure 2

ROC curve for neurotoxicity as a function of baseline albumin

Neurotoxicity with Ifosfamide-Based Chemotherapy

Sensitivity

Predicted probability

Predicted probability of neurotoxicity as a function of baseline albumin

Baseline albumin

1 â&#x20AC;&#x201C; specificity

Observed

AUC indicates area under the curve; ROC, receiver operating characteristic.

Howell and colleaguesâ&#x20AC;&#x2122; retrospective study characterized the occurrence of neurotoxicity in patients treated with ifosfamide and concurrent aprepitant.8 All 45 patients included in their study received a 2- to 4-day regimen of MAI. Eighteen percent (8 of 45) of these patients developed neurotoxicity during therapy. Their results revealed a trend toward increased neurotoxicity (P = .176) with the use of concomitant aprepitant. Similar to our results, they noted a significant difference in low albumin in patients who developed neurotoxicity. Subsequently, in a letter to the editor, Ho and Yuen share their retrospective experience with aprepitant- associated ifosfamide neurotoxicity.9 Twelve percent (7 of 54) of the patients they reviewed experienced neurotoxicity. Not surprising, and similar to our report and that of Howell and colleagues, the cases of neurotoxicity had significantly lower albumin levels than patients without neurotoxicity (P = .0021). But the described albumin levels (mean, 1.9) in neurotoxicity cases were clinically lower than ours (mean, 3.5; standard error, 0.2) and those of Howell and colleagues (mean, 2.88); 47% of their neurotoxicity cases and 59% of the controls received concomitant aprepitant.8 They found no significant association with aprepitant and the development of neurotoxicity.8

Journal of Hematology Oncology Pharmacy

Predicted

The methodologies, number of patients, and baseline characteristics were similar between all the studies. Our report is in direct agreement with Ho and Yuen9 in that aprepitant did not increase neurotoxicity with concomitant ifosfamide-based chemotherapy. This contrasts the results from Howell and colleagues, who found a trend toward increased neurotoxicity with the addition of aprepitant to ifosfamide.8 Putting our work in context, the drug-drug interaction models may be more complex than initially envisioned. Ifosfamide has been described as a prodrug that requires enzymatic activation by the liver via CYP3A4 to both active (4-hydroxy-ifosfamide) and neurotoxic metabolites (chloroacetaldehyde and 2- and 3dechloroethylifosfamide).12 It is plausible that drugs that induce or inhibit CYP3A4 can have a significant impact on ifosfamide pharmacokinetics. Dexamethasone, a known CYP3A4 inducer, has been shown to increase chloroacetaldehyde peak concentrations by 1.5-fold and the AUC time curve by 1.3-fold.13 Phenytoin has also been shown to increase dechloroethylation in pediatric patients receiving ifosfamide.14 But it must be noted that ifosfamide can induce its own metabolism within the first 24 hours, thereby complicating interpretation of the pharmacokinetic results.12,15 Also, no definitive evidence exists on

www.JHOPonline.com

June 2011

Vol 1, No 2

6-Jarkowski_Cover 6/7/11 4:06 PM Page 21

The Risk of Neurotoxicity with Aprepitant and Ifosfamide

whether CYP3A4 is the only relevant enzyme contributing to ifosfamide metabolism in vivo. In vitro studies document multiple liver microenzymes contributing to ifosfamide metabolism.12 Another important point, which has yet to be documented or described in the literature, to our knowledge, is the potential impact of aprepitant on the efficacy of ifosfamide. Ifosfamide is activated via hydroxylation in the liver by CYP3A4 to its active form. Therefore, inhibitors or inducers of CYP3A4 have the potential to affect formation of active metabolites. As Ho and Yuen note, both aprepitant and ifosfamide are highly protein-bound drugs.9 They postulate that low albumin levels can lead to increased free unbound aprepitant and ifosfamide, thereby increasing the formation of all ifosfamide active and inactive metabolites. Although this explanation is plausible, there are no pharmacokinetic data available to refute or to support this claim. Patients in our study who had documented neurotoxicity during ifosfamide therapy tended to be female, have a lower ideal body weight, and received ifosfamide infusions over less than 5 hours. It has been previously reported that females exhibit more neurotoxicity with ifosfamide than males.16 But the increased neurotoxicity rates with a lower ideal body weight and shorter ifosfamide infusion time were somewhat surprising. It has been previously reported in small groups of patients that longer infusion times of ifosfamide may lower toxicity and metabolites.17,18 But subsequent pharmacokinetic assessments comparing prolonged infusions did not show any difference in pharmacokinetic parameters.19,20 The results of our study are based on a convenience sample derived from retrospective chart reviews from a single institution. The use of sequential cases tends to reduce biases inherent in this approach. However the possibility of bias induced by important, perhaps unmeasured, factors remains a weakness common to all retrospective studies.

Conclusion Neurotoxicity is a potentially dose-limiting side effect occurring with ifosfamide-based chemotherapy, often necessitating at least temporary cessation of therapy. This study documents that aprepitant was not associated with increased risk of neurotoxicity in RPCI patients receiving ifosfamide-based chemotherapy. Our finding that low albumin levels were a risk factor for ifosfamide neurotoxicity is consistent with previously published studies and may be helpful in identifying patients at higher risk for neurotoxicity.

Vol 1, No 2

June 2011

Based on these data, the medical sarcoma service at our institute has made aprepitant part of the standard order set for patients with normal or near-normal albumin levels receiving ifosfamide-based chemotherapy deemed to be moderately high to highly emetogenic (ie, MAI). In patients with lower than normal albumin levels, we advocate ifosfamide dose reduction. Definitive resolution of this question will require pharmacokinetic study of both the active ifosfamide metabolites and the neurotoxic metabolites simultaneously. ■

Author Disclosure Statement Drs Jarkowski, Miller, Blustein, and Wong, and Ms Hecke have reported no actual or potential conflicts of interest. References 1. Zhang J, Tian Q, Zhou SF. Clinical pharmacology of cyclophosphamide and ifosfamide. Curr Drug Ther. 2006;1:55-84. 2. Patel PN. Methylene blue for management of ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40:299-303. 3. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276-1285. 4. Ettinger DS, Armstrong DK, Barbour S, et al. Antiemesis. Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2009;7:572-595. 5. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4112-4119. 6. Jarkowski A 3rd. Possible contribution of aprepitant to ifosfamide-induced neurotoxicity. Am J Health Syst Pharm. 2008;65:2229-2231. 7. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy. Ann Oncol. 2007;18:808-809. 8. Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract. 2008;14:157-162. 9. Ho H, Yuen C. Letter to the editor. J Oncol Pharm Pract. 2010;16:137-138. 10. Zou KH, O’Malley AJ, Mauri L. Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models. Circulation. 2007;115:654-657. 11. David KA, Picus J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol. 2005;28:277-280. 12. Kerbusch T, de Kraker J, Keizer HJ, et al. Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokinet. 2001;40:41-62. 13. Brüggemann SK, Pfäffle S, Peters SO, Wagner T. Influence of short-term use of dexamethasone on the pharmacokinetics of ifosfamide in patients. Drug Metab Dispos. 2007;35:1721-1724. 14. Ducharme MP, Bernstein ML, Granvil CP, et al. Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers. Cancer Chemother Pharmacol. 1997;40:531-533. 15. Lind MJ, Margison JM, Cerny T, et al. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res. 1989;49:753-757. 16. Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose ifosfamide: a retrospective cohort study and review of the literature. Drug Saf. 2008;31:989-996. 17. Kerbusch T, Mathôt RA, Keizer HJ, et al. Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites. Drug Metab Dispos. 2001;29:967-975. 18. Cerny T, Castiglione M, Brunner K, et al. Ifosfamide by continuous infusion to prevent encephalopathy. Lancet. 1990;335:175. 19. Brain EG, Rezai K, Weill S, et al. Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study. Cancer Chemother Pharmacol. 2007;60:375-381. 20. Singer JM, Hartley JM, Brennan C. The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study. Br J Cancer. 1998;77:978-984.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

