journal of hematology oncology pharmacy

HEMATOLOGYONCOLOGYPHARMACY™

JOURNAL OFVOL 1 I NO 2

JUNE 2011

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

©2011 Green Hill Healthcare Communications, LLCwww.JHOPonline.com

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

CASE REPORTReversible 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 RESEARCHThe Risk of Neurotoxicity with Concomitant Use of Aprepitant and IfosfamideAnthony 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 MANAGEMENTImplementation of a Pharmacist-Managed Interdisciplinary Oral Chemotherapy Programin a Community Cancer CenterRobert Mancini, PharmD; Lindsay M. Kaster, PharmD; Brian Vu, PharmD; Jessie Modlin, PharmD; David B. Wilson, RPh

From the LiteratureConcise Reviews of Studies Relevant to Hematology Oncology PharmacyRobert J. Ignoffo, PharmD, FASHP, FCSHP

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Nplate® (romiplostim)Brief Summary

WARNINGS AND PRECAUTIONSBone Marrow Reticulin Formation and Risk for BoneMarrow FibrosisNplate® administration increases the risk for development orprogression of reticulin fiber deposition within the bone marrow. Inclinical studies, Nplate® was discontinued in four of the 271patients because of bone marrow reticulin deposition. Six additionalpatients had reticulin observed upon bone marrow biopsy. All10 patients with bone marrow reticulin deposition had receivedNplate® doses ≥ 5 mcg/kg and six received doses ≥ 10 mcg/kg.Progression to marrow fibrosis with cytopenias was not reportedin the controlled clinical studies. In the extension study, one patientwith ITP and hemolytic anemia developed marrow fibrosis withcollagen during Nplate® therapy. Clinical studies have not excludeda risk of bone marrow fibrosis with cytopenias. Prior to initiation ofNplate®, examine the peripheral blood smear closely to establish abaseline level of cellular morphologic abnormalities. Followingidentification of a stable Nplate® dose, examine peripheral bloodsmears and CBCs monthly for new or worsening morphological ab-normalities (eg, teardrop and nucleated red blood cells, immaturewhite blood cells) or cytopenia(s). If the patient develops new orworsening morphological abnormalities or cytopenia(s), discontinuetreatment 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 greaterseverity than was present prior to Nplate® therapy. This worsenedthrombocytopenia may increase the patient’s risk of bleeding,particularly if Nplate® is discontinued while the patient is on anti-coagulants or antiplatelet agents. In clinical studies of patients withchronic ITP who had Nplate® discontinued, four of 57 patientsdeveloped thrombocytopenia of greater severity than was presentprior to Nplate® therapy. This worsened thrombocytopenia resolvedwithin 14 days. Following discontinuation of Nplate®, obtain weeklyCBCs, including platelet counts, for at least 2 weeks and consideralternative treatments for worsening thrombocytopenia, accordingto current treatment guidelines [see Adverse Reactions (6.1)].Thrombotic/Thromboembolic ComplicationsThrombotic/thromboembolic complications may result fromexcessive increases in platelet counts. Excessive doses of Nplate®

or medication errors that result in excessive Nplate® doses mayincrease platelet counts to a level that produces thrombotic/thromboembolic complications. In controlled clinical studies, theincidence of thrombotic/thromboembolic complications was similarbetween Nplate® and placebo. To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attemptto normalize platelet counts. Follow the dose adjustment guidelinesto achieve and maintain a platelet count of ≥ 50 x 109/L [see Dosageand Administration (2.1)].Lack or Loss of Response to Nplate®

Hyporesponsiveness or failure to maintain a platelet response withNplate® should prompt a search for causative factors, includingneutralizing 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 antibodiesto Nplate® and thrombopoietin (TPO). Discontinue Nplate® if theplatelet count does not increase to a level sufficient to avoid clinicallyimportant bleeding after 4 weeks at the highest weekly dose of10 mcg/kg.Malignancies and Progression of MalignanciesNplate® stimulation of the TPO receptor on the surface of hemato-poietic cells may increase the risk for hematologic malignancies.In controlled clinical studies among patients with chronic ITP, theincidence of hematologic malignancy was low and similar betweenNplate® and placebo. In a separate single-arm clinical study of44 patients with myelodysplastic syndrome (MDS), 11 patients werereported as having possible disease progression, among whom fourpatients had confirmation of acute myelogenous leukemia (AML)during follow-up. Nplate® is not indicated for the treatment ofthrombocytopenia due to MDS or any cause of thrombocytopeniaother than chronic ITP.Laboratory MonitoringMonitor CBCs, including platelet counts and peripheral bloodsmears, prior to initiation, throughout, and following discontinuationof Nplate® therapy. Prior to the initiation of Nplate®, examine theperipheral blood differential to establish the baseline extent of redand white blood cell abnormalities. Obtain CBCs, including plateletcounts and peripheral blood smears, weekly during the doseadjustment phase of Nplate® therapy and then monthly followingestablishment of a stable Nplate® dose. Obtain CBCs, includingplatelet counts, weekly for at least 2 weeks following discontinuationof Nplate® [see Dosage and Administration (2.1) and Warnings andPrecautions (5.1, 5.2)].Nplate® Distribution ProgramNplate® is available only through a restricted distribution programcalled Nplate® NEXUS (Network of Experts Understanding and

Supporting Nplate® and Patients) Program. Under the Nplate®

NEXUS Program, only prescribers and patients registered with theprogram are able to prescribe, administer, and receive Nplate®. Thisprogram provides educational materials and a mechanism for theproper use of Nplate®. To enroll in the Nplate® NEXUS Program, call1-877-Nplate1 (1-877-675-2831). Prescribers and patients arerequired to understand the risks of Nplate® therapy. Prescribersare required to understand the information in the prescribinginformation and be able to:

Educate patients on the benefits and risks of treatment withNplate®, ensure that the patient receives the Medication Guide,instruct them to read it, and encourage them to ask questions whenconsidering Nplate®. Patients may be educated by the enrolledprescriber or a healthcare provider under that prescriber’s direction.

Review the Nplate® NEXUS Program Healthcare Provider Enroll-ment Form, sign the form, and return the form according to Nplate®

NEXUS Program instructions.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 signedform in the patient’s medical record, send a copy accordingto Nplate® NEXUS Program instructions, and give a copy tothe patient.

Report any serious adverse events associated with the use ofNplate® to the Nplate® NEXUS Program Call Center at 1-877-Nplate1(1-877-675-2831) or to the FDA’s MedWatch Program at 1-800-FDA-1088.

Report serious adverse events observed in patients receivingNplate®, including events actively solicited at 6-month intervals.

ADVERSE REACTIONSClinical Studies ExperienceSerious adverse reactions associated with Nplate® in clinicalstudies were bone marrow reticulin deposition and worseningthrombocytopenia after Nplate® discontinuation [see Warnings andPrecautions (5.1, 5.2)].The data described below reflect Nplate® exposure to 271 patientswith chronic ITP, aged 18 to 88, of whom 62% were female. Nplate®

was studied in two randomized, placebo-controlled, double-blindstudies that were identical in design, with the exception that Study1 evaluated nonsplenectomized patients with ITP and Study 2 eval-uated splenectomized patients with ITP. Data are also reported froman open-label, single-arm study in which patients received Nplate®

over an extended period of time. Overall, Nplate® was administeredto 114 patients for at least 52 weeks and 53 patients for at least96 weeks.Because clinical studies are conducted under widely varying condi-tions, adverse reaction rates observed in the clinical trials of a drugcannot be directly compared to rates in the clinical trials of anotherdrug and may not reflect the rates observed in practice.In the placebo-controlled studies, headache was the mostcommonly reported adverse drug reaction, occurring in 35% ofpatients receiving Nplate® and 32% of patients receiving placebo.Headaches were usually of mild or moderate severity. Table 2presents adverse drug reactions from Studies 1 and 2 with a ≥ 5%higher patient incidence in Nplate® versus placebo. The majority ofthese adverse drug reactions were mild to moderate in severity.

Table 2. Adverse Drug Reactions Identified inTwo 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 thesingle-arm extension study, the incidence rates of the adversereactions occurred in a pattern similar to those reported in theplacebo-controlled clinical studies.ImmunogenicityAs with all therapeutic proteins, patients may develop antibodies tothe therapeutic protein. Patients were screened for immunogenicityto romiplostim using a BIAcore-based biosensor immunoassay. Thisassay is capable of detecting both high- and low-affinity bindingantibodies that bind to romiplostim and cross-react with TPO. Thesamples from patients that tested positive for binding antibodieswere further evaluated for neutralizing capacity using a cell-basedbioassay.In clinical studies, the incidence of preexisting antibodies toromiplostim was 8% (17/225) and the incidence of binding anti-body development during Nplate® treatment was 10% (23/225). Theincidence of preexisting antibodies to endogenous TPO was 5%(12/225) and the incidence of binding antibody development toendogenous 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 nonehad neutralizing activity to TPO. No correlation was observedbetween antibody activity and clinical effectiveness or safety.Immunogenicity assay results are highly dependent on thesensitivity and specificity of the assay used in detection and maybe influenced by several factors, including sample handling,concomitant medications, and underlying disease. For thesereasons, comparison of incidence of antibodies to romiplostim withthe incidence of antibodies to other products may be misleading.

DRUG INTERACTIONSNo formal drug interaction studies of Nplate® have been performed.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Nplate® usein pregnant women. In animal reproduction and developmentaltoxicity studies, romiplostim crossed the placenta, and adversefetal effects included thrombocytosis, postimplantation loss, and anincrease in pup mortality. Nplate® should be used during pregnancyonly if the potential benefit to the mother justifies the potential riskto the fetus.Pregnancy Registry: A pregnancy registry has been establishedto collect information about the effects of Nplate® use duringpregnancy. 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 fetalharm was observed at romiplostim doses up to 11 times (rats) and82 times (rabbit) the maximum human dose (MHD) based onsystemic exposure. In mice at doses 5 times the MHD, reductionsin maternal body weight and increased postimplantation lossoccurred. In a prenatal and postnatal development study in rats, atdoses 11 times the MHD, there was an increase in perinatal pupmortality. Romiplostim crossed the placental barrier in rats and in-creased fetal platelet counts at clinically equivalent and higher doses.Nursing MothersIt is not known whether Nplate® is excreted in human milk;however, human IgG is excreted in human milk. Published datasuggest that breast milk antibodies do not enter the neonatal andinfant circulation in substantial amounts. Because many drugs areexcreted in human milk and because of the potential for seriousadverse reactions in nursing infants from Nplate®, a decision shouldbe made whether to discontinue nursing or to discontinue Nplate®,taking into account the importance of Nplate® to the mother and theknown benefits of nursing.Pediatric UseThe safety and effectiveness in pediatric patients (< 18 years) havenot been established.Geriatric UseOf the 271 patients who received Nplate® in ITP clinical studies,55 (20%) were age 65 and over, and 27 (10%) were 75 and over. Nooverall differences in safety or efficacy have been observed betweenolder and younger patients in the placebo-controlled studies, butgreater sensitivity of some older individuals cannot be ruled out. Ingeneral, dose adjustment for an elderly patient should be cautious,reflecting the greater frequency of decreased hepatic, renal, orcardiac function, and of concomitant disease or other drug therapy.Renal ImpairmentNo clinical studies were conducted in patients with renalimpairment. Use Nplate® with caution in this population.Hepatic ImpairmentNo clinical studies were conducted in patients with hepaticimpairment. Use Nplate® with caution in this population.

OVERDOSAGEIn the event of overdose, platelet counts may increase excessivelyand result in thrombotic/thromboembolic complications. In thiscase, discontinue Nplate® and monitor platelet counts. Reinitiatetreatment with Nplate® in accordance with dosing and administra-tion recommendations [see Dosage and Administration (2.2)].

Rx Only. This brief summary is based on Nplate® prescribinginformation v. 1

Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, California 91320-1799

This product, its production, and/or its use may be covered by oneor more U.S. Patents, including U.S. Patent Nos. 6,835,809 and7,189,827, as well as other patents or patents pending.

© 2008 Amgen Inc. All rights reserved.www.Nplate.com <http://www.Nplate.com>1-877-Nplate1 (1-877-675-2831)

v1

MC46933-A-1

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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 otherthan 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.

Individual results will vary

Outpacing platelet destruction.Sustained response over time.1-3

Live rep support. E-learning. Patient resources.

Visit www.NplateHCP.com/Bvisit

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EDITORIAL BOARD

4 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com June 2011 l Vol 1, No 2

CLINICAL CONTROVERSIESChristopher Fausel, PharmD, BCPS, BCOP Clinical DirectorOncology Pharmacy ServicesIndiana University Simon Cancer CenterIndianapolis, IN

FROM THE LITERATURERobert J. Ignoffo, PharmD, FASHP, FCSHPProfessor of Pharmacy, College of Pharmacy, Touro University–California Atlanta, GA

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of PharmacyComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

ORIGINAL RESEARCH Gary C. Yee, PharmD, FCCP, BCOP Professor, Departmentof Pharmacy PracticeCollege of PharmacyUniversity of Nebraska Medical CenterOmaha, NE

REVIEW ARTICLESR. Donald Harvey, PharmD, FCCP, BCPS, BCOPAssistant Professor of Hematology/Medical OncologyDept of Hematology/Medical OncologyDirector, Phase 1 ProgramWinship Cancer InstituteEmory UniversityAtlanta, GA

Patrick J. Medina, PharmD, BCOPAssociate ProfessorDept of PharmacyUniversity of Oklahoma College of PharmacyOklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCPAssociate Professor, Pharmacy Program Director, PGY2 Specialty ResidencyHematology/OncologyUniversity of Kentucky College of PharmacyLexington, KY

SECTION EDITORS

CO-EDITORS-IN-CHIEF

Sandra Cueller, PharmD, BCOPDirectorOncology Specialty ResidencyUniversity of Illinois at Chicago Medical CenterChicago, IL

Sachin Shah, PharmD, BCOPAssociate ProfessorTexas Tech University Health Sciences CenterDallas, TX

Scott Soefje, PharmD, BCOP DirectorPharmacy OperationsUniversity of Texas Health Science Center at San Antonio, TX

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy PracticeSamford University McWhorter School of PharmacyBirmingham, AL

John M. Valgus, PharmD, BCOPHematology/Oncology Senior Clinical PharmacySpecialistUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Daisy Yang, PharmD, BCOP Clinical Pharmacy SpecialistUniversity of Texas M. D. Anderson Cancer CenterHouston, TX

EDITORS-AT-LARGE

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Senior Vice President, Sales & MarketingPhilip Pawelko

[email protected]

PublisherJohn W. Hennessy

[email protected]

Editorial DirectorDalia Buffery

[email protected]

Associate EditorsBrett Kaplan

[email protected] Reiman

[email protected]

Directors, Client ServicesJoe Chanley

[email protected] Iannaccone

[email protected]

Production ManagerStephanie Laudien

Quality Control DirectorBarbara Marino

Business ManagerBlanche Marchitto

[email protected]

Executive AdministratorAndrea Boylston

Circulation [email protected]

Editorial Contact:Telephone: 732-992-1892

Fax: 732-656-7938E-mail: [email protected]

TABLE OF CONTENTS

JUNE 2011 VOLUME 1, NUMBER 2

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 ofHematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Com munications, LLC. No part of this publication may be reproduced or transmitted in any form or by anymeans 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, NJ08831. E-mail: JHOP@greenhillhc. com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders willbe 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 publishedin this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Commun i cations, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ08831. 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. Publicationof 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 areencouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibilityfor 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 lit-erature 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 contraindi-cations. 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 thebest 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.

