May 2010 Vol 3, No 3

SECOND ANNUAL REVIEW

©2010 Green Hill Healthcare Communications, LLC

Emphasizing advances in patient management based on recently released data.

The Leader

in News and

Meeting

Coverage

MAY 2010 www.TheOncologyPharmacist.com VOL 3, NO 3

HEMATOLOGIC MALIGNANCIES

SUPPORTIVE CARE

SOLID TUMORS

Management ofChemotherapy-induced PeripheralNeuropathyVirginia Sun, RN, PhD(c)

Chemotherapy-induced Nausea and VomitingSandra E. Kurtin, RN, MS,AOCN, ANP-C

Infusion-relatedReactionsChristopher Campen, PharmD,BCPS; Nolan Ngo, PharmD, BCPS; and Ali McBride, PharmD, MS,BCPS

TreatmentUpdates: AcuteMyeloid LeukemiaMarc A. Earl, PharmD,

BCOP

Update on ChronicMyeloid LeukemiaBrian G. Cochran, PharmD,BCOP

Multiple Myeloma: A ReviewStephanie S. Taber, PharmD,BCOP

Advances inBreast SurgeryLaura Dominici, MD; and Mehra Golshan, MD

Advances in theTreatment ofColorectal Cancer Marlo Blazer, PharmD, BCOP

Personalizing Non–small-cell LungCancer TreatmentTara L. Rich, MSN, RN, CNP

Update onCastration-resistantProstate Cancer: AReview of SystemicInnovationsMegan McKee, PharmD, BCPS;Anita Aracelli Garcia, PharmD, BCOP; Bradi L. Frei, PharmD, BCPS, BCOP;and Scott Soefje, PharmD, BCOP

Advances in SkinCancer: Focus onMelanomaLois J. Loescher, PhD

Medical Managementof Breast Cancer Cynthia Frankel, RN, OCN

TOP_May2010:TON 5/4/10 12:21 PM Page Cov1

Totect® Kit (dexrazoxane) for injection is for intravenous infusion only. Totect is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

TWO PRICE OPTIONS AVAILABLE

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Demonstrates 98% overall e!cacy based on two biopsy-confirmed clinical trials1,2 inreducing or avoiding surgical intervention (i.e., surgical debridement, plastic surgery and their related costs), thereby reducing postponement of a patient’s chemotherapy treatments and the avoidance of long-term consequences.

Cited in nursing guidelines3,4 and oncology safety standards5.

For more information, call 866-478-8274 or visit our website at www.totect.comTo order Totect®, contact one of our authorized distributors.

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1 Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane).Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550.2 Totect® package insert.3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommenda-tions for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009.4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009.5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658.© 2010 TopoTarget USA. All rights reserved. TOT0111/4-10Totect and its logo mark are registered trademarks of TopoTarget A/SImage is copyright © Photo Researchers, Inc.

ARE YOU PREPARED?

Pharma Chemo Ad 4 23 10 indd 1 4/26/10 3:52:48 PM

TOP_May2010:TON 5/3/10 10:12 PM Page Cov2

Rx onlyTotect® is a registered trademark of TopoTarget A/SUS Patent No. 6,727,253B2NDC 38423-110-01

Manufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146

Hameln Pharmaceuticals GmbH31789 HamelnGermany

Manufactured for:TopoTarget A/SSymbion Science ParkFruebjergvej 3DK-2100 CopenhagenDenmark

TOT0111/4-10© 2010 TopoTarget USA

www.totect.com

Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Totect is a cytotoxic drug. Vial contents must be mixed and diluted before use. Totect should not be mixed or administered with any other drug during the infusion. Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasa-tion. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the !rst day. The Totect dose should be reduced 50% for patients with creati-nine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the a"ected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.3-5 Direct contact of Totect® with the skin or mucous membranes prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water. Contraindications: None.Warnings and Precautions: Myelosuppression: treatment with Totect is asso-ciated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Use in Pregnancy: Pregnancy Category D. Totect can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions: The most common adverse reactions (# 16%) are nausea, pyrexia, injection site pain and vomiting.

Drug Interactions: No drug interactions have been identi!ed. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treat-ment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Speci!c Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and e"ectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Be-cause elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused signi!cant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

Pharma Chemo Ad 4 23 10 indd 2 4/26/10 3:52:48 PM

TOP_May2010:TON 5/3/10 10:13 PM Page 1

CO-EDITOR-IN-CHIEFSusan Goodin,PharmD, FCCP,BCOPCancer Institute of New JerseyNew Brunswick, NJ

CO-EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer CenterCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C.Gammon, BS PharmUniversity ofMassachusetts Memorial HospitalWorcester, MA

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase Cancer CenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDNovant HealthWinston-Salem, NC

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud,PharmD, BCOP,FASHPThe University of TexasM. D. Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina College ofPharmacyColumbia, SC

Steve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Managed Care andPharmaceuticalManagementBurt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Editorial Board

2 MAY 2010 I VOL 3, NO 3 www.TheOncologyNurse.com • www.TheOncologyPharmacist.com


Developments in oncologycome at a rapid pace. Justin the past few days, as we

were preparing this issue for publi-cation, a new drug was approvedfor prostate cancer, a new indica-tion for a drug used in the treat-ment of lung cancer was granted,and updated results of a study ofdrug therapy for multiple myelo-ma were published. We justreturned from the annual meetingof the Hematology/Oncology

Pharmacy Association; the Academy of Managed CarePharmacy met last month; and the annual meetings ofthe American Society of Clinical Oncology (ASCO),the International Society of Oncology Pharmacy Prac -titioners, and the Oncology Nursing Society (ONS) willbe held in the next few weeks. Data presented at thesemeetings, even those not focused on the practice of phar-macy specifically, will likely impact the practice ofoncology pharmacy.

With time and budget constraints, most pharmacistscan attend only a limited number of meetings each year,

but keeping up to date on the latest treatment, support-ive care, and practice management trends presented atthese meetings is necessary to optimize our role in treatmentof cancer patients. Added to this is the near-impossible taskof keeping up with the latest medical and pharmacy jour-nals. That is why The Oncology Pharmacist each year asksexperts in various aspects of cancer care to review studiespresented at major meetings in the past year and publishedin the peer-reviewed literature and to comment on theirpotential clinical applications.

This annual review issue provides cutting-edge infor-mation from expert nurses, physicians, and pharmaciststo help keep us informed in these ever-changing times.The ever-growing number of new cancer therapiesenable us to personalize treatment to achieve optimalpatient outcomes, but with new agents come new deci-sions about selection of treatment and new potentialadverse effects. As pharmacists, we have to be preparedto consult with our fellow healthcare providers andcounsel patients about use of new agents and how tomanage side effects.

We encourage you to share this special issue with yourfriends and colleagues so that everyone can benefit fromthe information presented. !

SOLID TUMORS

8 Advances in breast surgery

10 Medical management of breastcancer: update from the SanAntonio Breast CancerSymposium 2009

12 Advances in skin cancer: focuson melanoma

16 Advances in the treatment ofcolorectal cancer

22 Update on castration-resistantprostate cancer: a review ofsystemic innovations

30 Personalizing non–small-cell lungcancer treatment

HEMATOLOGIC MALIGNANCIES

34 Treatment updates: acute myeloidleukemia

38 Update on chronic myeloidleukemia

51 Multiple myeloma: a review

SUPPORTIVE CARE

41 Management of chemotherapy-induced peripheral neuropathy

44 Chemotherapy-induced nauseaand vomiting: clinical updates

46 Infusion-related reactions

DEPARTMENTS4 Health Economics

Updates from the Academy of Managed CarePharmacy 22nd annual meeting & showcase

6 Specialty PharmacyThe NCCN Task Force on Specialty Pharmacyissues preliminary report

6 Recent FDA Approvals

MAY 2010 • VOL 3, NO 3

PUBLISHING STAFFPublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Associate EditorDawn [email protected]

Director, Client ServicesJohn W. [email protected]

Production ManagerStephanie Laudien

Business ManagerBlanche [email protected]

Executive AdministratorAndrea Boylston

Circulation [email protected]

Editorial Contact:Telephone: 732-992-1891 Fax: 732-656-7938

EDITORIAL CORRESPONDENCE should be addressedto EDITORIAL DIRECTOR, The Oncology Pharmacist®,241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: [email protected]. YEARLY SUBSCRIP-TION 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. Correspondenceregarding permission to reprint all or part of any article pub-lished in this journal should be addressed to REPRINT PER-MISSIONS DEPARTMENT, Green Hill HealthcareCommun i cations, LLC, 241 Forsgate Drive, Suite 205C,Monroe Twp, NJ 08831. The ideas and opinions expressed inThe Oncology Pharmacist® do not necessarily reflect those of theEditorial Board, the Editorial Director, or the Publisher.Publication of an advertisement or other product mention inThe Oncology Pharmacist® should not be construed as anendorsement of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damage to per-sons or property arising out of or related to any use of thematerial contained in this periodical. The reader is advised tocheck the appropriate medical literature and the product infor-mation currently provided by the manufacturer of each drug tobe administered to verify the dosage, the method and durationof administration, or contraindications. It is the responsibilityof the treating physician or other healthcare professional, rely-ing on independent experience and knowledge of the patient,to determine drug dosages and the best treatment for thepatient. Every effort has been made to check generic and tradenames, and to verify dosages. The ultimate responsibility, how-ever, lies with the prescribing physician. Please convey anyerrors to the Editorial Director. ISSN #1944-9607.

The Oncology Pharmacist® is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 Forsgate Drive,Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2010 by GreenHill Healthcare Communications LLC. All rights reserved.The Oncology Pharmacist® logo is a registered trademark ofGreen Hill Healthcare Com munications, LLC. No part of thispublication may be reproduced or transmitted in any form orby any means now or hereafter known, electronic or mechani-cal, including photocopy, recording, or any informational stor-age and retrieval system, without written permission from thePublisher. Printed in the United States of America.

Cover Art: Copyright CML–iStockphotos.com/Murat $en,MM–iStockphotos.com/Sebastian Kaulitzki, CIPN–iStockphotos.com/James Steide, CINV–iStockphotos.com/Catherine Yeulet, IRR–iStockphotos.com/Ernst Daniel Scheffler, Breast Surgery–iStockphotos.com/Les Palenik, Colorectal Cancer–iStockphotos.com/Sebastian Kaulitzki, Lung Cancer–iStockphotos.com/WILLSIE, Skin Cancer–Photo courtesy of Kenneth Tanabe, MD,Breast Cancer–iStockphotos.com/Mutlu Kurtbas, Prostate Cancer–Stockphotos.com/Mark Kostich

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INTRODUCTION

CONTENTS

www.TheOncologyNurse.com • www.TheOncologyPharmacist.com MAY 2010 I VOL 3, NO 3 3

Patrick Medina,PharmD, BCOP

TOP_May2010:TON 5/4/10 10:57 AM Page 3

www.TheOncologyNurse.com • www.TheOncologyPharmacist.com4 MAY 2010 I VOL 3, NO 3

Health Economics

Health Economic Updates from

The Academy of Managed Care Pharmacy 22ndAnnual Meeting & ShowcaseApril 7-10, 2010 • San Diego, California

By Jennifer Erickstad

Variant Methodology Impedes Cost-effectiveness ResearchDespite increasing interest in cost-effectiveness research (CER), the groups con-

ducting these analyses continue to use models that are very different from each other,hampering a more precise understand ing of drug comparability. This is what a teamof researchers from Parexel Consulting found when they examined CER on theworld’s highest-selling drugs.

The team analyzed CER published in peer-reviewed journals between 1999 and2008. For each analysis, they collected data on the com-parator drug used, indication, in cremental cost-effective nessratio (ICER), time duration, and the type of model, amongother characteristics.

The researchers found a large variability in CER for thesame drugs for different indications, as well as in themethodology used by groups when determining CER for thesame indications. Spec ifically, different groups selected var-ious comparator drugs, used distinct overall treatment costsin the calculation, and projected the costs over dissimilartime frames, which made it difficult to compare outcomes.Primary care drugs had less variability than specialty drugs.

Lead researcher Saurabh Aggarwal, PhD, noted that improvements should be madeto the US healthcare system’s ICER methodology. “Unlike single-payer systems, suchas the UK—which has in-house experts to evaluate manufacturers’ CER models—theUS system’s several hundred payers each evaluate CER differently; our system wouldbenefit immensely if organizations such as AMCP [Academy of Managed CarePharmacy] or ISPOR [International Society for Pharmacoeconomics and OutcomesResearch] would develop standards for building CER models,” he said. Ac cording toJim Smeeding, RPh, MBA, president of the JestaRx Group and former ISPOR presi-dent, ISPOR “continues to examine ideas such as CER modeling and has begun todevelop a task force to further investigate this issue.”

Pemetrexed as Maintenance Therapy Likely to Have “Minimal Impact” onHealth Plan Budget

In the first study to estimate the budgetary impact of accepting pemetrexed asma intenance ther apy for non–small-cell lung ca ncer (NSCLC), re search ers foundthat adopting the drug did not significantly affect a health plan’s budget.

Using a model designed to represent a 1 million–member health plan over a 1-year time frame, the re search team—consisting of members from the consultingfirm Medical Decision Modeling and Eli Lilly—in put a series of variables, includ-ing the estimated market shares of several maintenance therapies before and afterthe introduction of pemetrexed (garnered from a survey of oncologists); chemother-apy drug costs (ob-tained from Medicare reimbursement rates); nondrug treatmentcosts (derived from a claims database of patients with lung cancer); and the numberof NSCLC patients eligible for maintenance therapy (based on Surveillance,Epidemiology and End Results data).

The model showed that, assuming a 50% increase in the number of patientsreceiving maintenance therapy as a result of the adoption of pemetrexed, thetotal annual cost increase would be $365,323. However, considering savings frompatients who would switch to maintenance therapy from more expensive first-linetherapy, the net budget impact would be $317,070. This translated to a cost of$679.22 per treated member per month and a per member per month (PMPM)cost of $0.026.

The team concluded that only large increases in the number of maintenancepatients would likely cause PMPM costs to rise by more than $0.03. According tolead study author Robert W. Klein, MS, lead decision analyst with Medical DecisionModeling, the findings provide “valuable information to consider in evaluatingtreatment options available to plan members.” Outcomes researcher Bruce Hillner,a professor and associate chair of infor mation sciences in the Department of InternalMedicine at Virginia Com mon wealth University, who was not affiliated with thestudy, notes that anchoring future research in data from health plan audits willimprove the understanding of pemetrexed’s impact on health plan budgets.

Survey Provides a Window into Payers’ Decision-making ProcessPayers believe that prescribing information, national guidelines, and pro spec-

tive controlled randomized trials (PCRTs) are the most useful sources of infor-mation about oncology drugs, according to researchers from Genen tech, Inc.Presenting their findings, lead researcher Ellen Yang, PharmD, a medical com-munications fellow, noted that the study’s conclusions may help manufacturersmore easily meet the evidentiary needs of payers while remaining within regula-tory and legal boundaries.

The study consisted of a 22-item electronic survey that questioned payers ontheir oncology drug review process and the types of evidence they use when mak-ing formulary, coverage, and re -imbursement decisions. The overall response ratewas 15%. Of those who responded, 79% managed oral cancer drugs and 52%managed intravenous therapies; 83% were pharmacists.

Survey results showed that 83% said prescribing information was “useful” or“very useful,” followed by national treatment guidelines (80%), and PCRTs(76%). Economic models fell at the bottom of the list (13%), along with non-controlled trials/retrospective studies (13%), and published pharmacoeconomicstudies (17%). Approximately three fourths of survey respondents noted thatthey value Academy of Man aged Care Pharmacy dossiers and reprints of studyarticles from peer-reviewed journals.

Although the sample size was small, Yang believes the findings still providevaluable information for manufacturers looking to optimize their communica-tion with payers. According to Peter Neumann, ScD, director of the Center forthe Evaluation of Value and Risk in Health at Tufts New England MedicalCenter, the survey “underscores that payers are looking at multiple sources forevidence on the clinical effectiveness of oncology drugs and that they value rig-orous design and independently conducted or verified analyses.”

Researchers Analyze Relationship Between Pharmacogenomics andAppropriate Oncology Care

Pharmacogenomic (PGx) testing seeks to optimize treatment by ensuringpatients receive the best-suited drug based on interindividual genetic variation.Currently, no published data exist on how this may influence the appropriatenessof oncology treatment within a utilization management program. Seeking to reme-dy this, researchers from CVS Caremark analyzed data from their own utilization

management program, within which PGx testing requirements are im ple mented for certain oncology therapies andspecific in dications.

After gathering data on all of the pa tient assessmentsthat re quired PGx testing between July 1, 2009, andDecember 31, 2009, the researchers categorized them intothree groups: PGx performed and patient met criteria,PGx performed and patient did not meet criteria, and PGxnot performed and patient did not meet criteria. Theyfound that of the 801 total assessments, 424 required PGx;in 98% (417) of these, the test was actually conducted.

According to lead researcher Sherry Siegert, PharmD,the fact that such a “very high” percentage of patients

received PGx testing when it was required “may indicate that most oncologists areprescribing in accordance with currently accepted guidelines for cancer care.” In addi-tion, although she acknowledges that the study’s small sample size and short durationimpeded the team from developing a complete picture of agent utilization, she addsthat payers can still use certain practices to support therapy appropriateness, includ-ing requesting copies of PGx test results and ensuring the laboratory quality of suchtests meets standard requirements for clinical and analytical validity.

Researcher M. Eileen Dolan, PhD, professor of medicine and chair of theCommittee on Clinical Pharmacology and Pharmacogenomics at the Uni versity ofChicago, notes that using pharmacogenomics is “particularly im portant to reducethe likelihood that patients will receive an ineffective drug while enduring sideeffects that can be severe, possibly even life-threatening.”!

Saurabh Aggarwal, PhD

Sherry Siegert, PharmD


Protection is Prevention.

Readers of The Oncology Pharmacist

Thank you for being a part of the Second Annual National Safe Handling Awareness Month and for encouraging best practices in preventing hazardous drug exposure.

If you did not have the opportunity to participate in the free Safe Handling Awareness Day CE webinar presented April 20, a recorded version is now available online.

To take advantage of this free webinar – and additional pharmacy CE programs offered compliments of Carmel Pharma, the maker of PhaSeal® – visit www.carmelpharmausa.com/CE or call 877-487-9250.

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Specialty Pharmacy

The NCCN Task Force on Specialty PharmacyIssues Preliminary ReportBy Audrey Andrews

Hollywood, FL—As specialty pharma-cy (SP) expands rapidly into oncology,there is a need to better define its role.This was the aim of the NationalComprehensive Cancer Network(NCCN) Task Force on SpecialtyPharmacy, whose chair presented thegroup’s preliminary report at theNCCN 15th Annual Conference.

“There is a vibrant specialty phar-macy industry, and the impact in can-cer care is expanding,” said Rowena N.Schwartz, PharmD, BCOP, director ofoncology pharmacy, Johns HopkinsHospital in Baltimore, Maryland.

Much of the interest in SP comesfrom the evolving role of oral anti-neoplastic agents. Of the 400 newantineoplastic agents in the pipeline,25% are planned as oral drugs, andspending on oral agents has morethan doubled since 2002 (J NatlCompr Canc Netw. 2008;6[Suppl 3]:S1-S14). Specialty pharmacists mayprove to be a valuable source ofinformation on using these new med-ications safely, effectively, and eco-nomically, according to Schwartz.

The task force explored aspects ofSP that are unique to oncology andpresented recommendations for join-ing SP and oncology. In particular, thetask force addressed the mechanismsand potential benefits of SP as a distri-bution channel for oncology therapeu-tics. It identified opportunities as wellfor disease-state management, cost ofcare, clinical research, and safety.

“The task force wanted to demon-strate that there are opportunities tooptimize cancer care by partneringwith specialty pharmacy,” she said.“We wanted to show how specialtypharmacy is cost-saving and offersvalue to third-party payers.”

Defining specialty pharmacyThe task force defined SP as a

pharmacy service model designed to

fill the perceived gaps in pharmaceuti-cal care associated with traditionalcommunity pharmacy practices. Inoncology, the scope of the practiceincludes the oral antineoplastic agentsand supportive care medications, suchas erythropoiesis-stimulating agents.Health maintenance and managementof comorbidities is also part of SP.

The current operational modelsinclude limited-distribution medica-tions, infusion services, mail order,and distribution of medication viathe community pharmacy network.

SP serves as a “hub” between pre-scribers, the drug manufacturer, andthe patient, Schwartz explained.Within this hub is a patient/providerregistry, verification of insurancecoverage, and monitoring of treat-ment adherence and side effects. SPcan also be involved in outcomesassessment, which is a growing needin the current environment.

Advances in patient care“Patients are increasingly expected

to share more of the cost burden of theoral antineoplastics,” she observed.There are high copays, tiered coverage,and the infamous “doughnut hole” aswell as hidden costs, such as changes inmedication that lead to medicationwaste. “Specialty pharmacy offers cost-friendly strategies to reduce costs topatients,” according to Schwartz.

SP also enhances medication safetythrough product familiarity, productavailability and access, individualizedmonitoring, data tracking, and haz-ardous waste disposal. Additionally,patients in clinical trials can havetimely drug access, coordination ofcare (ie, modification of dose), andcoordination of information throughSP, the task force pointed out.

But coordination of cancer care isperhaps the most important concernof SP. “We need to find out how spe-

cialty pharmacy can impact positive-ly on cancer care,” Schwartz said,“and not fragment care or confusepatients about the care they receive.”

Optimal coordination of care willinclude not only authorization anddrug distribution but also patient edu-cation, treatment monitoring, and dis-ease management. This expandedresponsibility for oncology pharmacistshighlights the need for team collabora-tion and a change in mindset about therole of phar m acy. The specialty phar-macist’s unique training can be anasset to pa tients and oncologists alike,she pointed out.

“One of the great things about spe-cialty pharmacy is you are often work-

ing with pharmacists who are veryknowledgeable about the products theyare dealing with and therefore have alot of information for patients and theirfamilies,” Schwartz explained.

One area the task force did not tack-le, however, were drug costs and eco-nomic concerns—maintaining theseissues are too broad and complex for itsmission. However, the group did rec-ommend that an alternative financialmodel for pharmacy reimbursement bedesigned—one that will “get awayfrom selling a product to providingservices of value,” Schwartz explained,and that inefficiencies associated with increased cost be identified andeliminated. !

• Specialty pharmacy personnel should be “trained” in oncology.• Optimal coordination of care for patients and their families should be the

priority.• Communication among all members of the oncology team involved in drug

therapy decision-making should be standardized, using a common language.• Strategies should be created to assure coordination of care for patients treat-

ed in multiple healthcare settings.• Health information technology systems (ie, electronic health records) should

be developed and used to foster collaborative care.• Shared-data needs (ie, for integration of case management, insurance cover-

age, clinical information and outcomes) should be identified and nationalstandards established.

• Standards and requirements for care coordination and medication safetyshould be developed.

• Operational processes that support frequent changes of treatment should beestablished (eg, allowing dispensing of smaller amounts of medication at onetime).

• Regulations should be implemented for dispensing and handling of oralchemotherapy.

• The use of “brown bagging” (ie, purchases made at one place but administeredin another) for chemotherapy, antineoplastic agents, and supportive caremedications should be eliminated.

Preliminary Recommendationsby the NCCN Task Force onSpecialty Pharmacy

Recent FDA ApprovalsErlotinib for Initial Maintenance for NSCLC

The US Food and Drug Administration (FDA)has granted approval for a new indication thatexpands the use of erlotinib (Tarceva, OSIPharmaceuticals) to include first-line maintenancetherapy for locally ad vanced or metastatic non–small-cell lung cancer (NSCLC).

Approval was based on the results of the phase 3SATURN trial, a placebo-controlled, randomized,double-blind study with 889 advanced NSCLCpatients. Overall survival in patients treated witherlotinib improved 23% compared with those in theplacebo group (HR, 0.81; P = .0088). Patients in theerlotinib group also had a 41% improved progres-

sion-free survival compared with those in the place-bo group (HR, 0.7129; P <.0001).

The drug was previously approved for second-line therapy for locally advanced or metastaticNSCLC and for locally advanced, unresectable, ormetastatic pancreatic cancer (in combination withgemcitabine). !


Magenta, Y

© 2009 Genentech USA, Inc. All rights reserved. 9708400 Printed in USA.

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in oncology

At Genentech BioOncology, we’re leading the fi ght against cancer with innovative science. We believe that great science and the right people can lead to signifi cant advances in cancer treatment.

Dedicated scientists — Our researchers are dedicated to defi ning the molecular basis of cancer and developing groundbreaking treatments.

Gold standard clinical development — We identify biomarkers and develop companion diagnostics wherever possible, with the goal of matching each patient with the most appropriate therapy.

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Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

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TON_May2010_v3_TON 5/3/10 6:30 PM Page 7

The discipline of breast surgery,like many specialties, has movedtoward a minimally invasive

approach to local therapy. Radical sur-gery had previously been the standard;however, surgical approaches continueto evolve as we gather more data aboutthe oncologic safety of less invasive pro-cedures. In addition, we are placingmore emphasis on targeted therapy, andsurgery is an integrated portion ofpatient care. Most patients are diag-nosed with image-guided biopsies in -stead of surgical excision, allowing forbetter surgical planning and fewer proce-dures.1 Further more, most patients arebeing diagnosed at earlier stages due tothe increased use of screening mammog-raphy, and therefore most are candidatesfor breast conservation. For women withearly-stage breast cancer, the sentinellymph node biopsy procedure is widelyaccepted and its application is growing,which spares more women the morbidityof axillary lymph node dissection.

In some cases, we may still recom-mend or women may choose to undergomastectomy, but we are improving ourability to provide cosmetically accept-able procedures with oncologicallyacceptable outcomes. Most women arecandidates for immediate reconstruc-tion and skin-sparing mastectomy. Weare still exploring our ability to preservethe nipple-areola complex.

Breast-conservation therapyBreast-conserving surgery is the treat-

ment of choice for early-stage primarybreast cancers.2 For this surgery, the goalis to remove the tumor with clear mar-gins while preserving the cosmesis ofthe breast.3 This surgery is followed byradiation therapy to minimize the risk oflocal recurrence within the breast. TheNational Surgical Adjuvant Breast andBowel Project (NSABP) B-06 studyfound that postlumpectomy radiationdecreased the rate of local recurrencefrom 39% to 14%.4

The American College of Radiologyand the American College of Surgeonsissued guidelines for the selection ofpatients for breast-conserving surgery.They recommended5:

• Patients with unifocal disease areappropriate candidates.

• Diffuse calcifications may con-traindicate breast-conserving sur-gery. En bloc removal of calcifica-tions is preferred, but limitedresection and close imaging follow-up are possible when the radiologistis confident that calcifications arebenign.

• Previous therapeutic radiation tothe chest is a contraindication tobreast-conserving surgery.

• Radiation is traditionally contrain -dicated in pregnant women, butbreast conservation can be offeredto women using a thoughtful, multi-disciplinary approach when deliver-ing radiation postpartum does notcause too long a delay.6

• Inability to achieve negative mar-gins on a lumpectomy specimenmay result in increased risk oflocal recurrence, delay in adjuvanttherapy, and a change in cosmeticoutcome.

• Certain connective tissue disordersmay be associated with increasedmorbidity after delivery of radiation.