6-Jarkowski_Cover 6/7/11 4:06 PM Page 22

Pushing Your Limits

Scan Here to Register.

Current activities at www.COEXM.com include:

To use 2D barcodes, download the ScanLife app: â&#x20AC;˘ Text â&#x20AC;&#x153;scanâ&#x20AC;? to 43588 â&#x20AC;˘ Go to www.getscanlife.com on your smartphoneâ&#x20AC;&#x2122;s web browser, and select â&#x20AC;&#x153;Downloadâ&#x20AC;? â&#x20AC;˘ Visit the app store for your smartphone

ÂŠiStockphoto.com/altaykaya

COEAsize30211CE

7-Manchini_Cover 6/8/11 1:40 PM Page 23

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Implementation of a PharmacistManaged Interdisciplinary Oral Chemotherapy Program in a Community Cancer Center Robert Mancini, PharmD; Lindsay M. Kaster, PharmD; Brian Vu, PharmD; Jessie Modlin, PharmD; David B. Wilson, RPh Background: Traditionally, cancer chemotherapy has been given intravenously. However, in the past 15 years, the number of available oral chemotherapeutic agents has more than doubled. Oral formulations offer various advantages for patients including convenience, potential for reduced side effects, and enhanced quality of life. With every opportunity, however, comes challenge. In this case, potential challenges include procurement (ie, drug acquisition and insurance reimbursement issues), compliance, pharmacologic interactions, and patient safety factors (eg, appropriate patient education and safe handling of chemotherapeutic agents). In addition, when prescriptions are sent to an external pharmacy, there is no income provided to the cancer center despite use of resources. Goal: To describe the way a pharmacy program has dealt with the emerging challenges of managing oral chemotherapy, evaluate workload requirements, and show how the program self-sustains by retaining revenue within the specific health system. Methods: This pharmacist-managed program involved tracking of interventions, such as drugdrug interaction interventions, dose change suggestions based on laboratory results, and supportive care discussions. In addition, the annual costs and revenue of the program in fiscal year 2010 were tracked to ensure justification of the program and continued financial support of the required full-time equivalents. Other justification included surveying prescribing physicians and clinic nurses for satisfaction with the program. Results: Based on data generated from electronic medical records, an estimated 75% to 85% of prescriptions now remain within St Lukeâ&#x20AC;&#x2122;s health system compared with less than 25% before implementation of the program. Conclusion: Oncology pharmacists have a unique opportunity to manage patients receiving oral chemotherapy. The oral chemotherapy program established at St Lukeâ&#x20AC;&#x2122;s Mountain States Tumor Institute has become an integral collaborative practice, as well as a self-sustainable program for the health system.

here has recently been a paradigm shift in the treatment of patients with cancer. Traditionally, cancer chemotherapy has been given through the intravenous (IV) route. However, in the past 15 years, the number of available oral chemotherapeutic agents has more than doubled. In addition, approximately 30% to 35% of antineoplastics currently being developed are in an oral formulation.1 Oral formulations offer many advantages for patients, including conven-

Drs Mancini, Kaster, Vu, and Modlin are Oncology Pharmacists, and Mr Wilson is Oncology Pharmacy Manager, at St Lukeâ&#x20AC;&#x2122;s Mountain States Tumor Institute, Boise, ID.

Vol 1, No 2

June 2011

J Hematol Oncol Pharm. 2011;1(2):23-30 www.JHOPonline.com Disclosures are at end of text

ience, potential for reduced side effects, and enhanced quality of life. Several studies have shown that between 63% and 89% of patients would prefer an oral therapy if efficacy were not compromised.2-4 As oral chemotherapy becomes more widely utilized, many oncology healthcare providers will be unprepared for the challenges associated with these treatments. The potential challenges include procurement (ie, drug acquisition, insurance, and reimbursement issues), pharmacologic interactions, and patient safety factors (eg, appropriate patient education and safe handling of chemotherapeutic agents). In 2007, a study by Weingart and colleagues surveyed

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

7-Manchini_Cover 6/7/11 4:07 PM Page 24

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Figure 1 Standard Oral Chemotherapy Prescription

Journal of Hematology Oncology Pharmacy

www.JHOPonline.com

June 2011

Vol 1, No 2

7-Manchini_Cover 6/7/11 4:07 PM Page 25

Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program

54 National Cancer Institute (NCI)-designated cancer centers regarding their safety practices for oral chemotherapy and concluded that US cancer centers have no consensus on how to safely process oral chemotherapy agents.5 In addition, there are no standards for prescribing, educating, or assessing patient adherence.5 Two years later, the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) published joint guidelines on safe administration of chemotherapies, including requirements for standardization of ordering, preparation, patient education, monitoring, and follow-up with oral chemotherapy treatment.6 To date, these guidelines are the single source of guidance for institutions wishing to improve care of patients receiving oral antineoplastic agents. At St Luke’s Mountain States Tumor Institute (MSTI), a retrospective review from our 5 outpatient cancer clinics showed that less than 25% of patients prescribed oral chemotherapy had utilized St Luke’s hospital-based outpatient pharmacies for their prescribed oral anticancer therapies within a 6-month period. In addition, a fair number of patients utilized more than 2 pharmacies, because of difficulty in obtaining oral chemotherapeutic agents. In an effort to comply with published standards, increase patient safety and continuity of care, as well as expand clinical oncology pharmacist services, we established a pharmacist-managed, interdisciplinary oral chemotherapy program. The goals of the program were to develop prospective medication order review for oral chemotherapy; providing medication reconciliation; improving continuity of care, patient counseling, and patient education; monitoring for tolerability; follow-up for adherence; and increasing reimbursement revenue in the onsite outpatient pharmacies. We wanted to improve the oral chemotherapy prescription process in our facilities through standardized safeguards used during administration of IV therapy. This article describes a novel program at St Luke’s MSTI, an NCI community cancer center program serving a broad geographic area that includes most of southern Idaho, eastern Oregon, and northern Nevada. The article evaluates workload requirements and shows how the program self-sustains by retaining revenue within the specific health system.