PERSPECTIVE8 Ipilimumab: A New Era in Metastatic Melanoma Management

Timothy G. Tyler, PharmD, FCSHP

CASE REPORT10 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 RESEARCH16 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 MANAGEMENT23 Implementation of a Pharmacist-Managed Interdisciplinary Oral Chemotherapy

Program in a Community Cancer CenterRobert Mancini, PharmD; Lindsay M. Kaster, PharmD; Brian Vu, PharmD; Jessie Modlin, PharmD; David B. Wilson, RPh

FROM THE LITERATURE35 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor, Clinical ProfessorEmeritus, UCSF, Professor of Pharmacy, College of Pharmacy, Touro University –California, Mare Island Vallejo

PUBLISHING STAFF

MISSION STATEMENTThe Journal of Hematology OncologyPharmacy is an independent, peer-reviewed journal founded in 2011 to pro-vide hematology and oncology pharmacypractitioners and other healthcare pro-fessionals with high-quality peer-reviewed information relevant to hemato-logic and oncologic conditions to helpthem optimize drug therapy for patients.

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PERSPECTIVE


The development of ipilimumab (Yervoy) and itsapproval by the US Food and Drug Admin -istration (FDA) in March 2011 have opened a

new era in the treatment and management of patientswith metastatic melanoma. The continued innovationin cancer drug development has been focused on a dif-ferent mechanism of action that engages the patient’sown immune system in attacking malignancy in contrastto the more traditional myelosuppressive drugs that havebeen used in the past half century to kill rapidly dividingcancer cells.

The hallmark of successful therapy for melanoma hasalways been surgical excision. Although curative, thismethod does not necessarily reduce the likelihood ofrecurrence. To minimize this potentially lethal risk,interferon therapy has historically been instituted,administered as 1 month of induction therapy, followedby 11 months of injections; however, this is an intenseregimen for patients, who therefore benefit from a mul-tidisciplinary approach to treatment that can includepharmacy management of symptoms. Even then, thedisease can recur and progress. As a result, bioim-munotherapy, a rudimentary type of immunotherapy,was developed in the late 1990s.1 Like interferon ther-apy, however, bioimmunotherapy is intense and neces-sitates hospital services, sometimes including the inten-sive care unit.

Despite these efforts, melanoma all too often stillclaims a large number of lives. Although the cure rate ishigh for patients whose disease is detected early and sur-gically resected, the 5-year survival rate is fairly low forthose with disease that has metastasized—less than 15%according to the 2010 data from the American CancerSociety.2 In the United States alone, just under 70,000new cases of melanoma were diagnosed in 2010, and8700 deaths occurred, mostly from advanced or meta -static disease.3

For some time now, researchers have focused on thedevelopment of immune stimulants and vaccinesdesigned to enlist a patient’s immune system to attackcancer cells, culminating with the March 25, 2011, FDAapproval of ipilimumab—the first T-cell–mediated ther-

apy for unresectable or metastatic melaonoma.4 Thisdrug is a monoclonal antibody that binds CTLA-4 (cyto-toxic T-lymphocyte antigen 4), thereby blocking itsinteraction with the ligands CD80/CD86. This appearsto result in T-cell overproduction, which in turn stimu-lates an activated immune response.4

My professional experience with 5 patients provides aunique perspective for those who have not yet treatedany patient with this novel medication. My center is amultidisciplinary center involved in a robust clinical tri-als program that includes active pharmacist participationin symptom management. In one of these trials, 3 of ourpatients were treated with ipilimumab before the FDAapproval of the drug; in addition, 1 patient was in theexpanded access program created by Bristol-MyersSquibb (BMS), while awaiting final FDA approval forthe drug, and 1 patient had just begun to receive it onApril 11, 2011, the day ipilimumab became commercial-ly available.

Our experience with these 5 patients shows that thedrug indeed has a novel mechanism of action and it quitesimply “revs up” the immune system, and then standsback. There have been many previous attempts to devel-op vaccines and other products to stimulate the immunesystem in patients with melanoma by killing themelanoma-affected cells, but ipilimumab is the first prod-uct to receive FDA approval.

Although the activity of ipilimumab is impressive, itis also associated with a wide range of potential toxici-ties, which can manifest in almost any system in thebody, including gastrointestinal, liver, skin, neurologic,and endocrine toxicities that are highlighted in the riskevaluation and mitigation strategy (REMS) for thisagent. There is currently no way to predict the focus ofany of the immune system’s responses.

What is predictable is the response to ipilimumab ther-apy, which is associated with a 34% risk of death.5 Unliketraditional chemotherapy, the goal with ipilimumab is notto deliver as much drug as possible but rather to stimulatethe immune system properly—only 4 doses maximum canbe given, according to the FDA approval.4

Also noteworthy is the agent’s cost, which has capturedmuch media attention. The price is in the same range asthe prostate cancer drug sipuleucel-T (Provenge). Bothdrugs have a limited number of cycles (3 administrationsfor sipuleucel-T and 4 for ipilimumab).

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

Dr Tyler is Director of Pharmacy Services, ComprehensiveCancer Center, Desert Regional Medical Center, PalmSprings, California.

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PERSPECTIVE

www.JHOPonline.com l Journal of Hematology Oncology Pharmacy lVol 1, No 2 l June 2011

Ipilimumab will be distributed only through thewholesaler McKesson and the distributor OncologySupply. Because ipilimumab is approved with a REMS pro-

gram, BMS has designed a comprehensive plan thatemploys sales and medical science liaisons in coordinat-ed teams to ensure clinicians are properly educated aboutthe risks and benefits of the drug. The REMS programalso includes a medication guide for patients. At its cen-ter is a wallet card that a patient carries to alert anypotential urgent care and emergency department physi-cians to the possibility of immune-related toxicity andthe resultant need for steroids. The copious and early useof steroids has been found to ameliorate many toxicity-related problems, because the toxic effects in this case arenot from myelosuppressive chemotherapy but ratherfrom stimulated T lymphoctes. In addition, BMS has initiated a surveillance and

peer-to-peer education program in which medical serviceliaisons will contact clinicians within a very tight win-dow of a few days after receiving a new order for ipili-mumab, to provide educational services and follow-up. As the Pharmacy Practice Editor of the Journal of

Hematology Oncology Pharmacy, I urge those not experi-enced with this novel agent to accept any offer of educa-tion or assistance regarding its use. Despite the associat-ed risks involved, this new therapy offers benefits beyondthe standard myelosuppressive agents or monoclonalantibody drugs that we have become accustomed to inthe past decade and a half, when these therapies prolif-erated on the oncology scene. It is certainly not my wish to deter clinicians from

using this drug, but it does involve many occasions forerrors, including the aggressive use of corticosteroids asthe primary response to almost any toxicity—which iscounterintuitive for many clinicians. Getting the appro-priate education about the use of this drug is thereforecrucial for preventing adverse outcomes and potentially

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

The FDA has been criticized for having approved thefewest number of new drugs in decades, but the approvalof ipilimumab offers a novel agent with promising thera-peutic outcomes in an area of oncology that has had fewworthwhile choices. �

Author Disclosure StatementDr Tyler is on the Speakers’ Bureau of Bristol-Myers Squibb

and Eisai Pharmaceuticals.

References1. Elsevier/Gold Standard Clinical Pharmacology website. Aldesleukin FDAapproval date for MM. http://www.clinicalpharmacology-ip.com/Forms/Monograph/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. AccessedMay 21, 2011. 3. National Cancer Institute. General information about melanoma. http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page1#Reference1.1. 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 over-all survival benefit. http://www.yervoy.com/hcp/phase-3-study/efficacy-study-safety.aspx. Accessed June 2, 2011.

Despite the associated risks involved, thisnew therapy offers benefits beyond thestandard myelosuppressive agents ormonoclonal antibody drugs that we havebecome accustomed to in the past decadeand a half, when these therapiesproliferated on the oncology scene.

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CASE REPORT


Bevacizumab is a recombinant humanized mono-clonal antibody that binds to vascular endothe-lial growth factor (VEGF)-A, inhibiting the

activation of its receptors (FLT1 and KDR) on the sur-face of endothelial cells.1 This inhibition prevents theinitiation of angiogenesis, which contributes to tumorgrowth and proliferation by providing a blood supplyfor malignant cells.2 Bevacizumab is US Food andDrug Ad ministration approved for colorectal cancer,non–small-cell lung cancer (NSCLC), HER-2–nega-tive breast cancer, glioblastoma, and renal-cell cancer.Some of the common adverse reactions of bevacizum-ab include hypertension, epistaxis, headache, rhinitis,stomatitis, asthenia, proteinuria, taste alteration, dryskin, rectal hemorrhage, back pain, and exfoliativedermatitis.1Reversible posterior leukoencephalopathy syndrome

(RPLS) is a rare adverse event reported with the use ofbevacizumab. In clinical studies, the incidence has beenless than 0.1% and the onset of symptoms has occurred

from 16 hours to 1 year after initiation.1 This clinical-radiologic syndrome is characterized by headache,seizures, altered consciousness, visual disturbancesincluding cortical blindness, and radiographic abnormal-ities suggesting subcortical white matter edema of theposterior hemispheres.3-6Some of the risk factors associated with the incidence

of RPLS include acute elevations of blood pressure (suchas eclampsia), fluid overload, renal failure, and exposureto immunosuppressants, colony-stimulating factors, orcytotoxic drug therapy.2-5 Because there was some dis-agreement on whether the syndrome always represented aleukoencephalopathy, Casey and colleagues proposed theterm “posterior reversible encephalopathy syndrome” in2000.7 The term “hyperperfusion encephalopathy” hasalso been suggested, because the condition is not alwaysreversible.8This present case describes the presence of RPLS in a

patient with NSCLC who developed the symptomshours after undergoing monotherapy with bevacizumab.

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

Reversible Posterior LeukoencephalopathySyndrome Secondary to Bevacizumab: ACase ReportDiana Pinto, PharmD; William Kernan, PharmD, BCPS; James Hoffman, MD; Mohammed Ibrahim, PharmD, CRPH, BCOP, BCPS; Bruno Bastos, MD

This case report presents a case of a 77-year-old patient with stage IV non–small-cell lung carci-noma who developed reversible posterior leukoencephalopathy syndrome along with a hyper-tensive crisis after treatment with bevacizumab. Reversible posterior leukoencephalopathy syn-drome is a clinical-radiologic syndrome rarely seen in association with bevacizumab use. Thesyndrome manifests with symptoms such as headache, seizures, altered consciousness, andvisual disturbances. The typical imaging finding consists of subcortical white matter edema involv-ing the posterior circulation. The patient was being treated with bevacizumab monotherapy at adose of 15 mg/kg every 3 weeks. He presented with altered mental status and hypertensionhours after the completion of a bevacizumab infusion. Proteinuria and visual disturbances werealso associated with the event. The magnetic resonance imaging demonstrated widespreadhyperintense signals in the occipital white matter. The patient was managed with supportive careand blood pressure control. Most of his symptoms resolved during admission, except for the visu-al disturbances that required longer rehabilitation. The presence of hypertension and worseningof proteinuria may suggest endothelial damage as bevacizumab’s mechanism for the neurologictoxicity. A recurrent episode occurred 14 months after the discontinuation of bevacizumab.

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

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Reversible Posterior Leukoencephalopathy Syndrome

11www.JHOPonline.com l Journal of Hematology Oncology Pharmacy lVol 1, No 2 l June 2011

Case ReportA 77-year-old man presented to the outpatient oncol-

ogy clinic to receive maintenance chemotherapy withbevacizumab for the treatment of stage IV NSCLC,which had been diagnosed 4 years prior. He had beeninitially treated with left upper lobe lobectomy, butbecause of recurrent metastatic disease found 2 yearspostsurgery, he received chemotherapy with bevacizu -mab, carboplatin, and paclitaxel for a period of 6months. Because there was residual lung disease afterchemotherapy, he was included in a phase 2 clinical trialusing concurrent sunitinib and electron beam radiationtherapy to the chest (5000 cGy). After completion ofthis protocol, he initiated bevacizumab monotherapyevery 3 weeks for approximately 17 months. His medicalhistory was also significant for hypothyroidism, dyslipi-demia, hypertension, atrial fibrillation, and proteinuriasecondary to the chronic use of bevacizumab. His homemedications included nifedipine 25 mg daily, levothy-roxine 125 mcg daily, niacin 500 mg daily, and warfarinwith a total weekly dose of 25 mg.

On examination at the clinic visit, his vital signs werenormal (blood pressure, 122/60 mm Hg; pulse, 50 bpm;temperature, 97.3°F [36.3°C]) and his only complaintwas fatigue. The laboratory examinations were normal,except for an increase in his liver enzymes comparedwith our laboratory tests taken 7 days earlier (alkalinephosphatase increased from 88 U/L to 325 U/L, alanineaminotransferase [ALT] increased from 13 U/L to 93U/L, and aspartate aminotransferase [AST] increasedfrom 21 U/L to 45 U/L). The patient received 1165 mg(15 mg/kg, patient’s weight, 77.7 kg) of bevacizumab in100 mL of normal saline which was infused over a peri-od of 30 minutes. Before the infusion, he received 25 mgof diphenhydramine intravenously as premedication and1000 mL of normal saline for hydration.