• Tumors should be less than 5 cm,because clinical trials of breast-con-serving surgery involved T1 and T2lesions. Tumor size in comparisonwith breast size is also a considera-tion, both for ability to deliver ade-quate radiation and cosmesis.

Patients with larger tumors maybecome candidates for breast-conservingsurgery with the use of neoadjuvant orpreoperative chemo therapy, endocrine

therapy, and/or targeted therapy. In theNSABP B-18 trial, patients with largerunifocal tumors were found to haveimproved ability to undergo breast-con-serving surgery (68% vs 60%) with nostatistically significant difference in localrecurrence or survival at a median fol-low-up of 6 years.7,8

Previously, women with tumorsinvolving the nipple-areola complex orthe subareolar area were recommendedto undergo mastectomy. We now under-stand that women with disease confinedto that area who can achieve negativemargins may be candidates for centrallumpectomy. This course of action hasbeen shown to be oncologically safe.9These women can go on to have electivenipple-areola complex reconstructionafter completion of radiation therapy.

MastectomyFor women who prefer or are required

to undergo mastectomy, advances in sur-gical technique afford them an oncolog-ically safe procedure with greater atten-tion paid to patient satisfaction andcosmetic outcome. Mastectomies canoften be performed using a skin-sparingtechnique that preserves as much of thepatient’s own skin as possible as well asthe inframammary fold. The techniqueprovides a natural envelope, which canbe filled with implant or autogenous tis-sue during the reconstruction. This tech-nique allows for a closer match to thecontralateral breast when reconstructionis performed. With careful attention toflap thickness and removal of breastparenchyma, the rates of local recurrenceare shown to be equivalent to that ofstandard mastectomy.10,11 Women whowill definitely or may require postmastec-tomy radiation therapy (PMRT) are stillrecommended to undergo mastectomy,with most needing a delay in reconstruc-tion. Women who may require PMRT,however, may be afforded the benefit ofskin-sparing mastectomy and reconstruc-tion with the use of tissue expanders.These women still derive the benefit ofskin preservation as well as the psycho-logical benefit of waking from surgerywith a breast mound, without compro-mising the delivery of radiation thera-py.12 The area of reconstruction in thesetting of PMRT is still controversial,and most radiation oncologists andreconstruction surgeons would prefer a

delayed approach in this setting.Skin-sparing mastectomy has tradi-

tionally included removal of the nipple-areola complex, but in appropriate can-didates, preservation of the nipple-areolacomplex can be oncologically sound andprovide excellent cosmetic results. Thereis growing interest in the safety of thisprocedure, particularly as the numbers ofprophylactic mastectomy for risk reduc-tion grow. In recent studies, rates of localrecurrence have not been significantlydifferent from those for mastectomy orskin-sparing mastectomy.13 Patients withsmall peripheral tumors, as well as thoseseeking prophylactic mastectomy, mayundergo this procedure, potentiallyresulting in increased patient satisfactionand necessitating fewer reconstructiveprocedures. The best outcomes are seenin women with breasts that are nonptot-ic and small to medium in size, with noprevious history of radiation to thebreast, and with no prior periareolar inci-sions. With selection of appropriate can-didates, attention to nipple/areolaranatomy, and appropriate use of intraop-erative pathology and preoperativebreast imaging, the rate of nipple necro-sis is low and cosmetic outcomes areexcellent.14,15 The oncologic safety of thisprocedure will be better determinedwhen more of the current studies havelong-term follow-up data available orwhen a randomized trial comparing thetechnique with traditional mastectomytechniques is undertaken.

Management of axillary lymphnodes

Lymphatic mapping and sentinellymph node biopsy were introducedmore than 15 years ago and are now thestandard axillary evaluation for womenwith clinically node-negative, early-stage breast cancer in the United States.These procedures, their indications, andtheir outcomes have generated greatresearch interest. The sentinel lymphnode dissection procedure carries signif-icantly less morbidity than the axillarylymph node dissection procedure.16 Thede creased rates of wound infections,seromas, paresthesias, and incidence oflymp hedema17 improves quality of life inwomen with early-stage breast cancer.This is particularly important as thenumber of breast cancer survivors in -creases worldwide. Current research

Advances in Breast SurgeryBy Laura Dominici, MDAttending Surgeon, Department of Surgery, Brigham and Women’s Hospital, Dana-Farber Cancer Institute,Harvard Medical School, Boston

Mehra Golshan, MDDirector, Breast Surgical Service, Department of Surgery, Brigham and Women’s Hospital, Dana-Farber CancerInstitute, Harvard Medical School, Boston

Solid Tumors


Laura Dominici, MD

Mehra Golshan, MD


MAY 2010 I VOL 3, NO 3 9www.TheOncologyNurse.com • www.TheOncologyPharmacist.com

Solid Tumors

seeks to expand the indications for sen-tinel lymph node dissection.

Patients who are clinically node nega-tive and who undergo neoadjuvantchemotherapy are able to undergo axil-lary evaluation by sentinel lymph nodebiopsy before or after the administrationof chemotherapy with accurate re -sults.18,19 Further investigation is ongoingto determine whether women who areinitially node positive with excellentclinical response to neoadjuvant chemo -therapy may be candidates for sentinellymph node biopsy and, if pathologicallynode negative, this may obviate the needfor completion of node dissection.20 Ithas been shown to be safe for pregnantwomen to undergo mapping and sentinellymph node biopsy.21 As the indicationsfor the procedure expand, more womenmay be spared the morbidity of axillarylymph node dissection. The routine rec-ommendation for complete axillary dis-section in women with positive sentinelnodes or clinically positive nodes willcontinue to evolve toward axillary obser-vation or axillary radiation as we gainbetter understanding of tumor biology.

Minimally invasive ablation Nonsurgical removal or ablation of

breast tumors is a field of growing inter-est. Difficulties in assessing margins, con-firming complete destruction, and stan-dardizing postprocedure imaging stillprohibit acceptance of these techniques.Surgical removal of the primary breasttumor remains the gold standard. Thesetechniques, however, may be useful forbenign lesions as well as for palliativeablation of lesions for women withmetastatic disease or women who are notcandidates for surgery.

Percutaneous excisionMany women undergo percutaneous

biopsy of a breast mass to rule out malig-nancy or help in the planning of localtherapy. Percutaneous biopsy techniquesunder mammography or ultrasound canalso be employed to excise benign andmalignant breast lesions.22 The mostlikely indication for this technique willbe for benign lesions, because marginassessment is not possible. There are alsoanatomic restrictions in that the lesionshould not be too close to the skin, chestwall, or nipple-areolar complex.

Radiofrequency ablationThe effectiveness of radiofrequency

ablation (RFA) in treatment of primary

breast tumors has also been investigated.Tumors are visualized with ultrasound ormagnetic resonance imaging (MRI),and then a high-frequency alternatingcurrent creates frictional heating andablates the lesion. This technique hasshown promise in patients with smalltumors (<2 cm), although good resultsdepend on the imaging giving an appro-priate estimation of tumor size. Thistreatment is not appropriate for poorlydefined, extensive, multifocal, or multi-centric tumors. In addition, the tumormust be an adequate distance (1 cm)from the chest wall and skin to avoidburns.23 Other studies suggest that theuse of RFA after lumpectomy mayreduce the need for reexcision for inade-quate margins.24 This procedure couldalso be used for palliative ablation oftumors in women with metastatic dis-ease or women who are deemed to bepoor candidates for surgery.

Focused ultrasound ablationThis technique also uses thermal

tumor ablation. A 1.5-MHz ultrasoundsource ablates the lesion, and high-reso-lution imaging monitors tumor destruc-tion. No probe insertion is necessary.Thus far, the results are quite variable inregard to degree of tumor necrosis, rang-ing from 20% to 100%.25 Assessment ofmargins is also a concern. Tumors treatedby focused ultrasound ablation must bemore than 1 cm from the skin and chestwall to prevent thermal injury. Palliativetherapy is a possible indication for thisprocedure, as is the treatment of tumors2 cm or benign lesions.25

Laser ablationLess research has been done on the

technique of laser ablation for early-stagebreast cancer. This technique involvesdelivery of energy to the target via a fiber-optic probe inserted using imaging guid-ance. Ultrasound, mammography, andMRI have been used successfully in thistreatment. Although not extensivelystudied, this technique may be effectivefor treatment of small primary breasttumors and appears to be well tolerated.26

CryosurgeryWith cryosurgery, a freezing probe is

used to destruct cells by membrane rup-ture during successive freeze-thaw cycles.Using image guidance, the growth of thezone of freezing can be monitored. Thistechnique is successful at destroying thecenter of the lesion, but the periphery

often contains viable cells, so the zone ofablation needs to be larger than thetumor. The US Food and Drug Ad -ministration has approved this tech-nique for the destruction of fibroadeno-mas. Invasive tumors up to 1.5 cmwithout an extensive intraductal com-ponent also appear to be adequatelytreated by cryosurgery.27

ConclusionThe management of breast disease has

undergone a transformation from surgeryas the mainstay of therapy into a multi-disciplinary approach to treatmentinvolving surgeons, radiation oncolo-gists, medical oncologists, reconstructionsurgeons, pathologists, and radiologists.Further, more emphasis is being placedon the psychological and cosmetic out-come of surgery. More women are candi-dates for breast conservation surgery,either up front or with neoadjuvant ther-apy. Most wo men who undergo mastec-tomy have the benefit of a skin-sparingtechnique and the option of immediatereconstruction. Sentinel lymph nodebiopsy can be performed in women withearly-stage breast cancer to avoid themorbidity of axillary lymph node dissec-tion, and indications for sentinel lymphnode biopsy continue to grow. Treat mentwill evolve further as we emphasize theuse of targeted therapies tailored to anindividual patient’s breast cancer. In thefuture, minimally invasive techniquesmay be used to treat residual disease aftersuccessful treatment with targeted thera-py. As we continue to de monstrate onco-logic safety and equivalent outcomes tomore invasive techniques, these ap -proaches will continue to grow inacceptance. !

References1. Smith DN, Christian R, Meyer JE. Large-core

needle biopsy of nonpalpable breast cancers.The impact on subsequent surgical excisions.Arch Surg. 1997;132:256-260.

2. Mamounas, E. NSABP breast cancer clinical tri-als: recent results and future directions. CMR.2003;1:309-326.

3. Newman LA, Kuerer HM. Advances in breastconservation therapy. J Clin Oncol. 2005;23:1685-1697.

4. Fisher B, Anderson S, Bryant J, et al. Twenty-yearfollow-up of a randomized trial comparing totalmastectomy, lumpectomy, and lumpectomy plusirradiation for the treatment of invasive breastcancer. N Engl J Med. 2002;347:1233-1241.

5. Morrow M, Strom EA, Bassett LW, et al; forAmerican College of Radiology; AmericanCollege of Surgeons; Society of SurgicalOncology; College of American Pathology.Standard for breast conservation therapy in themanagement of invasive breast carcinoma. CACancer J Clin. 2002;52:277-300.

6. Rosenkranz KM, Lucci A. Surgical treatment ofpregnancy associated breast cancer. Breast Dis.2006;23:87-93.

7. Fisher B, Brown A, Mamounas E, et al. Effect ofpreoperative chemotherapy on local-regionaldisease in women with operable breast cancer:findings from National Surgical AdjuvantBreast and Bowel Project B-18. J Clin Oncol.1997;15:2483-2493.

8. Wolmark N, Wang J, Mamounas E, et al.

Preoperative chemotherapy in patients withoperable breast cancer: nine-year results fromNational Surgical Adjuvant Breast and BowelProject B-18. J Natl Cancer Inst Monogr. 2001;30:96-102.

9. Kawase K, DiMaio D, Tucker SL, et al. Paget’sdisease of the breast: there is a role for breast-conserving therapy. Ann Surg Oncol. 2005;12:391-397.

10. Carlson GW, Styblo TM, Lyles RH, et al. Theuse of skin sparing mastectomy in the treatmentof breast cancer: the Emory experience. SurgOncol. 2003;12:265-269.

11. Kroll SS, Khoo A, Singletary SE, et al. Localrecurrence risk after skin-sparing and conven-tional mastectomy: a 6-year follow-up. PlastReconstr Surg. 1999;104:421-425.

12. Kronowitz SJ, Robb GL. Radiation therapy andbreast reconstruction: a critical review of the lit-erature. Plast Reconstr Surg. 2009;124:395-408.

13. Gerber B, Krause A, Dieterich M, et al. Theoncological safety of skin sparing mastectomywith conservation of the nipple-areola complexand autologous reconstruction: an extended fol-low-up study. Ann Surg. 2009;249:461-468.

14. Vlajcic Z, Zic R, Stanec S, et al. Nipple-areolacomplex preservation: predictive factors of neo-plastic nipple-areola complex invasion. AnnPlast Surg. 2005;55:240-244.

15. Petit JY, Veronesi U, Orecchia R, et al. Nipplesparing mastectomy with nipple areola intraop-erative radiotherapy: one thousand and onecases of a five years experience at the EuropeanInstitute of Oncology of Milan (EIO). BreastCancer Res Treat. 2009;117:333-338.

16. Mansel RE, Fallowfield L, Kissin M, et al.Randomized multicenter trial of sentinel nodebiopsy versus standard axillary treatment inoperable breast cancer: the ALMANAC trial. JNatl Cancer Inst. 2006;98:599-609.

17. Lucci A, McCall LM, Beitsch PD, et al.Surgical complications associated with sentinellymph node dissection (SLND) plus axillarylymph node dissection compared with SLNDalone in the American College of SurgeonsOncology Group Trial Z0011. J Clin Oncol.2007;25:3657-3663.

18. Mamounas EP. Sentinel lymph node biopsyafter neoadjuvant systemic therapy. Surg ClinNorth Am. 2003;83:931-942.

19. Breslin TM, Cohen L, Sahin A, et al. Sentinellymph node biopsy is accurate after neoadjuvantchemotherapy for breast cancer. J Clin Oncol.2000;18:3480-3486.

20. Surgery to remove the sentinel lymph node andaxillary lymph nodes after chemotherapy intreating women with stage II, stage IIIA, orstage IIIB breast cancer. ClinicalTrials.gov iden-tifier: ACOSOG-Z1071. www.clinicaltrials.gov/ct2/show/NCT00881361?term=ACOSOG-Z1071&rank=1. Updated January 6, 2010.Accessed January 7, 2010.

21. Keleher A, Wendt R 3rd, Delpassand E, et al.The safety of lymphatic mapping in pregnantbreast cancer patients using Tc-99m sulfur col-loid. Breast J. 2004;10:492-495.

22. Fine RE, Whitworth PW, Kim JA, et al. Low-risk palpable breast masses removed using a vac-uum-assisted hand-held device. Am J Surg.2003;186:362-367.

23. Fornage BD, Sneige N, Ross MI, et al. Small (<or = 2-cm) breast cancer treated with US-guid-ed radiofrequency ablation: feasibility study.Radiology. 2004;231:215-224.

24. Klimberg VS, Kepple J, Shafirstein G, et al.eRFA: excision followed by RFA—a new tech-nique to improve local control in breast cancer.Ann Surg Oncol. 2006;13:1422-1433.

25. Schmitz AC, Gianfelice D, Daniel BL, et al.Image-guided focused ultrasound ablation of breastcancer: current status, challenges, and future direc-tions. Eur Radiol. 2008;18:1431-1441.

26. Dowlatshahi K, Francescatti DS, Bloom KJ, etal. Image-guided surgery of small breast cancers.Am J Surg. 2001;182:419-425.

27. Vlastos G, Kinkel K, Pelte MF, et al. MRI-guid-ed cryotherapy as a treatment option for earlystage breast cancer: preliminary results. BreastCancer Res Treat. 2004;88(suppl):S168.

More women are candidates for breast conservationsurgery, either up front or with neoadjuvant therapy.



Solid Tumors

The evolving epidemiology statis-tics relative to breast cancerworldwide are alarming. With

1 million breast cancers diagnosedannually, there are large differences inincidence between developed and un -developed countries. The cumulativeincidence of breast cancer is 6.3% indeveloped countries compared with1.0% in undeveloped countries.Western developed areas show increas-ing rates, with projections of 2 millioncases diagnosed annually.

Advances in understanding of thecauses of the disease, epidemiology, riskfactors, and both maturing data and

new findings on hormonal, cytotoxic,and biological approaches were present-ed at the 32nd annual San AntonioBreast Cancer Symposium.

Risk factorsKwan and associates reviewed the

relationship between alcohol use andbreast cancer recurrence and survival in1898 women with stage I, II, or IIIAbreast cancer who participated in theLife After Cancer Epidemiology (LACE)study.1 They found that those who con-sumed more than 6 g/day of alcohol hada 1.5-fold increase in death and a 1.3-foldincrease in recurrence.

Obesity is also associated with a poorprognosis after breast cancer. Results of apopulation-based cohort study of almost

19,000 patients by Ewertz and associatesshowed that although on univariateanalysis the risk of local or regional can-cer recurrence was not related to bodymass index (BMI), the risk of distantmetastases increased with in creasingBMI.2 The investigators also found thatthe risk of dying from breast cancerremain elevated for obese women (BMI25) throughout 30 years of observation.

On a more positive note, in a popula-tion-based case-control study, the use ofbisphosphonates for more than 1 yearwas shown to lead to a 29% reductionin the risk of postmenopausal breastcancer.3 When tumors did develop inbisphosphonate users, they tended tohave a more favorable prognostic fac-tors profile. In addition, women whohave more physical activity, for exam-ple, walking 3 hours per week, have bet-ter outcomes.

A head-to-head comparison of deno-sumab with zoledronic acid in 2048women revealed an 18% reduction inthe risk of developing a skeletal-relatedevent in those receiving denosumab.4 A6% absolute risk reduction and a 16%relative risk reduction were found in thedenosumab group. The findings alsoshowed a 22% reduction in skeletalmorbidity rate in the denosumab arm.Compared with zoledronic acid, deno-sumab significantly delayed the time tofirst radiation to bone and first on-studyskeletal-related event or hypercalcemiaof malignancy. At this time, however,the US Food and Drug Administrationhas not approved denosumab.

Sparano and colleagues presented asubanalysis from E1199, a phase 3 studyin which patients with axillary node-positive or high-risk node-ngativebreast cancer were treated with adju-vant chemohormonal therapy.5 Theresults revealed that, although blackwomen are one third less likely thanwomen of other races to develop breastcancer, they are 30% more likely thanother women to die if they are diag-

nosed with the disease. In this analysis,black race was associated with signifi-cantly poorer disease-free survival(DFS) and overall survival (OS).Potential explanations for the dispari-ties noted include poorer adherence toendocrine therapy, obesity and associat-ed hyperinsulinemia, or other factors.

Advances in drug therapyThe Tamoxifen Exemestane Ad -

juvant Multinational (TEAM) trialrandomized 9775 women with hormonereceptor–positive early breast cancer toeither 5 years of the aromatase inhibitor(AI) exemestane as initial therapy or 5years of tamoxifen followed by exemes-tane.6 The 5-year update showed therewas no advantage to switching and 5years of an AI provided superior efficacy.

The Intergroup Exemestane Study(IES) evaluated exemestane taken for2 to 3 years followed by randomizationto either exemestane or tamoxifen fora total of 5 years of adjuvant endocrinetherapy.7 The study showed a 2.4%increase in survival in those in theexemestane arm as well as fewerevents overall, including second pri-maries. As determined in the MA17trial of letrozole versus placebo, ex -tending hormonal therapy in the adju-vant setting beyond 5 years has beenfound to have a DFS advantage, par-ticularly for those with estrogen recep-torpositive disease.8

The role of bevacizumab in themetastatic setting was examined in sev-eral studies. In the AVADO trial (a dou-ble-blind, placebo-controlled, phase 3study of bevacizumab plus docetaxelcompared with placebo plus docetaxelfor the first-line treatment of locallyrecurrent or metastatic breast cancer),women who received bevacizumab 15mg/kg combined with docetaxel had a33% increase in progression-free sur-vival (PFS) as well as better responserates compared with the group thatreceived placebo. To date, however, no

Medical Management of BreastCancer: Update from the San AntonioBreast Cancer Symposium 2009By Cynthia Frankel, RN, OCNDirector, Breast Cancer Research and Development, Memorial Cancer Institute, Hollywood, Florida

The use of bisphosphonates for more than 1 year was shown to lead to a 29% reduction in the risk ofpostmenopausal breast cancer.

AC indicates doxorubicin/cyclophosphamide; AC-T, doxorubicin/cyclophosphamide followed by docetax-el; AC-TH, doxorubicin/cyclophosphamide followed by docetaxel and trastuzumab; AUC, area under thecurve; TCH, docetaxel/carboplatin/trastuzumab.Used with permission from Reference 13.

Stratified by nodes and hormonal receptor status

AC-T indicates doxorubicin/cyclophosphamide plus cyclophosphamide followed by docetaxel; AC-TH, doxorubicin/cyclophosphamide followed by docetaxel and trastuzumab; TCH, docetaxel/carbo-platin/trastuzumab.Used with permission from Reference 13.

Figure 1. BCIRG-006 Trial Design

HER2+ (central FISH)

N+ or high risk N–

4 @ AC 4 @ docetaxel60/600 mg/m2 100 mg/m2

4 @ AC 4 @ docetaxel60/600 mg/m2 100 mg/m2

1-year trastuzumab

6 @ docetaxel and carboplatin75 mg/m2 AUC 6

N = 3222

AC-T

AC-TH

TCH

1-year trastuzumab

AC-T n = 1018

AC-TH n = 1042

TCH n = 1031

Patients 91/102/114 180/189/194 82/89/97Patients, % 9/10/11 17/18/19 8/9/9

P <.001 P <.001

P = .19

First interim analysisSecond analysisThird analysis

Figure 2. Patients with >10% Relative LVEF Decline



Solid Tumors

survival advantage with the bevacizu -mab-docetaxel combination has beendemonstrated.9

The RIBBON 2 trial is the first phase3 study of bevacizumab used in combi-nation with chemotherapy in the sec-ond-line treatment of human epidermalgrowth factor receptor type 2 (HER2)-negative metastatic breast cancer toshow positive results.10 Patients eligiblefor this study had been previously treat-ed with one prior cytotoxic treatment.They were randomized to chemothera-py plus placebo or chemotherapy plusbevacizumab—the chemotherapy com-ponent being the investigator’s choice(a taxane [304], gemcitabine [160],capecitabine [144], or vinorelbine [76]).PFS, the primary end point of the study,was 7.2 months in the bevacizumab armcompared with 5.1 months in the place-bo arm. This was statistically significantand represented a 22% decrease in therisk of relapse. The OS rate of 15months for bevacizumab versus 16.4months for placebo was not significant-ly different between the two groups.

Another new approach to antiangio-genesis was studied in the SOLTI-0701phase 2b trial comparing sorafenib/capecitabine with capecitabine alone inthe second-line setting.11 The overallresponse rate of 38.3% (sorafenib/capecitabine) compared with 30%(capecitabine alone) in women withlocally advanced or metastatic breastcancer. PFS was 7.6 months comparedwith 4.1 months, respectively, in thefirst-line setting and 5.7 months com-pared with 4.1 months, respectively, inthe second-line setting. These improve-ments, however, were offset by toxicity,which included grade 3 hand-foot syn-drome in 45% of the participants.

A review of studies in HER2-positivebreast cancer included EGF104900, aphase 3 randomized trial.12 The popu-lation for this trial included womenwith HER2-positive metastatic breastcancer who had progressed on priortrastuzu mab-containing regimens. Thetrial compared lapatinib 1500 mg alonewith lapatinib 1000 mg combined withtrastuzumab. At relapse, patients treat-ed with lapatinib alone were allowed tocross over to the combination arm. Inthe intent-to-treat analysis, a 4.5-month improvement in OS wasdemonstrated in the combination armwith a statistically significant hazardratio of 0.76. PFS was 12 weeks with

the combination regimen comparedwith 8.1 weeks with lapatinib alone.Median survival was 14 months for lap-atinib/trastuzumab compared with 9.5months for lapatinib alone. There wasalso a survival benefit, which reflecteda 24% reduction in death.

Slamon and colleagues presentedthe third planned analysis of theBCIRG 006 trial, a multicenter, phase3, randomized trial comparing doxoru-bicin/cyclophosphamide followed bydocetaxel with doxorubicin/cyclophos-phamide followed by docetaxel/trastu -zumab (ACTH) and with docetax-el/carboplatin/trastuzu mab (TCH) inthe adjuvant treatment of node-posi-tive and high-risk, node-negativepatients with operable HER2-positivebreast cancer (Figure 1).13 With amedian follow-up of 65 months, theDFS rates were 84% for the ACTHarm and 81% for the TCH arm com-pared with 75% for the control arm.OS rates were 92% for the ACTHarm, 91% for the TCH arm, and 87%for the control arm. TCH continued toshow efficacy equivalent to ACTH,although the study was not designed todetermine equivalence. There were 21cases of congestive heart failure withthe ACTH regimen compared withfour with TCH. Also, 194 patients inthe ACTH arm had sustained reduc-tions in left ventricular ejection frac-tion compared with 97 in the TCHarm (Figure 2). These findings suggestthat a nonanthracycline-containingregimen is an effective alternative forpatients at high risk for anthracycline-associated cardiac toxicities.

Perez and colleagues presented anupdate to N9831, the only random-ized phase 3 trial comparing the safetyand efficacy of the addition of tras -tuzumab to doxorubicin/cyclophos-phamide (AC) either following pacli-taxel (ACpaclitaxeltrastuzumab)or starting concurrently with paclitax-el (ACpaclitaxel/trastuzumab) inwomen with stage I to III invasiveHER2-positive breast cancer.14 Theresearchers found that following theadministration of AC, giving pacli-taxel and trastuzumab concurrentlywas superior to the sequential ap -proach. Previously reported was the 5-year DFS increase from 72% withACpaclitaxel to 80% with ACpaclitaxel trastuzumab. Fol lowingthe enrollment of women in the

ACpaclitaxeltrastuzumab arm orthe ACpaclitaxel/trastuzumab arm,5-year DFS was increased from 80%with ACpaclitaxeltras tuzumabto 84% with ACpaclitaxel/tras t-uzumab. These results set the stage fortrastuzumab therapy being given concur-rently with paclitaxel chemotherapy.

A phase 2 study is investigating anovel HER2 antibody-drug conjugate,trastuzumab-DM1, which is being stud-ied in women with pretreated HER2-positive metastatic breast cancer.15,16

ConclusionApproaching the understanding of

breast cancer from a worldwide perspec-tive, while collaborating openly and col-lectively leads to important findings andadvances that are saving lives and curingsubsets of the disease. There continues tobe much to learn from an epidemiologystandpoint, much more to unravel at thescientific level, and an incalculable needto make available effective therapieswithout exorbitant costs. Nevertheless,the exciting developments reported inSan Antonio attest to the efforts of sci-entists, clinicians, patients, caregivers,and advocates who participate in clinicaltrials and work to advance our under-standing of breast cancer. !

References1. Kwan ML, Kushi LH, Weltzien E, et al.

Alcohol and breast cancer survival in aprospective cohort study. Presented at: SanAntonio Breast Cancer Symposium. December10, 2009. San Antonio, TX.