Methods As a result of the need for expanded pharmacy services by St Luke’s MSTI and the initiative of a residency project, the process of establishing a new pharmacy service was begun. The initiation of the project required evaluation of standard legal and operating requirements

Vol 1, No 2

June 2011

Figure 2 Oral Chemotherapy Process

Prescription written for oral chemotherapy Pharmacist: prescription processing (laboratory, evaluation, drug interactions, patient education)

Outpatient pharmacy: benefits investigation

Pharmacist: prior authorization

Patient advocate: copay assistance programs

Social worker: free medication programs

Coordinate with outpatient pharmacy

Medication filled and sent to patient

Patient follow-up for side effects

Physician: follow-up for drug efficacy

All patients: monthly follow-up New patient or dose change: weekly follow-up

of any pharmacy. Requirements included a physical space with basic necessities and meeting basic pharmacy needs, such as specialty licenses and insurance contracts. Although we were able to secure an office for an oncology pharmacist to staff the oral chemotherapy program, we decided to utilize our Boise hospital’s onsite outpatient pharmacy for the actual filling of the oral chemotherapy prescriptions. This allowed us to circumvent the need for acquiring additional licensure and insurance contracts because they were already held by a pharmacy within the institution. After securing the basic requirements, we determined a process of workflow based on the ASCO-ONS guide-

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

7-Manchini_Cover 6/7/11 4:07 PM Page 26

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Figure 3 Prescriptions by Oral Chemotherapeutic Agent, September 2009-September 2010 360 340 320 300 280 260 240 220 200 180 160 140 120 100 80 60 40 20

Te m

m Th

ali

olo

nit

ide

b ini

ib Su

ra f So

pa zo

nib

b ini Pa

lot Ni

lan elp

lid na

ide om

tin pa Le

b La

at Im

yu ox

ini

re a

us dr

oli

m Hy

er Ev

ide

b op Et

ini lot Er

clo

cit

ide

ine

lines,6 taking into consideration the needs of our patient population and our particular institution. Close collaboration with multiple healthcare disciplines played an integral role in determining the actual process of oral chemotherapy processing. The groups included the outpatient (filling) pharmacy, clinic nurses, triage nurses, patient financial advocates, social workers, physician committees, and administrators. As a result of initial process complications discovered in the early phases of

Close collaboration with multiple healthcare disciplines played an integral role in determining the actual process of oral chemotherapy processing. the program, we needed to solicit continual verbal feedback at monthly meetings from each of these groups in an ongoing process to improve our program and to best meet the needs of our patients and our facility. To begin the process of filling oral chemotherapy prescriptions, we created 2 preprinted order forms, one for lenalidomide (Revlimid) and thalidomide (Thalomid)

Journal of Hematology Oncology Pharmacy

and the second for the remaining oral chemotherapeutic agents. Physicians prescribing oral chemotherapy were required to utilize the standardized forms, which include the following elements: the goal of treatment (eg, firstline, second-line, salvage), cycle length, cycle structure, whether the goal is prior authorization only or active dispensing, and a provision to allow the pharmacist to fill based on available pill sizes (Figure 1, page 24). Initial contact with the patient was made within 24 hours to explain the filling process and to perform initial counseling on the medication. Once the patient had started the medication, the oncology pharmacist called the patient on a weekly basis for follow-up and assessment for the first cycle. Thereafter, the patient was called once per cycle before each refill to assess symptom management and adherence. The oncology pharmacist kept in close communication with the prescribing oncologist and clinic nurses to ensure appropriate follow-up and assessment (including things such as laboratory work and symptom management). The average time to fill was 2 to 5 days, which is largely a function of insurance requirements. The pharmacy technician also schedules pick-ups with the patient, verifies receipt of mailed prescriptions, and assists in preparing the dayâ&#x20AC;&#x2122;s schedule (Figure 2, page 25).

www.JHOPonline.com

June 2011

Vol 1, No 2

7-Manchini_Cover 6/7/11 4:07 PM Page 27

Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program

Table 1 Drug Interactions Requiring Pharmacist Intervention Oral chemotherapeutic agent Interacting medication Capecitabine (Xeloda) Cyclophosphamide (Cytoxan) Dasatinib (Sprycel) Erlotinib (Tarceva)

Imatinib (Gleevec) Lapatinib (Tykerb) Lenalidomide (Revlimid) Pazopanib (Votrient) Sorafenib (Nexavar) Sunitinib (Sutent) Total

Warfarin Phenytoin Warfarin Hydrochlorothiazide Proton pump inhibitor Proton pump inhibitor Warfarin Phenytoin Simvastatin Levothyroxine Dexamethasone Digoxin Fentanyl Warfarin Dexamethasone

To justify this program, the oral chemotherapy office kept a daily log of workload that included the number of prescriptions filled and the number of follow-up phone calls. Interventions such as drug-drug interaction interventions, dose change suggestions based on laboratory results, and supportive care discussions were tracked indirectly. Revenue generated from oral chemotherapy prescriptions filled was tracked at the onsite outpatient pharmacy during fiscal year 2010 (October 2009September 2010) and divided by month to determine the plateau of workload. In addition, the yearly costs and revenue of the program were tracked to ensure justification of the program and continued financial support of the required full-time equivalents. Other justification included surveying prescribing physicians and clinic nurses for satisfaction with the program. Finally, the program found a huge opportunity with lenalidomide counseling and distribution that is included.

Results Workload Assessment During a 16-month time period, the oral chemotherapy office had processed nearly 1500 prescriptions for 552 patients. One third of these prescriptions were new; the remaining two thirds were refills. The average workload was 30 prescriptions filled weekly, in addition to approximately 50 weekly follow-ups (via phone call or physician visit). All prior authorizations were completed by the oncology pharmacist and signed by the prescriber when necessary. Patients who were underinsured or uninsured were referred to our patient financial advocates to apply

Vol 1, No 2

June 2011

Number of patients 9 2 4 1 4 7 1 1 1 1 1 2 1 1 1 37

for copay assistance or free drugs from the manufacturer via that manufacturerâ&#x20AC;&#x2122;s drug assistance programs. The most common prescription filled was capecitabine (Xeloda), followed by lenalidomide and temozolomide (Temodar) (Figure 3, page 26). Because of insurance requirements and contracts, approximately 10% of prescriptions referred to the oral chemotherapy office were required to go to a specific mail-order pharmacy. Before becoming certified to dispense lenalidomide, this number approached 20%, inferring that our current mail-order base is approximately 5% to 10%.

During a 16-month time period, the oral chemotherapy office had processed nearly 1500 prescriptions for 552 patients. One third of these prescriptions were new; the remaining two thirds were refills. Although indirectly measured, the most common side effects discussed with patients included nausea/vomiting prophylaxis and treatment, management and prevention of hand-foot syndrome, diarrhea, stomatitis, and requirements for taking the medication (ie, with or without food). Of the 552 participating patients, 36 patients had a total of 37 drug interactions that required pharmacist intervention. The most common drug interactions found were with capecitabine, cyclophosphamide, and certain tyrosine kinase inhibitors, specifically erlotinib

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

7-Manchini_Cover 6/7/11 4:07 PM Page 28

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

140

$350,000

120

$300,000

100

$250,000

$200,000

$150,000

$100,000

$50,000

Sept 2009

Oct 2009

Nov 2009

Dec 2009

Jan 2010

Feb 2010

Mar 2010

Apr 2010

(Tarceva) and dasatinib (Sprycel) (Table 1, page 27). In addition, 11 patients required dose adjustments from the originally prescribed dose because of laboratory values (eg, serum creatinine, bilirubin). All dose adjustment recommendations were accepted by the physicians.