Twenty-four hours after the infusion of bevacizumab,the patient presented with disorientation along with dif-ficulty of ambulation. The movement of all 4 extremitieswas not affected and no acute changes in vision, speech,facial expressions, or facial symmetry were noted. He wasbrought to the emergency department, where he wasfound to be hypertensive (221/73 mm Hg), his mentalstatus was altered, and he was experiencing lightheaded-ness and decreased responsiveness. His first electrocar-diogram showed marked sinus bradycardia, with a ven-tricular rate of 44 bpm. The results of the laboratory testsconducted on admission were within normal limits,except for the consistent elevation of alkaline phos-phatase and ALT (290 U/L and 69 U/L, respectively).His blood pressure was initially managed withhydralazine 10 mg intravenous (IV) and subsequentlywith a nitroglycerin drip.

A computed tomography scan of the brain was per-formed, revealing cerebral atrophy and attenuationzones in the parietal lobes, temporal occipital lobes, andthe right cerebellum, without significant masses. Thedifferential diagnosis included underlying edema frommetastatic disease (although the absence of a mass madethis possibility unlikely), periventricular leukomalaciafrom underlying small vessel disease, or hypertensiveencephalopathy. However, the brain magnetic reso-nance imaging (MRI) obtained after admission demon-strated radiologic findings suggestive of RPLS.

There were large areas of abnormal fluid-attenuatedinversion recovery (FLAIR) signals involving the bilat-eral posterior parietal, occipital, and cerebellar hemi-spheres primarily involving the white matter. Some graymatter involvement was also identified. Cerebellarhemisphere lesions and areas of cortical enhancementseen within the left posterior parietal lobe and rightoccipital lobe were found suspicious for acute infarct,and no evidence of metastatic disease was observed(Figure).

A neurologic examination during the patient’s secondday of admission revealed diplopia, presence of bilateral

Fluid-Attenuated Inversion Recovery MagneticResonance Image Showing Bilateral HyperintenseSignals in Occipital White Matter

Figure

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

Babinski’s reflex, and possible right pronator drift. A uri-nalysis revealed worsening of proteinuria (500 mg/dLfrom a baseline of 182 mg/dL 1 month prior). His bloodpressure remained controlled with amlodipine 10 mgdaily, oral hydralazine 10 mg twice daily, and metoprolol5 mg IV as needed. His mental status improved slightly,but he still appeared confused.

Examination on day 5 of hospitalization showed thathis mental status had significantly improved, and he wasawake and interactive. However, his vision was diffuselyblurred on both eyes, and his reflexes were diminishedbilaterally. His laboratory values remained stable duringhis hospital stay. The changes in his liver function testsimproved. An abdominal ultrasound revealed that thesechanges were secondary to cholelithiasis. After dis-charge, the patient had gradual improvement of diplop-ia but continued to have difficulty reading words.

Bevacizumab’s treatment was discontinued, andmaintenance therapy was initiated with pemetrexedevery 21 days. Fourteen months after the initial episode,the patient presented with similar symptoms, includingaltered mental status, left-sided flank pain, lethargy,visual hallucinations, bilateral blindness, and hyperten-sion (218/95 mm Hg).

His only new medication besides pemetrexed wasmetoprolol 12.5 mg daily in place of nifedipine, andaccording to his family, his systolic home blood pressurereadings were usually between 100 mm Hg and 110 mmHg. Neurologic examination on admission was remark-able for altered mental status consistent withencephalopathy and bilateral cortical blindness.

A repeat MRI was performed showing areas of abnor-mal white matter FLAIR signals in the bilateral posteri-or parietal, occipital, and cerebellar hemispheres thatwere slightly improved when compared with the MRIperformed during the first episode. Encephalomalaciainvolving the bilateral occipital lobes that were thoughtto represent laminar necrosis from remote infarcts wereobserved. No evidence of acute infarct, mass, or hemor-rhage was identified.

The patient’s laboratory tests were significant for ele-vated liver and pancreatic enzymes (alkaline phos-phatase, 262 U/L; total bilirubin, 10.7 mg/dL; AST, 176U/L; ALT, 222 U/L; amylase, 242; lipase, 205), and hisurinalysis was negative for proteinuria. The results of anendoscopic retrograde cholangiopancreatography werenormal. The management consisted of IV and oral anti-hypertensive medications, as well as broad-spectrumantibiotics because of the presence of bacteremia.

DiscussionThis report describes a case of possible RPLS in a

patient receiving maintenance therapy with bevacizu -mab. He developed some of the typical manifestations,including decreased levels of consciousness, confusion,and visual disturbances.4 The findings in his MRI wereconsistent with the characteristic radiographic changesof RPLS described in previous reports, indicating whitematter involvement and bilateral abnormal FLAIR sig-nals in the posterior circulation areas, especially the pari-etal and occipital lobes.4,7 The observed gray matterinvolvement and cerebellar neuroimaging abnormalitieshave also been reported but are considered atypical fea-tures of RPLS.3,4,9

Resolution of the clinical symptoms was observedwithin the 6 days of hospitalization, except for the visu-al disturbances, which required longer rehabilitation.This is consistent with the time to recovery previouslypublished, which suggests a range of several days toweeks for the resolution of both clinical and MRI mani-festations.3-5,9 The intracranial findings in the repeatedneuroimaging study revealed that the radiologic lesionswere not fully reversible.

Other RPLS cases have reported the presence of irre-versible damage and the need of extended periods oftime (up to 17 months) for a complete resolution of theinitial findings.3,4,7-9 Residual infarcts have also been pre-viously observed, but the improvement or resolutionduring follow-up studies suggested that the abnormalitieswere secondary to edema, and for other cases it wasunknown whether the findings represented preexistingischemia.4,9

Different explanations have been proposed to under-stand the pathophysiology of RPLS. One theory associ-ates RPLS with a failure in the cerebral autoregulation tomaintain a constant cerebral blood flow, regardless ofchanges in systemic blood pressure through the constric-tion and dilation of the arterioles. According to thishypothesis, spontaneous and severe elevations in bloodpressure are not compensated, and the constricted arte-rioles dilate leading to brain hyperperfusion. Theincreased perfusion can result in the breakdown of theblood-brain barrier, which leads to extravasation of fluid,

CASE REPORT


Different explanations have been proposedto understand the pathophysiology ofRPLS. One theory associates RPLS with afailure in the cerebral autoregulation tomaintain a constant cerebral blood flow,regardless of changes in systemic bloodpressure through the constriction anddilation of the arterioles.


Reversible Posterior Leukoencephalopathy Syndrome


macromolecules, and red blood cells into the brainparenchyma.4,5,7

A second theory involving endothelial damage isoften associated with drug-induced RPLS. This mecha-nism, although not clearly understood, can alter the vas-cular permeability of the blood-brain barrier and the sys-temic blood pressure, decreasing the threshold for thedevelopment of RPLS.3,5 The pathogenesis of RPLS sec-ondary to bevacizumab appears to be related to those 2theories, because bevacizumab not only has the abilityto cause rapid elevations of blood pressure, but also caus-es VEGF alterations that may increase cerebral vascularpermeability.2,3,5

Vascular endothelial dysfunction also appears to bethe mechanism by which bevacizumab causes protein-uria and hypertension. A study comparing the amnioticfluid of healthy, diabetic, and preeclamptic women con-cluded that preeclampsia, a condition characterized byhypertension and proteinuria, was associated withincreased levels of soluble FLT1 suggesting endothelialcell alterations.10 A different study conducted in miceindicated that IV infusion of anti-VEGF–neutralizingantibodies caused rapid glomerular endothelial celldetachment and hypertrophy, inducing the develop-ment of proteinuria.11 Similarly, 2 articles describing themanagement of bevacizumab’s toxicities affirmed thatthe binding inhibition of VEGF-A to VEGF-R impairsprotein homeostasis by altering the permeability, devel-opment, and function of the glomerular vascularendothelium and the renal filtration system.2,6

After a review of current evidence, the Cardio -vascular Toxicities Panel from the National CancerInstitute (NCI) concluded that the elevations in bloodpressure caused by VEGF signaling pathway inhibitorswere a result of increased peripheral resistance second-ary to endothelial damage and decreased nitric oxideproduction.12

Using the Naranjo algorithm, the likelihood that theRPLS in the patient described in this report was causedby bevacizumab was estimated as probable, because thecalculated score was 6. The acute elevation of bloodpressure (221/73 mm Hg in the emergency departmentfrom 122/60 mm Hg before bevacizumab’s infusion) andthe worsening of proteinuria (500 mg/dL from a baselineof 182 mg/dL 1 month earlier) suggest the incidence ofendothelial cell dysfunction secondary to bevacizumab’santi-VEGF activity, which, as described, may explainthe development of RPLS.

Hypertension and proteinuria were present in anoth-er case of RPLS in a patient receiving chemotherapywith FOLFIRI (leucovorin, fluorouracil, irinotecan)plus bevacizumab, in which systemic endothelial celldysfunction was also suspected.13 This case was included

in a MEDLINE search that identified 24 cases of RPLSin patients treated with anticancer drugs. Five of thesecases (21%) were associated with the use of bevacizu -mab and similar to our patient; all these patients receiv-ing bevacizumab presented with elevations of bloodpressure (systolic blood pressure range, 140-190 mmHg), and the majority of them were managed witheither oral or IV antihypertensive medications.3,13-17

Because systemic hypertension predisposes to thedevelopment of RPLS, Tam and colleagues have con-cluded that patients with cancer who have significantfluid overload, mean blood pressure more than 25% ofbaseline, and/or creatinine greater than 0.16 mmol/Lare at high risk for the development of this syndrome.18Similarly, Koopman and colleagues have recommendedstrict blood pressure control to prevent RPLS in patientsundergoing therapy with bevacizumab and have sug-gested to withhold treatment when blood pressurereaches grade 2 severity or more based on the NCICommon Toxicity Criteria.19

In fact, the association between unmanaged hyper-tension and serious adverse events from endothelialgrowth factor signaling pathway inhibitors was one ofthe reasons the Investigational Drug SteeringCommittee of the NCI recently published the followingrecommendations for the management of blood pressurein patients receiving this type of chemotherapy agent12:

• Assess for potential cardiovascular complicationsbefore initiation of treatment, identify and addresspreexisting hypertension before initiation of therapy

• Monitor blood pressure weekly during the firstcycle and at least every 2 to 3 weeks throughouttreatment, set a blood pressure goal of <140/90 mmHg or lower based on patients’ comorbidities

• Aggressively manage emergent hypertension toprevent the development of complications.

In addition to hypertension, different reviews of caseshave identified other common features that may explainthe increased incidence of RPLS. It appears to developmore often in females, and it has been found in patientsas young as 12 years of age.3,9,20 The most common asso-ciated malignancies identified by Marinella and Marketinclude lymphoma, colorectal cancer, and lung cancer.3However, the authors conclude that because of thediversity of underlying malignancies, it is uncertainwhether the biology of the tumor has a causal rela-

Vascular endothelial dysfunction alsoappears to be the mechanism by whichbevacizumab causes proteinuria andhypertension.


tionship; they have found a better correlation with theuse of polychemotherapy and the emergence of newcytotoxic agents.3Similarly, Vaughn and colleagues have suggested that

the increased incidence of RPLS cases in patients withcancer was probably secondary to the toxic effects of mostmajor classes of chemotherapy in the vascular endotheli-um.5 It is undetermined whether the use of the otherchemotherapy agents might have put our patient at anincreased risk for the development of this adverse event.Sunitinib has demonstrated anti-VEGF activity, it can

cause hypertension similar to bevacizumab, and it hasbeen previously related to this syndrome.21 Another casealso reported the development of RPLS in a patientreceiving chemotherapy with pemetrexed and cisplatin,but the authors hypothesized that it was not related topemetrexed but rather to the extended use of dexametha-sone and cisplatin.22 Cases of recurrent RPLS have beenpreviously reported and include acute blood pressure ele-vations as a common finding.9,18,23

ConclusionIn this report we describe a case of a patient with

NSCLC who presented with clinical features and neuro -imaging findings suggestive of RPLS after the infusion ofbevacizumab. Although resolution of most of the clinicalsymptoms was observed within days, a repeat episodeoccurred 14 months later. The presence of hypertensivecrisis and worsening of proteinuria on the first presenta-tion suggests anti-VEGF–mediated endothelial dysfunc-tion as the mechanism for the development of RPLS.Strict blood pressure control appears to be essential for theprevention of this syndrome, but sudden elevations maybe difficult to anticipate. Further research for understand-ing the mechanism for bevacizumab’s neurologic toxicityand potential prevention measures for its developmentand recurrence is warranted. �

Author Disclosure StatementDrs Pinto, Kernan, Hoffman, Ibrahim, and Bastos

have reported no actual or potential conflicts of interest.

References1. Avastin (bevacizumab) [package insert]. San Francisco, CA: Genentech, Inc;2010.2. Shord SS, Bressler LR, Tierney LA, et al. Understanding and managing the pos-sible adverse effects associated with bevacizumab. Am J Health Syst Pharm.2009;66:999-1013.3. Marinella MA, Markert RJ. Reversible posterior leucoencephalopathy syn-drome associated with anticancer drugs. Int Med J. 2009;39:826-834.4. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoen-cephalopathy syndrome. N Engl J Med. 1996;334:494-500.5. Vaughn C, Zhang L, Schiff D. Reversible posterior leukoencephalopathy syn-drome in cancer. Curr Oncol Rep. 2008;10:86-91.6. Gressett SM, Shah SR. Intricacies of bevacizumab induced toxicities and theirmanagement. Ann Pharmacother. 2009;43:490-501.7. Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible encephalopa-thy syndrome: utility of fluid-attenuated inversion recovery MR imaging in thedetection of cortical and subcortical lesions. AJNR Am J Neuroradiol. 2000;21:1199-1206.8. Schwartz RB. A reversible posterior leukoencephalopathy syndrome. N Engl JMed. 1996;334:1743.9. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversibleposterior leukoencephalopathy syndrome. Arch Neurol. 2008;65:205-210. 10. Vuorela P, Helske S, Hornig C, et al. Amniotic fluid—soluble vascular endo -thelial growth factor receptor-1 in preeclampsia. Obstet Gynecol. 2000;95:353-357. 11. Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vas-cular endothelial growth factor (VEGF) by anti-VEGF antibodies and solubleVEGF 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, andmanagement of blood pressure in patients receiving vascular endothelial growthfactor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102:596-604.13. Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopa-thy 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 syn-drome and bevacizumab. N Engl J Med. 2006;354:981-982. 15. El Maalouf G, Mitry E, Lacout A, et al. Isolated brainstem involvement in pos-terior leukoencephalopathy induced by bevacizumab. J Neurol. 2008;255:295-296.16. Peter S, Hausmann N, Schuster A, Bohem HF. Reversible posterior leuko -encephalopathy syndrome and intravenous bevacizumab. Clin ExperimentOphthalmol. 2008;36:94-96.17. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syn-drome and bevacizumab. N Engl J Med. 2006;354:980-981.18. Tam CS, Galanos J, Seymour JF, et al. Reversible posterior leukoencephalopa-thy syndrome complicating cytotoxic chemotherapy for hematologic malignan-cies. Am J Hematol. 2004;77:72-76. 19. Koopman M, Muller EW, Punt CJ. Reversible posterior leukoencephalopathysyndrome 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 leukoen-cephalopathy induced by cancer chemotherapy. Pediatr Neurol. 2010;43:197-201.21. Martin G, Bellido L, Cruz JJ. Reversible posterior leukoencephalopathy syn-drome induced by sunitinib. J Clin Oncol. 2007;25:3559.22. Nguyen MT, Virk IY, Villano JL. Extended use of dexamethasone-associatedposterior 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 reversibleencephalopathy syndrome (PRES). J Hum Hypertens. 2004;18:287-289.