2. Ewertz M, Jensen M-B, Gunnarsdottir K, ColdS; for the Danish Breast Cancer Co-operativeGroup. Effect of obesity on prognosis after earlybreast cancer. Presented at: San Antonio BreastCancer Symposium. December 10, 2009. SanAntonio, TX.

3. Rennert G, Pinchev M, Rennert HS. Use ofbisphosphonates and risk of postmenopausalbreast cancer. Presented at: San Antonio BreastCancer Symposium. December 10, 2009. SanAntonio, TX.

4. Stopeck A, de Boer R, Fujiwara Y, et al. Acomparison of denosumab versus zoledronicacid for the prevention of skeletal-relatedevents in breast cancer patients with bonemetastases. Presented at: San Antonio BreastCancer Symposium. December 10, 2009. SanAntonio, TX.

5. Sparano JA, Wang W, Stearns V, et al; for theCancer and Leukemia Group B. Black race isassociated with a worse outcome in patientswith hormone receptor positive, HER2-normalbreast cancer treated with adjuvant chemohor-monal therapy. Presented at: San AntonioBreast Cancer Symposium. December 11, 2009.San Antonio, TX.

6. Rea D, Hasenburg A, Seynaeve C, et al. Fiveyears of exemestane as initial therapy comparedto 5 years of tamoxifen followed by exemestane:the TEAM trial, a prospective, randomized,phase III trial in postmenopausal women withhormone-sensitive early breast cancer.

7. Bliss JM, Kilburn LS, Coleman RE, et al.Disease related outcome with long term follow-up: an updated analysis of the IntergroupExemestane Study (IES). Presented at: San

Antonio Breast Cancer Symposium. December10, 2009. San Antonio, TX.

8. Goss PE, Mamounas E, Jakesz R, et al. Aromataseinhibitors vs not after 5 years tamoxifen in post-menopausal breast cancer: meta-analysis of therandomized trials. Presented at: San AntonioBreast Cancer Symposium. December 10, 2009.San Antonio, TX.

9. Miles DW, Chan A, Romieu G, et al. Finaloverall survival (OS) results from the ran-domised, double-blind, placebo-controlled,phase III AVADO study of bevacizumab (BV)plus docetaxel (D) compared with placebo (PL)plus D for the first-line treatment of locallyrecurrent (LR) or metastatic breast cancer(mBC). Presented at: San Antonio BreastCancer Symposium. December 11, 2009. SanAntonio, TX.

10. Brufsky A, Bondarenko IN, Smirnov V, et al.RIBBON-2: a randomized, double-blind,placebo-controlled, phase III trial evaluatingthe efficacy and safety of bevacizumab in com-bination with chemotherapy for second-linetreatment of HER2-negative metastatic breastcancer. Presented at: San Antonio BreastCancer Symposium. December 11, 2009. SanAntonio, TX.

11. Baselga J, Roché H, Costa F, et al. [SOLTI-0701]: a multinational double-blind, random-ized phase 2b study evaluating the efficacy andsafety of sorafenib compared to placebo whenadministered in combination with capecitabinein patients with locally advanced or metastaticbreast cancer (BC). Presented at: San AntonioBreast Cancer Symposium. December 11, 2009.San Antonio, TX.

12. Blackwell KL, Burstein HJ, Sledge GW, et al.Updated survival analysis of a randomized studyof lapatinib alone or in combination withtrastuzumab in women with HER2-positivemetastatic breast cancer progressing ontrastuzumab therapy. Presented at: SanAntonio Breast Cancer Symposium. December12, 2009. San Antonio, TX.

13. Slamon D, Eiermann W, Robert N, et al; for theBCIRG006 Investigators. Phase III randomizedtrial comparing doxorubicin and cyclophos-phamide followed by docetaxel (ACT) withdoxorubicin and cyclophosphamide followedby docetaxel and trastuzumab (ACTH) withdocetaxel, carboplatin and trastuzumab (TCH)in HER2/neu positive early breast cancerpatients: BCIRG 006 Study. Presented at: SanAntonio Breast Cancer Symposium. December12, 2009. San Antonio, TX.

14. Perez EA, Suman VJ, Davidson NE, et al.Results of chemotherapy alone, with sequentialor concurrent addition of 52 weeks oftrastuzumab in the NCCTG N9831 HER2-pos-itive adjuvant breast cancer trial. Presented at:San Antonio Breast Cancer Symposium.December 12, 2009. San Antonio, TX.

15. Krop I, LoRusso P, Miller KD, et al. A phase IIstudy of trastuzumab-DM1 (T-DM1), a novelHER2 antibody-drug conjugate, in patients pre-viously treated with lapatinib, trastuzumab, andchemotherapy. Presented at: San AntonioBreast Cancer Symposium. December 12, 2009.San Antonio, TX.

16. LoRusso P, Girish S, Burris HA, et al.Population pharmacokinetics of trastuzumab-DM1, a first-in-class HER2 antibody-drug con-jugate given every 3 weeks (q3w) and weekly(qw) to patients with HER2-positive metastat-ic breast cancer (MBC). Presented at: SanAntonio Breast Cancer Symposium. December12, 2009. San Antonio, TX.

A nonanthracycline-containing regimen is an effectivealternative for patients at high risk for anthracycline-associated cardiac toxicities.



Solid Tumors

One in five Americans willdevelop skin cancer in his orher lifetime.1 More than 1 mil-

lion cases of nonmelanoma skin cancer(NMSC) are estimated to go unreport-ed each year. In 2009, more than 68,720new cases of melanoma occurred, andmelanoma caused 8650 deaths.1

Skin cancer is a costly disease, and itsfinancial burden increases with ad -vanced stages. A 2009 study of mela -

noma costs documented that the 5-yearcosts of melanoma when diagnosed atstage IV reached $159,808, which repre-sents a 3438% increase from the costs ofmelanoma diagnosed in situ ($4648).Costs of stage IIIc and IV melanomawere 23 times greater than costs of early-stage disease.2

The overall burden of skin cancermerits a brief review of recent reportson secondary prevention, prognosticmarkers, therapies, symptom manage-ment, and survivorship. The founda-tion for this review consists of a selec-tion of large epidemiologic studies,randomized phase 3 clinical trials, sys-tematic reviews, or meta-analyses pre-sented at the 2009 annual meetings ofthe American Academy of Derm -atology, American Society of ClinicalOncology, European Society for Med -ical Oncology, and Society for In -vestigative Dermatology.

Secondary preventionThe increasing burden of skin can-

cer has led to more intensive efforts insecondary prevention, which focuseson risk assessment and education, skin

surveillance and detection, and re -moval of suspicious lesions.3 Findingskin cancer in its early stages is criticalfor favorable prognosis.4 To determinethe prevalence and predictors of skincancer screening among US adults,Lakhani and colleagues analyzed self-reported data from the 2000 and 2005National Health Interview Surveys.5Adult respondents (n, not reported)were asked if they had ever had a head-to-toe skin examination for cancer by adermatologist or other physician. Re -spondents answering “yes” were askedthe date of their most recent total bodyskin examination (TBSE). Over a 5-year period, TBSE prevalence in -creased from one in seven to one in sixrespondents. Significantly higher per-

centages of women as well as adultsaged 50 years and older reported hav-ing TBSE. Approximately one in fivenon-Hispanic white (NHW) partici-pants reported having TBSE, whichwas significantly higher than TBSEprevalence reported by respondents inother racial/ethnic groups. TBSE pre -valence was highest among individualsreporting a personal history of skincancer (69%). Persons who reported afamily history of melanoma were morethan twice as likely (odds ratio [OR],2.42; 95% confidence interval [CI],1.90-3.08) to have had TBSE, andthose with a family history of NMSCwere nearly twice as likely (OR, 1.76;95% CI, 1.40-2.21) than respondentswithout these histories. Overall, TBSEprevalence increased with more educa-tion, physical activity, sun sensitivity,recent sunburn, and sun-protectivebehaviors.

Other systems-related factors havebeen associated with differences in thestage of melanoma at diagnosis and inmelanoma survival, particularly amongethnic groups. These differences be -tween the two most common types of

Medicare healthcare delivery systems,health maintenance organization(HMO) and fee-for-service (FFS),were analyzed in 40,633 patients from1991 through 2005 using the Sur -veillance, Epidemiology and End Re -sults (SEER)-Medicare database. Spec -ifically evaluated were differences inmelanoma stage at diagnosis and medi-an survival in HMO versus FFS groupsby NHW versus Hispanic ethnicity.Among NHWs, the HMO group hadan earlier stage at diagnosis than theFFS group when melanoma was thefirst or subsequent cancer diagnosis.His panic HMO patients were signifi-cantly less likely than FFS patients toreceive a diagnosis at a later stage ver-sus earlier stages (OR, 0.50; 95% CI,0.31-0.81). Among HMO patients,there were no statistically significantdifferences in stage at diagnosis or sur-vival by race/ethnicity. Among FFSpatients, Hispanic patients were morethan twice as likely to be diagnosed ata later stage (OR, 2.31; CI, 1.75-3.03)than NHW patients; however, mediansurvival for all stages was slightlylonger for FFS patients than for HMOpatients (45.0 and 43.0 months,respectively; P <.01). This study is areminder that there are differences instage at diagnosis and survival betweenpatients in HMOs and those in FFShealthcare plans and by race/ethnicity.Stronger skin cancer educational inter-ventions for Hispanics along withTBSE have the potential to increasediagnosis at an earlier stage.6

Prognostic markersUlceration. Several melanoma studies

have focused on prognostic markers,including melanoma ulceration, sentinelnode (SN) tumor burden, and molecularbiomarkers. Ulcerated melanomas areknown to have a worse prognosis thannonulcerated mel anomas. Investigatorsfrom the Euro pean Organisation forResearch and Treat ment of Cancer(EORTC) Melanoma Group conducteda post hoc meta-analysis of the twolargest phase 3 trials (EORTC 18952and 18991) ever conducted in patients(n = 2644) with stage IIb to IIImelanoma.7 The goal of this analysis wasto determine the predictive value ofulceration on response to adjuvant inter-feron (IFN) alpha-2b on relapse-free sur-vival (RFS), distant metastasis-free sur-vival (DMFS), and overall survival

(OS), both overall and by stage (IIb, III-N1, or III-N2). In the ulcerated group,the impact of IFN was much greaterthan in the nonulcerated group for RFS(P = .02), DMFS (P <.001), and OS (P<.001). The greatest reductionsoccurred in patients with ulceration andstages IIb/III-N1; no reductions occurredin patients without ulceration. Theresults strongly indicate that patientswith an ulcerated primary melanoma arefar more sensitive to IFN than patientswith nonulcerated primary tumors.

SN tumor burden. Despite the lack ofclear evidence of survival benefit of sen-tinel lymph node (SLN) biopsy, thistechnique has been increasingly appliedin the staging of patients with thin (1mm) melanomas. Findings from a meta-analysis of 3651 patients enrolled in 34studies reporting rates of SLN positivitywere used to estimate the risk, potentialpredictors, and outcome of SLN positiv-ity.8 Significant heterogeneity (highquality and low quality) among studieswas detected (P = .005; test of non-combinability), suggesting high varia-tion among study outcomes. Eighteenstudies had a primary focus on SLNbiopsy for melanomas 1 mm, with theremainder including all melanoma-thickness groups. These studies report-ed selected clinical and histopatholog-ic data on SLN-positive patients only(n = 113). Among the tumors fromthese patients, six (6.1%) of 698 wereulcerated, 17 (31.5%) of 54 showedregression, and 48 (47.5%) of 101 wereinvasive to Clark level IV or V. Of 14(41.2%) studies that provided recur-rence and/or survival data, fourmelanoma-related deaths in SLN-posi-tive patients and four deaths in SLN-negative patients were reported. Thesefindings indicate that relatively fewpatients with thin melanoma have apositive SLN and that clinical orhistopathologic criteria for reliablyidentifying patients with thin mel -anoma who might benefit from thisintervention remain inadequate.

Also unclear is whether patientswith minimal SLN tumor burden, whomight be at risk for late recurrences(>5 years), can be managed safelywithout complete lymph node dissec-tion. The EORTC Melanoma Groupreported findings from two large pan-European long-term (5-10 years) fol-low-up studies of 595 and 663 patients,

Advances in Skin Cancer: Focus onMelanomaBy Lois J. Loescher, PhD, RNAssociate Professor, University of Arizona, Skin Cancer Institute at the Arizona Cancer Center, Tucson

Lois J. Loescher, PhD, RN

Continued on page 14

These findings indicate that relatively few patientswith thin melanoma have a positive SLN and thatclinical or histopathologic criteria for reliably identifyingpatients with thin melanoma who might benefit fromthis intervention remain inadequate.


IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information• ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components• Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache

(9%) and constipation (5%)

Please see the following brief summary of prescribing information.REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

When patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their fi rst cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3

ALOXI®:

A single IV dose lasts up to 5 days after MEC4,5*

The only IV 5-HT3 antiemetic specifi cally approved for prevention of both acute and delayed CINV associated with MEC6*

Can be used with multiple-day chemotherapy regimens6†

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc.

© 2009 Eisai Inc.

All rights reserved. Printed in USA. AL448-A 08/09

* Moderately emetogenic chemotherapy.† Based on sNDA approval in August 2007, the restriction on repeated dosing

of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

www.ALOXI.com

y-eir

mmmmeeeennnnssss6†6†6†6†


respectively, with minimal SN tumorburden (<1 mm) as defined by theRotterdam criteria.9,10

These patients had very low relapserates and excellent melanoma-specificsurvival that paralleled that of SLN-neg-ative patients. The authors point out

that no increases in relapses of any kindhave been seen with 5 to 10 years of fol-low-up and predict that 10-year survivalrates will be excellent.

Given the increasing diagnosis of thinmelanomas, in addition to the costs andpotential morbidity associated with SLN

biopsy, alternative strategies to identifypatients at risk for nodal disease,including molecular prognostic factors,are urgently needed.8 However, there isa dearth of validated biomarkers forassessing prognosis and monitoringafter complete resection of melanoma

in patients with stage IV disease. Twostudies addressed this void. In a prospec-tive, multicenter (29 sites) internationaltrial, investigators evaluated the clinicalutility of multimarker quantitativereverse-transcription polymerase chainreaction (qRT-PCR) for detecting circu-lating tumor cells (CTCs).11,12 Pre- andintratreatment serial blood samples from244 patients enrolled in a phase 3 trial ofposto perative adjuvant therapy (bacilleCalmette-Guerin [BCG] plus placeboor BCG plus melanoma vaccine) wereassessed by qRT-PCR for MART1,MAGEA3, and PAX3 gene messengerribonucleic acid (mRNA). Medianclinical follow-up time was 21.8 and24.2 months for disease-free survival(DFS) and OS, respectively. MART1,MAGEA3, and PAX3 were detected in26%, 23%, and 29% of patients, respec-tively. Biomarker-negative patients hadsignificantly higher DFS than biomark-er-positive patients (risk ratio [RR],1.56; 95% CI, 1.14-2.15; P = .006) andsignificantly higher OS than patientswith one to two (RR, 2.37; CI, 1.14-4.94; P = .021) or three positive bio-markers (RR, 2.90; 95% CI, 1.28-6.53;P = .01). Having one to two (RR, 2.44;95% CI, 1.1-5.12; P = .019) or threepositive biomarkers was a significantprognostic factor for poor OS (RR,3.08; 95% CI, 1.36-6.98; P = .007).11

The second study addressed the pres-ence of tumor infiltrating lymphocytes(TIL) as markers for meta static disease in504 patients who initially presented withlocal disease.12 Of these patients, 370 diedof melanoma, with a median survival of1.4 years after discovery of metastases.The presence of TIL was significantly andindependently associated with survival(HR, 0.74; 95% CI, 0.59-0.93, P = .01).These studies suggest that multimarkerqRT-PCR analysis of CTC and detectionof TIL may have clinical utility as prog-nostic markers for stage IV melanomapatients.11,12 However, further investiga-tion is needed.

Medical therapiesThe greatest treatment challenge in

melanoma is treatment of advanced dis-ease. This section focuses on medicaltherapies for advanced melanoma.Patients with metastatic melanoma gen-erally have a poor prognosis, with amedian survival of 6 to 9 months. Asmall proportion of patients achievelong-term survival (LTS); however, it isunclear whether LTS reflects sensitivityto systemic therapy, indolent tumorbiology, or host immune factors. There islimited information on the frequencyand duration of complete response (CR)following dacarbazine or temozolomidetherapy or whether LTS occurs only inpatients who achieve CR.

Advances in Skin Cancer: Focus on Melanoma Continued from page 12

ALOXI® (palonosetron HCl) injectionBRIEF SUMMARY OF PRESCRIBING INFORMATIONINDICATIONS AND USAGEChemotherapy-Induced Nausea and VomitingALOXI is indicated for:• Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses• Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat coursesDOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and VomitingDosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.Instructions for I.V. AdministrationALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.CONTRAINDICATIONSALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information]WARNINGS AND PRECAUTIONSHypersensitivityHypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not refl ect the rates reported in practice.In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ! 2% of patients in these trials (Table 1).Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ! 2% in any Treatment Group

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy:Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.Dermatological: < 1%: allergic dermatitis, rash.Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and fl atulence.

General: 1%: weakness, < 1%: fatigue, fever, hot fl ash, fl u-like syndrome.Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.Metabolic: 1%: hyperkalemia, < 1%: electrolyte fl uctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.Musculoskeletal: < 1%: arthralgia.Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.Psychiatric: 1%: anxiety, < 1%: euphoric mood.Urinary System: < 1%: urinary retention.Vascular: < 1%: vein discoloration, vein distention.Postmarketing ExperienceThe following adverse reactions have been identifi ed during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.DRUG INTERACTIONSPalonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically signifi cant drug interactions with palonosetron appears to be low.Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not signifi cantly altered (AUC: no change, Cmax: 15% increase).A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no signifi cant pharmacokinetic interaction.In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.Palonosetron did not inhibit the antitumor activity of the fi ve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Category BTeratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.Labor and DeliveryPalonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.Nursing MothersIt is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric UseSafety and effectiveness in patients below the age of 18 years have not been established.Geriatric UsePopulation pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ! 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ! 65 years old, while 71 (5%) were ! 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were !65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in effi cacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI effi cacy in geriatric patients has not been adequately evaluated.Renal ImpairmentMild to moderate renal impairment does not signifi cantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.Hepatic ImpairmentHepatic impairment does not signifi cantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.RaceIntravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.OVERDOSAGEThere is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fi xed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (17.2) in full prescribing informationInstructions for Patients• Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].• Patients should be instructed to read the patient insert.

Rx OnlyMfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677.© 2009 Eisai Inc.All rights reserved. Printed in USA. AL449 08/09

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)Headache 60 (9%) 34 (8%) 32 (16%)

Constipation 29 (5%) 8 (2%) 12 (6%)Diarrhea 8 (1%) 7 (2%) 4 (2%)Dizziness 8 (1%) 9 (2%) 4 (2%)Fatigue 3 (< 1%) 4 (1%) 4 (2%)

Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%)Insomnia 1 (< 1%) 3 (1%) 3 (2%)


Solid Tumors



Solid Tumors

An epidemiologic study of 397patients treated with either dacarbazineor temozolomide over an 18-year periodsought to document LTS (defined as 18months posttherapy).13 Specific out-comes were CR (no evidence of diseaseby diagnostic imaging), progressive dis-ease (PD; any tumor growth), and par-tial response (PR) or stable disease(SD). Of the 45 patients who met thecriterion of LTS, the best response to

dacarbazine or temozolomide was CR,18%; PR/SD, 67%; and PD, 13%. The5-year OS and progression-free survival(PFS) rates were 33% and 12%, respec-tively. Eleven patients survived morethan 5 years (range, 5-27.5 years), andsix patients remained in remission (5 CR, 1 PR). Disease progressionoccurred in five patients in less than 1year; however, they remained alive forat least 5 years (range, 5.2-17.9 years).The authors concluded that althoughLTS occurs in patients with metastaticmelanoma treated with dacarbazine ortemozolomide, few patients have a sus-tained response to chemotherapy; mostcases of LTS are likely the result ofindolent disease or host biology.

PFS (defined as >90% power todetect a 2-month improvement) wasthe end point in a 2-year study of 651patients with stage IV metastaticmelanoma who were randomized toreceive either 213 mg/m2 of elesclomol(an investigative drug that increasesoxidative stress in cancer cells leadingto mitochondria-induced apoptosis) incombination with 80 mg/m2 of pacli-taxel (ELPAC) or 80 mg/m2 of pacli-taxel alone.14 Both regimens were givenweekly for 3 weeks followed by 1 weekof rest, until disease progression.Patients were stratified by prior noncy-totoxic treatment, M1 grade, and lac-tate dehydrogenase. Median PFS in theELPAC arm was 3.5 months (95% CI,2.7-3.7) compared with 1.9 months(95% CI, 1.9-3.3) in the paclitaxelalone arm (HR, 0.88; 95% CI, 0.67-1.16; P = .3695). Improved PFS in theELPAC arm did not achieve statisticalsignificance, however. The mediannumber of cycles was three in theELPAC arm and two in the paclitaxelalone arm. In February 2009, the study

was halted after increased deathsoccurred on the ELPAC arm, whichmay or may not have been related tothe treatment. The investigators con-tinue to collect OS data to determinewhether the observed imbalance in OSpersists as the data mature.

A prospective, randomized phase 3trial of high-dose (HD) interleukin(IL)-2 alone (arm 1) versus gp100:209-217(210M) synthetic peptide cancer

vaccine plus Montanide ISA followedby HD IL-2 (arm 2) was conducted in185 patients with stage IV or locallyadvanced stage III melanoma treated at21 centers.15 The primary outcome wasclinical response; secondary outcomesincluded toxicity and PFS. Numbers ofpatients enrolled, treated, and evalu-able for response in arm 1 were 94, 93,and 93, respectively; in arm 2, 91, 86,and 86. Toxicities were consistent withthose that were seen with HD IL-2 ±vaccine. Arm 2 demonstrated signifi-cant im provement in overall responserate (22.1% vs 9.7%, P = .0223, chi-square) and PFS (2.9 months [1.7-4.5]vs 1.6 [1.5-1.8], P = .0101). Median OSwas 17.6 months (11.8-26.6) in arm 2versus 12.8 months (8.7-16.3) in arm 1(P = .0964). The authors concludedthat response rate and PFS were superi-or with peptide vaccine plus HD IL-2compared with HD IL-2 alone, andstated that this study represents the firstevidence of clinical benefit of vaccina-tion in patients with melanoma.

Symptom managementHD IFN for patients with melanoma

has consistently demonstrated benefitsas an adjuvant treatment. Side effectsand impaired quality of life (QOL)affect patients’ motivation to continuetreatment. A 4-year evaluation of self-reported QOL in 300 patients enrolledin an adjuvant, randomized, controlledphase 3 trial of pulsed, HD intravenous(IV) IFN alpha-2b and subcutaneous(SC) IFN treatment revealed that HDIV IFN treatment led to a globallydecreased QOL score in 84% ofpatients.16 Im paired QOL during HDIV IFN was caused mainly by physicalsymptoms. During SC IFN treatment,global QOL remained reduced by an

average of 24% in a majority ofpatients, despite dose adjustments.Fatigue was the most important deter-minant of reduced QOL, especiallyduring continuous treatment. De -pression was minor and rated as lessimportant than physical and cognitiveimpairment. These findings demon-strate that fatigue remains the symp-tom that most affects QOL in patientsreceiving IFN.

Survivorship issuesPatients with melanoma are at high

risk for subsequent primary cancers.An epidemiologic study evaluated79,901 white patients who survived atleast 2 months after melanoma diag-nosis and reported to one of nine pop-ulation-based cancer registries in theSEER program between 1973 and2004.17 Of those patients, 7943 devel-oped one or more subsequent primarytumors; 24% of which were cutaneousmelanoma. Patients aged 30 years andyounger had a markedly higher rela-tive risk of developing subsequentmelanoma (observed to expected ratio[O/E], 14.44; 95% CI, 12.40-16.71) asdid female patients (O/E, 14.04; 95%CI, 12.00-16.33) or patients withtheir initial melanoma on the headand neck (O/E, 10.04; 95% CI, 9.21-10.92). Risk of subsequent cancers didnot vary substantially by histology.The authors concluded that patientswith cutaneous melanoma have anapproximate ninefold increased risk ofdeveloping a subsequent melanomacompared with the general populationand require active surveillance forfuture melanoma.

ConclusionWith the increasing incidence of skin

cancer and costs associated with it, wemust focus on risk assessment and edu-cation as well as skin surveillance anddetection. To do this, we must keepabreast of the latest studies on prognos-tic markers and QOL for patients receiv-ing adjuvant therapies and those whoare survivors of the disease. !

References1. Cancer Facts and Figures, 2009. American Cancer

Society. www.cancer.org/downloads/STT/500809web.pdf. Accessed February 19, 2010.

2. Alexandrescu DT. Melanoma costs: a dynamicmodel comparing estimated overall costs of var-ious clinical stages. Dermatol Online J. Nov -ember 15, 2009. dermatology.cdlib.org/1511/originals/melanoma_costs/alexandrescu.html.Accessed February 22, 2010.

3. Rigel DS, Friedman RJ, Kopf AW, Polsky D.ABCDE—an evolving concept in the earlydetection of melanoma. Arch Dermatol. 2005;141:1032-1034.

4. Balch CM, Buzaid AC, Soong SJ, et al. Finalversion of the American Joint Committee on

Cancer staging system for cutaneous melanoma.J Clin Oncol. 2001;19:3635-3648.

5. Lakhani N, Shaw K, Saraiya M. Skin cancerscreening among US adults: 2000 and 2005national health interview surveys. J Am AcadDermatol. 2009;60(suppl 1):Abstract P1900.

6. Rouhani P, Kirsner R. Health care delivery sys-tem effect on disparities in melanoma outcomesamong Medicare-aged Hispanic patients. J AmAcad Dermatol. 2009;60(suppl 1):AbstractP604.

7. Eggermont AM, Suciu S, Testori A, Patel P,Spatz A, for the EORTC Melanoma Group.Ulceration of primary melanoma and respon-siveness to adjuvant interferon therapy: analysisof the adjuvant trials EORTC18952 andEORTC18991 in 2,644 patients. J Clin Oncol.2009;27(15S):Abstract 9007.

8. Warycha M, Polsky D, Osman I, Mazumdar M.Metaanalysis of sentinel lymph node positivityin thin melanoma (1 mm). J Am AcadDermatol. 2009;60(suppl 1):Abstract P601.

9. van Akkooi AC, Rutkowski P, van der PloegIM, et al. Long-term follow-up of patients withminimal sentinel node tumor burden (<0.1mm) according to Rotterdam criteria: a study ofthe EORTC Melanoma Group. J Clin Oncol.2009;27(15S):Abstract 9005.

10. van Akkooi ACJ, Rutkowski P, van der PloegIM, et al. Excellent long-term survival ofpatients with minimal sentinel node tumor bur-den (<0.1 mm) according to Rotterdam criteria:a study of the EORTC melanoma group. Eur JCancer Supplements. 2009;7:Abstract 9302.

11. Hoshimoto S, Shingai T, Wang H, et al.MMAIT-IV Clinical Trial Group Centers.Validation of a multimarker blood assay forpostoperative assessment of stage IV melanomapatients in a prospective international phase IIItrial. J Clin Oncol. 2009;27(15S):9045.