Revenue and Program Sustainment During fiscal year 2010, the number of prescriptions had an average 3-fold increase from 40 new and refill prescriptions per month in October 2009 to 120 per month by September 2010. The revenue generated matched this trend by increasing from $100,000 per month to $300,000 per month by the end of the fiscal year (Figure 4).

Based on current monthly estimates, this program will result in yearly gross revenue of $2.4 million, double the original estimate of $1.2 million. Based on typical profit margins from the gross revenue, this program more than pays for itself. Based on current monthly estimates, this program will result in yearly gross revenue of $2.4 million, double the original estimate of $1.2 million. The total annual operating costs for the program were approximately $230,000, including salaries, overhead, educational brochures, and mailings. Based on typical profit margins from the gross revenue, this program more than pays for itself. In addition, with the increased revenue from the

Journal of Hematology Oncology Pharmacy

May 2010

June 2010

July 2010

Aug 2010

Sept 2010

Oral chemotherapy revenue, $

Number of prescriptions per month

Figure 4 Oral Chemotherapy Prescriptions and Revenue

Prescriptions filled by month Revenue

program, several patients were able to get free drugs for their first cycle, while assistance paperwork was pending, to ensure timely initiation of therapy within a couple days as opposed to weeks or more until insurance issues were resolved. A total of 15 oncology nurses, of the 25 who were approached, responded to a satisfaction survey initiated by the outpatient chemotherapy program pharmacists. Of the 15, 83% were very satisfied or satisfied with the process overall. Also, 80% were at least satisfied with the refill process, and 86% were at least satisfied with the copay assistance work integrated between the financial advocates and the oral chemotherapy office. According to the nurses, most patients spoke highly about the ease of obtaining/picking up medications and refills, copay assistance, and follow-up phone calls. All the nurses commented that it was moderately to very easy to contact the pharmacist working in the oral chemotherapy office. Most nurses had very positive interactions with the oral chemotherapy pharmacists (Table 2, page 29). Some of the positive comments from the nurses were, “This process is a HUGE improvement over what we were doing; patients LOVE it.” And, “The benefit of this program is that it takes the detailed work and attention given to IV chemotherapy for years and finally applies it to oral chemotherapy. It’s all about patient safety and teaching.” With regard to future improvements, nurses requested the pharmacy provide follow-up for patients utilizing mail-order pharmacy, as well as for those whose prescriptions are filled at the onsite outpatient pharmacy. A total of 7 of our 10 medical oncologists at 5 sites responded to our physician-prescriber satisfaction survey. Of these 7 respondents, 5 were extremely satisfied

www.JHOPonline.com

June 2011

Vol 1, No 2

7-Manchini_Cover 6/7/11 4:07 PM Page 29

Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program

Table 2 Nursing Satisfaction Survey Improvement parameter

Respondents agreeing, % (N = 15) 73 60 60 53 53 53 40 40 40

Improved financial assistance Better documentation in electronic medical record Better patient follow-up and monitoring Ease of collaboration with pharmacy staff Improved patient outcomes Faster access to medication Reduced workload for registered nurse/medical doctor Improved refill process Better assistance with drug information questions

with the way the program is operating, all of whom believed this program has provided better access and thus better outcomes for their patients. Two physicians were indifferent, because they personally did not see a change in their workload but felt that the best response to the survey questions should be ascertained from their patients. The physicians also recommended some changes in how the pharmacists document fill dates, interventions, and follow-ups so that they can more easily determine when the patients start their cycles and/or pick up their medications.

Lenalidomide and RevAssist REMS program Lenalidomide is more time-intensive and challenging to fill compared with other oral chemotherapeutics, because of the risk evaluation and mitigation strategy (REMS) restrictions.7 For a pharmacy to fill lenalidomide, the pharmacy must complete a training program for certification of educators, which can be either nurses or pharmacists. Each month before the fill, the certified counselors call the patient to review a standardized counseling checklist. The counselors are also responsible for reporting any adverse reaction(s) the patient experiences while receiving this medication. The pharmacy is responsible for keeping a recorded inventory that includes the strength, lot number, and quantity of lenalidomide dispensed to the patient. Because of the workload required, it is essential to assess whether it is feasible for the health system to take on this responsibility. After the first 6 months of evaluating the program, a significant potential loss to follow-up in patients taking lenalidomide was discovered. Therefore, a decision was made to enroll the oral oncology pharmacists as certified RevAssist counselors so that the institution could maintain these patients internally. This allowed the second most common prescription to be brought back within the health system, further enhancing care for patients

Vol 1, No 2

June 2011

and retaining revenue for the institution. In addition, St Luke’s MSTI was able to justify a half-time technician position and a pharmacy biller to assist the oncology pharmacist.

Since the approval of capecitabine in 1998, there has been a shifting paradigm in cancer care toward oral chemotherapeutics. An estimated 75% to 85% of prescriptions now remain within our health system, thus allowing consistent follow-up our patients previously did not receive. This change has the potential to improve compliance and accessibility and decrease patient concerns. Conclusion Since the US Food and Drug Administration approval of capecitabine in 1998, there has been a shifting paradigm in cancer care toward oral chemotherapeutics.8 The implications for this are huge—not just for patients, but for cancer centers as well. When prescriptions are sent to an external pharmacy, there is no income provided to the cancer center. This is potentially problematic, because staff time involved in assisting patients with obtaining their medications is not billable.9 St Luke’s MSTI’s oral chemotherapy program has allowed for revenue to stay within the health system each year to continually fund this program. Previously, only 25% of patients were filling their prescriptions at our health system pharmacies. Based on data generated from the electronic medical records, an estimated 75% to 85% of prescriptions now remain within our health

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

7-Manchini_Cover 6/7/11 4:07 PM Page 30

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

system, thus allowing consistent follow-up our patients previously did not receive. This change has the potential to improve compliance and accessibility and decrease patient concerns.10 A unique advantage to keeping these prescriptions within our health system is that drug interactions, dose adjustments, and supportive care referrals can be done in a more timely fashion, thereby preventing further delays in initiation of treatment. In addition, consistent documentation and follow-up within one system allows for improved continuity of care for patients and for enhanced safety outcomes.6