CASE REPORT



ORIGINAL RESEARCH


Structurally related to cyclophosphamide, ifos-famide is an alkylating chemotherapeutic agentused to treat a variety of solid tumors and hemato-

logic malignancies.1 Ifosfamide is a prodrug that is metab-olized by the cytochrome P450 3A4 (CYP3A4) enzyme toits active (ifosfamide mustard and 4-hydroxy-ifosfamide)

and neurotoxic metabolites. Neurotoxicity is a well-known adverse effect of ifosfamide occurring in up to60% of patients.2

The signs and symptoms of neurotoxicity may includeconfusion, drowsiness, seizures, blurred vision, auditoryor visual paranoid hallucinations, extrapyramidal symp-

Dr Jarkowski is Clinical Pharmacy Specialist, Department of Pharmacy; Dr Miller is Assistant Professor of Biostatistics andOncology, 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, LosAngeles, Cailfornia. This manuscript was presented as an oral abstract presentation in Salt Lake City, UT, at the 7thHematology/Oncology Pharmacy Association 2011 Annual Conference.

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

Background: Ifosfamide-based chemotherapy is the standard of care for treatment of soft-tissue sarcomas. Previous studies have shown an increased risk for ifosfamide neurotoxici-ty among patients with low albumin levels, but the association between aprepitant use andthe risk of neurotoxicity in patients receiving ifosfamide-based chemotherapy is still unknownand controversial.Objective: The primary objective was to determine whether concomitant aprepitant was asso-ciated with an increased risk of neurotoxicity in patients with sarcoma receiving high-dose ifos-famide-based chemotherapy. Other variables associated with ifosfamide-induced neurotoxici-ty were also assessed. Method: This retrospective cohort analysis was conducted over a 54-month period betweenJanuary 2005 and July 2009 in 65 patients with sarcoma receiving ifosfamide-based chemother-apy. Wilcoxon rank sum and Pearson chi square tests were used to assess statistical significancein univariate associations with aprepitant use. The probability of aprepitant use or neurotoxicitywas assessed using multivariable logistic regression analyses. Results: Sixty-five patients (mean age, 41.6 years; standard deviation, 2.5) received a total of 308cycles of ifosfamide-based chemotherapy. Twenty-nine (45%) patients received aprepitant duringifosfamide-based chemotherapy. Sixteen (25%) patients had a documented neurotoxic eventduring ifosfamide chemotherapy, as documented by the attending physician. Of the 222 cycleswithout 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 analy-ses, 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 analy-ses (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 multivariatemodel (P = .025).Conclusion: We found no association between aprepitant use and the risk of neurotoxicity inpatients receiving ifosfamide-based chemotherapy. The increased risk for ifosfamide neurotoxici-ty among patients with low albumin levels is consistent with previously published studies and mayhelp identify patients at risk for neurotoxicity.


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

The Risk of Neurotoxicity with Aprepitant and Ifosfamide


toms, and urinary incontinence. Female sex, hepatic orrenal dysfunction, and low albumin have been associat-ed with increased ifosfamide neurotoxicity. The risk of neurotoxicity may also increase when ifos-

famide is administered with other drugs metabolizedthrough the CYP3A4. Dechloroethylation via CYP3A4results in the release of potential neurotoxic metabolites.Thus CYP3A4 inducers have the potential to increaseformation of both active and neurotoxic metabolites.Conversely, CYP3A4 inhibitors may impede with theactivation of ifosfamide.Ifosfamide-based chemotherapy is the standard of

care for treatment of soft-tissue sarcomas. It is one of themost active single agents used to treat sarcoma, usuallygiven in conjunction with doxorubicin and occasionallya platinum analog.3 Ifosfamide is a key component in thetreatment for metastatic sarcoma and as adjuvant thera-py in surgically resected soft-tissue sarcomas. These regi-mens, including mesna, doxorubicin, and ifosfamide(MAI), can be very emetogenic. The National Comprehensive Cancer Network

guidelines identify ifosfamide-based chemotherapycombinations used to treat sarcoma as moderate tohigh in emetogenic potential.4 Dose-limiting nauseaand vomiting are common, adversely affecting patients’ability to tolerate further chemotherapy and overallquality of life. Dexamethasone and a 5-hydroxytrypta-mine-3 (5-HT3) antagonist are considered standard ofcare for nausea and vomiting prevention in moderate-high regimens, with a strong consideration given forthe addition of aprepitant.4Aprepitant is approved by the US Food and Drug

Administration for use in combination with cortico -steroids and 5-HT3 receptor antagonists in moderatelyto highly emetogenic chemotherapy regimens. In clin-ical practice and clinical trials, aprepitant has provedto benefit patients by preventing acute and delayednausea and vomiting.5Concomitant use of aprepitant with ifosfamide is

controversial because of a perceived potential druginteraction. Aprepitant is known to inhibit and induceCYP3A4, making it a potentially significant problemin patients receiving medications metabolized byCYP3A4.6 Dexamethasone can also induce CYP3A4.In combination, these 2 agents contribute to the phar-macokinetic variability of ifosfamide and its activemetabolites. A 2007 case report first reported increases of 66.7%

and 37.3% in the neurotoxic 2 and 3 dechloroethylifos-famide metabolites 2 hours after aprepitant administra-tion.7 Another recent case report described a patientreceiving ifosfamide-based chemotherapy who exhibitedsymptoms of neurotoxicity after adding aprepitant to the

antiemetic regimen.6 Howell and colleagues noted anincreased trend of neurotoxicity with the addition ofaprepitant to ifosfamide-containing regimens in sarco-ma,8 whereas a subsequent letter to the editor reportedno change in neurotoxicity rates with the combination.9The debate about the significance of the drug inter-

action between aprepitant and ifosfamide is important,because nausea/vomiting and neurotoxicity directlyimpact patients’ tolerance of the therapy designed toimprove their prognosis. The primary objective of thisstudy was to determine whether concomitant aprepitantwas associated with an increased risk of neurotoxicity inpatients with sarcoma receiving high-dose ifosfamide-based chemotherapy. In addition, we considered otherpatient and treatment factors that may influence ifos-famide-induced neurotoxicity.

MethodsA retrospective study was conducted on all patients

(the total number by the end of the study was 65) diag-nosed with any histologic subtype of sarcoma whoreceived ifosfamide-based chemotherapy at Roswell ParkCancer Institute (RPCI) between January 2005 and July2009. Patients were identified through the RPCI phar-macy system. Patients could receive any number ofchemotherapy regimens, as long as the treatment includ-ed ifosfamide. The treatment regimens had various schedules of

5-HT3 antagonists based on physician preference andthe drug formulary at the time of treatment. All patientswere assessed on whether they received a concomitantcorticosteroid (ie, dexamethasone) or aprepitant fornausea and vomiting prophylaxis. Data on ifosfamide dose, regimen, cycle number, infu-

sion length (hours), and cumulative dose at the time ofthe 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 amino-transferase (ALT), total bilirubin, hemoglobin, serumcreatinine, and calculated creatinine clearance based onideal body weight at time of admission were collected.The written notes from nurses, mid-level practition-

ers, and physicians in each patient case report form werereviewed to identify neurotoxic events. There had to beclear documentation by the provider that neurotoxicitywas suspected or probable, but other potential con-founding variables could not be ruled out. Treatment ofneurotoxicity with methylene blue or by discontinuingifosfamide was also recorded.Our primary research concern was the effect of

aprepitant use on the incidence of neurotoxicity. All 65patients in this study received a high dose of ifosfamide.


Other independent variables of interest included bodyweight, infusion schedule (continuous vs 5 hours or less),ideal body weight, and baseline measures of albumin,liver function tests, and hemoglobin. Preliminary analy-sis showed the natural log transformation of ALT to bebetter suited for statistical modeling. The primary neurotoxicity model was fit, using multi-

variable logistic regression to control for potential con-founding variables. The full model was specified toinclude the independent variables discussed above andthe plausible interaction of infusion schedule. The fullmodel was reduced using manual backward select with a Pvalue threshold of .05, starting with the interaction term,and constrained to retain the aprepitant main effect. Forthe final model, goodness of fit was assessed using theHosmer-Lemeshow test. Similar methods were used toinvestigate the probability of receiving aprepitant.In our sample, all 65 patients received high doses of

ifosfamide. Approximately 25% of the patients experi-enced neurotoxicity. The primary null hypothesisassumed no association between aprepitant use andtoxicity rate. If the true neurotoxicity rate amongaprepitant users in this population is 42% (correspond-ing to an odds ratio of 2.2), logistic regression modelingwith a 2-sided significance level of 0.05 would correct-ly reject the null hypothesis in 80% of similarly con-ducted experiments. When the variability in the toxic-ity rate explained by additional covariates offsets theincremental loss in degree(s) of freedom, a lower mini-mum detectable odds ratio would be obtained. Somepower is lost if other covariates in the model are corre-lated with aprepitant use.To be useful, predictions for the probability of neuro-

toxicity generated from the final model should accuratelyseparate patients who experienced neurotoxicity fromthose who did not. A statistically significant factor in alogistic regression model may not be useful in predictingneurotoxicity in an individual patient. The predictiveability of the final logistic regression model was assessed in2 ways. First, the receiver operating characteristic (ROC)curve plots the sensitivity as a function of (1 – specificity)for all possible predicted probabilities est imated from thefinal model.10 This plot summarizes the predictive powerof the model, with larger gaps between the ROC curveand the 45-degree reference line indicating greater pre-dictive power. Second, the concordance index estimatesthe probability of concordance between the predictedprobability and the observed neurotoxicity outcomes. Theconcordance index is the area under the ROC curve(AUC). An AUC of 0.5 suggests the model predictionsare no better than random guessing. AUC values >0.8 aregenerally considered useful for predicting neurotoxicityin individual patients.

These primary results were supplemented with uni-variate descriptions of associations between baselinepatient or disease characteristics and aprepitant use orpresence of neurotoxicity. Statistical significance ofthese associations were assessed using Wilcoxon ranksum test (for continuous covariates) and the Pearsonchi square test (for categorical covariates). P <.05 wasdeemed statistically significant. No adjustments weremade to this threshold to control the effects of multipletesting on the overall type I error rate. Confidenceintervals (CIs) of 95% were presented as the plausiblerange of values for the true (unknown) populationparameter that is supported by the data. All analyseswere completed with SAS version 9.2 (SAS Institute,Cary, NC).

ResultsThe 65 patients received a total of 308 cycles of ifos-

famide-based chemotherapy. The Table (page 19)shows patient characteristics. Twenty-nine (45%)patients received aprepitant during ifosfamide-basedchemotherapy. Of the 65 patients, 16 (25%) had a neurotoxicity

event during ifosfamide chemotherapy as documentedby the attending physician. Of the 16 patients, 7(43.8%) received aprepitant during ifosfamide-basedchemotherapy. 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 significantdifference (P = .57). Subgroup comparisons were performed on patients

who experienced a neurotoxic event versus those whodid not (Table). Patients with documented neurotoxici-ty during ifosfamide therapy tended to be female, have alower albumin level and ideal body weight, and receivedifosfamide infusions over 5 hours or less. Five of the 16patients who had neurotoxicity were treated with meth-ylene blue. Three patients who had previous ifosfamide-related neurotoxicity received methylene blue as pro-phylaxis on the subsequent cycle.Univariate results suggest a significant association

between neurotoxicity, sex (P = .01, women more like-ly), low albumin (P = .007), and ideal body weight (P =.038). Neither univariate analysis (P = .936) nor themultivariate model (P = .86) detected a significant asso-ciation between aprepitant use and the probability ofneurotoxicity. Low albumin was the only significantvariable predicting for neurotoxicity in the multivariatemodel (P = .025).The adjusted odds ratio for neurotoxicity in patients

treated with aprepitant versus those treated without itwas 1.15 (95% CI, 0.2-5.5), and it was not significant

ORIGINAL RESEARCH





Table Baseline Patient Characteristics

Characteristic No aprepitant Aprepitant P value No neurotoxicity Neurotoxicity P value

Mean age, yrs (SE) 40.8 (3.4) 42.5 (3.9) .4 40.3 (3.0) 45.4 (4.9) .39Female, N (%) 15 (41.7) 16 (55.2) .3 19 (38.8) 12 (75.0) .01Chemotherapy

IE, N (%) 16 (44.4) 5 (17.2) .1 15 (30.6) 6 (37.5) .09

MAI, N (%) 15 (41.7) 11 (37.9) 23 (46.9) 3 (18.8)Other, N (%) 5 (13.9) 13 (44.9) 11 (22.4) 7 (43.8)Mean actual body weight, kg (SE)

73.9 (3.7) 82.5 (4.2) .19 79.1 (3.2) 73.5 (5.7) .3

Mean ideal body weight, kg (SE)

60.4 (2.1) 63.9 (2.2) .3 63.5 (1.8) 57.0 (2.6) .038

Mean albumin, g/dL (SE) 3.8 (0.1) 3.9 (0.1) .7 3.9 (0.1) 3.5 (0.2) .007Mean alanine aminotransferase, IU/L (SE)

35.0 (3.7) 23.5 (2.3) .02 29.5 (2.7) 30.9 (5.1) .7

Mean aspartate aminotransferase, IU/L (SE)

30.5 (2.7) 26.6 (1.5) .6 27.9 (2.0) 31.3 (3.0) .2

Mean total bilirubin, mg/dL (SE)

0.3 (0.0) 0.3 (0.0) .9 0.3 (0.0) 0.3 (0.0) .9

Mean CrCl, mL/min (SE) 108.7 (8.4) 104.1 (8.5) .8 108.2 (6.3) 101.9 (14.9) .47

Mean SCr, mg/dL (SE) 0.9 (0.1) 0.8 (0.0) .9 0.8 (0.0) 0.8 (0.1) .9

Mean hemoglobin, g/dL (SE) 11.3 (0.2) 12.2 (0.3) .03 11.8 (0.2) 11.2 (0.4) .2624-hour infusion, N (%) 12 (33.3) 7 (24.2) .4 17 (34.7) 2 (12.5) .09Neurotoxicity, N (%) 9 (25) 7 (24.1) .9Total dose, g (SE) 59.2 (7.2) 47.8 (5.3) .43 58.1 (5.7) 41.8 (6.7) .19

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

(P = .9). This estimate was adjusted for sex, infusionschedule, and other covariates that may influence theassociation 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 albu-min and neurotoxicity is illustrated in Figures 1 and 2(page 20). Figure 1 shows the protective effect of higheralbumin levels on the predicted probability of neurotoxi-city. The ROC curve indicates how accurately albuminlevels can be used to categorize patients by neurotoxicitystatus. The AUC of 0.73 suggests a moderate degree ofaccuracy for predicting neurotoxicity in individualpatients (Figure 1).