12. Wriston CC, Troxel DB, Shin A, et al. Tumorinfiltrating lymphocytes are a prognostic markerfor survival in patients who develop melanomametastases. J Invest Dermatol. 2009;129(S1):Abstract 363.

13. Kim C, Lee CW, Klasa R, Shah A, Savage KJ.Long-term survival of patients with metastaticmelanoma (MM) treated with dacarbazine(DTIC) or temozolomide (TMZ). J Clin Oncol.2009;27(15S):Abstract 9054.

14. Hauschild A, Eggermont AM, Jacobson E,O’Day SJ. Phase III, randomized, double-blindstudy of elesclomol and paclitaxel versus pacli-taxel alone in stage IV metastatic melanoma(MM). J Clin Oncol. 2009;27(18S):AbstractLBA9012.

15. Schwartzentruber DJ, Lawson D, Richards J, etal. A phase III multi-institutional randomizedstudy of immunization with the gp100: 209-217(210M) peptide followed by high-dose IL-2compared with high-dose IL-2 alone in patientswith metastatic melanoma. J Clin Oncol.2009;27(18S):Abstract CRA9011.

16. Mohr P, Hauschild A, Rass K, et al; for theDeCOG Melanoma Study Group. Quality-of-life (QoL) impairment in melanoma patientsreceiving high-dose interferon alpha 2b(IFNa2b). J Clin Oncol. 2009;27(15S):e20011.

17. Bradford PT, Freedman DM, Goldstein AM,Tucker MA. Increased risk of second primarycancers after diagnosis of melanoma. J InvestDermatol. 2009;129(S1):S138.

The authors concluded that response rate and PFSwere superior with peptide vaccine plus HD IL-2compared with HD IL-2 alone, and stated that thisstudy represents the first evidence of clinical benefit of vaccination in patients with melanoma.


Colorectal cancer (CRC) is thethird most common cancerworldwide, and the fourth most

common cause of death from cancer.1,2 Itis estimated that in 2009, 146,970 menand women will have been diagnosedwith cancer of the colon and rectum inthe United States, and that 49,920 willhave died from the disease.3 From 2002to 2006 the median age of diagnosis was71 years.3

Stage at diagnosis is the most impor-tant determinant of 5-year survival.Data from 2002 show that 39% ofpatients with CRC were diagnosed atthe localized stage (tumor, node, metas-tasis [TNM] stage I and II), 37% werediagnosed as “regional disease” or in -volving lymph nodes (TNM stage III),and 19% were diagnosed with metastat-ic disease (TNM stage IV), leaving 5%unstaged at diagnosis.3 The 5-year sur-vival rates were 90.8% for localized dis-ease, 69.5% for regional disease, and11.3% for metastatic disease, and 38.4%for unstaged disease.3

The treatment options for metastaticCRC (mCRC) have greatly increasedin the past decade, and the therapeuticefficacy of multiple-drug regimens hasimproved. This, in turn, has made treat-ment choices for first, second, and sub-sequent lines of therapy a complex deci-sion. Further, issues not yet fullyelucidated remain at the crux of thiscomplexity. This review will focus onthe treatment of metastatic/advanceddisease and these issues.

Irinotecan or oxaliplatin: Is there abest first-line choice?

Most patients will receive some com-bination of oxaliplatin or irinotecan plus

fluorouracil in the first line. Oxaliplatinplus infusional fluorouracil (as in leuco -vorin/fluorouracil/oxaliplatin [FOLFOX]4) has been shown to be superior toirinotecan plus bolus fluorouracil (IFL)and is equivalent to irinotecan plus infu-sional fluor ouracil (as in leucovorin/fluorouracil/irinotecan [FOLFIRI]).4,5

Further, FOLFOX6, which, for practicalreasons, has largely taken the place ofFOLFOX4, was studied as first-line therapy followed by FOLFIRI versusFOLFIRI followed by FOLFOX6.6 Thisstudy revealed no significant differencesin overall survival (OS; 21.5 vs 20.6months), initial response rates (54% vs56%), or progression-free survival (PFS;8 vs 8.5 months) when either an oxali-

platin-based or an irinotecan-based reg-imen was used as first-line therapy. Thequestion of whether there is a betterfirst-line regimen, it seemed, could beput to rest. With the approval of beva-cizumab and its rise to the standard ofcare in first-line treatment, this ques-tion has again resurfaced.

Bevacizumab was first studied incombination with bolus fluorouracil/leucovorin and with IFL, and wasshown to improve OS in combinationwith IFL compared with IFL alone byjust more than 3 months (18.3 vs 15.1months).7 This study resulted in theapproval of bevacizumab in the UnitedStates in March 2004. At the time ofapproval, IFL was beginning to losefavor, largely due to higher toxicitiesand less efficacy when compared withinfusional fluorouracil regimens (ie,FOLFOX6 or FOLFIRI). The questionthen became: Would bevacizumab addefficacy to these other, more commonfirst-line regimens?

In a small phase 2 study with oxali-platin-based therapy, bevacizumab didappear to improve OS when added toFOLFOX4; however, that comparisonwas to historical controls.8 A second-line, phase 3 trial was published in2007, which showed that bevacizumab

combined with FOLFOX4 improvedsurvival over FOLFOX4 alone.9

Patients in this trial had to have pro-gressed on irinotecan and could nothave received bevacizumab as first-linetherapy. However, validation in phase 3studies of bevacizumab’s ability toimprove survival in combination witheither FOLFOX6 or FOLFIRI in thefirst line did not come until almost 4years after its initial approval.10,11

In one trial, bevacizumab or placebowas combined with three different oxali-platin-based regimens (one using bolusfluorouracil, one with infusional fluor -ouracil, and one with capecitabine).10

The results were contrary to the earlierphase 2 trials. Bevacizumab had no sig-nificant impact on OS or PFS. Criticswill cite that the stopping rules of thetrial may have resulted in undue bias,because only 29% of patients were takenoff therapy because of disease progres-sion. The remaining patients had theirtherapy discontinued because of toxici-ty (largely oxaliplatin-induced neuro-toxicity). It should also be noted, how-ever, that response rates measured at 3months (when most patients were stillon therapy) were also not significantlyimpacted by the addition of bevacizum-ab (49% vs 47%). Another issue thatmay have contributed to these results isthe dose of bevacizumab. In the second-line trial previously mentioned, thedose of bevacizumab was 10 mg/kg com-bined with FOLFOX4. This is doublethe conventional 5-mg/kg dose used inCRC regimens and in the first-line trial.The question of whether bevacizumabin combination with oxaliplatin-basedtherapy in the first line adds any benefitor only significant cost is an ongoingdebate, given the results of this phase 3trial. To date, however, the only positivephase 3 data to support this combinationis with bevacizumab dosed at 10 mg/kg inpatients who have failed irinotecan andwho are bevacizumab-naïve.

In contrast, another phase 3 trial eval-uated the addition of bevacizumab toirinotecan-containing regimens. Thetrial was initially designed to comparethree different irinotecan-containing regimens: IFL versus FOLFIRI versuscapecitabine/irinotecan (CAPIRI). How - ever, during the accrual period (February2003 to December 2004) bevacizumabgained approval. The CAPIRI arm wasdiscontinued, and a second study periodwas initiated in which bevacizumab was

added to the IFL and the FOLFIRI arms.The results showed that patients treatedwith bevacizumab plus FOLFIRI hadgreater OS and PFS (28 and 11.2months) when compared with patientstreated with FOLFIRI alone (23.1 and7.6 months).11-13 Further, the investiga-tors concluded that bevacizumab plusFOLFIRI was superior to bevacizumabplus IFL.11 It should be noted that the for-mer comparison cannot be statisticallyvalidated because of the different accrualperiods. However, given the current datafrom phase 3 trials, bevacizumab, whenadded to irinotecan-containing regimensin the first line, does seem to provide aconsistent benefit in both prolonged PFSand OS.

Should bevacizumab be continuedafter progression?

Since bevacizumab’s approval, it hasbecome standard to add it to first-linetherapy in mCRC. The question thathas yet to be answered is whether thereis any benefit in continuing bevacizu -mab after a patient has progressed on itwithin the first-line regimen. It hasbeen theorized that not only does bev -acizumab, as a vascular endothelialgrowth factor inhibitor, impair a tumor’sability to secure a blood supply viaantiangiogenesis, but that it also stabi-lizes the existing vasculature by inhibit-ing formation of collateral vessels thatare too small to deliver cytotoxics to thetumor bed. Should this be the case, itwould make sense to change cytotoxicregimens, but to continue the beva-cizumab to add synergy via continuedenhancement of drug delivery.However, this theorized benefit has yetto be tested in a randomized controlledtrial. In an observational study, Grotheyand colleagues compared one cohort inwhich patients received bevacizumabbeyond first progression with twomatched cohorts, one in which thepatients were treated beyond progres-sion without bevacizumab and anotherin which patients were not treated afterprogression.13 The results seem to indi-cate that there is, indeed, benefit tocontinuing bevacizumab into second-line treatment. When compared withthe cohort treated beyond progressionwithout bevacizumab, the cohort thatreceived bevacizumab beyond progres-sion had a longer OS (31.8 vs 19.9months) and longer beyond-first-pro-gression survival (19.2 vs 9.5 months).


Solid Tumors

Advances in the Treatment ofColorectal Cancer By Marlo Blazer, PharmD, BCOPSpecialty Practice Pharmacist, Hematology/Oncology, The Arthur G. James Cancer Hospital and Richard J.Solove Research Institute, The Ohio State University Medical Center, Columbus

A second-line, phase 3 trial was published in 2007,which showed that bevacizumab combined withFOLFOX4 improved survival over FOLFOX4 alone.



Solid Tumors

It should be noted, however, that thiswas an observational study. There isconcern regarding selection bias, specif-ically which patients were prescribedbevacizumab in the second line versuswhich were not. The bevacizumab-beyond-first-progression group not onlyhad a higher percentage of patients withbetter performance status (reported asEastern Cooperative Oncology Group0), but also 45% of the group were notreceiving bevacizumab at the time offirst progression.13 In addition, progres-sion was assessed by the treating physi-cian with no control over the measureused (ie, response evaluation criteria insolid tumors vs other clinical evalua-tion) to standardize what progressionactually meant.13 In other words, wecannot conclude from this study that thepatients in the bevacizumab-beyond-first-progression cohort actually pro-gressed by RECIST definition on beva-cizumab in the first line. Therefore, untila randomized controlled study cananswer this question, there are no datato support continued bevacizumab useafter progression on bevacizumab inmCRC.

Can patients with mCRC take abreak from treatment?

Although there has been greatimprovement in OS for patients withmetastatic disease, the thought of beingtreated with some form of intravenouschemotherapy every 2 weeks for the restof one’s life can be daunting. So, thequestion of breaks from therapy has beenan interesting one, keeping in mind thatthe goal for these patients is palliativecare. Three studies have attempted toanswer this question. Labianca and col-leagues looked at a stop-and-go version ofFOLFIRI in which previously untreatedpatients received either FOLFIRI in astop-and-go pattern involving 2-monthrotations of “on therapy” followed by“chemotherapy-free intervals” (arm A, n= 163) or continuously until progression(arm B, n = 168). OS benefit was compa-rable in arm A and arm B (16.9 vs 17.6months).14 Two other studies employedthe same idea using FOLFOX. In theOPTIMOX1 study, patients receivedeither FOLFOX until tumor progression(arm A, n = 309) or FOLFOX with a

higher dose of oxaliplatin (FOLFOX7)for 3 months followed by 6 months of fluorouracil/leucovorin only. FOLFOX7was then restarted at 6 months or at pro-gression, whichever came first (arm B, n= 303).15 In OPTIMOX2, FOLFOX was given either as in arm B of the OPTIMOX1 study with a “maintenancephase” of only leucovorin/fluorouracil (n= 100) or with a chemotherapy-freeinterval (n = 102).16 In evaluating the lat-ter two trials, it appears that a mainte-nance phase of leucovorin/fluorouracildid not impact the OS benefit of oxali-platin-based therapy in the first line (19.3months for FOLFOX4 vs 21.2 months forFOLFOX7 with maintenance phase).15

In the second trial, however, the investi-gators used an end point called durationof disease control (DDC), which is thefirst PFS (time to progression back tobaseline tumor size) plus the second PFS(time to progression after reinitiatingFOLFOX7).16 In this trial, DDC was bet-ter with a maintenance approach ratherthan a chemotherapy-free interval (12.9vs 11.7 months, P = .41), as was PFS (8.7vs 6.9 months, P = .009).

From these trials, and with the goal ofpalliation in mind, it is feasible to proposea break in treatment to patients whohave achieved a response to first-linetherapy. Further, it seems that this breakmay favor more of a maintenanceapproach with infusional fluorouracilthan a complete chemotherapy-freeinterval. However, a patient’s clinicalsymptoms, toxicities to chemotherapy,and quality of life play a major role indetermining how and when this breakshould be executed.

EGFR inhibition: When, how, andwith what other agents

With two inhibitors of the epidermalgrowth factor receptor (EGFR), cetux-imab and panitumumab, on the marketand given the cost of these therapies,EGFR inhibition is an important topicto discuss in mCRC. It is well docu-mented that both of these agents haveno benefit in patients with a mutatedKRAS gene.17,18 The mutated geneencodes for a “gain-in-function” for theKRAS protein, which is downstreamfrom the EGFR signal transductionpathway. With the commercial avail-

ability of KRAS testing, it has becomethe standard of care to test for themutation before initiating therapy withEGFR inhibitors to spare those whowould not respond to therapy the toxi-cities and expense of these agents.

Both EGFR inhibitors are currentlyindicated after failure of oxaliplatin-and irinotecan-containing regimens.Panitu m umab is currently labeled onlyfor monotherapy by the US Food and

Drug Administration and cetuximab’slabeling is for either monotherapy or incombination with irinotecan only. How -ever, both these agents are currentlybeing studied in combination with moreagents, and both have been studied withbevacizumab. Studies looking at combi-nation cytotoxics in patients with non-mutated KRAS have had encouragingresults, although studies indicate that


aDoes not typically exceed 2400 mg/m2 in United States; btypically given at dose of 85 mg/m2.

CIV indicates continuous intravenous infusion; FN, febrile neutropenia; FOLFIRI, leucovorin/fluorouracil/irinotecan;FOLFOX, leucovorin/fluorouracil/oxaliplatin; IFL, irinotecan plus bolus fluorouracil; IV, intravenous; N/V,nausea/vomiting.

1. André T, Boni C, Mounedji-Boudiaf L, et al; for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. N Engl J Med.2004;350:2343-2351.

2. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237.

3. Saltz LB, Cox JV, Blanke C, et al; for the Irinotecan Study Group. Irinotecan plus fluorouracil and leucovorin formetastatic colorectal cancer. N Engl J Med. 2000;343:905-914.

Chemotherapeutic Regimens Grade 3/4 Adverse Drug Reactions

FOLFOX41

Oxaliplatin 85 mg/m2 on day 1 Neutropenia: 41%

Leucovorin 200 mg/m2 on days 1 and 2 Paresthesia: 12%

Fluorouracil 400 mg/m2 IV bolus followed by600 mg/m2,a IV over 22 hours on days 1 and 2

Diarrhea: 11%

(Cycle repeated every 14 days) N/V: 5%/6%

FOLFOX62

Oxaliplatin 100 mg/m2,b on day 1 Neutropenia: 44%

Leucovorin 200 mg/m2 on day 1 Neuropathy: 34%

Fluorouracil 400 mg/m2 IV bolus followed by2400-3000 mg/m2,a CIV over 46 hours on day 1

Diarrhea: 11%

(Cycle repeated every 14 days)

IFL3

Irinotecan 125 mg/m2 IV over 90 min Neutropenia: 53.8%

Leucovorin 20 mg/m2 as IV bolus Diarrhea: 22.7%

Fluorouracil 500 mg/m2 as IV bolus Vomiting: 9.7%

(Repeated weekly for 4 weeks followed by2 weeks off in each 6-week cycle)

FN: 7.1%

FOLFIRI2

Irinotecan 180 mg/m2 on day 1 Neutropenia: 24%

Leucovorin 200 mg/m2 on day 1 Diarrhea: 14%

Fluorouracil 400 mg/m2 IV bolus followed by2400-3000 mg/m2,b CIV over 46 hours on day 1

N/V: 13%/10%

(Cycle repeated every 14 days)

Chemotherapeutic Regimens for Treatment of MetastaticColorectal CancerThe bevacizumab-beyond-first-progression group not

only had a higher percentage of patients with betterperformance status (reported as Eastern CooperativeOncology Group 0), but also 45% of the group werenot receiving bevacizumab at the time of firstprogression.


Supportive care: The most common initial MDS treatment90% of patients with newly diagnosed myelodysplastic syndromes (MDS) present withanemia, and most patients eventually become red blood cell (RBC) transfusion dependent.1

For years, MDS was treated with best supportive care—RBC or platelet transfusions andantibiotics.2 With the advent of hematopoietic growth factor therapy, supportive careexpanded to include erythropoiesis-stimulating agents (ESAs), with or without G-CSF,† whichwere used to reduce the need for transfusions.3,4

Survival decreases with increasing transfusion requirements5

Therefore, it is critical to achieve transfusion independence in patients with transfusion-dependent MDS. While ESAs can effectively relieve the symptoms of anemia, they are notsufficient to provide RBC transfusion independence in all MDS patients.6-9 Some of yourpatients with lower-risk MDS may need treatment other than growth factors (GFs).

Use baseline serum erythropoietin (sEPO) levels to guide treatmentdecisionsBecause the response to ESAs declines with increasing baseline sEPO levels, it is critical tomeasure endogenous levels of erythropoietin before initiating treatment with ESAs. As many as 85% of patients with MDS have elevated baseline sEPO levels,10 making them lesslikely to respond to growth factors. Patients with high sEPO levels (>500 U/L) and hightransfusion needs (!2 RBC units/month) have a low chance of response to erythropoietin.3

Current treatment guidelines recommend that the determination of baseline sEPO levelsshould be a required part of the initial evaluation of patients with cytopenias.11

©2008 Celgene Corporation 11/08 CELG08071T

*MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk MDS per International Prognostic Scoring System (IPSS).†G-CSF, granulocyte colony-stimulating factor. Growth factor therapy includes ESA ± G-CSF or granulocyte/macrophage (GM)-CSF.3

1st in a series on understanding MDS

Clinical challenge: Treatment selection for patients with lower-risk MDS*

718.482.1800 1


23%Chance of

responding to ESAs‡

74% 7%

References: 1. Italian Cooperative Study Group For rHuEpo in Myelodysplastic Syndromes. A randomized double-blind placebo-controlled study with subcutaneous recombinant humanerythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998;103:1070-1074. 2. Nimer SD. ASH 50th anniversary review: Myelodysplastic syndromes. Blood.2008;111(10):4841-4851. 3. Sekeres MA, Fu AZ, Maciejewski JP, Golshayan A-R, Kalaycio ME, Kattan MW. A decision analysis to determine the appropriate treatment for low-riskmyelodysplastic syndromes. Cancer. 2007;109(6):1125-1132. 4. Fenaux P, Kelaidi C. Treatment of the 5q- syndrome. American Society of Hematology Education Program–MyelodysplasticSyndromes. Hematology. 2006;192-198. 5. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica.2006;91(12):1588-1590. 6. Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietinand G-CSF. Blood. 2005;106(3):803-811. 7. Miller KB, Kim HT, Greenberg P, et al. Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone inthe treatment of myelodysplastic syndromes (MDS): results of the ECOG-CLSG trial (E1996). Blood. 2004;104(11):24a. Abstract 70. 8. Musto P, Lanza F, Balleari E, et al. Darbepoetin alphafor the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2004;128(2):204-209. 9. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120(6):1037-1046. 10. Hofmann W-K, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16. 11. National Comprehensive Cancer Network®.Myelodysplastic Syndromes. V.1.2009. NCCN Clinical Practice Guidelines in Oncology™. http:www.nccn.org. Accessed September 26, 2008.

If your patients have a predicted intermediate or poor response to ESAs, you may want to consider non-growth factor therapies.3 §

‡The Hellström-Lindberg study defined complete erythroid response as an increase in hemoglobin (HgB) to !11.5 g/dL. Partial response was defined as an increase in HgB of !1.5 g/dLin patients with anemia who are not transfusion dependent, and for RBC transfusion-dependent patients, a stable HgB level for !4 weeks and transfusion independence.9

§Non-growth factor therapy includes differentiation agents, immunomodulators, and nonablative cytotoxic therapies.3

Consider baseline sEPO levels and transfusion burden when determining the most appropriate initialtreatment option for your RBC transfusion-dependent patients with lower-risk MDS. It is also important to continually evaluate these patients.

Low(<2 units/month)

Low("500 U/L)

High(!2 units/month)

Low ("500 U/L)

High(!2 units/month)

High (>500 U/L)

Two variables can be used to predict response to growth factor therapy: Baseline sEPO levels and RBC transfusion burden9

Low (<2 units/month)

High (>500 U/L)

POORINTERMEDIATEGOOD

sEPO Level

Transfusion Requirement

Adapted from Hellström-Lindberg et al (2003).9

718.482.1800 1



Solid Tumors

EGFR inhibition with bevacizumab mayhave a negative impact.19-21

Panitumumab has been studied in a phase 3 trial in combination withFOLFIRI in patients who had progressedon oxaliplatin and/or bevacizumab.22

This trial reported an in crease of 2months for both PFS and OS when pan-

itumumab was added to FOLFIRI; how-ever, the increase in OS was not statisti-cally significant. Panitumumb has alsobeen studied in the first line with FOL-FOX therapy. Although OS in the pan-itumumab arm had not yet been reachedat 20.3 months, panitumumab didincrease PFS in patients without theKRAS mutation by 1.5 months com-pared with FOLFOX alone.23

Cetuximab has been studied in the firstline with both FOLFIRI and with oxali-platin combined with either fluor ouracilor capecitabine. In patients with out theKRAS mutation, OS was increased from

21 months with FOLFIRI alone to 24.9months with the addition of cetuximab(P = .022).24,25 In contrast, cetuximab,when combined with oxaliplatin-basedtherapy, failed to show significant sur-vival benefit in the first line in patientswith nonmutated KRAS (17 monthswith cetuximab vs 17.9 months with-

out cetuximab, P = ns).26

Both agents have utility beyond first-line therapy and may have benefit inthe first line, although the gold stan-dard first-line biologic remains beva-cizumab. Currently, neither of theEGFR inhibitors should be used incombination with bevacizumab or inpatients with the KRAS mutation.Further, cetuximab in combinationwith oxaliplatin-containing regimensappears to have no impact on OS.

ConclusionManagement of the patient with

mCRC is complex, with many cytotoxicregimens to choose from. We can drawfrom multiple phase 3 studies regardingchoice of therapy, but with data beingconstantly generated, it seems that “stan-dard of care” is a moving target.Healthcare providers need to balanceefficacy data with toxicity managementand with cost. All members of the multi-disciplinary team can use the data pre-sented to raise these questions in anattempt to get patients the most effectivetreatments in terms of clinical efficacy,toxicity, and cost. !

References1. Parkin DM, Bray F, Ferlay J, Pisani P. Global

cancer statistics, 2002. CA Cancer J Clin.2005;55:74-108.

2. Colon and rectum cancer (invasive). NationalCancer Institute, SEER cancer statistics review,1975-2004. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_06_colon_rectum.pdf.Based on November 2006 SEER data submis-sion, posted to the SEER website, 2007.Accessed February 9, 2010.

3. SEER stat fact sheets, 1975-2006. Colon andrectum. National Cancer Institute. http//seer.cancer.gov/statfacts/html/colorect.html. Basedon November 2008 SEER data submission, post-ed to the SEER website, 2009. AccessedFebruary 9, 2010.

4. Sanoff HK, Sargent DJ, Campbell ME, et al.Five-year data and prognostic factor analysis ofoxaliplatin and irinotecan combinations foradvanced colorectal cancer: N9741. J ClinOncol. 2008;26:5721-5727.

5. Colucci G, Gebbia V, Paoletti G, et al; for theGruppo Oncologico Dell’Italia Meridionale. PhaseIII randomized trial of FOLFIRI versus FOLFOX4in the treatment of advanced co lorectal cancer: amulticenter study of the Gruppo OncologicoDell’Italia Meridionale. J Clin Oncol. 2005;23:4866-4875.

6. Tournigand C, Andre T, Achille E, et al.FOLFIRI followed by FOLFOX6 or the reversesequence in advanced colorectal cancer: a ran-domized GERCOR study. J Clin Oncol. 2004;22:229-237.

7. Hurwitz HI, Fehrenbacher L, Hainsworth JD, etal. Bevacizumab in combination with flu orouraciland leucovorin: an active regimen for first-linemetastatic colorectal cancer. J Clin Oncol. 2005;23:3502-3508.

8. Hochester HS, Hart LL, Ramanathan RK, et al.Safety and efficacy of oxaliplatin and fluoropy-rimidine regimens with or without bevacizumabas first-line treatment of metastatic colorectalcancer: results of the TREE study. J Clin Oncol.2008;26:3523-3529.

9. Cohen MH, Gootenberg J, Keegan P, Pazdur R.FDA drug approval summary: bevacizumab plusFOLFOX4 as second-line treatment of colorec-tal cancer. Oncologist. 2007;12:356-361.

10. Saltz LB, Clarke S, Diaz-Rubio E, et al.Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy inmetastatic colorectal cancer: a randomized phaseIII study. J Clin Oncol. 2008;26:2013-2019.

11. Fuchs CS, Marshall J, Mitchell E, et al.Randomized, controlled trial of irinotecan plusinfusional, bolus, or oral fluoropyrimidines infirst-line treatment of metastatic colorectal can-cer: results from the BICC-C study. J Clin Oncol.2007;25:4779-4786.

12. Fuchs CS, Marshall J, Barrueco J. Randomized,controlled trial of irinotecan plus infusional,bolus, or oral fluoropyrimidines in first-linetreatment of metastatic colorectal cancer:updated results from the BICC-C study. J ClinOncol. 2008;26:689-690.

13. Grothey A, Sugrue MM, Purdie DM, et al.Bevacizumab beyond first progression is associ-ated with prolonged overall survival in metasta-tic colorectal cancer: results from a large obser-vational cohort study (BRiTE). J Clin Oncol.2008;26:5326-5334.

14. Labianca R, Floriani I, Cortesi E, et al; for theItalian Group for the Study of Digestive TractCancer. Alternating versus continuous“FOLFIRI” in advanced colorectal cancer(ACC): a randomized “GISCAD” trial. J ClinOncol. 2006;24(18S):Abstract 3505.

15. Tournigand C, Cervantes A, Figer A, et al.OPTIMOX1: a randomized study of FOLFOX4or FOLFOX7 with oxaliplatin in a stop-and-gofashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394-400.

16. Maindrault-Goebel F, Lledo G, Chibaudel B, etal. OPTIMOX2, a large randomized phase IIstudy of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patientswith metastatic colorectal cancer (MRC). AGERCOR study. J Clin Oncol. 2006;24 (18S):Abstract 3504.

17. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacyin patients with metastatic colorectal cancer. JClin Oncol. 2008;26:1626-1634.

18. Leivre A, Bachet JB, Boige V, et al. KRAS muta-tions as an independent prognostic factor inpatients with advanced colorectal cancer treatedwith cetuximab. J Clin Oncol. 2008; 26:374-379.