We believe that many patients do not continue taking oral chemotherapeutics as long as may be predicted and often stop after a few cycles as a result of toxicity and/or disease progression. This program could not have been a success without the strong collaboration among individuals with varying areas of specialization, including the oncologists, nurses, pharmacists, retail pharmacy team, billing specialists, patient financial advocates, and social workers, as well as the insight of our pharmacy business analyst. Future directions of this program involve continued adaptation of new oral oncologic agents, as well as integration of the supportive care medications prescribed in the oncology population, such as deferasirox (Exjade) or eltrombopag (Promacta). An additional challenge is to find a way to include follow-up for the 5% to 10% of patients who receive oral chemotherapy from mail-order pharmacies. With our current workload, patients who utilize mailorder pharmacies are difficult to include, but future changes may allow us to integrate them into our system to improve monitoring and follow-up with these patients. In addition, examination of the impact of this program,

Journal of Hematology Oncology Pharmacy

including adherence rates, average duration of time on oral chemotherapeutics, and supportive care management and counseling, are also needed. Because one third of our fills are new prescriptions, we believe that many patients do not continue taking oral chemotherapeutics as long as may be predicted and often stop after a few cycles as a result of toxicity and/or disease progression. The ultimate finding is that oncology pharmacists have a unique opportunity to manage patients’ prescribed oral chemotherapy. This includes the ability to help the health system comply with REMS programs, as seen with lenalidomide, and improve safe-handling practices by helping establish procedures for ordering, filling, and dispensing oral chemotherapy. The program described here has become an integral collaborative practice, as well as a self-sustainable program for our not-for-profit health system. ■

Author Disclosure Statement Drs Mancini, Kaster, Vu, Modlin, and Mr Wilson have reported no actual or potential conflicts of interest. References 1. DeCardenas R, Helfrich J. Oral therapies and safety issues for oncology practices. Oncology Issues. 2010;(March/April):40-42. 2. Fallowfield L, Atkins L, Catt S, et al. Patients’ preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol. 2006;17:205-210. 3. Borner M, Schöffski P, de Wit R, et al. A randomized crossover trial comparing oral UFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV for patient preference and pharmacokinetics in advanced colorectal cancer. Proc Am Soc Clin Oncol. 2000;19:Abstract 741. 4. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110-115. 5. Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety practices at US cancer centres: questionnaire survey. BMJ. 2007;334:407. 6. Jacobsen JO, Polovich M, McNiff KK, et al. American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. Oncol Nurs Forum. 2009;36:651-658. 7. Revlimid (lenalidomide) [package insert]. Celgene Corporation: Summit, NJ; January 2009. 8. Choi S, Boehnke L. Oral chemotherapy: a shifting paradigm affecting patient safety. Hem Onc Today. November 25, 2008. www.hemonctoday.com/article. aspx?rid=33070. Accessed April 28, 2011. 9. Hede K. Increase in oral cancer drugs raises thorny issues for oncology practices. J Natl Cancer Inst. 2009;101:1534-1536. 10. Increased use of oral chemotherapy drugs spurs increased attention to patient compliance. J Oncol Pract. 2008;4:175-177.

www.JHOPonline.com

June 2011

Vol 1, No 2

7-Manchini_Cover 6/7/11 4:07 PM Page 31

BUILDING

pillars of knowledge

IN SUPPORTIVE CARE NEUTROPENIA LIVE WEBINAR DATES

LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace06

ACTIVITY LENGTH: 1 HOUR Monday, July 11, 2011 12:00 PM ET • 11:00 AM CT • 10:00 AM MT • 9:00 AM PT

Wednesday, July 13, 2011 3:00 PM ET • 2:00 PM CT • 1:00 PM MT • 12:00 PM PT

Friday, July 15, 2011 1:00 PM ET • 12:00 PM CT • 11:00 AM MT • 10:00 AM PT

TARGET AUDIENCE The educational series is intended for nurses, pharmacists, and others with clinical, research, and management interests of neutropenia management

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • Outline the risk factors for neutropenia in patients with cancer undergoing chemotherapy • Review advances in the prevention and management of neutropenia, including updated evidence-based guidelines • Examine approaches for improving patient outcomes by identifying patients at risk and preventing or reducing the incidence of neutropenia

ACCREDITATION STATEMENTS Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This knowledge-based activity has been assigned ACPE # 02450000-11-016-L01-P and will award 1.0 contact hour (0.10 CEUs) of continuing pharmacy education credit. CEC complies with the Criteria for Quality for continuing education programming. NURSING Creative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Monday, July 18, 2011 3:00 PM ET • 2:00 PM CT • 1:00 PM MT • 12:00 PM PT

Friday, July 22, 2011 1:00 PM ET • 12:00 PM CT • 11:00 AM MT • 10:00 AM PT

FACULTY LeAnne Kennedy, PharmD, BCOP Pharmacy Clinical Coordinator Hematology and Oncology Wake Forest Baptist Health Winston-Salem, NC

Kathleen Colson, RN, BSN, BS Clinical Research Nurse Multiple Myeloma Dana Farber Cancer Institute Boston, MA

Regina Cunningham, PhD, RN, AOCN Senior Director, Oncology The Tisch Cancer Institute Mount Sinai Medical Center New York, NY

For further information and to participate, please go to: www.coexm.com/ace06

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. Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form.

This activity is supported by an educational grant from Amgen Inc.

8-Guidelines_Cover 6/8/11 1:48 PM Page 32

AUTHOR GUIDELINES MISSION STATEMENT—Journal of Hematology Oncology Pharmacy (JHOP) is an independent, peerreviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals in these fields with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients. GENERAL INFORMATION—Manuscripts submitted to JHOP must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP. The editors invite readers to submit a articles on a variety of points of view and approaches to meet the mission of the journal. Articles will be divided into four main categories, including (1) original research, to provide an outlet for translational and practice-based research, including case reports and case series; (2) review articles that focus on drug and disease state as well as on basic science regarding the complex molecular biology of cancer with a pharmacy focus; (3) clinical controversies that discuss common clinical issues for which treatment is unclear; this could include “point, counterpoint” and “how I treat” type of articles; (4) practical issues in pharmacy management will focus on real-world issues involving logistics, economics, and other practice-related topics. Manuscripts submitted must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP. All authors must sign an appropriate disclosure form and a copyright transfer/authorship form. PEER REVIEW/EDITING—All articles undergo an initial internal review for topic appropriateness and manuscript format. Manuscripts that are not submitted according to the guidelines in this document will be returned to the author. All manuscripts are subject to a strict, blinded peer review (by 2-4 reviewers), and acceptance is based entirely on that review. Reviewers look for the accuracy of the information and data presented, as well as the relevance to the objectives of JHOP. All authors’ identifying information is removed from the article for the purpose of the peer review, but any study