DiscussionOf the 65 patients in our study who received ifos-

famide-based chemotherapy for sarcoma, 16 experi-enced (25%) a neurotoxic event. This number is with-in the range described in previous literature reports.2

We found no evidence to show that aprepitantincreased the rate of neurotoxicity with high-dose ifos-famide therapy. Less than half of the patients (7 of 16)with a neurotoxic event received aprepitant duringifosfamide-based chemotherapy. There was no signifi-cant difference in the number of cycles of chemother-apy with or without aprepitant and neurotoxicity rates(P = .57). However, consistent with previous stud-ies,8,9,11 low albumin was a significant indicator ofincreased risk for neurotoxicity.

Durand and colleagues were first to report a positiveassociation between aprepitant and the developmentof neurotoxicity during ifosfamide treatment.7 Theydescribed a case of a 57-year-old woman who experi-enced neurotoxicity while receiving ifosfamide to treatosteosarcoma. Their pharmacokinetic results revealeda significant increase in the formation of neurotoxicmetabolites from ifosfamide when used concomitantlywith aprepitant. A subsequent case report describeddevelopment of neurotoxicity when aprepitant wasadded to ifosfamide-based chemotherapy.6

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

Howell and colleagues’ retrospective study character-ized the occurrence of neurotoxicity in patients treatedwith ifosfamide and concurrent aprepitant.8 All 45patients included in their study received a 2- to 4-day regimen of MAI. Eighteen percent (8 of 45) of thesepatients developed neurotoxicity during therapy. Theirresults revealed a trend toward increased neurotoxicity (P = .176) with the use of concomitant aprepitant.Similar to our results, they noted a significant differencein low albumin in patients who developed neurotoxicity. Subsequently, in a letter to the editor, Ho and Yuen

share their retrospective experience with aprepitant- asso-ciated ifosfamide neurotoxicity.9 Twelve percent (7 of 54) of the patients they reviewed experienced neu-rotoxicity. Not surprising, and similar to our report and that of

Howell and colleagues, the cases of neurotoxicity hadsignificantly lower albumin levels than patients withoutneurotoxicity (P = .0021). But the described albuminlevels (mean, 1.9) in neurotoxicity cases were clinicallylower than ours (mean, 3.5; standard error, 0.2) andthose of Howell and colleagues (mean, 2.88); 47% oftheir neurotoxicity cases and 59% of the controlsreceived concomitant aprepitant.8 They found no signif-icant association with aprepitant and the developmentof neurotoxicity.8

The methodologies, number of patients, and baselinecharacteristics were similar between all the studies. Ourreport is in direct agreement with Ho and Yuen9 in thataprepitant did not increase neurotoxicity with concomi-tant ifosfamide-based chemotherapy. This contrasts theresults from Howell and colleagues, who found a trendtoward increased neurotoxicity with the addition ofaprepitant to ifosfamide.8Putting our work in context, the drug-drug interac-

tion models may be more complex than initially envi-sioned. Ifosfamide has been described as a prodrug thatrequires enzymatic activation by the liver via CYP3A4to both active (4-hydroxy-ifosfamide) and neurotoxicmetabolites (chloroacetaldehyde and 2- and 3-dechloroethylifosfamide).12 It is plausible that drugs thatinduce or inhibit CYP3A4 can have a significant impacton ifosfamide pharmacokinetics. Dexamethasone, aknown CYP3A4 inducer, has been shown to increasechloroacetaldehyde peak concentrations by 1.5-fold andthe AUC time curve by 1.3-fold.13 Phenytoin has alsobeen shown to increase dechloroethylation in pediatricpatients receiving ifosfamide.14 But it must be noted that ifosfamide can induce its

own metabolism within the first 24 hours, thereby com-plicating interpretation of the pharmacokineticresults.12,15 Also, no definitive evidence exists on

ORIGINAL RESEARCH


Association Between Baseline Albumin andEstimated Probability of NeurotoxicityFigure 1

ROC curve for neurotoxicity as a function of baseline albumin

Sensitivity

1 – specificity

AUC indicates area under the curve; ROC, receiver operating

characteristic.

Neurotoxicity with Ifosfamide-Based ChemotherapyFigure 2

Predicted probability of neurotoxicity as a function of baseline albumin

Predicted probability

Baseline albumin

Observed Predicted




whether CYP3A4 is the only relevant enzyme con-tributing to ifosfamide metabolism in vivo. In vitrostudies document multiple liver microenzymes con-tributing to ifosfamide metabolism.12Another important point, which has yet to be doc-

umented or described in the literature, to our knowl-edge, is the potential impact of aprepitant on the effi-cacy of ifosfamide. Ifosfamide is activated viahydroxylation in the liver by CYP3A4 to its activeform. Therefore, inhibitors or inducers of CYP3A4have the potential to affect formation of activemetabolites.As Ho and Yuen note, both aprepitant and ifos-

famide are highly protein-bound drugs.9 They postulatethat low albumin levels can lead to increased freeunbound aprepitant and ifosfamide, thereby increasingthe formation of all ifosfamide active and inactivemetabolites. Although this explanation is plausible,there are no pharmaco kinetic data available to refuteor to support this claim.Patients in our study who had documented neuro-

toxicity during ifosfamide therapy tended to be female,have a lower ideal body weight, and received ifos-famide infusions over less than 5 hours. It has been pre-viously reported that females exhibit more neurotoxic-ity with ifosfamide than males.16 But the increasedneurotoxicity rates with a lower ideal body weight andshorter ifosfamide infusion time were somewhat sur-prising. It has been previously reported in small groupsof patients that longer infusion times of ifosfamide maylower toxicity and metabolites.17,18 But subsequentpharmacokinetic assessments comparing prolongedinfusions did not show any difference in pharmacoki-netic parameters.19,20The results of our study are based on a convenience

sample derived from retrospective chart reviews from asingle institution. The use of sequential cases tends toreduce biases inherent in this approach. However thepossibility of bias induced by important, perhapsunmeasured, factors remains a weakness common to allretrospective studies.

ConclusionNeurotoxicity is a potentially dose-limiting side

effect occurring with ifosfamide-based chemotherapy,often necessitating at least temporary cessation of ther-apy. This study documents that aprepitant was notassociated with increased risk of neurotoxicity in RPCIpatients receiving ifosfamide-based chemotherapy. Ourfinding that low albumin levels were a risk factor forifosfamide neurotoxicity is consistent with previouslypublished studies and may be helpful in identifyingpatients at higher risk for neurotoxicity.

Based on these data, the medical sarcoma service atour institute has made aprepitant part of the standardorder set for patients with normal or near-normalalbumin levels receiving ifosfamide-based chemother-apy deemed to be moderately high to highly emeto-genic (ie, MAI). In patients with lower than normalalbumin levels, we advocate ifosfamide dose reduc-tion. Definitive resolution of this question willrequire pharmacokinetic study of both the active ifos-famide metabolites and the neurotoxic metabolitessimultaneously. �

Author Disclosure StatementDrs Jarkowski, Miller, Blustein, and Wong, and Ms

Hecke have reported no actual or potential conflicts ofinterest.

References1. Zhang J, Tian Q, Zhou SF. Clinical pharmacology of cyclophosphamide and ifos-famide. Curr Drug Ther. 2006;1:55-84.2. Patel PN. Methylene blue for management of ifosfamide-induced encephalopa-thy. Ann Pharmacother. 2006;40:299-303.3. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomizedstudy of doxorubicin and dacarbazine with or without ifosfamide and mesna inadvanced soft tissue and bone sarcomas. J Clin Oncol. 1993;11:1276-1285.4. Ettinger DS, Armstrong DK, Barbour S, et al. Antiemesis. Clinical PracticeGuidelines in Oncology. J Natl Compr Canc Netw. 2009;7:572-595.5. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonistaprepitant for the prevention of chemotherapy-induced nausea and vomiting: amultinational, randomized, double-blind, placebo-controlled trial in patientsreceiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J ClinOncol. 2003;21:4112-4119.6. Jarkowski A 3rd. Possible contribution of aprepitant to ifosfamide-induced neu-rotoxicity. Am J Health Syst Pharm. 2008;65:2229-2231.7. Durand JP, Gourmel B, Mir O, Goldwasser F. Antiemetic neurokinin-1 antagonistaprepitant and ifosfamide-induced encephalopathy. Ann Oncol. 2007;18:808-809.8.Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of theoccurrence 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 forevaluating diagnostic tests and predictive models. Circulation. 2007;115:654-657.11. David KA, Picus J. Evaluating risk factors for the development of ifosfamideencephalopathy. Am J Clin Oncol. 2005;28:277-280.12. Kerbusch T, de Kraker J, Keizer HJ, et al. Clinical pharmacokinetics andpharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokinet.2001;40:41-62.13. Brüggemann SK, Pfäffle S, Peters SO, Wagner T. Influence of short-term useof dexamethasone on the pharmacokinetics of ifosfamide in patients. Drug MetabDispos. 2007;35:1721-1724.14. Ducharme MP, Bernstein ML, Granvil CP, et al. Phenytoin-induced alterationin the N-dechloroethylation of ifosfamide stereoisomers. Cancer ChemotherPharmacol. 1997;40:531-533.15. Lind MJ, Margison JM, Cerny T, et al. Comparative pharmacokinetics andalkylating activity of fractionated intravenous and oral ifosfamide in patients withbronchogenic carcinoma. Cancer Res. 1989;49:753-757.16. Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose ifosfamide: a ret-rospective 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 dura-tion 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 toprevent encephalopathy. Lancet. 1990;335:175.19. Brain EG, Rezai K, Weill S, et al. Variations in schedules of ifosfamide admin-istration: a better understanding of its implications on pharmacokinetics througha randomized cross-over study. Cancer Chemother Pharmacol. 2007;60:375-381.20. Singer JM, Hartley JM, Brennan C. The pharmacokinetics and metabolism ofifosfamide during bolus and infusional administration: a randomized cross-overstudy. Br J Cancer. 1998;77:978-984.


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� �� 6-Jarkowski_Cover 6/7/11 4:06 PM

PRACTICAL ISSUES IN PHARMACY MANAGEMENT


There has recently been a paradigm shift in thetreatment of patients with cancer. Traditionally,cancer chemotherapy has been given through

the intravenous (IV) route. However, in the past 15years, the number of available oral chemotherapeuticagents has more than doubled. In addition, approxi-mately 30% to 35% of antineoplastics currently beingdeveloped are in an oral formulation.1 Oral formulationsoffer many advantages for patients, including conven-

ience, potential for reduced side effects, and enhancedquality of life. Several studies have shown that between63% and 89% of patients would prefer an oral therapy ifefficacy were not compromised.2-4

As oral chemotherapy becomes more widely utilized,many oncology healthcare providers will be unpreparedfor the challenges associated with these treatments. Thepotential challenges include procurement (ie, drugacquisition, insurance, and reimbursement issues), phar-macologic interactions, and patient safety factors (eg,appropriate patient education and safe handling ofchemotherapeutic agents).

In 2007, a study by Weingart and colleagues surveyed

Drs Mancini, Kaster, Vu, and Modlin are OncologyPharmacists, and Mr Wilson is Oncology Pharmacy Manager,at St Luke’s Mountain States Tumor Institute, Boise, ID.

Implementation of a Pharmacist-Managed Interdisciplinary OralChemotherapy Program in aCommunity Cancer CenterRobert 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 thepast 15 years, the number of available oral chemotherapeutic agents has more than doubled. Oralformulations offer various advantages for patients including convenience, potential for reducedside effects, and enhanced quality of life. With every opportunity, however, comes challenge. Inthis case, potential challenges include procurement (ie, drug acquisition and insurance reim-bursement issues), compliance, pharmacologic interactions, and patient safety factors (eg, appro-priate patient education and safe handling of chemotherapeutic agents). In addition, when pre-scriptions are sent to an external pharmacy, there is no income provided to the cancer centerdespite use of resources.Goal: To describe the way a pharmacy program has dealt with the emerging challenges ofmanaging oral chemotherapy, evaluate workload requirements, and show how the programself-sustains by retaining revenue within the specific health system.Methods: This pharmacist-managed program involved tracking of interventions, such as drug-drug interaction interventions, dose change suggestions based on laboratory results, and sup-portive care discussions. In addition, the annual costs and revenue of the program in fiscal year2010 were tracked to ensure justification of the program and continued financial support of therequired full-time equivalents. Other justification included surveying prescribing physicians andclinic 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 Luke’s health system compared with less than 25% beforeimplementation of the program. Conclusion: Oncology pharmacists have a unique opportunity to manage patients receiving oralchemotherapy. The oral chemotherapy program established at St Luke’s Mountain States TumorInstitute has become an integral collaborative practice, as well as a self-sustainable program forthe health system.