19. Hecht JR, Mitchell E, Chidiac T, et al. Anupdated analysis of safety and efficacy of oxali-platin(Ox)/bevacizumab (bev) +/- panitumu -mab (pmab) for first-line treatment (tx) ofmetastatic colorectal cancer (mCRC) from arandomized, controlled trial (PACCE).Presented at: 2008 ASCO GastrointestinalCancers Symposium; January 2008; Orlando,Florida. Abstract 273.

20. Hecht JR, Mitchell E, Chidiac T, et al. Interimresults form PACCE: irinotecan (iri)/beva-cizumab (bev) +/- panitumumab (pmab) as first-line treatment (tx) for metastatic colorectalcancer (mCRC). Presented at: 2008 ASCOGastrointestinal Cancers Symposium; January2008; Orlando, Florida. Abstract 279.

21. Tol J, Koopman M, Cats A, et al. Chemotherapy,bevacizumab, and cetuximab in metastic colorec-tal cancer. N Engl J Med. 2009;360:563-572.

22. Peeters M, Price T, Hotko Y, et al. Randomizedphase 3 study of panitumumab with FOLFIRI vsFOLFIRI alone as second-line treatment (tx) inpatients (pts) with metastatic colorectal cancer(mCRC). Eur J Cancer. 2009;7(suppl):Abstract14LBA.

23. Douillard J, Siena S, Cassidy J, et al. Ran -domized phase 3 study of panitumumab withFOLFOX4 compared to FOLFOX4 alone as 1st-line treatment (tx) for metastatic colorectalcancer (mCRC): the PRIME trial. Eur J Cancer.2009;7(suppl):Abstract 10LBA.

24. Van Cutsem E, Lang I, D’haens G, et al. KRASstatus and efficacy in the first-line treatment ofpatients with metastatic colorectal cancer(mCRC) treated with FOLFIRI with or withoutcetuximab: the CRYSTAL experience. J ClinOncol. 2008;26(suppl):Abstract 2.

25. Van Cutsem E, Lang I, D’Haens G, et al. KRASstatus and efficacy in the CRYSTAL study: 1st-line treatment of patients with metastatic col-orectal cancer (mCRC) receiving FOLFIRIwith or without cetuximab. Ann Oncol.2008;19(suppl 8):Abstract 710.

26. Maughan T, Adams RA, Smith CG, et al.Addition of cetuximab to oxaliplatin-basedcombination chemotherapy (CT) in patientswith KRAS wild-type advanced colorectal can-cer (ACRC): a randomised superiority trial(MRC COIN). Eur J Cancer. 2009;7(suppl):Abstract 6LBA.

FDA indicates US Food and Drug Administration; FOLFIRI, leucovorin/fluorouracil/irinotecan; FOLFOX, leucovorin/fluorouracil/oxaliplatin.

Targeted Agents Adverse Events

Bevacizumab

5 mg/kg every 2 weeks in the first line withFOLFIRI and with FOLFOX4, and 10 mg/kgevery 2 weeks in the second line in combination with FOLFOX4

When added to traditional cytotoxic regmens, increased incidence of:

• intestinal perforation• hemorrhage• hypertension• arteriothromboembolic events• proteinuria

Panitumumab

6 mg/kg every 2 weeks (FDA labeled currently as monotherapy only)

Skin toxicity: grade 3/4, 16%; all grades,90%

Hypomagnesemia: all grades, 39%

Diarrhea: all grades, 21%

Severe infusion reaction: 1%

Cetuximab

FDA labeled dosing, 400 mg/m2 loadingdose with 250 mg/m2 weekly, for subse-quent doses as either monotherapy or in combination with irinotecan only

Skin toxicity: grade 3/4, 8%; all grades,76.3%

Hypomagnesemia: all grades, 33.8%

Diarrhea: grade 3/4, 28.4% (irinotecan alone, 15.7%)

Targeted Agents for Treatment of Metastatic Colorectal Cancer

Advances in the Treatment of Colorectal Cancer Continued from page 17

Both agents have utility beyond first-line therapy andmay have benefit in the first line, although the goldstandard first-line biologic remains bevacizumab.


For more information about GEMZAR, please see your Lilly sales professional or visit GEMZAR.com.

GEMZAR® is a registered trademark of Eli Lilly and Company. GC58323 0509 PRINTED IN USA © 2010, Lilly USA, LLC. ALL RIGHTS RESERVED.



Solid Tumors

Approximately 192,000 mendeveloped prostate cancer in2009 and 27,000 died from the

disease.1 Prostate cancer is the most fre-quently diagnosed cancer in NorthAmerica and the second most commoncause of cancer death in men. Althoughthe number of new cases of prostate can-cer has increased in the past decade, theabsolute number of deaths has slowlydeclined.1 As the incidence of prostatecancer increases, controversies continueabout the best possible methods forscreening, detection, and treatment.

The optimal management of prostatecancer is dependent on patient age,overall health, and tumor risk assess-ment. Just as the history of prostatecancer ranges from an incidental find-ing to widespread metastatic disease,management varies widely. Localizedprostate cancer is treated with radical

prostatectomy, external-beam radiationtherapy, brachytherapy, or observationalone. Treatment of locally advanceddisease involves a multimodality ap -proach, including radiation, androgenablation, and possible androgen-depri-vation therapy.2

Unfortunately, even after initial suc-cessful treatment of localized prostatecancer, recurrence is common, withapproximately 10% to 50% of men pro-gressing to advanced or metastatic dis-ease.3 Prostate cancer is an androgen-dependent malignant disease, andandrogen-deprivation therapy is com-monly used following local therapy(Figure). One method to suppress andro-

gen levels is to reduce circulating andro-gens by surgical or chemical castrationwith the use of luteinizing hormone-releasing hormone agonists. Unfor -tunately, although castration removesthe gonadal testosterone source, andro-gens from other sources many continueto act as ligands and result in androgen-receptor signaling. Androgen-mediatedeffects on prostate cancer cells may alsobe blocked with androgen-receptorantagonists or a combination of thera-pies. An increasing prostate-specificantigen (PSA) level after definitivelocal therapy is termed recurrence. Mostpatients will experience progressionwithin a median of 12 to 20 months4

and will eventually develop androgen-independent prostate cancer.

Androgen-independent prostate can-cer is also known as hormone-resistantprostate cancer, hormone-refractory

prostate cancer, and more recentlyreferred to as castration-resistant pro -state cancer (CRPC). Therapies forpatients who develop CRPC includewithdrawal of the androgen-receptorantagonist, secondary hormonal thera-py, and chemotherapy. Hormone-refrac-tory prostate cancer arises when diseaseprogression continues despite antian-drogen withdrawal. CRPC represents aspectrum of disease ranging from asymp-tomatic patients to those with metasta-sis or debilitating cancer symptoms.

Current therapies for CRPCMitoxantrone, an anthracenedione,

has been studied in patients with

metastatic CRPC. Three randomizedcontrolled trials compared mito xantroneand low-dose corticosteroids with thesame corticosteroid alone.5-7 All threerandomized controlled trials havereported overall survival (OS) resultsbut none detected an improvement dueto mitoxantrone. In addition to exam-ining survival, the two trials byTannock and associates assessed painand quality of life through self-reportedquestionnaires.7,8 In these early trials,objective response rates were low, andmedian survival did not exceed 12months. Mitoxantrone was approved in 1996 by the US Food and DrugAdministration (FDA) based on thefinding of symptomatic improvement ina large randomized, phase 3 trial.8 It wasalmost a decade later when newer regi-mens, particularly those including tax-anes, were shown to improve objectivetumor response and increase survival.

Docetaxel was approved by the FDAin 2004 for advanced prostate cancerfollowing the results of the TAX 327trial.7 In this trial, 1006 men were ran-domized to docetaxel plus prednisone ormitoxantrone plus prednisone. Mediansurvival of all patients treated with doc-etaxel was 18.2 months compared with16.5 months for those treated withmitoxantrone. Following this trial,Southwest Oncology Group (SWOG)9916 compared docetaxel and estramus-tine with mitoxantrone and prednisone.The docetaxel arm was favored, with amedian OS of 17.5 months compared

with 15.6 months for mitoxantrone.5Hormone manipulations, systemic

chemotherapy, palliation of bone painwith bisphosphonates, and external-beam irradiation are included in thetreatment of CRPC. In addition to thechemotherapeutic agents discussed,vinblastine, vinorelbine, paclitaxel,cyclophosphamide, 5-fluorouracil, car-boplatin, and prednisone have beenstudied extensively. Unfortunately, theresults of many of the trials with con-ventional cytotoxic agents were disap-pointing, leaving an apparent need toidentify novel agents and drug targetsthat not only improve quality of life, butalso prolong survival. This review willfocus on newly approved and investiga-tional agents in CRPC.

New therapySipuleucel-T (Provenge). Sipuleucel-

T, a novel cellular immunotherapy, wasFDA-approved for the treatment ofmetastatic CRPC on April 29, 2010.Given the possibility that there aremany active targets in prostate cancer(including PSA and prostatic acidphosphatase [PAP]), biologic targetedtherapies make sense in this diseasestate.9 Sipuleucel-T is derived fromautologous peripheral blood cells thatare collected during leukapheresis.10

After removing erythrocytes, granulo-cytes, platelets, and lymphocytes, theremaining product consists of den-drites, T-cells, monocytes, and naturalkiller cells. The cellular product con-

Update on Castration-resistant ProstateCancer: A Review ofSystemic InnovationsBy Megan McKee, PharmD, BCPSOncology Pharmacy Resident, Investigational Drug Section, CancerTherapy and Research Center, University of Texas Health SciencesCenter, San Antonio

Anita Aracelli Garcia, PharmD, BCOPClinical Oncology Pharmacist, Investigational Drug Section, CancerTherapy and Research Center, University of Texas Health SciencesCenter, San Antonio

Bradi L. Frei, PharmD, BCPS, BCOPAssistant Professor, Feik School of Pharmacy, University of the IncarnateWord Clinical Oncology Pharmacist, Investigational Drug Section, CancerTherapy and Research Center, University of Texas Health SciencesCenter, San Antonio

Scott Soefje, PharmD, BCOPDirector, Investigational Drug Section, Cancer Therapy and ResearchCenter, University of Texas Health Sciences Center, San Antonio

Left to right: Anita Aracelli Garcia, PharmD, BCOP; Scott Soefje, PharmD, BCOP;Megan McKee, PharmD, BCPS; Bradi L. Frei, PharmD, BCPS, BCOP

In this multicenter, randomized, double-blind,placebo-controlled study, sipuleucel-T extendedmedian survival by 4.1 months and improved 3-yearsurvival by 38%.


sisting of a patient’s antigen-presentingcells is processed and cultured ex vivowith a recombinant fusion proteincontaining PAP.

A phase 3 randomized, placebo-con-trolled trial evaluated the safety andefficacy of sipuleucel-T for metastatic,asymptomatic CRPC (D9901).11 Onehundred twenty-seven men with a pro-gressive PSA level and an EasternCooperative Oncology Group perform-ance score of zero or one were enrolled.Patients were randomized to receive asingle sipuleucel-T infusion on weeks1, 2, and 4 or placebo infusions givenon the same schedule. Patients in theplacebo group were allowed to receivesalvage treatment with sipuleucel-T ifdisease progression occurred after week8 of therapy. The primary outcome wastime to progression (TTP). A differ-ence for median TTP was not detectedwhen comparing the treatment armwith placebo; however, patients in thetreatment arm had improved OS ofapproximately 4.5 months comparedwith the placebo (P = .01). At a 36-month follow-up, 34% of patientsreceiving sipuleucel-T were alive com-pared with 11% of patients re ceivingplacebo (P = .0046). Sipuleucel-T waswell tolerated, the most commonadverse events reported being feverand chills lasting for 1 to 2 days. Thistrial had several limitations, includingthe small number of patients and theuse of TTP as a primary outcome.

A second phase 3 trial (D9902)10 wasterminated early when the results fromD9901 were published demonstrating alack of improvement with sipuleucel-T.Following termination, 98 men en -rolled in D9902 and were followed forfurther safety and efficacy data. Theinvestigators revised secondary endpoints for D9902 to include OS andrenamed the trial D9902A. Again, nodifference was detected in TTP or OSin the 98 subjects.10

Approval was based on a third trial ofmore than 500 patients, Identificationof Men with a Genetic Predisposition toProst Ate Cancer: Targeted Screening inBRCA1 and BRCA2 Mutation Carriersand Controls (IMPACT), or D9902B.12

In this multicenter, randomized, double-blind, placebo-controlled study, sipuleu-cel-T extended median survival by 4.1months and improved 3-year survival by38%. As reported at the 2009 AmericanUrological Association annual meeting,sipuleucel-T successfully met the pre-specified statistical significance definedby the protocol and reduced the overallrisk of death by 22.5% compared withplacebo (P = .032).12

Overall, sipuleucel-T appears to bewell tolerated, with most adverseevents of grade 1 or 2 severity resolvingwithin 48 hours10-12 (Table 1). No dif-ference in significant serious adverse

events has been reported for patientstreated with sipuleucel-T comparedwith placebo. Various administrationfrequencies were examined through-out the phase 1, 2, and 3 trials. Mostrecently, a biweekly dosing intervalhas been used to avert delays in ther-

apies at weeks 0, 2, and 4 followingstandard leukapheresis.

Although the primary end point ofTTP has not been met in the studiesdiscussed, final results are pendingfrom the ongoing phase 2 Treatment ofProstate Cancer with Active Cellular

Immun otherapy (ProACT) trial.10

Investigational systemic therapiesAtrasentan (ABT-627 or Xinlay).

Endothelins have been implicated innumerous physiologic and pathologic


Solid Tumors

There is A place you can go for user-friendly online tools and reimbursement forms…

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Amgen Assist™ and Amgen Inc. do not guarantee success in obtaining reimbursement. Third party payment for medical products and services is affected by numerous factors, not all of which can be anticipated or resolved by our Amgen Assist™ staff.©Amgen. All rights reserved. MC48319 11/09

www.amgenassist.com1-800-272-9376



conditions, including cancer.13 Evidencesuggests that endothelin-1, a small vaso-constrictor peptide, is produced by sev-eral tumor cell lines. Endothelin-1 levelsare increased in prostate cancer andmodulate mitogenesis and apoptosis onbinding to the endothelin-A (ETA)receptor. Multiple in vivo models haveexamined the role of endothelin antago-nism in tumorigenesis. Atrasentan, anorally bioavailable investigational agent,is a selective ETA receptor antagonistthat exhibits low-level inhibition of theendothelin-B (ETB) receptor in additionto inhibition of the ETA receptor.14

Xenograft studies conducted with atras -entan in combination with paclitaxeldemonstrated a significant reduction intumor growth compared with monother-apy alone.15 Following additional phase 1and 2 trials, multiple phase 3 trials havefocused on the efficacy of atrasentan inCRPC (Table 2).

Beginning in June 2001, a multina-tional, phase 3, randomized, controlled,double-blind study was conducted inpatients with metastatic CRPC.16 Eight-hundred nine patients were randomizedto receive atrasentan 10 mg by mouthdaily (n = 408) or placebo (n = 401). Theprimary end point was time to diseaseprogression, defined by the first occur-rence to a radiographic or clinical event,including bone lesion and metastatic

pain. Atrasentan did not reduce the riskof disease progression (P = .136) com-pared with placebo; however, increasesfrom baseline in bone alkaline phos-phatase and PSA were significantly lowerwith atrasentan treatment.16 Given therelative success in patients with metasta-tic cancer, a follow-up phase 3, random-ized controlled trial was conducted inpatients with nonmetastatic CRPC.Patients who had adequate androgen sup-pression and no radiographic evidence ofmetastases were randomized to receiveatrasentan 10 mg daily or placebo.Secondary end points included time toPSA progression and OS. A 3-monthdelay in the median TTP was demon-strated with atrasentan compared withplacebo (P = .288). Although there wasno difference in the median OS, atrasen-tan lengthened the PSA doubling timeand slowed the increase in bone alkalinephosphatase (P <.01).16-18

Phase 1 and 2 trials with atrasentanhave demonstrated safety and tolerabili-ty with mild side effects, includingedema, rhinitis, and headache17,18 (Table1). To date, phase 3 trials of atrasentanas monotherapy have not establishedsignificant changes in disease progres-sion but have demonstrated changes inobjective markers including PSA. Thephase 3 SWOG S0421 trial continues to


Solid Tumors


Figure. Androgen-signaling Axis and Targets for Novel TherapiesAR indicates androgen receptor; ARE, androgen-response element; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulphate; DHT, dihydrotestoterone.

Reprinted with permission from reference 27.

Update on Castration-resistant Prostate Cancer Continued from page 23

Toxicity Gradea Incidence Comments Phase of Source Study

Sipuleucel-T Chills Grade 1 and 2 >20% Resolved within 48 hours Phase 1

Fatigue Grade 1 and 2 >20% Phase 1 and 2

Pyrexia Grade 1 and 2 >20% Phase 1 and 2

Atrasentan Peripheral edema Grade 2 35% One patient discontinued drug in phase 2 trial

Phase 2 and 3

Nasal stuffiness Grade 1 29% Phase 1 and 2

Headache Grade 1 and 2 20% Phase 1, 2, and 3

Zibotentan Headache Grade 2 50% Likely due to vasodilatory pharmacology of agent

Phase 1 and 2

Peripheral edema Grade 1 and 2 30% Managed with furosemide Phase 1 and 2

Fatigue All grades 30% Managed with furosemide Phase 1 and 2

Abiraterone acetate Hypokalemia All grades 88% Managed by eplerenone Phase 2

Hypertension All grades 40% Managed by eplerenone Phase 2

Fluid overload All grades 31% Managed by eplerenone Phase 2

MDV3100 Rash All grades 2 patients Dose-limiting toxicity Phase 1

Seizure Not reported Not reported Dose-limiting toxicity Phase 1

Fatigue Not reported Not reported Dose reductions requiredsecondary to fatigue

Phase 1

aGrading criteria established by Common Terminology for Grading Adverse Events.

Table 1. Common Toxicities Associated with Novel Therapies


TON_May2010_v3:TON 5/3/10 11:02 PM Page 25

investigate docetaxel plus atrasentancompared with docetaxel alone.19

Zibotentan (ZD4054). Zibotentan,another endothelin receptor antagonist,is being investigated in CRPC.20

Zibotentan is an orally bioavailableinhibitor of the ETA receptor. Pre -

clinical mouse models demonstratedhigh affinity for the ETA receptor withoutmeasurable activity on the ETB receptor.A multicenter, open-label, phase 1 studybegun in June 2003 was conducted todetermine the safety and tolerability ofzibotentan in patients with metastatic

CRPC.20 Sixteen patients were enrolledand treated with escalating doses of oralzibotentan starting at 10 mg once daily.The primary outcome, maximum tolerat-ed dose, was determined to be 15 mg, andsecondary end points, including diseaseassessment, revealed stable disease in

nine of the 16 patients. Following thecompletion of the phase 1 trial, a phase 2randomized, double-blind, placebo-con-trolled trial was conducted in patientswith CRPC and bone metastasis.21 Atotal of 312 patients were randomized in


Soild Tumors

Study Design Population Treatment Primary end point Secondary end point Comments

Sipuleucel-T

Burch PA , et al. Clin CancerRes. 2000;6:2175-2182.

Phase 1, single-arm N = 13Progressive (increasing levels of PSA) CRPC

Infusions of autologous pre-senting cells (APC8015) atweeks 0 and 4, followed byrecombinant fusion protein(PA2024 without T cells) atweeks 8, 12, and 16

Response to treatment: three patients experienced adecrease in PSA by 50% ormore from baseline, andnine men had a stimulationof T cells by 75%

Tolerability: grade 3 fatiguereported in one patient

Well-tolerated

Small EJ, et al. J Clin Oncol.2000;18:3894-3903.

Phase 1/2 N = 13Progressive CRPC

Sipuleucel-T at weeks 0, 4, and 8

Change in PSA: six patientshad at least a 25% reduc-tion from baseline in serumPSA

Median TTP: 12 weeks forphase 1 patients, and 29weeks for phase 2 patients

Burch PA, et al. Prostate.2004;60:197-204.

Phase 2 N = 21Progressive CRPC

All patients received twoinfusions of APC8015 atweeks 0 and 2, followed bysubcutaneous injections ofPA2024 at weeks 4, 8, and 12

Median TTP: 118 days Change in PSA: serum PSAlevels were reduced by 25%to 50% in two patients; onepatient had an initialincrease followed by adecrease to undetectablelevels by week 24

Small EJ, et al. J Clin Oncol.2006;24:3089-3094.

Phase 3, placebo-controlled N = 127Metastatic, asymptomaticCRPC

Sipuleucel-T versus placebo TTP: 11.7 versus 10 weeks(HR, 1.45; 95% CI, 0.992.11; P = .052)

OS: 25.9 versus 21.4months(HR, 1.7; 95% CI, 1.13-2.56;P = .01)

Atrasentan

Michaelson MD, et al.Cancer. 2006;107:530-535.

Phase 3, placebo-controlled N = 44CRPC men with metastaticbone involvement

Atrasentan versus atrasentan plus zoledronicacid

Bone turnover makers: nodifference between groups in serum levels of bone-specific alkaline phos-phatase

Minimal clinical efficacy,with no objective responsesand only one PSA response

Abiraterone acetate

Attard G, et al. J Clin Oncol.2008;26:4563-4571.

Phase 1, single-center, open-label

N = 21Chemotherapy-naïve, CRPC

Abiraterone acetate PSA decline of 50% after1 month and maintained for 3 months: 57% experienced PSA decline

62% of patients with measurable diseaseattained a PR

Plateau of endocrine effects reported at doses>750 mg

No treatment-related grade3 or 4 toxicities

Attard G, et al. J Clin Oncol.2009;27:3742-3748.

Phase 1/2 single-center, open-label

Chemotherapy-naïve menwith CRPCN = 54 (n = 42 included inantitumor efficacy analysis)

Abiraterone acetate Sustained PSA decline50% at any time after 12 weeks: 67%

TTP: 225 days (95% CI,162-287 days); 37.5% ofpatients with measurabledisease attained a PR

Adverse reactions: 88% hypokalemia; 49% hypertension(eplerenone used to controlmineralcorticoid symptoms);asymptomatic grade 3 ele-vation in transaminases

MDV3100

Scher HI, et al. Proc Am SocClin Oncol. 2009;27 (15 suppl):5011.

Phase 1/2, dose-finding with extension at optimaldose

N = 140Phase 1: Metastatic progressive CRPCPhase 2: Chemotherapy-naïve and postchemo -therapy CRPC

MDV3100 Maximum tolerated dose:240 mg/day

Change in PSA: 32% to 58% decline

DLT at 600 mg/day including rash and seizure;fatigue resulted in dosereductions at 360 mg/dayand 480 mg/day

CI indicates confidence interval; CRPC, castration-resistant prostate cancer; DLT, dose-limiting toxicity; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; TTP, time to progression.

Table 2. Additional Studies Investigating Systemic Therapy in Castration resistant Prostate Cancer




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Solid Tumors

a 1:1:1 design to receive zibotentan 10mg, zibotentan 15 mg, or placebo. Theprimary end point was progression-freesurvival (PFS) with secondary end pointsincluding OS, time to PSA progression,and safety. Preliminary analyses did notreveal a difference in PFS between thecontrol and placebo arms; however, amedian OS of 24.5 months was foundin the 10-mg zibotentan arm and 23.5months in the 15-mg zibotentan arm,

compared with 17.3 months in theplacebo arm (P = .008). The earlyresults of the phase 2 trials suggest thatzibotentan may provide clinical effica-cy in prostate cancer.

Phase 3 trials are currently being per-formed to further investigate the efficacyof zibotentan in CRPC. The EndothelinA Antagonist in Hormone ResistantProstate Cancer with Bone Metastases(ENTHUSE M1) trial is randomizingchemotherapy-naïve CRPC patients toreceive zibotentan 10 mg daily or placebowith best supportive care.22 The primaryend point in this study is OS with an esti-mated accrual of 1000 patients. Otherphase 3 trials are addressing combinationtherapies with docetaxel to determinepotential additive or synergistic effects ofzibotentan and chemotherapy (Table 2).

Abiraterone acetate (CB7630). Abira -terone acetate is an orally available,selective and irreversible inhibitor ofcytochrome P17, a key enzyme in thegeneration of androgens and estrogens bythe adrenal gland and tumor tissue.23 In2004, the first human studies reportedsuccessful suppression of testosterone lev-els in noncastrated patients given a 12-day regimen of daily abiraterone acetate.Suppression of testosterone was not sus-tained, however, because of effects ofluteinizing hormone.24 Therefore, furtherinvestigations with this agent requiredconcomitant castration.

Attard and colleagues25 reported aphase 1 trial with abiraterone acetate inchemotherapy-naïve men with CRPC.This dose-escalating trial investigateddoses ranging from 250 mg to 2000 mgdaily. Although no dose-limiting toxicitywas found, a plateau effect was identifiedfor the endocrine effects of abirateroneacetate in doses exceeding 750 mg. Inaddition to endocrine levels, a decline inPSA 50% occurred after 1 month ofcontinuous therapy and was maintainedfor 3 months in 57% of patients. A target

dose of 1000 mg daily was identified forabiraterone acetate and was furtherinvestigated in a phase 2 trial.

During the phase 2 clinical trial, thechemotherapy-naïve CRPC patientswere given abiraterone acetate 1000 mgdaily to evaluate the possibility of adurable response to treatment in a largercohort of patients.26 Forty-two patientswere included in the efficacy analysis. Ofthese 42 patients, 67% met the primary

end point of a decline in PSA 50%after 12 weeks of abiraterone acetatetreatment confirmed by an additionalPSA test 4 weeks later. PSA declines of 90% were observed in 19% ofpatients. Median time to PSA progres-sion on abiraterone acetate alone for allphase 2 patients was 225 days (95%confidence interval, 162-287 days).Thirty-seven percent of patients withmeasurable disease attained a partialresponse by independent radiologicevaluation. For patients who had dis-ease progression, an a priori addition ofdaily dexamethasone of 0.5 mg wasallowed. Tumor response was 33% inpatients who received dexamethasonein addition to abiraterone acetate atdisease progression.26

These early clinical trials demon-strated good tolerability in addition totumor response. There were no treat-ment-related grade 3 or 4 toxicities dur-ing the phase 1 trial and limited toxic-ities in the phase 2 trial. However,abiraterone acetate treatment causesimpairment of androgen biosynthesisand increased production of deoxycor-ticosterone and corticosterone, result-ing in secondary mineralocorticoid syn-drome (Table 1). In the phase 1 trial byAttard and colleagues, the incidence ofhypertension appeared to be similaracross all doses with a rate of 33%; thisestimate may not be accurate, however,given the limited number of patients inthe phase 1 trial.

According to phase 1 and 2 clinicaltrial data, abiraterone acetate has beenshown to be safe and moderately effec-tive in CRPC. Several phase 3 studiesare currently under way and will pro-vide further information concerningthis agent’s potential future role inprostate cancer care.