Journal of Hematology Oncology Pharmacy

funding information is provided to reviewers. Authors are notified as soon as possible regarding the initial decision of acceptance or rejection of the article. The majority of articles that are accepted for publication, however, will require revisions and resubmission. A second review is conducted when recommended by reviewers. Routine editorial changes are made on all articles to conform to house style, following the AMA Manual of Style, 10th ed.1 The edited manuscript is sent to the corresponding author for a final review and for any outstanding editorial queries. Time from submission to publication is generally 4 to 7 months, but could be longer, depending on the peer-review and editing processes. AUTHORSHIP/COPYRIGHT—Authors listed on the manuscript should only include those who have made a direct contribution to the content of the article, in accordance with the authorship criteria provided by the International Committee of Medical Journal Editors (ICMJE).2 Credit for authorship is based on a substantial contribution to (1) conception and design, or data analysis/interpretation, (2) drafting or revising the article critically for intellectual content, and (3) approval of the final version to be published. These 3 criteria must all be met.2 Those who have contributed to the article but do not meet these authorship criteria should be acknowledged at the end of the article. Provide authors’ highest academic degree and professional affiliations. Also provide the name, address, telephone number, e-mail, and fax number of the corresponding author. The corresponding author is responsible for securing signatures for all forms from all authors. All authors are required to sign an Authorship/Copyright Transfer Form, assigning all copyrights for the manuscript to Green Hill Healthcare Communications, LLC, publisher of JHOP. For an article to be considered for publication, authors must adhere to the manuscript format described in this document and follow the general ICMJE guidelines.2 DISCLOSURE STATEMENTS—All authors must disclose any relationship that could be viewed as a potential conflict of interest, based on ICMJE guidelines,2 including any financial interests, direct or indirect, and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript.

www.JHOPonline.com

June 2011

Vol 1, No 2

8-Guidelines_Cover 6/8/11 1:29 PM Page 33

Each author must sign the Financial Disclosure Form in accordance with the ICMJE guidelines.2 JHOP discloses all information regarding employment, consultancies, stock ownership, honoraria, grants, or other financial sources with potential conflict of interest in relation to a manuscript, or if authors discuss any products or services with such commercial interest. Any information regarding funding, grants, or other financial compensation must be listed on the title page of the manuscript. All published articles will include disclosure statements listing any relationships with real or potential conflict of interest for all authors and for the manuscript/research. PERMISSIONS—Authors must secure written permission to reuse or adapt any graphic elements (table, figure) from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. Authors are responsible for acknowledging all information that has been published previously. MANUSCRIPT FORMAT—Manuscripts that do not adhere to the format described in this document will be returned to the author.

Conclusion: The conclusion is not a summary of the article. Rather, it should add something new to the article, a point of view or comments related to the rationale for the article and what the article adds to the literature. Tables and figures: Cite all figures, tables, algorithms, and other graphics in the text, but place the graphic elements at the end of the article, after the references. Type all tables and all figure heads and captions in the Word document. Figures and other images must also be provided as individual graphic files, saved at high resolution (300 dpi), as jpg or pdf file. Attach an individual file for each image. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact JHOP@greenhillhc.com. References: Use most up-to-date, post-1990, primary sources only, cited consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Avoid automatic numbering or footnote/endnote features. Try to limit the number of references to 35. Use citation format according to the AMA Manual of Style.1 Examples:

Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author. List all funding sources for the study/article.

1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295: 676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news? pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

Abstract: Articles must include an abstract (200-300 words) that describes the main objectives of the article, why this article is important, and what it adds to the literature. The abstract must be divided into these categories: Background, Objectives, Methods (and Study Design, if relevant), Results, and Conclusion.

HOW TO SUBMIT MANUSCRIPTS—Articles that do not follow the guidelines described in this document will not be considered for publication.

An abstract for an article that does not represent research findings should include the following categories to suggest why the article is important and what its main objectives are: Background, Objectives, Discussion, Conclusion. Text: The entire text must be provided as a doublespaced Word file and all pages numbered consecutively. Cite any graphic elements (tables, figures, algorithms, appendix) consecutively in the text, but place actual tables/figures at the end of the article, after the references. Limit the length of the text to 3500 words (excluding references, tables, and figures).

Vol 1, No 2

June 2011

Save the manuscript as a Word file and attach individual files for each image or figure. Save images (figures) individually as an image file (jpg or pdf). Digital images must be saved at a high resolution (300 dpi). Submit the entire manuscript and cover letter stating the objectives of the article to JHOP@greenhillhc. com. For assistance call 732-992-1890. REPRINTS—Reprints may be ordered for a nominal fee by contacting JHOP@greenhillhc.com.

1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007. 2. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated April 2010. www.icmje.org/urm_full.pdf. Accessed June 1, 2010.

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

8-Guidelines_Cover 6/7/11 4:08 PM Page 34

Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

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

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkin Lymphoma â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is supported by educational grant from Cephalon Oncology, Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEAsize40611MM

9-From theLit_Cover 6/7/11 4:10 PM Page 35

FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, UCSF, Professor of Pharmacy, College of Pharmacy, Touro University â&#x20AC;&#x201C; California, Mare Island Vallejo

â&#x2013; Abiraterone Improves Overall Survival in Patients with Metastatic Prostate Cancer Background: Androgen deprivation has long been the standard of care for men with advanced prostate cancer, demonstrating efficacy in preventing or delaying the recurrence of metastases in this patient population. The selective androgen biosynthesis inhibitor abiraterone acetate, administered either alone or in combination with low-dose prednisone, has demonstrated significant antitumor activity in men with advanced prostate cancer, regardless of any previous chemotherapy treatment. However, whether abiraterone prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer whose disease progressed after docetaxelbased chemotherapy was not previously known. Design: This phase 3 multinational, double-blind, placebo-controlled trial included patients from 147 sites in 13 countries; they were followed from May 2008 through July 2009. A total of 1195 patients who had previously received docetaxel chemotherapy were randomly assigned in a 2:1 ratio to 2 groups to receive 1000 mg daily of abiraterone acetate (administered as four 250-mg tablets) plus prednisone 5 mg twice daily (N = 797), or placebo plus prednisone (N = 398). The primary end point was OS; the secondary end points included time to prostate-specific antigen (PSA) progression; progressionfree survival (PFS), determined from radiologic findings; and PSA response rate. Summary: The primary and secondary end points in this study all showed significantly improved outcomes in the active treatment group compared with the placebo group. After a median follow-up period of 12.8 months, patients receiving abiraterone demonstrated significantly longer OS (14.8 months) than those receiving placebo (10.9 months; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.54-0.77; P <.001). For the interim analysis, the data were unblinded, because these results exceeded the preplanned criteria for study termination. Secondary end points also showed improvement with abiraterone compared with placebo: the PFS period was longer with abiraterone compared with placebo (5.6 months vs 3.6 months, respectively; P <.001), as was time to PSA progression (10.2 months vs 6.6 months, respectively; P<.001), and the PSA response rate was Vol 1, No 2

June 2011

greater (29% vs 6%, respectively; P <.001). Treatment with abiraterone had a low frequency of treatment-related toxic effects. Patients receiving abiraterone plus prednisone, however, had more mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, than those receiving placebo plus prednisone. Takeaway: This phase 3 study of a novel testosterone biosynthetic inhibitor demonstrated a significant improvement in OS, PFS, and PSA responses in patients with castrate-resistant prostate cancer who had been previously treated with docetaxel. Furthermore, adverse events were low grade and largely minimized by concurrent low-dose prednisone therapy. The results of this study provide a proof of the principle that metastatic castrate-resistant prostate cancer is still driven by endogenous androgens. Therefore, hormonal therapy can be considered for a patient in whom previous chemotherapy has failed. The next study that should be conducted would involve a comparison between firstline therapy with abiraterone acetate versus docetaxelbased chemotherapy in the setting of castrate-resistant prostate cancer. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005.