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



Figure 1 Standard Oral Chemotherapy Prescription


54 National Cancer Institute (NCI)-designated cancercenters regarding their safety practices for oralchemotherapy and concluded that US cancer centershave no consensus on how to safely process oralchemotherapy agents.5 In addition, there are no stan-dards for prescribing, educating, or assessing patientadherence.5 Two years later, the American Society ofClinical Oncology (ASCO) and the Oncology NursingSociety (ONS) published joint guidelines on safeadministration of chemotherapies, including require-ments for standardization of ordering, preparation,patient education, monitoring, and follow-up withoral chemotherapy treatment.6 To date, these guide-lines are the single source of guidance for institutionswishing to improve care of patients receiving oralantineoplastic agents.

At St Luke’s Mountain States Tumor Institute(MSTI), a retrospective review from our 5 outpatientcancer clinics showed that less than 25% of patients pre-scribed oral chemotherapy had utilized St Luke’s hospi-tal-based outpatient pharmacies for their prescribed oralanticancer therapies within a 6-month period. In ad -dition, a fair number of patients utilized more than 2pharmacies, because of difficulty in obtaining oralchemotherapeutic agents. In an effort to comply withpublished standards, increase patient safety and continu-ity of care, as well as expand clinical oncology phar -macist services, we established a pharmacist-managed,interdisciplinary oral chemotherapy program.

The goals of the program were to develop prospectivemedication order review for oral chemotherapy; provid-ing medication reconciliation; improving continuity ofcare, patient counseling, and patient education; moni-toring for tolerability; follow-up for adherence; andincreasing reimbursement revenue in the onsite out -patient pharmacies. We wanted to improve the oralchemotherapy prescription process in our facilitiesthrough standardized safeguards used during administra-tion of IV therapy.

This article describes a novel program at St Luke’sMSTI, an NCI community cancer center program serv-ing a broad geographic area that includes most of south-ern Idaho, eastern Oregon, and northern Nevada. Thearticle evaluates workload requirements and shows howthe program self-sustains by retaining revenue withinthe specific health system.

MethodsAs a result of the need for expanded pharmacy serv-

ices by St Luke’s MSTI and the initiative of a residencyproject, the process of establishing a new pharmacy serv-ice was begun. The initiation of the project requiredevaluation of standard legal and operating requirements

of any pharmacy. Requirements included a physicalspace with basic necessities and meeting basic pharmacyneeds, such as specialty licenses and insurance contracts.

Although we were able to secure an office for anoncology pharmacist to staff the oral chemotherapy pro-gram, we decided to utilize our Boise hospital’s onsiteoutpatient pharmacy for the actual filling of the oralchemotherapy prescriptions. This allowed us to circum-vent the need for acquiring additional licensure andinsurance contracts because they were already held by apharmacy within the institution.

After securing the basic requirements, we determineda process of workflow based on the ASCO-ONS guide-

Pharmacist-Managed Interdisciplinary Oral Chemotherapy Program


Figure 2 Oral Chemotherapy Process

Social worker:free medication

programs

Pharmacist: prescription processing (laboratory,

evaluation, drug inter actions,patient education)

Patient advocate:copay assistance

programs

Prescription written for oral chemotherapy

Outpatient pharmacy: benefits investigation

Medication filled and sent to patient

Patient follow-up for side effects

Physician:follow-up for drug efficacy

Coordinate with outpatient pharmacy

New patient or dose change:

weekly follow-up

All patients: monthly follow-up

Pharmacist: prior authorization


lines,6 taking into consideration the needs of our patientpopulation and our particular institution. Close collabo-ration with multiple healthcare disciplines played anintegral role in determining the actual process of oralchemotherapy processing. The groups included the out-patient (filling) pharmacy, clinic nurses, triage nurses,patient financial advocates, social workers, physiciancommittees, and administrators. As a result of initialprocess complications discovered in the early phases of

the program, we needed to solicit continual verbal feed-back at monthly meetings from each of these groups inan ongoing process to improve our program and to bestmeet the needs of our patients and our facility.

To begin the process of filling oral chemotherapy pre-scriptions, we created 2 preprinted order forms, one forlenalidomide (Revlimid) and thalidomide (Thalomid)

and the second for the remaining oral chemotherapeuticagents. Physicians prescribing oral chemotherapy wererequired to utilize the standardized forms, which includethe following elements: the goal of treatment (eg, first-line, second-line, salvage), cycle length, cycle structure,whether the goal is prior authorization only or active dis-pensing, and a provision to allow the pharmacist to fillbased on available pill sizes (Figure 1, page 24).

Initial contact with the patient was made within 24hours to explain the filling process and to perform initialcounseling on the medication. Once the patient hadstarted the medication, the oncology pharmacist calledthe patient on a weekly basis for follow-up and assess-ment for the first cycle. Thereafter, the patient wascalled once per cycle before each refill to assess symptommanagement and adherence.

The oncology pharmacist kept in close communica-tion with the prescribing oncologist and clinic nurses toensure appropriate follow-up and assessment (includingthings such as laboratory work and symptom manage-ment). The average time to fill was 2 to 5 days, which islargely a function of insurance requirements. The phar-macy technician also schedules pick-ups with thepatient, verifies receipt of mailed prescriptions, andassists in preparing the day’s schedule (Figure 2, page 25).



Capecitabine

Cyclophosphamide

Erlotinib

Etoposide

Everolimus

Hydroxyurea

Imatinib

Lapatinib

Lenalidomide

Melphalan

Nilotinib

Pazopanib

Sorafenib

Thalidomide

Temozolom

ide

Sunitinib

360

340

320

300

280

260

240

220

200

180

160

140

120

100

80

60

40

20

0

Figure 3 Prescriptions by Oral Chemotherapeutic Agent, September 2009-September 2010

Close collaboration with multiple healthcaredisciplines played an integral role indetermining the actual process of oralchemotherapy processing.


To justify this program, the oral chemotherapy officekept a daily log of workload that included the number ofprescriptions filled and the number of follow-up phonecalls. Interventions such as drug-drug interaction inter-ventions, dose change suggestions based on laboratoryresults, and supportive care discussions were trackedindirectly. Revenue generated from oral chemotherapyprescriptions filled was tracked at the onsite outpatientpharmacy during fiscal year 2010 (October 2009-September 2010) and divided by month to determinethe plateau of workload. In addition, the yearly costs andrevenue of the program were tracked to ensure justifica-tion of the program and continued financial support ofthe required full-time equivalents. Other justificationincluded surveying prescribing physicians and clinicnurses for satisfaction with the program. Finally, the pro-gram found a huge opportunity with lenalidomide coun-seling and distribution that is included.

ResultsWorkload AssessmentDuring a 16-month time period, the oral chemothera-

py office had processed nearly 1500 prescriptions for 552patients. One third of these prescriptions were new; theremaining two thirds were refills. The average workloadwas 30 prescriptions filled weekly, in addition to approxi-mately 50 weekly follow-ups (via phone call or physicianvisit). All prior authorizations were completed by theoncology pharmacist and signed by the prescriber whennecessary. Patients who were underinsured or uninsuredwere referred to our patient financial advocates to apply

for copay assistance or free drugs from the manufacturervia that manufacturer’s drug assistance programs.The most common prescription filled was cape -

citabine (Xeloda), followed by lenalidomide and temo-zolomide (Temodar) (Figure 3, page 26). Because ofinsurance requirements and contracts, approximately10% of prescriptions referred to the oral chemotherapyoffice were required to go to a specific mail-order phar-macy. Before becoming certified to dispense lenalido-mide, this number approached 20%, inferring that ourcurrent mail-order base is approximately 5% to 10%.

Although indirectly measured, the most common sideeffects discussed with patients included nausea/vomitingprophylaxis and treatment, management and preventionof hand-foot syndrome, diarrhea, stomatitis, and require-ments for taking the medication (ie, with or withoutfood). Of the 552 participating patients, 36 patients hada total of 37 drug interactions that required pharmacistintervention. The most common drug interactionsfound were with capecitabine, cyclophosphamide, andcertain tyrosine kinase inhibitors, specifically erlotinib



During a 16-month time period, the oralchemotherapy office had processed nearly1500 prescriptions for 552 patients. Onethird of these prescriptions were new; the remaining two thirds were refills.

Table 1 Drug Interactions Requiring Pharmacist InterventionOral chemotherapeutic agent Interacting medication Number of patients

Capecitabine (Xeloda) Warfarin 9Phenytoin 2

Cyclophosphamide (Cytoxan) Warfarin 4Hydrochlorothiazide 1

Dasatinib (Sprycel) Proton pump inhibitor 4Erlotinib (Tarceva) Proton pump inhibitor 7

Warfarin 1Phenytoin 1

Imatinib (Gleevec) Simvastatin 1Levothyroxine 1

Lapatinib (Tykerb) Dexamethasone 1Lenalidomide (Revlimid) Digoxin 2Pazopanib (Votrient) Fentanyl 1Sorafenib (Nexavar) Warfarin 1Sunitinib (Sutent) Dexamethasone 1Total 37




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

Revenue and Program SustainmentDuring fiscal year 2010, the number of prescriptions

had an average 3-fold increase from 40 new and refillprescriptions per month in October 2009 to 120 permonth by September 2010. The revenue generatedmatched this trend by increasing from $100,000 permonth to $300,000 per month by the end of the fiscalyear (Figure 4).

Based on current monthly estimates, this programwill result in yearly gross revenue of $2.4 million, doublethe original estimate of $1.2 million. The total annualoperating costs for the program were approximately$230,000, including salaries, overhead, educationalbrochures, and mailings. Based on typical profit marginsfrom the gross revenue, this program more than pays foritself. In addition, with the increased revenue from the

program, several patients were able to get free drugs fortheir first cycle, while assistance paperwork was pending,to ensure timely initiation of therapy within a coupledays as opposed to weeks or more until insurance issueswere resolved.A total of 15 oncology nurses, of the 25 who were

approached, responded to a satisfaction survey initiatedby the outpatient chemotherapy program pharmacists.Of the 15, 83% were very satisfied or satisfied with theprocess overall. Also, 80% were at least satisfied with therefill process, and 86% were at least satisfied with thecopay assistance work integrated between the financialadvocates and the oral chemotherapy office. Accordingto the nurses, most patients spoke highly about the easeof obtaining/picking up medications and refills, copayassistance, and follow-up phone calls. All the nursescommented that it was moderately to very easy to con-tact the pharmacist working in the oral chemotherapyoffice. Most nurses had very positive interactions withthe oral chemotherapy pharmacists (Table 2, page 29). Some of the positive comments from the nurses were,

“This process is a HUGE improvement over what wewere doing; patients LOVE it.” And, “The benefit of thisprogram is that it takes the detailed work and attentiongiven to IV chemotherapy for years and finally applies itto oral chemotherapy. It’s all about patient safety andteaching.” With regard to future improvements, nurses request-

ed the pharmacy provide follow-up for patients utilizingmail-order pharmacy, as well as for those whose pre-scriptions 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 sur-vey. Of these 7 respondents, 5 were extremely satisfied

Based on current monthly estimates, thisprogram will result in yearly gross revenueof $2.4 million, double the originalestimate of $1.2 million. Based on typical profit margins from the grossrevenue, this program more than pays for itself.

Figure 4 Oral Chemotherapy Prescriptions and Revenue

140

120

100

80

60

40

20

0 Sept 2009 Oct 2009 Nov 2009 Dec 2009 Jan 2010 Feb 2010 Mar 2010 Apr 2010 May 2010 June 2010 July 2010 Aug 2010 Sept 2010

$350,000

$300,000

$250,000

$200,000

$150,000

$100,000

$50,000

$0

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f prescrip

tions per m

onth

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with the way the program is operating, all of whombelieved this program has provided better access andthus better outcomes for their patients. Two physicianswere indifferent, because they personally did not see achange in their workload but felt that the best responseto the survey questions should be ascertained from theirpatients. The physicians also recommended somechanges in how the pharmacists document fill dates,interventions, and follow-ups so that they can moreeasily determine when the patients start their cyclesand/or pick up their medications.

Lenalidomide and RevAssist REMS programLenalidomide 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 lenalido-mide, the pharmacy must complete a training programfor certification of educators, which can be either nursesor pharmacists. Each month before the fill, the certifiedcounselors call the patient to review a standardizedcounseling checklist. The counselors are also responsible for reporting any

adverse reaction(s) the patient experiences while receiv-ing this medication. The pharmacy is responsible forkeeping a recorded inventory that includes the strength,lot number, and quantity of lenalidomide dispensed tothe patient. Because of the workload required, it is essen-tial to assess whether it is feasible for the health systemto take on this responsibility.After the first 6 months of evaluating the program, a

significant potential loss to follow-up in patients takinglenalidomide was discovered. Therefore, a decision wasmade to enroll the oral oncology pharmacists as certifiedRevAssist counselors so that the institution could main-tain these patients internally. This allowed the secondmost common prescription to be brought back withinthe health system, further enhancing care for patients

and retaining revenue for the institution. In addition, StLuke’s MSTI was able to justify a half-time technicianposition and a pharmacy biller to assist the oncologypharmacist.

ConclusionSince the US Food and Drug Administration

approval of capecitabine in 1998, there has been ashifting paradigm in cancer care toward oral chemo -therapeutics.8 The implications for this are huge—notjust for patients, but for cancer centers as well. Whenprescriptions are sent to an external pharmacy, there isno income provided to the cancer center. This ispotentially problematic, because staff time involved inassisting patients with obtaining their medications isnot billable.9St Luke’s MSTI’s oral chemotherapy program has

allowed for revenue to stay within the health systemeach year to continually fund this program. Previously,only 25% of patients were filling their prescriptions atour health system pharmacies. Based on data generatedfrom the electronic medical records, an estimated 75%to 85% of prescriptions now remain within our health

Since the approval of capecitabine in 1998, there has been a shifting paradigmin cancer care toward oralchemotherapeutics. An estimated 75% to85% of prescriptions now remain withinour health system, thus allowing consistentfollow-up our patients previously did notreceive. This change has the potential toimprove compliance and accessibility anddecrease patient concerns.