MDV3100. Drug resistance in CRPCis thought to be due to increased andro-gen receptors. Current antiandrogens

have agonistlike properties when an -dro gen receptors are overexpressed.MDV3100 is a second-generation anti -androgen that attempts to overcome thisresistance (Figure).27 Built on the struc-ture backbone of a nonsteroidal thiohy-dantoin agonist, MDV3100 was selectedfrom a panel of about 200 derivatives forits high affinity and selectivity for andro-gen receptors.28

In preclinical studies, MDV3100demonstrated a five-time to eight-timegreater affinity for androgen receptors,and was only two to three times less selec-tive than native dihydrotestosterone. Itshowed androgen-receptor antagonism incells engineered to express in creasednumbers of androgen receptors andincreased activity in mouse models ofCRPC when compared with bicalu-tamide. The in vitro and in vivo activity,combined with optimal pharmacokineticand structure activity relationship proper-ties, resulted in MDV3100 moving frompreclinical testing into human trials.28

At the 2009 annual meeting of theAmerican Society of Clinical On cology,data from phase 1 and 2 trials ofMDV3100 were presented. After a safedose was determined in the phase 1 por-tion with 114 patients, the phase 2 por-tion enrolled patients into one of twogroups: one consisting of chemo therapy-naïve patients (n = 65), the other con-sisting of postchemotherapy patients (n= 49). The investigators followed PSA,circulating tumor cells (CTCs), tumorresponse time, and time on treatment ina total of 140 patients. At the 600-mgdaily dose, two of three patients experi-enced dose-limiting toxicities of rash andseizure (Table 1). At the next two lowerdoses (480 mg/day and 360 mg/day),fatigue was a problem, and thus the dosewas reduced to 240 mg daily, which wasdetermined to be the optimal dose. Adose-responsive decline in PSA wasnoted, with 58% of patients respondingat the 240-mg and 360-mg doses com-pared with only 32% of patient at the 60-mg and 150-mg doses. At 12 weeks, aPSA decline of greater than 50% wasnoted in 57% of the chemotherapy-naïve patients and 45% of thepostchemotherapy patients. No progres-sion was seen on radiograph in 74% ofpatients with mea surable disease in thesoft tissue or in 62% of patients withbone lesions. Ninety-two percent ofpatients with CTC in the favorablerange (defined as less than five cells)maintained the response over time. Theauthors concluded that MDV3100 was apromising compound and that the 240-mg/day dose should be developed fur-ther.29 A phase 3 trial evaluatingMDV3100 versus placebo in docetaxel-resistant metastatic prostate cancer isunder way.30

In a phase 3 study presented at the2010 Genitourinary Cancers Symposium,the second-generation taxane cabazitaxelcombined with prednisone significantlyimproved OS by 30% in men withmetastatic CRPC who progressed aftertreatment with a docetaxel-containingregimen.31 Median OS was 15.1 monthsin men who received cabazitaxel plusprednisone compared with 12.7 monthsin those who received mitoxantrone withpredisone. PFS was also significantlygreater in the cabazitaxel group (2.8 vs1.4 months).

DiscussionLong-term survival after the diagnosis

of prostate cancer is dependent on age atdiagnosis, comorbid illnesses, stage, andgrade of disease. With an increase inawareness and screenings, more men arebeing diagnosed at earlier stages; however, given the slow progression of thedisease most patients present with ad -vanced or metastatic disease. In patientswith localized or locally ad vanced dis-ease, adjuvant hormonal therapy is usedto decrease androgens and eradicateresidual disease. Initially, prostate cancerpatients have effective responses withsurgical or medical castration; however,up to half of these men will relapse, andnearly all relapsed patients will progressto CRPC.

Systemic therapy has become animportant component for the treat-ment of CRPC, but even chemothera-py agents have little success in extend-ing survival. Important innovationsincluding therapies targeting both sig-nal transduction and hormonal manip-ulation have been studied. Sipuleucel-T, a novel immunotherapy made bycombining autologous dendritic cellswith a recombinant fusion protein, hasdemonstrated survival advantage in thepivotal phase 3 IMPACT trial. In addi-tion, atrasentan and zibotentan are twoinvestigational agents that target en -dothelin receptors. Atrasentan hasbeen extensively studied, and recentlytwo randomized, placebo-controlled,phase 3 trials have been reported in theCRPC setting. Atra sentan did not affecttime to disease progression comparedwith placebo, despite evidence of bio-logic effects on PSA and bone alkalinephosphatase. In contrast, zibotentan,which potentially is more selective, wasshown in a double-blind, phase 2 trial,to produce a significant improvement inOS compared with placebo. Finally, themore recent agents, abiraterone andMDV3100, have been described as “superandrogen in hibitors” by reducing andro-gen production in the testis, adrenals,and prostate. Abiraterone acetate, anenzyme in hibitor, has shown early success



The more recent agents, abiraterone and MDV3100,have been described as “super androgen in hibitors” by reducing androgen production in the testis,adrenals, and prostate.


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Lung cancer is the leading cause ofcancer death in both men andwomen in the United States.1 It is

estimated that in 2009, 219,440 menand women were diagnosed with lungcancer and 159,390 men and womendied from the disease.2 From 1975 to2001, non–small-cell lung cancer(NSCLC) 5-year survival rates haveincreased from 11.9% to 15.6%. Thesestatistics are independent of sex, race,age, and stage at diagnosis, and makeacutely evident that there have been fewadvances in the treatment of NSCLC.This lack of progress may be a result ofnot analyzing the patient population

thoroughly. It is only in the past 5 yearsthat researchers have put more emphasison analyzing patient- and disease-relatedfactors, including race, age, sex, histol-ogy, and genomic testing results. Recenttrial results are leading us to a new hori-zon of patient-centered cancer care,which includes genomic testing, histol-ogy-focused treatment plans, and theconcept of maintenance drugs.

Chemotherapy doublet du jourPublished in 2002, the Eastern Co -

operative Oncology Group (ECOG)1594 study compared platinum-baseddoublets in the treatment of advancedNSCLC.3 The four doublets in the trialincluded cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, andcarboplatin/paclitaxel. No differencesin overall survival (OS) between thefour doublets were found. Althoughthese findings increased options interms of selecting chemotherapy basedon side effect profile, they offer onlymodest hope for better outcomes.

In 2004, several studies looked at theefficacy of platinum-based doublets in

the setting of adjuvant use. TheInternational Adjuvant Lung Trial(IALT) compared platinum-based dou-blets (cisplatin plus etoposide, vinorel-bine, vinblastine, or vindesine) versusobservation in postoperative stage I toIIIA patients.4 The result was a 5%improvement in disease-free survival aswell as 5-year OS with adjuvant chemo -therapy. That same year, JBR.10 com-pared cisplatin/vinorelbine versus obser-vation in patients with stage I to IINSCLC and confirmed that adjuvantcisplatin-based chemotherapy providesbenefit.5 The results were grossly positivewith a difference of 15% in 5-year sur-vival between the two arms (69% cis-platin/vinorelbine arm vs 54% observa-tion arm). As with palliative regimens,these results offer convincing evidencefor meaningful survival with platinum-based doublets in the adjuvant setting,but improving survival hinges on thehope of finding new drugs and better

understanding the utility of the drugscurrently available.

Focusing on detailsWith this groundwork laid, we can

begin to look at personalizing medicinefor patients with NSCLC. In 2008, theJMBD phase 3 randomized study com-pared gemcitabine/cisplatin with peme-trexed/cisplatin in the treatment ofadvanced NSCLC.6 The researchersperformed two analyses, one in whichthey did not look at the histology andone in which histology was included. Inthe analysis not including histology, theregimens were equivalent, with a medi-an survival of 10.3 months in each arm.In the analysis including histology, a sig-nificant difference in OS was found.Patients with squamous cell histologydemonstrated a significant improve-ment in survival with the gemcitabine/cisplatin compared with cis-platin/pemetrexed. Conversely, patientswith adenocarcinoma and large cell his-tologies demonstrated a significantimprovement in survival with cis-platin/pemetrexed. One of the targets of

pemetrexed is thymidalate synthetase.7Therefore, the differential benefit ofpemetrexed may be due to lower expres-sion of thymidalate synthetase in ade-nocarcinoma, compared with squamouscell carcinoma.

Maintenance therapyRecently, three trials opened the door

to the idea of maintenance therapy. In2008, the hypothesis of maintenancepemetrexed after first-line therapy foradvanced NSCLC was tested in a dou-ble-blind study.8 The study included allhistologies of NSCLC. Patients weretreated with four cycles of one of sixapproved platinum-based doublets. Theywere then randomized to either mainte-nance pemetrexed plus best support care(BSC) or placebo plus BSC. The primaryend point was progression-free survival(PFS), with a secondary end point of OS.The result was a significant increase inboth PFS and OS. In July 2009, the USFood and Drug Administration (FDA)approved pemetrexed for maintenancetherapy in patients with advanced non-squamous NSCLC, after receiving fourcycles of a platinum-based doublet in thefirst-line setting.

In 2009, a phase 3 clinical trial byFidias and colleagues compared imme-diate versus delayed second-line do c-etaxel (75 mg/m2, 21-day cycle) afterfour cycles of first-line gemcitabine(days 1 and 8)/carboplatin (day 1).9 Inthe delayed arm, docetaxel was startedat the first sign of disease progression.The results showed a significantincrease in PFS in the immediate doc-etaxel arm. However, this increase wasnot statistically significant, possiblybecause of the small number ofpatients in the trial.

The same hypothesis was tested witherlotinib in the SATURN study.10

After four cycles of chemotherapy,patients were randomized to eitherimmediate erlotinib or observation.Patients in the erlotinib arm showed aclinically meaningful improvement inboth PFS and OS. On the basis of thistrial, erlotinib was approved by theFDA as maintenance therapy forNSCLC in April 2010.11

Targeted agentsIn 2005, the ECOG 4599 trial intro-

duced the use of bevacizumab, a mono-clonal antibody against the vascularendothelial growth factor, in conjunc-

tion with the standard doublet of pacli-taxel/carboplatin.12 The trial comparedsix cycles of paclitaxel/carboplatin withbevacizumab (15 mg/kg) followed bymaintenance bevacizumab until progres-sive disease versus six cycles of paclitax-el/carboplatin alone. Results showed astatistically significant improvement inOS with the paclitaxel/carboplatin withbevacizumab arm. The overall responserate was 35%, compared with 15% withpaclitaxel/ carboplatin alone. Patientswith squamous histology, history ofhemoptysis, un treated brain metastasis,uncontrolled hypertension, who weretaking anti coagulants, or had had arecent cerebrovascular accident wereexcluded because of the increased risk ofbleeding.13 Because of the study’s design,in which bevacizumab was used as main-tenance until progressive disease, wecontinue to use it as maintenance thera-py in this setting. To date, there havebeen no studies comparing bevacizumabmaintenance with placebo.

In 2005, the BR.21 trial showed thaterlotinib, a small molecule designed totarget the human epidermal growthfactor receptor (EGFR)/HER1 path-way by inhibiting the tyrosine kinaseactivity of HER1, was better than BSCas a second- or third-line therapy forpatients with NSCLC.14 Patients wereallowed to have received one or twoprevious lines of therapy. The double-blind study demonstrated a statisticallysignificant improvement in both OSand PFS.

In 2008, the preliminary results ofthe Iressa Pan-Asia Study (IPASS)were reported.15 Gefitinib, a tyrosinekinase inhibitor (TKI), was comparedwith paclitaxel/carboplatin as a first-line therapy. The primary end pointwas PFS, with a secondary end point ofOS. EGFR mutation status was alsoanalyzed. The results showed thatpatients who were EGFR-mutationpositive had a significant increase inOS with gefitinib, compared with stan-dard chemotherapy. Con versely,patients who were EGFR- mutationnegative had an increased response tostandard chemotherapy in comparisonwith gefitinib.

Genomic testing: markers ofchemotherapy response

As previously discussed, thymidalatesynthetase expression in adenocarcino-ma potentially affects the utility of peme-


Solid Tumors

Personalizing Non–small-cell LungCancer TreatmentBy Tara L. Rich, MSN, RN, CNPCertified Nurse Practitioner, Thoracic OncologyTaussig Cancer Institute, Cleveland Clinic, Ohio

Tara L. Rich, MSN, RN, CNP

Patients with squamous cell histology demonstrated a significant improvement in survival with the gem citabine/cisplatin compared withcisplatin/pemetrexed.

TON_May2010_v3:TON 5/4/10 10:36 AM Page 30


Solid Tumors

trexed. Another potential marker ofchemotherapy response is the excisionrepair cross-complementation group 1(ERCC1) protein. In 2006, the IALTBio Investigators performed a subgroupanalysis of the IALT trial, looking atexpression of the ERCC1 protein andthe outcomes of receiving adjuvant cis-platin-based chemotherapy.16 The inves-tigators used immunohistochemical(IHC) analysis to determine the expres-sion of the ERCC1 protein in operativespecimens of NSCLC. The IALT trialcompared the effect of adjuvant cis-platin-based chemotherapy on survival,which was now being compared withERCC1 expression. The investigatorslooked for a validated clinical or biologicpredictor of the benefit of chemotherapy.Among 761 tumor specimens, ERCC1expression was positive in 335 (44%)and negative in 426 (56%). The resultsindicated that a benefit from cisplatin-based adjuvant chemotherapy was asso-ciated with the absence of ERCC1.Adjuvant chemotherapy significantly

prolonged survival in patients who wereERCC1-negative. Conversely, patientswith ERCC1-positive tumors whoreceived adjuvant chemotherapy did nothave prolonged survival. Among thepatients who did not receive adjuvantchemotherapy, those with ERCC1-posi-tive tumors survived longer than thosewith ERCC1-negative tumors. Thesefindings indicate that people withERCC1-negative tumors benefit fromadjuvant chemotherapy, whereaspatients with ERCC1-positive tumors donot. Further, these results suggest thatthe development of genomic profiles,including ERCC1, may help us betterselect which patients will benefit fromadjuvant chemotherapy.

Genomic testing: markers of TKIresponse

As discussed, the IPASS trial re -vealed the relationship between EGFR-mutation status and response to TKItherapy.14 Another potential novelmolecular marker, a fusion of echino-

derm microtubule-associated protein-like 4 (EML4) and the anaplastic lym-phoma kinase (ALK), has recently beenidentified in a small subset of NSCLC.17

Shaw and colleagues examined theclinical characteristics, as well as treat-ment outcomes, of NSCLC patientswith and without the EML4-ALKoncogene. EML4-ALK was identifiedusing fluorescent in situ hybridizationfor ALK rearrangements and was con-firmed by IHC for ALK expression.Patients with NSCLC were selected forgenetic screening on the basis of two ormore of the following characteristics:female sex, Asian ethnicity, never/lightsmoking history, and adenocarcinoma

histology. Of the 141 tumors screened,19 (13%) were EML4-ALK mutant, 31(22%) were EGFR mutant, and 91(65%) were wild-type (WT/ WT) forboth ALK and EGFR. Compared withthe EGFR-mutant and WT/WTcohorts, patients with EML4-ALK–mutant tumors were significantlyyounger and more likely to be men.Patients with EML4-ALK–positivetumors, like patients who have EGFRmutations, also were more likely to benever/light smokers compared with theWT/WT cohort. Eighteen of 19 EML4-ALK–positive tumors were adenocarci-nomas, predominantly the signet-ring

Case StudyA47-year-old woman was re -

ferred by her primary carephysician. She had a 3-month

history of a very mild nonproductivecough followed by a 4-week history ofleft hip pain, which led her to the pri-mary care physician’s office. Her physi-cian first ordered a hip radiograph,which revealed some abnormality butwas not conclusive. He also ordered achest film, which revealed a left upperlobe (LUL) mass, followed by a chestcomputed tomography (CT) scanwith contrast that confirmed the LULmass and revealed a slightly enlarged(1.4 cm) contralateral mediastinallymph node.

Her medical history showed noknown exposures. She was a pre-school teacher for 8 years, but is nowa homemaker raising two children.She has never smoked and drinkssocially. Her husband does not smokeand works as an engineer at an elec-trical firm. She has a history of acesarean section and tonsillectomy,but no other significant health prob-lems. Her mother had a history ofbreast cancer, but has been in remis-sion for 10 years. Her paternal grand-father, a long-standing smoker, diedof lung cancer at the age of 79 years.

Diagnostic workupThe first steps were to complete the

staging process and obtain a biopsyspecimen for histologic diagnosis.Although the tumor was extremely

suspicious on the CT scan, it couldhave been infectious or benign in etiol-ogy. After reviewing the films with boththe pulmonologist and interventionalradiologist, it was decided that the bestmethod to obtain tissue would be abronchoscopy. She was sent for thebronchoscopy, where the surgeon wasable to biopsy the LUL mass. The sur-geon attempted to biopsy the contralat-eral mediastinal lymph node that wasenlarged on the CT scan but wasunable to obtain a sufficient sample.Then the patient was sent for a whole-body positron-emission tomography(PET)/CT scan (which did not includethe head) and brain magnetic reso-nance imaging with contrast.

ResultsThe PET/CT scan revealed a PET-

avid bone lesion in the left pelvis, the4.1 cm 3.2 cm LUL lung mass,which is highly PET-avid, and moder-ate activity in the enlarged contralater-al mediastinal lymph node. The bron-choscopy revealed that the LUL masswas positive for adenocarcinoma. Thediagnosis was T2 N2 M1, stage IV, ade-nocarcinoma of the lung.

Patient-centered plan of careIn view of the diagnosis of adeno-

carcinoma, especially in the setting ofa nonsmoking history, we sent the tis-sue for epidermal growth factor recep-tor–mutation analysis. The resultscame back negative. This status ruled

out the idea of treating with a tyrosinekinase inhibitor as first-line therapy. IfEML4-ALK fusion oncogene testingwere standardized and available out-side the setting of a clinical trial, wewould have sent the tissue for thatanalysis as well. We are still collectinginformation on this new finding, so itdid not have utility in our treatmentdecisions for this patient. Therefore,we discussed standard chemotherapy,including bevacizumab eligibility. Shehad nonsquamous histology, a non-cavitating mass, and no significant

health risks that would prohibit herfrom receiving bevacizumab. Wedecided on the combination of pacli-taxel/carboplatin/bevacizumab. Be -cause bevacizumab was given as main-tenance until progressive disease inclinical trials, we planned to give ituntil progressive disease. We consid-ered the idea that erlotinib may havea role as a maintenance drug forpatients as well, but at this time thereis no direct comparison of erlotinibversus bevacizumab maintenance inthis setting. !


These results suggest that the development ofgenomic profiles, including ERCC1, may help us betterselect which patients will benefit from adjuvantchemotherapy.



Solid Tumors

cell subtype. Among patients withmetastatic disease, EML4-ALK positivitywas associated with resistance to EGFRTKIs. Patients in the EML4-ALK cohortand the WT/WT cohort showed similarresponse rates to platinum-based combi-nation chemotherapy and no differencein OS. These findings provide informa-tion about the clinical characteristics ofNSCLC patients who harbor this fusion,as well as the lack of benefit from EGFRTKIs in this population.

Currently, Pfizer has a phase 3 clinicaltrial investigating an oral c-Met andALK inhibitor, PF-02341066, versusstandard-of-care chemotherapy in pa -tients with advanced NSCLC carryingthe EML4-ALK oncogene who haveprogressed on one prior treatment with aplatinum-based chemotherapy.18 Theprimary end point is PFS, and secondaryoutcomes include OS, objective re sponserate, duration of response, disease-con-trol rate, and patient-reported outcomes.Patients will be randomized to receivePF-02341066 (250 mg orally twicedaily), pemetrexed (500 mg/m2 on day 1of each 21-day cycle), or docetaxel (75mg/m2 on day 1 of each 21-day cycle).

ConclusionThe past 5 years have brought us to

an era with choices and possibilities intreating lung cancer—an era of person-alizing NSCLC treatment. These newadvances give us hope for improvingoutcomes and survival; hope that wecan pass on to our patients. !

References1. American Cancer Society. Cancer Facts and

Figures 2009. Atlanta, GA: American CancerSociety; 2009.

2. Ries LAG, Eisner MP, Kosary CL, et al, eds.SEER Cancer Statistics Review, 1975-2001.National Cancer Institute. http://seer.cancer.gov/csr/1975_2001/. 2004. Accessed January21, 2010.

3. Schiller JH, Harrington D, Belani CP, et al; forthe Eastern Cooperative Oncology Group.Comparison of four chemotherapy regimens foradvanced non-small-cell lung cancer. N Engl JMed. 2002;346:92-98.

4. Le Chevalier T; for the IALT Investigators.Results of the randomized international adju-vant lung cancer trial (IALT): cisplatin-basedchemotherapy (CT) vs no CT in 1867 patients(pts) with resected non-small cell lung cancer(NSCLC). Proc Am Soc Clin Oncol. 2003;22:Abstract 6.

5. Winton TL, Livingston R, Johnson D, et al. Aprospective randomised trial of adjuvantvinorelbine (VIN) and cisplatin (CIS) in com-pletely resected stage 1B and II non small cell

lung cancer (NSCLC) Intergroup JBR.10. JClin Oncol. 2004;22(14S):Abstract 7018.

6. Scagliotti GV, Parikh P, von Pawel J, et al.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed inchemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol.2008;26:3543-3551.

7. Scagliotti G, Monica V, Ceppi P, et al. Baselinethymidylate synthase expression according to his-tological subtypes of non-small cell lung cancer. JClin Oncol. 2009;27(15S):Abstract 7521.

8. Ciuleanu TE, Brodowicz T, Belani CP, et al.Maintenance pemetrexed plus best supportivecare (BSC) versus placebo plus BSC: as phaseIII study. J Clin Oncol. 2008;26(May 20suppl):Abstract 8011.

9. Fidias PM, Dakhil SR, Lyss AP, et al. Phase IIIstudy of immediate compared with delayed doc-etaxel after front-line therapy with gemcitabineplus carboplatin in advanced non-small-celllung cancer. J Clin Oncol. 2009;27:591-598.

10. Cappuzzo F, Ciuleanu T, Stelmakh L, et al; forthe SATURN Investigators; Istituto ClinicoHumanitas IRCCS. SATURN: a double-blind,randomized, phase III study of maintenanceerlotinib versus placebo following nonprogres-sion with first-line platinum-based chemother-apy in patients with advanced NSCLC. J ClinOncol. 2009;27(15S):Abstract 8001.

11. Erlotinib approved as maintenance therapy fornon-small cell lung cancer. NCI CancerBulletin. April 20, 2010.

12. Sandler AB, Gray R, Brahmer J, et al.Randomized phase II/III trial of paclitaxel (P)plus carboplatin (C) with or without beva-

cizumab (NSC # 704865) in patients withadvanced non-squamous non-small cell lung can-cer (NSCLC): an Eastern Cooperative OncologyGroup (ECOG) Trial—E4599. J Clin Oncol.2005;23(16S pt 1):Abstract LBA4.

13. Johnson DH, Fehrenbacher L, Novotny WF, et al.Randomized phase II trial comparing bevaciz -umab plus carboplatin and paclitaxel with carbo-platin and paclitaxel alone in previously untreat-ed locally advanced or metastatic non-small-celllung cancer. J Clin Oncol. 2004;22:2184-2191.

14. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, etal; for the National Cancer Institute of CanadaClinical Trials Group. Erlotinib in previouslytreated non-small-cell lung cancer. N Engl J Med.2005;353:123-132.

15. The IPASS study. www.iressa.com/ipass-study/.Accessed February 5, 2010.

16. Olaussen KA, Dunant A, Fouret P, et al; for theIALT Bio Investigators. DNA repair by ERCC1in non-small-cell lung cancer and cisplatin-basedadjuvant chemotherapy. N Engl J Med. 2006;355:983-991.

17. Shaw AT, Yeap BY, Mino-Kenudson M, et al.Clinical features and outcome of patients withnon-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253.

18. Pfizer presents data with novel investigationalagents in select patient groups with non-small celllung cancer [press release]. May 30, 20009.www.pfizer.com/news/press_releases/pfizer_press_releases.jsp?rssUrl=http://mediaroom.pfizer.com/portal/site/pfizer/index.jsp?ndmViewId=news_view&ndmConfigId=1016273&newsId=20090530005019&newsLang=en. Accessed January 29,2010.

in phase 1 and 2 trials in reducing PSAlevels and decreasing tumor size.MDV3100, an oral antiandrogen, hasdemonstrated androgen suppression inpreclinical studies as well as the abilityto induce cell death in bicalutamide-resistant tumors. Phase 1 and 2 trialshave found that MDV3100 can reducePSA levels and decrease CTC.

ConclusionSipuleucel-T offers a new treatment

option for men with metastatic CRPC. Inaddition, a number of different agents arecurrently being investigated in this dis-ease. Therapies that work through en -zyme inhibition, receptor blockade, andeven immunogenetic stimulation canmanipulate the growth and progressionof prostate tumors. Research efforts areongoing, and it is hoped that publica-tion of results of current trials will pro-vide additional data to support the use ofthese agents in improving outcomes andsurvival for patients with CRPC. !

References1. Jemal A, Siegal R, Ward E, et al. Cancer statis-

tics 2009. CA Cancer J Clin. 2009;59:225-249.2. Moul JW, Armstrong AJ, Hollenbeck BK, et al.

Prostate cancer. In: Pazdur R, Wagman LD,Camphausen KA, Hoskins WJ, eds. CancerManagement: A Multidisciplinary Approach. 11thed. Lawrence, KS: CMP; 2008:393-423.

3 Goktas S, Crawford ED. Optimal hormonaltherapy for advanced prostatic carcinoma.Semin Oncol. 1999;26:162-173.

4. Sharifi N, Gulley JL, Dahut WL. Androgendeprivation therapy for prostate cancer. JAMA.

2005;294:238-244.5. Petrylak DP, Tangen CM, Hussain MA, et al.

Docetaxel and estramustine compared withmitoxantrone and prednisone for advancedrefractory prostate cancer. N Engl J Med.2004;351:1513-1520.

6. Oudard S, Banu E, Beuzeboc P, et al. Multicenterrandomized phase II study of two schedules of do -cetaxel, estramustine, and prednisone versusmitoxantrone plus prednisone in patients withmetastatic hormone-refractory prostate cancer. JClin Oncol. 2005;23:3343-3351.

7. Tannock IF, de Wit R, Berry WR, et al; for theTAX 327 Investigators. Docetaxel plus pred-nisone or mitoxantrone plus prednisone foradvanced prostate cancer. N Engl J Med.2004;351:1502-1512.

8. Tannock IF, Osobo D, Stockler MR, et al.Chemotherapy with mitoxantrone plus pred-nisone or prednisone alone for symptomatichormone-resistant prostate cancer: a Canadianrandomized trial with palliative end points. J Clin Oncol. 1996;14:1756-1764.

9. Hurwitz AA, Yanover P, Markowitz, et al.Prostate cancer: advances in immunotherapy.BioDrugs. 2003;17:131-138.

10. Dendreon Corporation. Cellular, Tissue and GeneTherapies Advisory Committee. Sipuleucel-Tbriefing document. BLS STN 1251970. March27, 2007. www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_01.pdf. Accessed January3, 2010.

11. Small EJ, Schellhammer PF, Higano CS, et al.Placebo-controlled phase III trial of immuno-logic therapy with Sipuleucel-T (APC8015) inpatients with metastatic, asymptomatic hor-mone refractory prostate cancer. J Clin Oncol.2006;24:3089-3094.