â&#x2013; Comparing Denosumab and Zoledronic Acid for Treatment of Bone Metastases in Men with Castration-Resistant Prostate Cancer Background: The development of bone metastases is common in men with advanced prostate cancer. Researchers have therefore been investigating therapies for the treatment or prevention of bone metastases in this patient population. In a new study, denosumab, a human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), was compared in a phase 3 study with zoledronic acid for the prevention of skeletalrelated events (SREs) in men with bone metastases caused by castration-resistant prostate cancer. Design: Men from 342 centers in 39 countries with castration-resistant prostate cancer and no previous exposure to intravenous (IV) bisphosphonates were randomly assigned to receive 120 mg of subcutaneous denosumab plus IV placebo or 4 mg of IV zoledronic acid plus

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

9-From theLit_Cover 6/7/11 4:10 PM Page 36

FROM THE LITERATURE

subcutaneous placebo every 4 weeks. The primary end point was the time to a first on-study SRE (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), which was assessed first for noninferiority and then for superiority as a secondary end point. An intention-to-treat analysis was performed to assess efficacy, and safety was assessed according to the incidence of treatment-emergent adverse events and changes in hematology and laboratory findings. Summary: Among 1901 patients who were assigned to treatment and were eligible for the efficacy analysis, 950 received denosumab and 951 received zoledronic acid. The median duration on study at the primary analysis cutoff date was 12.2 months (interquartile range, 5.9-18.5) for patients given denosumab and 11.2 months (5.6-17.4) for those given zoledronic acid. The median time to a first on-study SRE was 20.7 months (95% CI, 18.8-24.9) with denosumab versus 17.1 months (15.0-19.4) with zoledronic acid (HR, 0.82; 95% CI, 0.71-0.95; P = .0002 for noninferiority; P = .008 for superiority). Adverse events occurred in 916 patients (97%) given denosumab and 918 (97%) given zoledronic acid, and serious adverse events occurred in 594 (63%) and 568 patients (60%), respectively. More episodes of hypocalcemia occurred with denosumab (121 [13%]) than with zoledronic acid (55 [6%]; P <.0001). The occurrence of osteonecrosis of the jaw was not significant (22 [2%] vs 12 [1%], respectively; P = .09). Takeaway: Denosumab is a human monoclonal antibody that binds to RANKL, leading to inhibition of osteoclast-mediated bone destruction. In this study, denosumab therapy delayed the time to first SREs by 18% compared with zoledronic acid. Furthermore, the decrease in markers of bone turnover was greater with denosumab than with zoledronic acid. However, OS and time to progression were not different between the groups. The authors concluded that denosumab is better than zoledronic acid for preventing SREs. This is the first monoclonal antibody shown to be an effective agent in bone metastases caused by castrate-resistant prostate cancer. Its role in this setting would be further defined by the results of a comparative pharmacoeconomics study. Fizazi K, et al. Lancet. 2011;377:813-822.

tion-resistant prostate cancer. Previous research, however, has not confirmed improved OS with the drug. Design: Researchers in the double-blind, placebocontrolled, multicenter Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T or placebo administered intravenously every 2 weeks for a total of 3 infusions. The primary end point was OS, determined from a stratified Cox regression model adjusted for baseline levels of serum PSA and lactate dehydrogenase. Summary: The relative risk of death among 341 patients given sipuleucel-T was 22% lower than that among 171 patients given placebo (HR, 0.78; 95% CI, 0.61-0.98; P = .03), translating to a 4.1-month longer median survival (25.8 months vs 21.7 months, respectively). In addition, the 36-month survival probability was 31.7% and 23.0%, respectively. The treatment effect was also demonstrated in an unadjusted Cox model and a log-rank test (HR, 0.77; 95% CI, 0.61-0.97; P = .02) and after adjustment for the use of docetaxel after the study therapy (HR, 0.78; 95% CI, 0.62-0.98; P = .03). The time to objective disease progression was similar in the 2 study groups. Patients who received sipuleucel-T also demonstrated immune responses to the immunizing antigen. Adverse events that occurred more frequently among patients given sipuleucel-T than among those given placebo included chills, fever, and headache. Takeaway: Vaccine immunotherapy has been studied but has not been proved beneficial until this study. Compared with placebo, sipuleucel-T improved OS by 4 months in patients with castrate-resistant prostate cancer and was consistent among all subgroups of prognostic factors. About half of the patients in the placebo group crossed over to the cancer vaccine group. OS was almost 24 months with the active treatment compared with 12 months in the placebo group. Adverse effects were minimal and well tolerated, mainly consisting of infusion reactions. This study establishes sipuleucel-T as a useful agent, especially in the setting of asymptomatic advanced prostate cancer. Because several therapies are now available that are effective in this setting, placebocontrolled trials in patients with castrate-resistant prostate cancer may no longer be ethical. Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

â&#x2013; Sipuleucel-T Immunotherapy Extends Overall Survival for Patients with Castration-Resistant Prostate Cancer Background: Sipuleucel-T, an autologous active cellular immunotherapy, has demonstrated efficacy in reducing the risk of death among men with metastatic castra-

Journal of Hematology Oncology Pharmacy

â&#x2013; Improving Survival with Ipilimumab in Metastatic Melanoma Background: In phase 3 randomized trials involving patients with metastatic melanoma, no therapy has been demonstrated to extend OS to 1 year or beyond.

www.JHOPonline.com

June 2011

Vol 1, No 2

9-From theLit_Cover 6/7/11 4:10 PM Page 37

FROM THE LITERATURE

Ipilimumab, a fully human monoclonal antibody that potentiates an antitumor T-cell response by blocking cytotoxic T-lymphocyte–associated antigen, has shown activity as monotherapy in phase 2 studies. Previous research suggests glycoprotein 100 (gp100) peptide vaccine, which also induces immune response but has limited antitumor activity as monotherapy, may improve the efficacy of high-dose interleukin-2 in patients with metastatic melanoma. In this phase 3 study, ipilimumab, administered with and without gp100, was compared with gp100 alone in patients who had previously undergone therapy for metastatic melanoma. Design: In a randomized, double-blind, phase 3 study, HLA-A*0201–positive patients with unresectable stage III or IV melanoma that had progressed during previous therapy for metastatic disease were enrolled between September 2004 and August 2008 at 125 centers in 13 countries in North America, South America, Europe, and Africa. All were randomly assigned in a 3:1:1 ratio to receive either ipilimumab (3 mg/kg body weight) plus gp100, ipilimumab alone, or gp100 alone every 3 weeks for a total of 4 treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was OS. Summary: Among a total of 676 patients, 403 received ipilimumab plus gp100, 137 received ipilimumab alone, and 136 received gp100 alone. The median OS was 10.0 months among patients who received ipilimumab plus gp100, versus 6.4 months among those who received gp100 alone (HR for death, 0.68; P <.001) and 10.1 months among those given ipilimumab alone (HR for death in the comparison with gp100 alone, 0.66; P = .003). OS did not differ between patients who received ipilimumab alone and those given the combination (HR with ipilimumab plus gp100, 1.04; P = .76). Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients who received ipilimumab and in 3% who received gp100 alone. Fourteen deaths were related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Takeaway: This randomized, 3:1:1 ratio trial showed that ipilimumab, with or without gp100, improved OS by 32% to 34% compared with gp100 alone. This is the first agent to show such an improvement in OS in metastatic melanoma. Furthermore, gp100 did not improve patient outcomes compared with ipilimumab alone. The primary adverse effects associated with ipilimumab are immune-mediated, manifested as gastrointestinal tract or dermatologic reactions (ie, rash, pruritus, or vitiligo). A total of 14 patients (2.1%) had their mortality associated with ipilimumab therapy, 7 of