Table 2 Nursing Satisfaction SurveyImprovement parameter Respondents agreeing, %

(N = 15)

Improved financial assistance 73Better documentation in electronic medical record 60Better patient follow-up and monitoring 60Ease of collaboration with pharmacy staff 53Improved patient outcomes 53Faster access to medication 53Reduced workload for registered nurse/medical doctor 40Improved refill process 40Better assistance with drug information questions 40


system, thus allowing consistent follow-up our patientspreviously did not receive. This change has the potentialto improve compliance and accessibility and decreasepatient concerns.10

A unique advantage to keeping these prescriptionswithin our health system is that drug interactions, doseadjustments, and supportive care referrals can be done ina more timely fashion, thereby preventing further delaysin initiation of treatment. In addition, consistent docu-mentation and follow-up within one system allows forimproved continuity of care for patients and forenhanced safety outcomes.6

This program could not have been a success withoutthe strong collaboration among individuals with varyingareas of specialization, including the oncologists, nurses,pharmacists, retail pharmacy team, billing specialists,patient financial advocates, and social workers, as well asthe insight of our pharmacy business analyst.

Future directions of this program involve continuedadaptation of new oral oncologic agents, as well as inte-gration of the supportive care medications prescribed inthe oncology population, such as deferasirox (Exjade) oreltrombopag (Promacta). An additional challenge is tofind a way to include follow-up for the 5% to 10% ofpatients who receive oral chemotherapy from mail-orderpharmacies.

With our current workload, patients who utilize mail-order pharmacies are difficult to include, but futurechanges may allow us to integrate them into our system toimprove monitoring and follow-up with these patients. Inaddition, examination of the impact of this program,

including adherence rates, average duration of time onoral chemotherapeutics, and supportive care managementand counseling, are also needed. Because one third of ourfills are new prescriptions, we believe that many patientsdo not continue taking oral chemotherapeutics as long asmay be predicted and often stop after a few cycles as aresult of toxicity and/or disease progression.

The ultimate finding is that oncology pharmacistshave a unique opportunity to manage patients’ pre-scribed oral chemotherapy. This includes the ability tohelp the health system comply with REMS programs,as seen with lenalidomide, and improve safe-handlingpractices by helping establish procedures for ordering,filling, and dispensing oral chemotherapy. The programdescribed here has become an integral collaborativepractice, as well as a self-sustainable program for ournot-for-profit health system. �

Author Disclosure StatementDrs Mancini, Kaster, Vu, Modlin, and Mr Wilson have

reported no actual or potential conflicts of interest.

References1. 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 ofendocrine treatments by injection or tablets: results from a study of women with breastcancer. Ann Oncol. 2006;17:205-210.3. Borner M, Schöffski P, de Wit R, et al. A randomized crossover trial comparing oralUFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV forpatient preference and pharmacokinetics in advanced colorectal cancer. Proc Am SocClin Oncol. 2000;19:Abstract 741.4. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intra-venous palliative chemotherapy. J Clin Oncol. 1997;15:110-115.5. Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety practices at UScancer centres: questionnaire survey. BMJ. 2007;334:407.6. Jacobsen JO, Polovich M, McNiff KK, et al. American Society of ClinicalOncology/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 com-pliance. J Oncol Pract. 2008;4:175-177.



We believe that many patients do notcontinue taking oral chemotherapeutics aslong as may be predicted and often stopafter a few cycles as a result of toxicityand/or disease progression.


BUILDINGpillars of knowledgeIN SUPPORTIVE CARE

LOG ON TODAY TO PARTICIPATE

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TARGET AUDIENCEThe educational series is intended for nurses, pharmacists, and otherswith clinical, research, and management interests of neutropeniamanagement

EDUCATIONAL OBJECTIVESOn 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 theincidence of neutropenia

ACCREDITATION STATEMENTSCreative Educational Concepts, Inc. (CEC) is accreditedby the Accreditation Council for Pharmacy Education as aprovider of continuing pharmacy education.

This knowledge-based activity has been assigned ACPE # 0245-0000-11-016-L01-P and will award 1.0 contact hour (0.10 CEUs) ofcontinuing pharmacy education credit. CEC complies with theCriteria for Quality for continuing education programming.

NURSINGCreative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American NursesCredentialing Center’s Commission on Accreditation.

CEC provides this activity for 1.0 contact hour.

Learners are advised that accredited status does not imply endorse-ment 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.

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

FACULTYLeAnne Kennedy, PharmD, BCOPPharmacy Clinical CoordinatorHematology and OncologyWake Forest Baptist HealthWinston-Salem, NC

Kathleen Colson, RN, BSN, BSClinical Research Nurse Multiple Myeloma Dana Farber Cancer InstituteBoston, MA

Regina Cunningham, PhD, RN, AOCNSenior Director, Oncology The Tisch Cancer InstituteMount Sinai Medical CenterNew York, NY

This activity is supported by an educational grantfrom Amgen Inc.

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www.coexm.com/ace06

NEUTROPENIALIVE WEBINAR DATESACTIVITY LENGTH: 1 HOURMonday, July 11, 201112:00 PM ET • 11:00 AM CT • 10:00 AM MT • 9:00 AM PT

Wednesday, July 13, 20113:00 PM ET • 2:00 PM CT • 1:00 PM MT • 12:00 PM PT

Friday, July 15, 20111:00 PM ET • 12:00 PM CT • 11:00 AM MT • 10:00 AM PT

Monday, July 18, 20113:00 PM ET • 2:00 PM CT • 1:00 PM MT • 12:00 PM PT

Friday, July 22, 20111:00 PM ET • 12:00 PM CT • 11:00 AM MT • 10:00 AM PT

� �� 7-Manchini_Cover 6/7/11 4:07 PM


MISSION STATEMENT—Journal of HematologyOncology Pharmacy (JHOP) is an independent, peer-reviewed journal founded in 2011 to provide hema-tology and oncology pharmacy practitioners andother healthcare professionals in these fields withhigh-quality peer-reviewed information relevant tohematologic and oncologic conditions to help themoptimize drug therapy for patients.

GENERAL INFORMATION—Manuscripts submit-ted to JHOP must be original and must not have beenpublished previously, either in print or in electronic form.Manuscripts cannot be submitted elsewhere while underconsideration by JHOP.

The editors invite readers to submit a articles on a varietyof points of view and approaches to meet the mission ofthe journal. Articles will be divided into four main cate-gories, including (1) original research, to provide an outletfor translational and practice-based research, includingcase reports and case series; (2) review articles that focus ondrug and disease state as well as on basic science regard-ing the complex molecular biology of cancer with a phar-macy focus; (3) clinical controversies that discuss commonclinical issues for which treatment is unclear; this couldinclude “point, counterpoint” and “how I treat” type ofarticles; (4) practical issues in pharmacy management willfocus on real-world issues involving logistics, economics,and other practice-related topics.

Manuscripts submitted must be original and must nothave been published previously, either in print or in elec-tronic form. Manuscripts cannot be submitted elsewherewhile under consideration by JHOP. All authors mustsign an appropriate disclosure form and a copyright trans-fer/authorship form.

PEER REVIEW/EDITING—All articles undergo aninitial internal review for topic appropriateness and man-uscript format. Manuscripts that are not submittedaccording to the guidelines in this document will bereturned to the author.

All manuscripts are subject to a strict, blinded peer review(by 2-4 reviewers), and acceptance is based entirely onthat review. Reviewers look for the accuracy of the infor-mation and data presented, as well as the relevance to theobjectives of JHOP.

All authors’ identifying information is removed from thearticle for the purpose of the peer review, but any study

funding information is provided to reviewers. Authors arenotified as soon as possible regarding the initial decisionof acceptance or rejection of the article. The majority ofarticles that are accepted for publication, however, willrequire revisions and resubmission. A second review isconducted when recommended by reviewers.

Routine editorial changes are made on all articles to con-form to house style, following the AMA Manual of Style,10th ed.1 The edited manuscript is sent to the correspon-ding author for a final review and for any outstanding edi-torial queries. Time from submission to publication is gen-erally 4 to 7 months, but could be longer, depending onthe peer-review and editing processes.

AUTHORSHIP/COPYRIGHT—Authors listed onthe manuscript should only include those who have madea direct contribution to the content of the article, inaccordance with the authorship criteria provided by theInternational Committee of Medical Journal Editors(ICMJE).2 Credit for authorship is based on a substantialcontribution to (1) conception and design, or data analy-sis/interpretation, (2) drafting or revising the article criti-cally for intellectual content, and (3) approval of the finalversion to be published. These 3 criteria must all be met.2Those who have contributed to the article but do notmeet these authorship criteria should be acknowledged atthe end of the article.

Provide authors’ highest academic degree and profession-al affiliations. Also provide the name, address, telephonenumber, e-mail, and fax number of the correspondingauthor. The corresponding author is responsible for secur-ing signatures for all forms from all authors.

All authors are required to sign an Authorship/CopyrightTransfer Form, assigning all copyrights for the manuscriptto Green Hill Healthcare Communications, LLC, pub-lisher of JHOP.

For an article to be considered for publication, authorsmust adhere to the manuscript format described in thisdocument and follow the general ICMJE guidelines.2

DISCLOSURE STATEMENTS—All authors mustdisclose any relationship that could be viewed as a poten-tial conflict of interest, based on ICMJE guidelines,2including any financial interests, direct or indirect, andany affiliations or involvement (competitive or amiable)with organizations that have a financial interest in thesubject matter or materials discussed in the manuscript.

AUTHOR GUIDELINES

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

33www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 1, No 2 l June 2011

Each author must sign the Financial Disclosure Form inaccordance with the ICMJE guidelines.2

JHOP discloses all information regarding employment,consultancies, stock ownership, honoraria, grants, orother financial sources with potential conflict of interestin relation to a manuscript, or if authors discuss any prod-ucts or services with such commercial interest. Any infor-mation regarding funding, grants, or other financial com-pensation must be listed on the title page of themanuscript. All published articles will include disclosurestatements listing any relationships with real or potentialconflict of interest for all authors and for the manu-script/research.

PERMISSIONS—Authors must secure written permis-sion to reuse or adapt any graphic elements (table, figure)from a previously published (online or in print) article orfrom any other source. Provide the letter of permissionwhen submitting the manuscript, or indicate that permis-sion will be provided, and cite the original source withthe graphic element in the manuscript. Authors areresponsible for acknowledging all information that hasbeen published previously.

MANUSCRIPT FORMAT—Manuscripts that do notadhere to the format described in this document will bereturned to the author.

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

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

An abstract for an article that does not represent researchfindings should include the following categories to suggestwhy the article is important and what its main objectivesare: Background, Objectives, Discussion, Conclusion.

Text: The entire text must be provided as a double-spaced Word file and all pages numbered consecutively.Cite any graphic elements (tables, figures, algorithms,appendix) consecutively in the text, but place actualtables/figures at the end of the article, after the references.Limit the length of the text to 3500 words (excluding ref-erences, tables, and figures).

Conclusion: The conclusion is not a summary of the arti-cle. Rather, it should add something new to the article, apoint of view or comments related to the rationale for thearticle 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 ele-ments at the end of the article, after the references. Typeall tables and all figure heads and captions in the Worddocument.

Figures and other images must also be provided as indi-vidual graphic files, saved at high resolution (300 dpi), asjpg or pdf file. Attach an individual file for each image.Images not saved appropriately will delay the peer-reviewprocess significantly. For help with images, please [email protected].

References: Use most up-to-date, post-1990, primarysources only, cited consecutively in the text (as super-script numbers), then place each complete reference atthe end of the article under heading “References.” Avoidautomatic numbering or footnote/endnote features. Try tolimit the number of references to 35.

Use citation format according to the AMA Manual ofStyle.1

Examples:1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detectpublication bias in meta-analysis. JAMA. 2006;295: 676-680.2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception tobirth. 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 genericuse surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news?pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

HOW TO SUBMIT MANUSCRIPTS—Articles thatdo not follow the guidelines described in this documentwill not be considered for publication.

Save the manuscript as a Word file and attach individualfiles for each image or figure. Save images (figures) indi-vidually as an image file (jpg or pdf). Digital images mustbe saved at a high resolution (300 dpi).

Submit the entire manuscript and cover letter statingthe objectives of the article to [email protected]. For assistance call 732-992-1890.

REPRINTS—Reprints may be ordered for a nominalfee by contacting [email protected].

1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007.2. International Committee of Medical Journal Editors. Uniform Requirements forManuscripts Submitted to Biomedical Journals. Updated April 2010.www.icmje.org/urm_full.pdf. Accessed June 1, 2010.

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

�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

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Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

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Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (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 EducationGroup and Medical Learning Institute, Inc.

Coordination for this activity provided by Center of Excellence Media, LLC.

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YOUR QUESTIONS ANSWERED

COEAsize40611MM

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or [email protected].

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

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

� �� 8-Guidelines_Cover 6/7/11 4:08 PM

FROM THE LITERATURE


� Abiraterone Improves Overall Survival in Patientswith Metastatic Prostate CancerBackground:Androgen deprivation has long been the

standard of care for men with advanced prostate cancer,demonstrating efficacy in preventing or delaying therecurrence of metastases in this patient population. Theselective androgen biosynthesis inhibitor abirateroneacetate, administered either alone or in combinationwith low-dose prednisone, has demonstrated significantantitumor activity in men with advanced prostate can-cer, regardless of any previous chemotherapy treatment.However, whether abiraterone prolongs overall survival(OS) in patients with metastatic castration-resistantprostate cancer whose disease progressed after docetaxel-based chemotherapy was not previously known.

Design: This phase 3 multinational, double-blind,placebo-controlled trial included patients from 147 sitesin 13 countries; they were followed from May 2008through July 2009. A total of 1195 patients who had pre-viously received docetaxel chemotherapy were randomlyassigned in a 2:1 ratio to 2 groups to receive 1000 mgdaily of abiraterone acetate (administered as four 250-mgtablets) plus prednisone 5 mg twice daily (N = 797), orplacebo plus prednisone (N = 398). The primary endpoint was OS; the secondary end points included time toprostate-specific antigen (PSA) progression; progression-free survival (PFS), determined from radiologic findings;and PSA response rate.