12. Schellhammer PF, Higano C, Berger ER, et al;for the IMPACT Study Investigators. A ran-domized, double-blind, placebo-controlled,multi-center, phase III trial of sipuleucel-T inmen with metastatic, androgen independentprostatic adenocarcinoma (AIPC). Presentedat: American Urological Association 104thAnnual Scientific Meeting; April 28, 2009;Chicago, IL. Late Breaking Abstract 9.

13. Nelson JB. Endothelin receptor antagonists.World J Urol. 2005;23:19-27.

14. Herrmann E, Bögemann M, Bierer S, et al. The

endothelin axis in urologic tumors: mechanismsof tumor biology and therapeutic implications.Expert Rev Anticancer Ther. 2006;6:73-81.

15. Godara G, Cannon GW, Cannon GM, et al.Role of endothelin axis in progression to aggres-sive phenotype of prostate adenocarcinoma.Prostate. 2005;65:27-34.

16. Carducci MA, Saad F, Abrahamsson PA, et al;for the Atrasentan Phase III Study GroupInstitutions. A phase 3 randomized controlledtrial of the efficacy and safety of atrasentan inmen with metastatic hormone-refractoryprostate cancer. Cancer. 2007;110:1959-1966.

17. Nelson JB, Love W, Chin JL, et al; for theAtrasentan Phase 3 Study Group. Phase 3, ran-domized, controlled trial of atrasentan in patientswith nonmetastatic, hormone-refractory prostatecancer. Cancer. 2008;113:2478-2487.

18. Zonnenberg BA, Groenewegen G, Janus TJ, et al.Phase I dose-escalation study of the safety andpharmacokinetics of atrasentan: an endothelinreceptor antagonist for refractory prostate cancer.Clin Cancer Res. 2003;9:2965-2972.

19. Docetaxel and prednisone with or withoutatrasentan in treating patients with stage IVprostate cancer and bone metastases that did notrespond to previous hormone therapy. Clinical tri-als.gov identifier NCT00134056. First received:August 22, 2005. Last updated: March 30, 2010.www.clinicaltrials.gov/ct2/show/NCT00134056?term=docetaxel+and+prednisone&rank=13.Accessed April 1, 2010.

20. Schelman WR, Liu G, Widing G, et al. A phase Istudy of zibotentan (ZD4054) in patients withmetastatic, castrate-resistant prostate cancer. InvestNew Drugs. 2009 Sep 19. Epub ahead of print.

21. James ND, Caty A, Borre M, et al. Safety andefficacy of the specific endothelin-A receptorantagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastaseswho were pain free or mildly symptomatic: adouble-blind, placebo controlled randomized,phase II trial. Eur Urol. 2009;55:1112-1123.

22. A Phase III Trial of ZD4054 (Endothelin-AAntagonist) in Hormone Resistant ProstateCancer With Bone Metastases (ENTHUSEM1). Clinicaltrials.gov identifier NCT00554229. First received: November 2, 2007. Lastupdated: January 14, 2010. http://clinicaltrials.gov/ct2/show/NCT00554229. Accessed February

20, 2010.23. Potter GA, Barrie E, Jarman M, Rowlands MG.

Novel steroidal inhibitors of human cytochromeP450 (17-hydroxylase-C17,20-lyase): poten-tial agents for the treatment of prostatic cancer.J Med Chem. 1995;38:2463-2471.

24. O’Donnell A, Judson I, Dowsett M, et al.Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate(CB7630) in patients with prostate cancer. Br JCancer. 2004;90:2317-2325.

25. Attard G, Reid A, Yap T, et al. Phase I clinicaltrial of a selective inhibitor of CYP17, abi-raterone acetate, confirms that castration-resis-tant prostate cancer commonly remains hor-mone driven. J Clin Oncol. 2008;26:4563-4571.

26. Attard G, Reid A, A’Hern R, et al. Selectiveinhibition of CYP17 with abiraterone acetate ishighly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-3748.

27. Chen Y, Clegg NJ, Scher HI. Anti-androgensand androgen-depleting therapies in prostatecancer: new agents for an established target.Lancet Oncol. 2009;10:981-991.

28. Tran C, Ouk S, Clegg NJ, et al. Development ofa second-generation antiandrogen for treatmentof advanced prostate cancer. Science. 2009;324:787-790.

29. Scher HI, Beer TM, Higano CS, et al. Antitumoractivity of MDV3100 in a phase I/II study of cas-tration-resistant prostate cancer (CRPC). J ClinOncol. 2009;27(15S):Abstract 5011.

30. Safety and efficacy study of MDV3100 inpatients with castration-resistant prostate can-cer who have been previously treated with do -cetaxel-based chemotherapy. Clinicaltrials.govidentifier NCT00974311. First received:September 9, 2009. Last updated: March 10,2010. www.clinicaltrials.gov/ct2/show/NCT00974311?term=MDV3100&rank=2. AccessedApril 1, 2010.

31. Sartor AO, Oudard S, Ozguroglu M, et al.Cabazitaxel or mitoxantrone with prednisone inpatients with metastatic castration-resistantprostate cancer (mCRPC) previously treatedwith docetaxel: final results of a multinationalphase III trial (TROPIC). Presented at 2010Genitourinary Cancers Symposium. March 5,2010. San Francisco, CA.

PROSTATE CANCER


Personalizing Non–small-cell Lung Cancer Treatment Continued from page 31


Acute myeloid leukemia (AML)is a heterogeneous disease affec t- ing approximately 13,000 peo-

ple in the United States each year.1 Foryounger adults (<60 years) standardinduction treatment includes 7 days ofcytarabine and 3 days of an anthracy-cline. Adults 60 years and older may alsobe treated with this regimen or a lessintensive approach using outpatientchemotherapy or supportive care. Theintensive chemotherapy regimens havebeen in use since the 1970s, with littleimprovement in complete re sponse(CR) rate or overall survival (OS). Manyof the clinical trials that have beenreported in the past year investigate theability to improve the efficacy of theseintensive chemotherapy regimens byincreasing dose intensity or adding novelagents to induction therapy.

More intensive regimensOne significant update was an inten-

sified induction approach in adults whowere younger than 60 years. In theEastern Cooperative Oncology Group

E1900 phase 3 trial, investigators ran-domized patients to either intensifieddaunorubicin (90 mg/m2 intravenous[IV] 3 days) or standard daunorubicin(45 mg/m2 IV 3 days).2 All patientsalso received 7 days of cytarabine (100mg/m2 continuous IV infusion).

End points were evaluated in a totalof 547 patients. The median age was 48years, with other demographics, cytoge-netics, and characteristics well matchedat baseline. Median OS was significant-ly increased in the intensified-daunoru-bicin arm at 23.7 months comparedwith 15.7 months in the standard arm(P <.003). The CR rate was also higherin the intensified-daunorubicin arm(71% vs 57%; P <.001). The combina-tion of an increased CR rate and an OSadvantage is important, especially con-sidering that previous trials with moreintensive induction regimens haveshown an increased CR rate without asignificant increase in OS, presumablybecause of the increased toxicity profilesof the more intensive regimens.

In the current trial, both regimenshad similar overall toxicity. The deathrate during the induction period was5.5% for the intensified-daunorubicingroup and 4.5% for the standard-dosegroup (P = .6). Cardiotoxicity withhigher doses of daunorubicin was notsignificantly higher than with the stan-dard dose. Symptomatic heart failure

was seen in 7.9% in the intensified-daunorubicin group and 7.2% in thestandard-dose group (P = NS). Theinvestigators concluded that an intensi-fied induction regimen using >45mg/m2 of daunorubicin for 3 days (alongwith cytarabine) should be the newstandard treatment for adults with AMLwho are younger than 60 years. Becauseoncologists may be uncomfortable pre-scribing such a high dose, some oncolo-gy associations recommend giving atleast 60 mg/m2 of daunorubicin for 3 daysduring AML induction for youngeradults, which may be more acceptable toproviders. It should be noted that it isunknown whether 60 mg/m2 of daunoru-bicin would provide the same benefit asthe 90-mg/m2 dose used in this trial.

Novel regimensMany of the updates in AML were

presented at the 2009 annual meeting ofthe American Society of Hematology(ASH). In one trial (MRC-AML 15),the Medical Research Council investi-gated various induction and consolida-tion regimens (Figure).3 Patients wererandomized to induction therapy withtwo courses of cytarabine/daunorubicin(DA), cytarabine/daunorubicin/etopo-side (ADE), or fludarabine/cytarabine/idarubicin/granulocyte colony-stimulat-ing factor (FLAG-IDA). As consoli-dation therapy, patients were random-

ized to ams acrine/cytarabine/etoposide(MACE)/mitozantrone/cytarabine(MidAC) or two courses of high-dosecytarabine. There was also a randomiza-tion for an additional cycle of high-dosecytarabine.

All the groups were well matched atbaseline. Eighty-four percent of patientswere between 15 and 59 years of age atdiagnosis, and 90% had de novo AML.The majority (70%) of cytogenetic pro-files were intermediate prognostic.Although there was a statistically signif-icant increase in CR rate for DA com-pared with ADE, the rates are clinicallysimilar. OS was also similar in all induc-tion arms (Table 1). When focusing onthe consolidation data, no major differ-ence in OS was noted betweenMACE/MidAC and high-dose cytara-bine (52% vs 54%; P = .2). OS also didnot differ whether the patient receivedfour or five courses of therapy (58% vs60%; P = .7). The most meaningfulinformation from this trial may comefrom the comparison of cytarabinedosed at 1.5 g/m2 6 versus 3 g/m2 6.The 5-year OS was not significantly dif-ferent between the two groups (54% vs52%; P = .7).2 The negligible differencein clinical outcomes produced by thesetwo different dosing regimens suggeststhat it may be in the best interest of thepatient to forego the risks of cerebellartoxicity associated with higher doses ofcytarabine, and instead treat patientswith the 1.5-g/m2 consolidation regimen.

The preliminary results of the South -western Oncology Group S0106 trialalso were presented at ASH. This trialrandomized adults aged between 18 and60 years with de novo AML to receivegemtuzumab ozogamicin in addition tostandard 7+3 therapy (daunorubicin 60mg/m2 IV days 1-3 and cytarabine 100mg/m2/day continuous IV infusion days1-7) with or without gemtuzumabozogamicin for induction.4 Prior studieshad shown that adding gemtuzumab toinduction therapy may increase disease-free survival (DFS) without increasingtoxicity.5 In the current trial, the treat-ment arm received daunorubicin 45mg/m2 IV on days 1 to 3, cytarabine 100mg/m2 IV on days 1 to 7, and gemtuzum-ab 6 mg/m2 IV on day 4. Patients in thecontrol arm received daunorubicin at 60mg/m2 IV on days 1 to 3 and cytarabine100 mg/m2 continuous IV infusion ondays 1 to 7. Those who entered into CR


Hematologic Malignancies

Treatment Updates: Acute MyeloidLeukemiaBy Marc A. Earl, PharmD, BCOPHematology/Oncology Clinical Specialist, Cleveland Clinic, Ohio

Marc A. Earl, PharmD, BCOP

Randomize

DA (n = 994)Daunorubicin 50 mg/m2 days 1, 3, 5Ara-C 100 mg/m2 every 12 hrs days 1-10

ADE (n = 989)Daunorubicin 50 mg/m2 days 1, 3, 5Ara-C 100 mg/m2 every 12 hrs days 1-8Etoposide 100 mg/m2 days 1-5

FLAG-IDA (n = 635)Fludarabine 30 mg/m2 days 2-6Ara-C 2 g/m2 days 2-6Idarubicin 10 mg/m2 days 4-6

ADE (n = 633)Daunorubicin 50 mg/m2 days 1, 3, 5Ara-C 100 mg/m2 every 12 hrs days 1-8Etoposide 100 mg/m2 days 1-5

Randomize – Consolidation 2 cycles

MACE (cycle 1) Amsacrine 100 mg/m2 days 1-5Ara-C 200 mg/m2 days 1-5Etoposide 100 mg/m2 days 1-5

MidAC (cycle 2)Mitoxantrone 10 mg/m2 days 1-5Ara-C 1 g/m2 days 1-3

(n = 723)

Ara-C 1.5 g/m2 twice daily days 1, 3, 5

(n = 329)

Ara-C 3 g/m2 twice daily days 1, 3, 5

(n = 328)

Randomize – Additional 1 cycle

Ara-C 1.5 g/m2 twice daily days 1, 3, 5

(n = 112)

No additional therapy

(n = 115)

Figure. Induction and Consolidation Regimens in MRC-AML15Source: Reference 2. Continued on page 36




after induction were given three cycles ofconsolidation therapy with cytarabine 3g/m2 IV 6 doses. There was an addi-tional randomization to three doses ofgemtuzumab 5 mg/m2 IV or observation.4

Both groups in this trial were wellmatched (Table 2). At the second inter-im analysis, 596 patients were availablefor evaluation. The addition of gem-tuzumab to standard 7+3 therapy wasfound not to affect the CR rate. The CRrate was 66% in the gemtuzumab armand 69% in patients receiving standard7+3 therapy. There was also no statisti-cally significant difference in DFS (haz-ard ratio [HR], 1.35; 95% confidenceinterval [CI], 0.85-2.14; P = .9) or OS(HR, 1.15; 95% CI, 0.86-1.35; P = .35).Despite no benefit in efficacy, moreadverse events were seen in the gem-tuzumab group. Grade 4 and 5 infec-tions were more frequent (11% vs 6%)in the gemtuzumab group as were deathsduring induction (9% vs 2%).4 Based onthe lack of efficacy benefit (CR, DFS,and OS) along with an increase inadverse events, the study was stoppedbefore full accrual. Although gem-tuzumab is US Food and Drug Ad -ministration–approved for relapsedAML in older adults, it appears that foryounger adults, adding it to inductiontherapy provides no benefit.

Lenalidomide is approved for low- orintermediate-1-risk myelodysplastic syn-drome. It is not completely clear why

lenalidomide is effective, but its efficacyis thought to be due to immunomodula-tory and antiangiogenic effects. It ishypothesized that there are common fea-tures between myelodysplastic syndromeand AML. Based on this theory,lenalidomide was studied as initial ther-apy for adults 60 years and older in anopen-label, phase 2 trial.6 Patients hadto have untreated AML with a goodperformance status. In the inductionphase, patients received 50 mg oflenalidomide daily for 28 days. Thosepatients not in CR underwent another28-day induction cycle with the samedosing scheme. Afterward, nonprogress-ing patients received lenalidomide 10mg daily for up to twelve 28-day cycles.Therapy was stopped for progressive dis-ease or severe toxicity. Patients wereallowed to receive transfusions andgrowth factors during the trial.

Thirty-three patients with a medianage of 71 years (60-88 years) wereenrolled. Seventy percent had de novoAML, and 36% had poor-risk cytoge-netics. The CR rate was 30%, includingthree cytogenic CRs, two morphologicCRs, and five CRs with with incom-plete blood count recovery. The 60-daymortality rate was 27%, with the major-ity of the deaths resulting from diseaseprogression. The most common toxici-ties experienced were related to myelo-suppression and infections.

One of the benefits of this proposed

therapy is that it can be taken orally.The median time spent in the hospitalwas 6 days (range, 0-40 days) for theentire group. Those who achieved CRhad a median hospitalization time of 3days (range, 0-14 days). For patientswho elect to receive intensive induc-tion therapy, a typical hospital stay canlast 4 to 6 weeks. The mortality rate of27% seen with lenalidomide is consis-tent with that of intensive inductiontherapy. This high-dose lenalidomideregimen is promising for older patientswith AML. Further studies are ongoingto delineate the mechanism of action oflenalidomide and to discover ways toenhance the CR duration for thesepatients. The benefit of this therapy isnot only that it is an oral option to treatAML, but also that it may be a novelapproach for older adults.

One area of interest in AML researchhas been the effect of different tyrosinekinases on cell proliferation and apop-tosis. A recent focus has been FMS-liketyrosine kinase 3 (FLT3) internal tan-dem duplication (ITD) domain muta-tions. More than 20% of de novo AMLis associated with an FLT3 ITD muta-tion.7 Recent trials show that this muta-tion is associated with worse OS and anincrease in relapse rates. Because of theincidence and pathophysiology of theFLT3 mutation it has become a targetfor pharmacologic therapy.8 One agentthat has shown to be synergistic follow-ing chemotherapy and may affect FLT3is lestaurtinib.9

In a phase 2 study, patients (n = 224)with relapsed AML and mutated FLT3status were randomized to receive mitox-antrone/etoposide/cytarabine or high-dose cyta rabine alone, or either chemo -therapy regimen followed by lestaurtinib80 mg twice daily starting on day 7 or 8.The median age at relapse was 55 years,and 88% of patients had an FLT3 ITDmutation. The CR rate was not signifi-cantly different between the two groups(26% vs 21%; P = .35). OS was also notsignificantly different (P = .92).Lestaurtinib was well tolerated, and theside effect profile for the lestaurtinibarm was similar to that of the controlarm. One of the secondary end points ofthe study was the pharmacokinetic pro-file of lestaurtinib. The investigatorsnoted that the level of FLT3 inhibitionwas low (58% adequately inhibited atday 15) and not sustained at this level(27% had adequate inhibition at days15 and 42). Further investigationshowed that achieving FLT3 inhibitionmay have correlated with CR rate. Inpatients who had ample FLT3 inhibi-tion on day 15, the CR rate was 39%compared with 9% in patients who didnot have FLT3 inhibition. This findingmay have been due to the dosing used

in this trial or the pharmacokinetics ofthe drug. Further trials are looking atother methods to achieve more ade-quate FLT3 inhibition and the affectthis may have on AML outcomes.

SummaryMuch of the information presented

in 2009 focused on more intensive ornovel chemotherapy regimens to treatAML. Some of the data (high-doselenalidomide, FLT3 inhibitors) werepositive, and although other data (gem-tuzumab) showed that no extra benefitwas achieved, all the trials provide valu-able information about a vastly hetero-geneous disease. The most excitingnews from 2009 were the data pertain-ing to higher doses of daunorubicin usedduring AML induction for adults 60years and younger. It remains unclearthe precise dose of daunorubicin thatprovides the most benefit withoutundue side effects, but the increase inCR rate and OS were welcomed newsfor a difficult-to-treat disease. !

References1. American Cancer Society. Cancer facts and fig-

ures 2009. www.cancer.org. Acessed April 21,2010.

2. Fernandez HF, Sun Z, Litzow MR, et al. A ran-domized trial of anthracycline dose intensificationduring induction of younger patients with acutemyeloid leukemia: results of Eastern CooperativeOncology Group study E1900. J Clin Oncol.2009;27(15S):Abstract 7003.

3. Burnett AK, Hills RK, Milligan D, et al; for theNCRI AML Working Group. Attempts to opti-mise induction and consolidation chemotherapyin patients with acute myeloid leukaemia: resultsof the MRC-AML15 trial. Blood (ASH AnnualMeeting Abstracts). 2009;114:Abstract 484.

4. Petersdorf S, Kopecky K, Stuart RK, et al.Preliminary results of Southwest Oncology Groupstudy S0106: an international intergroup phase 3randomized trial comparing the addition of gem-tuzumab ozogamicin to standard induction thera-py versus standard induction therapy followed bya second randomization to post-consolidationgemtuzumab ozogamicin versus no additionaltherapy for previously untreated acute myeloidleukemia. Blood (ASH Annual Meeting Abstracts).2009;114:Abstract 790.

5. Burnett AK, Kell WJ, Goldstone AH, et al. Theaddition of gemtuzumab ozogamicin to inductionchemotherapy for AML improves disease free sur-vival without extra toxicity: preliminary analysisof 1115 patients in the MRC AML15 trial. Blood(ASH Annual Meeting Abstracts). 2006;108:Abstract 13.

6. Vij R, Nelson A, Uy GL, et al. A phase II study ofhigh dose lenalidomide as initial therapy for acutemyeloid leukemia in patients > 60 years old. Blood(ASH Annual Meeting Abstracts). 2009;114:Abstract 842.

7. Applebaum F, Meshinchi S. Structural and func-tional alterations of FLT3 in acute myeloidleukemia. Clin Cancer Res. 2009;15:4263-4269.

8. El-Shami K, Stone R, Smith D. FLT3 inhibitorsin acute myeloid leukemia. Expert Rev Hematol.2008;1:153-160.

9. Levis M, Ravandi F, Wang ES, et al. Results froma randomized trial of salvage chemotherapy fol-lowed by lestaurtinib for FLT3 mutant AMLpatients in first relapse. Blood (ASH AnnualMeeting Abstracts). 2009;114:Abstract 788.

Treatment Updates: Acute Myeloid Leukemia Continued from page 34

Table 1. Complete Response (CR) and Overall Survival (OS) Ratesfrom MRC-AML15

End point Treatment P valueDA ADE

CR 77% 81% 0.045-year OS 42% 39% 0.7

FLAG-IDA ADECR 84% 81% 0.25-year OS 46% 41% 0.5

ADE indicates cytarabine/daunorubicin/etoposide; DA, cytarabine/daunorubicin; FLAG-IDA,fludarabine/cytarabine/idarubicin/granulocyte colony-stimulating factor.

Source: Reference 2.

Table 2. Baseline Characteristics for SWOG S0106

7+3 and gemtuzumab 7+3 alone(n = 297) (n = 299)

Median age, years 48 47Cytogenetics, %

Favorable 15 12Intermediate 41 42Poor 19 20Indeterminate/unavailable 26 26

7+3 indicates daunorubicin 60 mg/m2 IV days 1-3 and cytarabine 100 mg/m2/day continuous IV infusion days 1-7;SWOG, Southwestern Oncology Group.



TARGET AUDIENCEThis activity is intended for hematologists, oncologists and other healthcare professionals who are involved with the care of patients withfollicular lymphoma.

STATEMENT OF NEEDNon-Hodgkin's lymphoma (NHL), the most common hematologicmalignancy, represents a large proportion of the case load for the typicaloncology practitioner. That load is likely to grow, since NHL is increasingin prevalence. The introduction of rituximab, the monoclonal antibodyagainst CD20, changed the treatment landscape of lymphoma and it has been advanced further by immunotherapies that combine CD20-directed targeting with radiotherapy. The recent rapid advances intherapeutics and impressive research across this broad, heterogeneousgroup of malignancies represent an educational challenge for the clinician trying to stay current and provide the most appropriate, up-to-date therapy tailored for the individual patient. Immunotherapyplays a key role at all stages of the disease in reaching the goal of thehighest quality response.

EDUCATIONAL OBJECTIVESOn completion of this activity, participants should be able to:

• Define the goals of therapy for follicular lymphoma (FL)• Describe strategies for patient selection for immunotherapy

(including radioimmunotherapy [RIT]), in both the up-front andrelapsed/refractory setting

• Define different immunotherapy approaches in terms of efficacy,safety, and tolerability

• Propose strategies to overcome adverse events and access issues thatcreate barriers to the provision of optimal immunotherapy in FL

The Essential Role of Immunotherapy in Follicular Lymphoma Management

www.coexm.com/ace03.aspLOG ON TODAY TO PARTICIPATE

Release Date: March 19, 2010 Expiration Date: March 18, 2011

In collaboration with

FACULTYStephanie A. Gregory, MDProfessor of MedicineDirector, Section of HematologyRush University Medical CenterChicago, Illinois

David Maloney, MD, PhDAssociate Professor of MedicineDivision of OncologyUniversity of WashingtonMember Fred Hutchinson Cancer Research Center Seattle, Washington

With commentary by:Peter S. Conti, MD, PhDProfessorNuclear MedicineKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, California

This activity has been approved for 1.0 AMA PRA Category 1 Credits™. For further information and to participate, please go to: www.coexm.com/ace03.asp

This activity is supported by an educational grant from Spectrum Pharmaceuticals.




In 2000, before imatinib was market-ed, it was estimated that there wouldbe 4400 new diagnoses of chronic

myeloid leukemia (CML) and 2300patients would die as a result of the dis-ease in the United States.1 In 2009, thenumber of estimated new cases of CMLincreased to 5050, but the number ofpatients who were expected to succumbto the cancer decreased to 470 patients.2The US Food and Drug Administration’s(FDA) approval of imatinib in 2001 wasseen as a giant leap toward improvingand prolonging the lives of patients diag-nosed with CML. In the imatinib era,research in CML has focused on improv-ing the utility of imatinib, developing

more potent tyrosine kinase inhibitors(TKIs), and working to overcome drugresistance and intolerability.

The clinical course of CML is char-acterized by three phases: chronicphase (CP), accelerated phase (AP),and blast crisis (BC), with the majorityof patients diagnosed in CP.Historically, patients progressed within3 to 5 years to AP and BC, which areultimately fatal if untreated.3 Theimprovements in treating CML arerelated to it being the first cancerdefined by a specific karyotypic abnor-mality, specifically a reciprocal chro-mosomal translocation between chro-mosomes 9 and 22.4 This chromosomaltranslocation, referred to as thePhiladelphia (Ph) chromosome, resultsin the production of the BCR-ABLtyrosine kinase protein. Im atinibinhibits the activity of the BCR-ABLprotein with high selectivity. Based onresults from the International Ran -domized Study of Interferon andSTI571 published in 2003, imat inib hasbecome the standard frontline therapyfor Ph-positive (Ph+) CML.5,6

ImatinibThe 8-year follow-up results to this

clinical trial, which recently becameavailable, demonstrated an estimatedevent-free survival (EFS) of 81%, withfreedom from progression to AP/BC at92% in the imatinib arm.7 Most occur-rences of progression to AP and BCoccurred early, and the risk of progres-sion decreased after 3 years of treat-ment. Also noted, imatinib’s adverseevent profile did not change over time.

The FDA-approved dose of imatinibfor first-line treatment of CP CML is 400mg/day or 600 mg/day in AP or BC.8 Forpatients with disease progression orintolerance to imatinib, current TKIoptions include higher-dose imatinib,dasatinib, or nilotinib (Table). Allo -geneic stem-cell transplant (SCT) is alsoan option. In CP CML, increasing thedose of imatinib to 800 mg/day when theinitial dose failed to achieve a completecytogenetic re sponse (CCyR) has beenevaluated. In this analysis, 13 (38%) of34 patients achieved a CCyR with thehigher dose.12

Recently, a phase 3 trial comparedimatinib 400 mg/day with 800 mg/dayas initial treatment in CP CML.13 Theprimary objective was major molecularresponse (MMR) at 12 months withseveral secondary objectives, includingtime to MMR and time to CCyR. Nosignificant difference was observed forthe primary objective, but MMR andCCyR occurred sooner at the higherdose. At 6 months, 17.2% of patients onthe lower dose and 33.5% of patients onthe higher dose had achieved an MMR.Adverse effects, including rash, edema,and gastrointestinal problems, occurredmore often at the higher dose, but over-all, both doses were considered well tol-erated. Continued follow-up is stillneeded to determine whether earlierresponse affects survival.

DasatinibDasatinib is FDA-approved for adults

with CML that is resistant or intolerantto prior therapy. The recommendeddose is 100 mg/day for CP CML and 140mg/day for patients in AP or BC CML.9

Dasatinib’s inhibition of unmutatedBCR-ABL is 300 times more potent invitro than imatinib’s and it has the abil-ity to overcome mutations that lead toimatinib resistance, with the notableexception of the T315I mutation.