Vol 1, No 2

June 2011

which were related to immune-mediated adverse events affecting the gastrointestinal tract: colitis and septicemia associated with bowel perforation—inflammatory colitis, bowel perforation, or multiorgan failure—peritonitis. Ipilimumab may be considered for patients in whom previous therapies have failed. Hodi FS, et al. N Engl J Med. 2010;363:711-723.

■ Beta-Blocker Therapy Linked to Reduced Progression of Thick Melanoma Background: The association between beta-adrenoceptor antagonist (beta-blocker) therapy and the overall risk of cancer or of specific, prevalent cancers, such as breast cancer, has not been established. However, the results of a new study suggest that beta-blockers may reduce the risk of prostate cancer, and findings from preclinical studies indicate that beta-blockers inhibit tumor growth and metastasis in animal models of melanoma. Design: Researchers at a dermatology clinic in Florence, Italy, prospectively reviewed clinical records from 1993 through 2009 of all patients with histologically confirmed malignant melanoma (Breslow thickness >1 mm). Disease progression was indicated by evidence of sentinel lymph node metastasis and lymphatic, intransit, or visceral metastasis. Deaths by any cause and those due to melanoma were recorded, and medication use patterns were determined from patient interviews during the first visit and at each 6-month follow-up visit and from the patients’ general practitioner once a year during the study period. Patients who had reported betablocker use for at least 1 year were considered to have undergone treatment. Median OS and median diseasefree survival (DFS) were calculated, and a Cox proportional hazards model was used to evaluate the influence of treatment on DFS and OS, adjusting for significant confounders. Summary: Of 121 consecutive patients documented with a thick melanoma, 30 had been undergoing beta-blocker therapy for 1 year or more, whereas the other 91 had not undergone treatment. After a median follow-up period of 2.5 years, tumor progression was observed in 3.3% of patients prescribed beta-blockers and in 34.1% of those who were not. The Cox model on disease progression indicated a 36% (95% CI, 11%-54%; P = .002) risk reduction for each year of beta-blocker use. No deaths were observed among those taking betablockers, but among those who were not taking betablockers, 24 had died. Takeaway: This retrospective study produced an interesting outcome—beta-blocker therapy for more

www.JHOPonline.com

Journal of Hematology Oncology Pharmacy

9-From theLit_Cover 6/8/11 10:37 AM Page 38

IN THE LITERATURE

than 1 year significantly decreased the death rate from thick (>1 mm in Breslow thickness) melanoma. The mechanism for this effect is not yet well understood, but it has been suggested that its antiangiogenic properties, as well as its ability to decrease stress mediators, including norepinephrine, may be responsible for this effect. This study was limited by a small number of patients and by its observational methodology. The results of this study, however, suggest that a prospective randomized trial in malignant melanoma is indicated. De Giorgi V, et al. Arch Intern Med. 2011;171:779-781.

â&#x2013; Bisphosphonates May Reduce the Risk of Colorectal Cancer in Postmenopausal Women Background: Bisphosphonates are often used to treat osteoporosis and bone metastases caused by breast cancer and, in fact, have been shown recently to reduce the risk of that type of cancer, possibly by acting through the mevalonate pathway. Their effect on the risk of other cancers, however, is unknown. Design: Computerized health service pharmacy records were examined to evaluate the dose-response relationship between the duration of long-term bisphosphonate use and the risk of colorectal cancer (CRC) among 933 pairs of postmenopausal women and age-, sex-, clinic-, and ethnic groupâ&#x20AC;&#x201C;matched individuals

Journal of Hematology Oncology Pharmacy

recruited between 2000 and 2006 in the ongoing population-based, case-controlled Molecular Epidemiology of Colorectal Cancer Study in Israel. Summary: Bisphosphonate therapy lasting for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk of CRC (relative risk, 0.50; 95% CI, 0.35-0.71), even after adjustment for possible confounders or effect modifiers such as vegetable consumption, sports activity, family history of CRC, body mass index, and the use of lowdose aspirin, statins, vitamin D, or postmenopausal hormones (relative risk, 0.41; 95% CI, 0.25-0.67). Bisphosphonate therapy combined with statin use, however, did not lower the risk for CRC further. Takeaway: Bisphosphonates have been associated with a low risk for breast cancer. Inhibition of angiogenesis and of tumor-cell adhesion and promotion of apoptosis are other antitumor mechanisms that have been suggested for the benefits associated with bisphosphonates. This retrospective study of bisphosphonate therapy for more than 1 year significantly decreased the risk for CRC by 59%. Alendronate was used in almost 95% of patients in the bisphosphonate group. Patient adherence was estimated to be 89% to 96% and depended on the dosing schedule. These data suggest that bisphosphonates should be considered for future cancer prevention studies. Rennert G, et al. J Clin Oncol. 2011;29:1146-1150.

www.JHOPonline.com

June 2011

Vol 1, No 2

1-Cover_Layout 1 6/8/11 1:16 PM Page 39

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

Docetaxel Injection, For intravenous infusion only. Initial U.S. Approval: 1996

• • • •

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinumbased therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

–––––––––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS –––––––––––––––––––––––––––––––––––––––––––––– • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) –––––––––––––––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS –––––––––––––––––––––––––––––––––––––––––– • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ––––––––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS ––––––––––––––––––––––––––––––––––––––––––––––– Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA

Reference EN-2761

1-Cover_Layout 1 6/8/11 1:05 PM Page 40

Single Vial

Docetaxel Injection (10 mg/mL concentration) • Larger 160 mg Multiple Dose Vial • More convenient 80 mg Multiple Dose Vial • Requires NO dilution with a diluent prior to adding to the infusion solution

Clarity of glass

Barrier sheath

Exclusive Onco-Tain™ packaging for safe handling1

PVC reinforced bottom

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention See full prescribing information for complete boxed warning • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy • Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 • Severe fluid retention may occur despite dexamethasone

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

Indications and Usage

Safety Information

Docetaxel Injection is a microtubule inhibitor indicated for: Breast Cancer (BC): single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC

1. Data on file at Hospira P11-3247-8.125x10.875-Apr., 11

only

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See brief Prescribing Information on reverse side.