Summary: The primary and secondary end points inthis study all showed significantly improved outcomes inthe active treatment group compared with the placebogroup. After a median follow-up period of 12.8 months,patients receiving abiraterone demonstrated significant-ly longer OS (14.8 months) than those receiving place-bo (10.9 months; hazard ratio [HR], 0.65; 95% confi-dence interval [CI], 0.54-0.77; P <.001). For the interimanalysis, the data were unblinded, because these resultsexceeded the preplanned criteria for study termination.Secondary end points also showed improvement withabiraterone compared with placebo: the PFS period waslonger with abiraterone compared with placebo (5.6months vs 3.6 months, respectively; P <.001), as wastime to PSA progression (10.2 months vs 6.6 months,respectively; P<.001), and the PSA response rate was

greater (29% vs 6%, respectively; P <.001). Treatmentwith abiraterone had a low frequency of treatment-relat-ed toxic effects. Patients receiving abiraterone plus pred-nisone, however, had more mineralocorticoid-relatedadverse events, including fluid retention, hypertension,and hypokalemia, than those receiving placebo plusprednisone.

Takeaway: This phase 3 study of a novel testosteronebiosynthetic inhibitor demonstrated a significant im -provement in OS, PFS, and PSA responses in patientswith castrate-resistant prostate cancer who had beenpreviously treated with docetaxel. Furthermore, adverseevents were low grade and largely minimized by con-current low-dose prednisone therapy. The results of thisstudy provide a proof of the principle that metastaticcastrate-resistant prostate cancer is still driven byendogenous androgens. Therefore, hormonal therapycan be considered for a patient in whom previouschemotherapy has failed. The next study that should beconducted would involve a comparison between first-line therapy with abiraterone acetate versus docetaxel-based chemotherapy in the setting of castrate-resistantprostate cancer.de Bono JS, et al. N Engl J Med. 2011;364:1995-2005.

� Comparing Denosumab and Zoledronic Acid forTreatment of Bone Metastases in Men withCastration-Resistant Prostate CancerBackground: The development of bone metastases is

common in men with advanced prostate cancer.Researchers have therefore been investigating therapiesfor the treatment or prevention of bone metastases in thispatient population. In a new study, denosumab, a humanmonoclonal antibody against receptor activator of nuclearfactor kappa-B ligand (RANKL), was compared in a phase3 study with zoledronic acid for the prevention of skeletal-related events (SREs) in men with bone metastases causedby castration-resistant prostate cancer.

Design: Men from 342 centers in 39 countries withcastration-resistant prostate cancer and no previousexposure to intravenous (IV) bisphosphonates were ran-domly assigned to receive 120 mg of subcutaneous deno-sumab plus IV placebo or 4 mg of IV zoledronic acid plus

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

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

FROM THE LITERATURE


subcutaneous placebo every 4 weeks. The primary endpoint was the time to a first on-study SRE (pathologicalfracture, radiation therapy, surgery to bone, or spinal cordcompression), which was assessed first for noninferiorityand then for superiority as a secondary end point. Anintention-to-treat analysis was performed to assess effica-cy, and safety was assessed according to the incidence oftreatment-emergent adverse events and changes inhematology and laboratory findings.

Summary: Among 1901 patients who were assignedto treatment and were eligible for the efficacy analysis,950 received denosumab and 951 received zoledronicacid. The median duration on study at the primaryanalysis cutoff date was 12.2 months (interquartilerange, 5.9-18.5) for patients given denosumab and11.2 months (5.6-17.4) for those given zoledronic acid.The median time to a first on-study SRE was 20.7months (95% CI, 18.8-24.9) with denosumab versus17.1 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 in916 patients (97%) given denosumab and 918 (97%)given zoledronic acid, and serious adverse eventsoccurred in 594 (63%) and 568 patients (60%),respectively. More episodes of hypocalcemia occurredwith denosumab (121 [13%]) than with zoledronicacid (55 [6%]; P <.0001). The occurrence ofosteonecrosis of the jaw was not significant (22 [2%] vs12 [1%], respectively; P = .09).

Takeaway: Denosumab is a human monoclonal anti-body that binds to RANKL, leading to inhibition ofosteoclast-mediated bone destruction. In this study,denosumab therapy delayed the time to first SREs by18% compared with zoledronic acid. Furthermore, thedecrease in markers of bone turnover was greater withdenosumab than with zoledronic acid. However, OS andtime to progression were not different between thegroups. The authors concluded that denosumab is betterthan zoledronic acid for preventing SREs. This is the firstmonoclonal antibody shown to be an effective agent inbone metastases caused by castrate-resistant prostatecancer. Its role in this setting would be further defined bythe results of a comparative pharmacoeconomics study. Fizazi K, et al. Lancet. 2011;377:813-822.

■ Sipuleucel-T Immunotherapy Extends OverallSurvival for Patients with Castration-ResistantProstate CancerBackground: Sipuleucel-T, an autologous active cellu-

lar immunotherapy, has demonstrated efficacy in reduc-ing the risk of death among men with metastatic castra-

tion-resistant prostate cancer. Previous research, howev-er, has not confirmed improved OS with the drug.

Design: Researchers in the double-blind, placebo-controlled, multicenter Immunotherapy for ProstateAdenocarcinoma Treatment (IMPACT) study randomlyassigned 512 patients in a 2:1 ratio to receive either sipu -leucel-T or placebo administered intravenously every 2weeks for a total of 3 infusions. The primary end pointwas OS, determined from a stratified Cox regressionmodel adjusted for baseline levels of serum PSA and lac-tate dehydrogenase.

Summary: The relative risk of death among 341patients given sipuleucel-T was 22% lower than thatamong 171 patients given placebo (HR, 0.78; 95% CI,0.61-0.98; P = .03), translating to a 4.1-month longermedian survival (25.8 months vs 21.7 months, respec-tively). In addition, the 36-month survival probabilitywas 31.7% and 23.0%, respectively. The treatment effectwas also demonstrated in an unadjusted Cox model anda log-rank test (HR, 0.77; 95% CI, 0.61-0.97; P = .02)and after adjustment for the use of docetaxel after thestudy therapy (HR, 0.78; 95% CI, 0.62-0.98; P = .03).The time to objective disease progression was similar inthe 2 study groups. Patients who received sipuleucel-Talso demonstrated immune responses to the immunizingantigen. Adverse events that occurred more frequentlyamong patients given sipuleucel-T than among thosegiven placebo included chills, fever, and headache.

Takeaway: Vaccine immunotherapy has been studiedbut has not been proved beneficial until this study.Compared with placebo, sipuleucel-T improved OS by 4months in patients with castrate-resistant prostate can-cer and was consistent among all subgroups of prognosticfactors. About half of the patients in the placebo groupcrossed over to the cancer vaccine group. OS was almost24 months with the active treatment compared with 12months in the placebo group. Adverse effects were min-imal and well tolerated, mainly consisting of infusionreactions. This study establishes sipuleucel-T as a usefulagent, especially in the setting of asymptomaticadvanced prostate cancer. Because several therapies arenow available that are effective in this setting, placebo-controlled trials in patients with castrate-resistantprostate cancer may no longer be ethical.Kantoff PW, et al. N Engl J Med. 2010;363:411-422.

■ Improving Survival with Ipilimumab in MetastaticMelanomaBackground: In phase 3 randomized trials involving

patients with metastatic melanoma, no therapy has beendemonstrated to extend OS to 1 year or beyond.


FROM THE LITERATURE


Ipilimumab, a fully human monoclonal antibody thatpotentiates an antitumor T-cell response by blockingcytotoxic T-lymphocyte–associated antigen, has shownactivity as monotherapy in phase 2 studies. Previousresearch suggests glycoprotein 100 (gp100) peptide vac-cine, which also induces immune response but has limit-ed antitumor activity as monotherapy, may improve theefficacy of high-dose interleukin-2 in patients withmetastatic melanoma. In this phase 3 study, ipilimumab,administered with and without gp100, was comparedwith gp100 alone in patients who had previously under-gone therapy for metastatic melanoma.

Design: In a randomized, double-blind, phase 3 study,HLA-A*0201–positive patients with unresectable stageIII or IV melanoma that had progressed during previoustherapy for metastatic disease were enrolled betweenSeptember 2004 and August 2008 at 125 centers in 13countries in North America, South America, Europe,and Africa. All were randomly assigned in a 3:1:1 ratioto receive either ipilimumab (3 mg/kg body weight) plusgp100, ipilimumab alone, or gp100 alone every 3 weeksfor a total of 4 treatments (induction). Eligible patientscould receive reinduction therapy. The primary endpoint was OS.

Summary: Among a total of 676 patients, 403received ipilimumab plus gp100, 137 received ipilim -umab alone, and 136 received gp100 alone. The medi-an OS was 10.0 months among patients who receivedipilimumab plus gp100, versus 6.4 months among thosewho received gp100 alone (HR for death, 0.68; P<.001) and 10.1 months among those given ipilimum-ab alone (HR for death in the comparison with gp100alone, 0.66; P = .003). OS did not differ betweenpatients who received ipilimumab alone and thosegiven the combination (HR with ipilimumab plusgp100, 1.04; P = .76). Grade 3 or 4 immune-relatedadverse events occurred in 10% to 15% of patients whoreceived ipilimumab and in 3% who received gp100alone. Fourteen deaths were related to the study drugs(2.1%), and 7 were associated with immune-relatedadverse events.

Takeaway: This randomized, 3:1:1 ratio trial showedthat ipilimumab, with or without gp100, improved OSby 32% to 34% compared with gp100 alone. This is thefirst agent to show such an improvement in OS inmetastatic melanoma. Furthermore, gp100 did notimprove patient outcomes compared with ipilimumabalone. The primary adverse effects associated with ipi -limumab are immune-mediated, manifested as gastroin-testinal tract or dermatologic reactions (ie, rash, pruri-tus, or vitiligo). A total of 14 patients (2.1%) had theirmortality associated with ipilimumab therapy, 7 of

which were related to immune-mediated adverse eventsaffecting the gastrointestinal tract: colitis and sep-ticemia associated with bowel perforation—inflammato-ry colitis, bowel perforation, or multiorgan failure—peri-tonitis. Ipilimumab may be considered for patients inwhom previous therapies have failed.Hodi FS, et al. N Engl J Med. 2010;363:711-723.

■ Beta-Blocker Therapy Linked to ReducedProgression of Thick MelanomaBackground: The association between beta-adreno-

ceptor antagonist (beta-blocker) therapy and the over-all risk of cancer or of specific, prevalent cancers, suchas breast cancer, has not been established. However, theresults of a new study suggest that beta-blockers mayreduce the risk of prostate cancer, and findings frompreclinical studies indicate that beta-blockers inhibittumor growth and metastasis in animal models ofmelanoma.

Design: Researchers at a dermatology clinic inFlorence, Italy, prospectively reviewed clinical recordsfrom 1993 through 2009 of all patients with histological-ly confirmed malignant melanoma (Breslow thickness>1 mm). Disease progression was indicated by evidenceof sentinel lymph node metastasis and lymphatic, in-transit, or visceral metastasis. Deaths by any cause andthose due to melanoma were recorded, and medicationuse patterns were determined from patient interviewsduring the first visit and at each 6-month follow-up visitand from the patients’ general practitioner once a yearduring the study period. Patients who had reported beta-blocker use for at least 1 year were considered to haveundergone treatment. Median OS and median disease-free survival (DFS) were calculated, and a Cox propor-tional hazards model was used to evaluate the influenceof treatment on DFS and OS, adjusting for significantconfounders.

Summary: Of 121 consecutive patients documentedwith a thick melanoma, 30 had been undergoing beta-blocker therapy for 1 year or more, whereas theother 91 had not undergone treatment. After a medianfollow-up period of 2.5 years, tumor progression wasobserved in 3.3% of patients prescribed beta-blockersand in 34.1% of those who were not. The Cox model ondisease 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 beta-blockers, but among those who were not taking beta-blockers, 24 had died.

Takeaway: This retrospective study produced aninter esting outcome—beta-blocker therapy for more


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

■ Bisphosphonates May Reduce the Risk ofColorectal Cancer in Postmenopausal WomenBackground: Bisphosphonates are often used to treat

osteoporosis and bone metastases caused by breast can-cer and, in fact, have been shown recently to reduce therisk of that type of cancer, possibly by acting throughthe mevalonate pathway. Their effect on the risk ofother cancers, however, is unknown.

Design: Computerized health service pharmacyrecords were examined to evaluate the dose-responserelationship between the duration of long-term bispho-sphonate use and the risk of colorectal cancer (CRC)among 933 pairs of postmenopausal women and age-,sex-, clinic-, and ethnic group–matched individuals

recruited between 2000 and 2006 in the ongoing popu-lation-based, case-controlled Molecular Epidemiologyof Colorectal Cancer Study in Israel.

Summary: Bisphosphonate therapy lasting for morethan 1 year before diagnosis, but not for less than 1 year,was associated with a significantly reduced relative risk ofCRC (relative risk, 0.50; 95% CI, 0.35-0.71), even afteradjustment for possible confounders or effect modifierssuch as vegetable consumption, sports activity, familyhistory of CRC, body mass index, and the use of low-dose aspirin, statins, vitamin D, or postmenopausal hor-mones (relative risk, 0.41; 95% CI, 0.25-0.67).Bisphosphonate therapy combined with statin use, how-ever, did not lower the risk for CRC further.

Takeaway: Bisphosphonates have been associated witha low risk for breast cancer. Inhibition of angiogenesis andof tumor-cell adhesion and promotion of apoptosis areother antitumor mechanisms that have been suggested forthe benefits associated with bisphosphonates. This retro-spective study of bisphosphonate therapy for more than 1year significantly decreased the risk for CRC by 59%.Alendronate was used in almost 95% of patients in thebisphosphonate group. Patient adherence was estimatedto be 89% to 96% and depended on the dosing schedule.These data suggest that bisphosphonates should be con-sidered for future cancer prevention studies.Rennert G, et al. J Clin Oncol. 2011;29:1146-1150.

IN THE LITERATURE


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

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

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

–––––––––––––––––––––––––––––––––––––––––––––––––– 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

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONSee full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1)

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFTelevations 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)

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, AustraliaManufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, IndiaDistributed by: Hospira, Inc., Lake Forest, IL 60045 USA Reference EN-2761

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

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

Exclusive Onco-Tain™ packaging for safe handling1

Clarity of glass

Barrier sheath

PVC reinforced bottom

P11-3247-8.125x10.875-Apr., 11 � only

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

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

1. Data on fi le at Hospira

Indications and Usage Safety Information

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fl uid 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.

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid RetentionSee 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

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

• 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 fl uid retention may occur despite dexamethasone

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

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