A randomized, open-label studyfound that patients resistant or intoler-ant to imatinib achieved a completehematologic response (CHR) of 92%, amajor cytogenetic response (MCyR) of63%, and a CCyR of 50%, with 93% ofpatients who achieved a MCyR main-taining response for 18 months.9

Dasatinib was originally evaluatedwith twice-daily dosing but has sincebeen shown to have comparable effica-cy and less toxicity when given oncedaily. In CP CML, 3-year follow-up datashowed that patients treated with 100mg once daily had fewer drug-relatedpleural effusions and cytopenias thanthose who received other dosing regi-mens (70 mg twice daily, 140 mg daily,or 50 mg twice daily).14 In AP CML, 15-month median follow-up data evaluat-ing dasatinib 140 mg once daily versus70 mg twice daily have also becomeavailable. Efficacy results with the tworegimens were similar, with a majorhematologic response (MHR) of 66%versus 68%, MCyR of 39% versus 43%,and overall survival (OS) rates of 63%versus 72%, respectively. Patients whoreceived once-daily dosing had signifi-cantly fewer pleural effusions at 20%versus 39% (P <.001).15

Preliminary results are currentlyavailable for an ongoing phase 2 trialevaluating dasatinib in the frontline set-ting of CML at 100 mg once daily or 50mg twice daily.16 Of the 50 patients who had been evaluated for at least 3 months, 49 (98%) had achieved aCCyR, and 41 (82%) had achieved anMMR. No difference in efficacy wasseen between the two arms, and 90% ofpatients achieved a CCyR within thefirst 6 months of treatment. As with theuse of high-dose imatinib as frontlinetherapy, it is unclear whether the earlierresponse will translate into improvedsurvival. The adverse effect profile hasbeen similar to that in past trials con-

Update on Chronic Myeloid LeukemiaBy Brian G. Cochran, PharmD, BCOPOncology Clinical Pharmacist, Indiana University Simon Cancer Center, Indianapolis, Indianapolis

Brian G. Cochran, PharmD, BCOP

100%

50%

0%

Association Between Adherence Rate to Imatinib andProbability of a Major Molecular Response (MMR)

MM

R

At 6 Years>90% Adherence

90% Adherence

50%

40%

30%

20%

10%

0%

Association Between Adherence Rate to Imatinib andProbability of a Complete Molecular Response (CMR)

CMR

At 6 Years>90% Adherence

90% Adherence

Dasatinib was originally evaluated with twice-dailydosing but has since been shown to have comparableefficacy and less toxicity when given once daily.

Figure. Importance of Imatinib Adherence to Molecular ResponseSource: Reference 20.




taining high-dose imatinib. One sideeffect that had not been prominentlyreported in previous trials with dasa-tinib was peripheral neuropathy, whichwas seen in 31% of patients. Mostevents were grade 1 or 2 severity, but5% were grade 3, requiring dose inter-ruption and dose reduction. Toxicitywith once- and twice-daily dosing wassimilar, with a trend toward more pleu-ral effusions with twice-daily dosing.

NilotinibNilotinib is FDA-approved for treat-

ment of CP and AP Ph+ CML in adultpatients resistant or intolerant to priortherapy that included imatinib.10

Nilotinib has been shown to prolongthe QT interval, and five sudden deathshave been reported in patients receiv-ing nilotinib, prompting a black-boxwarning. It is recommended thatpatients initiated on this drug obtainelectrocardiograms at baseline, afterweek 1, and then periodically thereafteror with any dose adjustment.10 Nilotinibis a 25 times more potent inhibitor ofBCR-ABL than imatinib, with the abili-ty to overcome imatinib resistance relat-ed to multiple mutations, with theexception of T315I. Data are availableafter a minimum of 19 months of follow-up in patients with CP CML treatedwith nilotinib following imatinib fail-ure.17 At a dose of 400 mg twice daily,nilotinib induced a CHR of 94%, with59% of patients achieving an MCyR ata median of 2.8 months. At 24 months,78% of patients maintained an MCyR,with an estimated OS rate of 88%.Nilotinib was well tolerated; pleural orpericardial effusions (grade 3/4) wereuncommon (<1%), which distinguishesit from dasatinib. The grade 3/4 adverseevents that were most often reportedincluded asymptomatic laboratoryabnormalities and hematologic toxici-ties. To date, this ongoing study has pro-vided no further update with regard toQT prolongation.

Follow-up data after a minimum of 11months of treatment with nilotinib inAP CML are available.18 At a mediantime to first hematologic response (HR)of 1 month, 56% of patients had a con-firmed HR, with 31% achieving a CHR.At 24 months, 54% of these patients hadmaintained their HR. An MCyR wasachieved in 32% of patients and a CCyRin 20% of patients. This response waslong lasting, with 70% of these patientsmaintaining their MCyR at 24 monthsand 83% maintaining their CCyR at 12months. The estimated OS at 24 monthswas 67%, with a similar side-effect profileas reported for CP treatment.

Data evaluating nilotinib in thefrontline setting are now available froma phase 2 clinical trial that used theapproved dose of 400 mg twice daily

administered on an empty stomach andprovided information on 51 patientswith a median follow-up of 3 months.19

Of those evaluated, 50 (98%) hadachieved a CCyR, and 39 (76%) hadachieved an MMR. Responses occurredmore quickly than historically reportedwith standard-dose imatinib, with 90%of patients achieving CCyR by 3months and 96% achieving CCyR by 6months. Grade 3 or 4 toxicities didoccur but were rare and were similar tothose previously reported. There weretwo reported incidences each of hyper-tension and QT prolongation, but nonewere grade 3 or 4. Prospective clinicaltrials are ongoing to determine whether

nilotinib will be superior to imatinibwith regard to EFS and OS in newlydiagnosed patients.

Patient adherenceEnsuring patient adherence is pivotal

to optimizing expected outcomes withdrug therapy in CML. Healthcareproviders can provide education toenable patients to achieve the best out-come on these oral therapies. Patientadherence to imatinib was measured in87 consecutive patients with CP CMLover 3 months. All patients hadreceived imatinib 400 mg/day as first-line therapy for a median of 59.7months before enrollment.20 Several

prognostic factors and imatinib plasmalevels were also evaluated. Althoughthe median adherence rate was 97.6%,23 (26.4%) patients had an adherencerate of 90%, and in 12 patients, 80%.Adherence was found to be the soleindependent factor for complete molec-ular response (CMR) and one of twopredictors for MMR. None of thepatients with a 90% adherence rateachieved CMR at 6 years, and only28.4% achieved MMR (Figure). Patientswho had been prescribed an increaseddose of imatinib had worse adherencerates, reported at a median of 86.4%.This study concluded that patient adher-

Table. FDA-approved Oral TKIs for Adult Ph+ CML

Drug Dosing per FDA approval Main adverse effects Warnings/precautions Drug interactions

Imatinib8 • CP: 400 mg once daily

• AP/BC: 600 mg once daily

• Take with meal and full glass of water

In 30%:• edema• diarrhea• rash• nausea• vomiting• fatigue• muscle cramps

• musculoskeletal pain

• abdominal pain

The following haveoccurred and should bemonitored:

• grade 3/4 hemorrhage

• severe congestive heart failure

• severe hepatotoxicity

• bullous dermatologic reactions

• gastrointestinal perforations

• fetal harm

• CYP3A4 inducer/inhibitor

• Patients should not receive warfarin

• Systemic exposure toacetaminophen is expect-ed to increase

Dasatinib9 • CP: 100 mg once daily

• AP/BC: 140 mg once daily

• Take with or without a meal

In 20%:• fluid retention events• diarrhea• skin rash• nausea• fatigue• headache• myelosuppression• dyspnea• hemorrhage

The following haveoccurred and should bemonitored:

• severe bleeding-related events

• QT prolongation

• fetal harm


• Avoid other drugs that prolong the QT interval

• Antacids: if needed,administer the antacid atleast 2 hours prior to or 2hours after the dose

• H2 antagonist/proton pumpinhibitor

Nilotinib10 • CP: 400 mg twice daily

• AP: 400 mg twice daily

• BC: Not FDA-approved

• Must be taken approximately 12hours apart with water

• No food for at least 2 hours beforethe dose and at least 1 hour afterthe dose

In >10%:• diarrhea• rash• nausea• vomiting• fatigue• headache• constipation• pruritus

Contraindicated inpatients with:• hypokalemia• hypomagnesemia• long QT syndrome

The following have occurredand should be monitored: • QT prolongation• elevated serum lipase• LFT abnormalities• hypophosphatemia• hypokalemia• hypocalcemia• hyponatremia• hyperkalemia• fetal harm


• Avoid other drugs that prolong the QT interval

• Inhibitor of CYP2C8,CYP2C9, and CYP2D6

• May also induce CYP2B6,CYP2C8, and CYP2C9

• May alter serum concentration of otherdrugs

• No drug interaction reported with warfarin11

AP indicates accelerated phase; BC, blast crisis; CML, chronic myeloid leukemia; CP, chronic phase; CY, cytochrome P450; FDA, US Food and Drug Administration; LFT, liver function test; Ph+, Philadelphia-positive; TKI, tyrosine kinase inhibitor.





ence to therapy was the major determi-nant of response to imatinib.

Second-line therapy after imatinibThere are no prospective, compara-

tive clinical trials to delineate a second-line therapy when standard-dose imat -inib achieves a suboptimal response orwhen a patient is not able to toleratethe drug. A recent retrospective analysisevaluated the adverse events experi-enced by patients who either had theirimatinib dose increased after subopti-mal response or were switched to dasa-tinib after initial imatinib failure. Fourhundred seventy-four patients had theirdose of imatinib increased at some pointto >400 mg/day, whereas 175 patientswere switched to dasatinib. The studydid not record the dosing schedule ofdasatinib.21 Patients who switched treat-ments experienced a significantly higherrisk of adverse effects, including fluidretention, pleural effusion, thrombocy-topenia, neutropenia, dyspnea, constipa-tion, nausea, vomiting, and congestiveheart failure.

A previously published phase 2 trialevaluated imatinib 400 mg twice daily

versus dasatinib 70 mg twice daily inpatients who failed first-line imatinib.In this trial, more grade 3 and 4 pleuraleffusions and dyspnea occurred withdasatinib than with high-dose imatinib.The incidence of grade 3 and 4 diar-rhea, fatigue, and headache was similarwith high-dose imatinib and dasatinib.22

It is important to note that the recom-mended starting dose of dasatinib waschanged to 100 mg once daily after itwas shown that 100 mg once daily wasequally efficacious as 70 mg twice dailywith significantly fewer adverse events.

Allogeneic SCTThe presence of the T315I mutation

precludes treatment with any of thecommercially available TKIs indicatedfor CML and, consequently, thesepatients have a poor prognosis. Outsideof a clinical trial, allogeneic SCT is therecommended option for patients har-boring this mutation if a suitable donoris available.6 Prior treatment with TKIshas not been shown to adverselyimpact outcome for patients undergo-ing allogeneic SCT.6 In a retrospectivereview, the impact of the T315I muta-tion on transplant outcome was evalu-ated.23 Of the 33 patients meetingstudy criteria, 26 patients were in CP,

one patient was in AP, and twopatients were in BC. The remainingpatients were being treated for Ph+acute lymphoblastic leukemia. The 1-year OS rates following transplantwere 69% for CP, 71% for AP, and 16%for BC CML. The OS remained similarat 3 years for CP and AP, but nopatients were still alive who were inBC at transplantation.

Novel agentsLack of a suitable donor and/or med-

ical comorbidities preclude the wideapplication of allogeneic SCT in CML.Intensive research is centered on thedevelopment of novel compounds thatare active in this disease. Three suchcompounds show promise. Bosutinib isan oral TKI with dual inhibition of SRC-ABL and has shown activity in patientswith CP CML who failed prior imatinibor other TKI therapy.24 This drug is cur-rently being compared with imatinib in aphase 3 trial for initial treatment innewly diagnosed CP CML.25

Omacetaxine is a first-in-class taxineand does not depend on tyrosine kinaseinhibition for activity.26 The safety and

efficacy of this compound was evaluatedin a phase 2/3 clinical trial in patientswho were considered imatinib-resistantand positive for the T315I mutation.The drug was administered with aninduction and maintenance schedule.The induction schedule was 1.25 mg/m2

subcutaneously (SC) twice daily for 14days every 28 days until HR. After anHR was achieved, the dose was adjustedto 1.2 mg/m2 SC twice daily for 7 daysevery 28 days. At the time of publica-tion of the abstract, data were availablefor 66 patients, with 40 patients in CP,16 patients in AP, and 10 patients inBC. The most promising results were inpatients who initiated treatment in CP,with an overall CHR rate of 85% with amedian duration of 7.7+ months. TheMCyR was 15%, with a median dura-tion of 6+ months. An MMR occurredin 15% of patients, with a reduction ofbaseline T315I mutated clone in 56.7%of CP patients. The median OS is notyet available for CP patients. The mostcommonly reported grade 3/4 toxicitieswere thrombocytopenia, anemia, andneutropenia. Grade 3/4 nonhematolog-ic toxicities were uncommon.

The final agent with data reported inthis patient population is another oralTKI. This agent, AP24534, was evalu-

ated in a phase 1 clinical trial inpatients refractory to other availableoptions.27 At the time of the abstractrelease, 12 enrolled patients had theT315I mutation, and nine of thesepatients remained on study without pro-gression. Patients in CP had the greatestHR, with a CHR in 83%. Patients inAP achieved an MHR, and one patientin BC had resolution of extramedullarysymptoms. At abstract submission, twopatients had achieved a CCyR after 2and 5 months. The dose of 30 mgadministered orally once daily producedno dose-limiting toxicities and achievedblood levels that allowed in vitro inhi-bition of the T315I mutation. This drugwas considered generally well tolerated,with side effects including myelosup-pression, QT prolongation, and dry eye.

ConclusionProgress in treating CML continues

at a rapid pace. Within a 10-year period,three new highly effective drugs becameavailable, which have greatly improvedand prolonged the lives of patients diag-nosed with CML. The healthcareteam’s ability to work together in assist-ing patients in acquiring the appropri-ate drug, educating patients on themanagement of side effects, and encour-aging medication adherence providesthe best chance for successful treatmentand survival. !

References1. American Cancer Society. Cancer Facts &

Figures 2000. Atlanta, GA: American CancerSociety; 2000.

2. American Cancer Society. Cancer Facts &Figures 2009. Atlanta, GA: American CancerSociety; 2009.

3. Di Bacco A, Keeshan K, McKenna SL, CotterTG. Molecular abnormalities in chronicmyeloid leukemia: deregulation of cell growthand apoptosis. Oncologist. 2000;5:405-415.

4. Kavalerchik E, Goff D, Jamieson CH. Chronicmyeloid leukemia stem cells. J Clin Oncol.2008;17:2911-2915.

5. O’Brien SG, Guilhot F, Larson RA, et al; forthe IRIS Investigators. Imatinib compared withinterferon and low-dose cytarabine for newlydiagnosed chronic-phase chronic myeloidleukemia. N Engl J Med. 2003;348:994-1004.

6. Baccarani M, Cortes J, Pane F, et al; forEuropean LeukemiaNet. Chronic myeloidleukemia: an update of concepts and manage-ment recommendation of European LeukemiaNet. J Clin Oncol. 2009;27:6041-6051.

7. Deininger M, O’Brien SG, Guilhot F, et al.International randomized study of interferon vsSTI571 (IRIS) 8-year follow up: sustained sur-vival and low risk for progression or events inpatients with newly diagnosed chronic myeloidleukemia in chronic phase (CML-CP) treatedwith imatinib. Blood (ASH Annual MeetingAbstracts). 2009;114:Abstract 1126.

8. Gleevec (imatinib mesylate) [package insert].East Hanover, NJ: Novartis PharmaceuticalsCorp; 2009.

9. Sprycel (dasatinib) [package insert]. Princeton,NJ: Bristol-Myers Squibb Co; 2009.

10. Tasigna (nilotinib) [package insert]. EastHanover, NJ: Novartis Pharmaceuticals Corp;2009.

11. Yin O, Gallagher NJ, Fischer D, et al. Effect ofnilotinib on the pharmacokinetics and pharma-codynamics of warfarin. J Clin Oncol. 2009;27(15S):Abstract 7063.

12. Kantarjian HM, Talpaz M, O’Brien S, et al.

Dose escalation of imatinib mesylate can over-come resistance to standard-dose therapy inpatients with chronic myelogenous leukemia.Blood. 2003;101:473-475.

13. Cortes JE, Baccarani J, Guilhot F, et al. PhaseIII, randomized, open-label study of daily imat -inib mesylate 400 mg versus 800 mg in patientswith newly diagnosed, previously untreatedchronic myeloid leukemia in chronic phaseusing molecular end points: tyrosine kinaseinhibitor optimization and selectivity study. J Clin Oncol. 2010;28:424-430.

14. Stone RM, Kim DW, Kantarjian HM, et al.Dasatinib dose-optimization study in chronicphase chronic myeloid leukemia (CML-CP):three-year follow-up with dasatinib 100 mgonce daily and landmark analysis of cytogenet-ic response and progression-free survival (PFS).J Clin Oncol. 2009;27(15S):Abstract 7007.

15. Kantarjian H, Cortes J, Kim DW, et al. Phase 3study of dasatinib 140 mg once daily versus 70mg twice daily in patients with chronic myeloidleukemia in accelerated phase resistant or intol-erant to imatinib: 15-month median follow-up.Blood. 2009;113:6322-6329.

16. Cortes JE, Jones D, O’Brien S, et al. Results ofdasatinib therapy in patients with early chron-ic-phase chronic myeloid leukemia. J ClinOncol. 2010;28:398-404.

17. Kantarjian H, Giles F, Bhalla K, et al. Nilotinibin chronic myeloid leukemia patients in chron-ic phase (CML-CP) with imatinib (IM) resist-ance or intolerance: longer follow-up results ofa phase II study. J Clin Oncol. 2009;27(15S):Abstract 7029.

18. Le Coutre PD, Giles F, Hochhaus A, et al.Nilotinib in chronic myeloid leukemia patientsin accelerated phase (CML-AP) with imatinib(IM) resistance or intolerance: longer follow-upresults of a phase II study. J Clin Oncol. 2009;27(15S):Abstract 7057.

19. Cortes JE, Jones D, O’Brien S, et al. Nilotinibas front-line treatment for patients with chron-ic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392-397.

20. Bazeos A, Khorashad J, Mahon FX et al. Long-term adherence to imatinib therapy is the criticalfactor for achieving molecular responses in chron-ic myeloid leukemia patients. Blood (ASH AnnualMeeting Abstracts). 2009;114:Abstract 3290.

21. Wu E, Guo A, Williams D, et al. Adverseevents associated with escalating imatinib ver-sus switching to dasatinib in patients withchronic myelogenous leukemia. J Clin Oncol.2009;27(15S):Abstract 7092.

22. Kantarjian H, Pasquini R, Hamerschlak N, etal. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure offirst-line imatinib: a randomised phase 2 trial.Blood. 2007;109:5143-5150.

23. Nicolini FE, Zhou W, Martinelli G, et al.Impact of allogeneic stem cell transplantationas salvage therapy after T315I mutation detec-tion in chronic myeloid leukemia (CML) andPh+ acute lymphoblastic leukemia (ALL)patients. Blood (ASH Annual MeetingAbstracts). 2009;114:Abstract 645.

24. Bruemmendorf TH, Cervantes F, Kim D, et al.Bosutinib is safe and active in patients (pts) withchronic phase (CP) chronic myeloid leukemia(CML) with resistance or intolerance to imatiniband other tyrosine kinase inhibitors. J Clin Oncol.2008;26(15S):Abstract 7001.

25. Compare bosutinib to imatinib in subjects withnewly diagnosed chronic phase Philadelphiachromosome positive CML. ClinicalTrials.govidentifier: NCT00574873. www.clinicaltrials.gov/ct2/show/NCT00574873?term=3160A4-3000&rank=1:. December 10, 2009. AccessedFebruary 1, 2010.

26. Cortes-Franco J, Khoury HJ, Nicolini FE, et al.Safety and efficacy of subcutaneous-adminis-tered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML)patients who harbor the Bcr-Abl T315I muta-tion—results of an ongoing multicenter phase2/3 study. Blood (ASH Annual MeetingAbstracts). 2009;114:Abstract 644.

27. Cortes J, Talpaz M, Deininger M, et al. A phase1 trial of oral AP24534 in patients with refrac-tory chronic myeloid leukemia and other hema-tologic malignancies: first results of safety andclinical activity against T315I and resistantmutations. Blood (ASH Annual MeetingAbstracts). 2009;114:Abstract 643.

Omacetaxine is a first-in-class taxine and does notdepend on tyrosine kinase inhibition for activity.

Update on Chronic Myeloid Leukemia Continued from page 39



Supportive Care

One of the most debilitating tox-icities related to chemotherapyis peripheral neuropathy. Neur -

opathy is defined as a condition arisingfrom the damage and dysfunction of theperipheral nerves (motor, sensory, auto-nomic) that connect the brain andspinal cord to the rest of the body.1Chemotherapy-induced peripheral neu-ropathy (CIPN) is defined as toxic neu-ropathy that results from the directinjury of the peripheral nervous systemby chemotherapeutic agents.2 The inci-dence of CIPN is variable (30%-40%)and is largely dependent on several fac-tors, including patient age, dose intensi-ty, cumulative dose, duration of therapy,use of regimens containing multiple neu-rotoxic chemotherapy agents, and any

preexisting conditions that are associatedwith peripheral neuropathy, such as dia-betes and alcohol abuse.3 When symp-toms are severe or irreversible, CIPN canlead to serious clinical and quality-of-life(QOL) consequences for patients. Thisarticle presents an overview of the cur-rent strategies for assessment, preven-tion, and management of CIPN.

Presentation and assessmentChemotherapeutic and biologic

agents associated with symptomaticneuropathy include the platinum com-pounds, vinca alkaloids, taxanes, andothers such as bortezomib, ixabepilone,and thalidomide. Agents associatedwith CIPN cause structural damage toperipheral nerves that result in abnor-mal sensory processing of the peripheraland/or central nervous systems.4,5 CIPNcan affect both small fiber axons (tem-perature, pinpricks) and large sensoryaxons (vibrations, proprioception).3

CIPN typically manifests as sensorysymptoms, such as paresthesia anddysesthesia (numbness and tingling).Patients often describe the neuropathicpain as burning, shock-like, or electric.Other sensations, such as allodynia(normal touch perceived as painful) andhyperpathia (normal painful sensationsperceived as excruciating), may occur.

In general, motor symptoms are uncom-mon and may manifest as weakness ofthe lower limbs. On examination,reflexes may be diminished or absent,and some patients may present withabnormal proprioception, which canlead to falls and other safety concerns.Several diagnostic features can aid clini-cians in the differential diagnosis ofCIPN, including predominant sensorysymptoms and onset after chemothera-py administration (Table 1). With plat-inum agents, a “coasting” effect may bepresent, which is characterized by pro-gressive symptoms for weeks to monthsafter treatment completion.6

A notable exception to symptomcharacterization for CIPN can be foundwith the platinum agent oxaliplatin.

Peripheral neuropathy in colorectal can-cer (CRC) is primarily related to oxali-platin. The dose-limiting toxicity of thisagent is a neurotoxicity that induces twodistinct neuropathies: a transient acutesyndrome and a cumulative chronic neu-rotoxicity. Acute oxaliplatin-inducedperipheral nerve hyperexcitability, re -ferred to as “acute ch an nel opathy,” ischaracterized by an increased excitabili-ty of nerve and muscle cells triggered byexposure to cold.7 The acute neuropa-thy observed with oxaliplatin occurs in85% to 95% of all patients.7 Symptomsinclude distal or perioral paresthesias ordysesthesias that peak within the first 24to 48 hours after treatment.8 Thesesymptoms can occur during or immedi-ately after the first oxaliplatin infusionbut are generally mild, short-lived, andcompletely reversible within hours ordays. Between 1% and 2% of patientsalso report a pharyngolaryngeal dysesthe-sia, which they describe as the sensationof difficulties in breathing or swallow-ing.8 Symptoms related to oxaliplatin-associated chronic neurotoxicity aregradually prolonged and eventually per-sist be tween treatments and increasewith cumulative doses of greater than1000 mg/m2.9 The chronic neurotoxicitymay lessen over time, with partial recov-eries seen at 13 weeks after treatment.7,10

The onset of symptoms of CIPN canbe sudden or progressive. Symptomseverity ranges from mild discomfort tosevere disabilities that result in signifi-cant loss of function and diminishingQOL. In severe cases, CIPN can beextremely painful, and can result in dosereductions, treatment delays, and discon-tinuation of treatment. These representsignificant limitations to the successfultreatment of cancer and directly impactpatient outcomes and overall survival.

The assessment of CIPN continues tobe a clinical challenge for healthcareprofessionals because of great variabilityin symptom characteristics and lack ofempirical evidence on optimal evalua-tion methods. The first step in assessingCIPN is to take a comprehensive histo-ry that includes information such asneuropathic symptom characteristics,duration and onset of symptoms, comor-bidities, and history of chemotherapeu-tic/medication administration. A physi-cal examination that includes as sessmentof reflexes (ankle jerks) and sensoryevaluation (vibrations, proprioception,pinpricks, temperature) should also beperformed. The clinician should assesswhether symptoms are severe enough tomandate intervention and whichoptions for intervention are optimalbased on symptom severity. The needfor modification or discontinuation ofpresent cancer treatments should alsobe determined.1

Several grading systems have beendeveloped in recent years for CIPNassessment, including the NationalCancer Institute-Common Term inologyCriteria for Adverse Events (NCI-CTCAE), Ajani Sensory Neuro pathy,World Health Organization ToxicityCriteria, and that of the Eastern Coop -erative Oncology Group.1,11,12 Data com-paring these scales in the assessment ofCIPN show great variability in interob-server agreement, which highlights vari-ations in grading and interpretation dis-parities.13 A new tool, the TotalNeuro pathy Score, was recently report-ed to be more sensitive in detectingchanges in CIPN compared with theNCI-CTCAE.14,15 The Chemotherapy-Induced Peripheral Neuropathy Out -come Measures Study (CI-PERINOMS)is a current international collaborativeeffort that is aiming to identify the bestmethods to assess and monitor CIPN.16

Objective, quantitative measures such aselectromyography, nerve-conduction

studies, and sensory-threshold testinghave also been used in the assessment ofCIPN. To date, these measures have notbeen completely adopted into clinicalsettings because of concerns such as cost,need for subspecialty expertise, invasive-ness, and potential low patient adher-ence.1,17 Research also shows that objec-tive neurophysiologic findings correlatepoorly with subjective, patient-reportedoutcomes, with a trend toward under-assessment.18-21

PreventionTable 2 provides a list of agents that

have been tested for prevention ofCIPN. A calcium plus magnesium(Ca/Mg) infusion has been tested as aneuroprotectant for oxaliplatin-inducedneuropathy in two randomized con-trolled trials, the North Central CancerTreatment Group’s N04C7 and theCombined Oxaliplatin NeurotoxicityPrevention Trial (CONcePT). Un -fortunately, both trials were terminatedearly after reports of diminished re sponseto chemotherapy in the CONcePTstudy,22 although subsequent radiologyreview suggested no effect on tumorresponse.3,23 The N04C7 trial reported areduction in CIPN incidence in the armthat received the Ca/Mg infusions.24

Results from a randomized trial testingthe efficacy of xaliproden, a nonpeptide

Management of Chemotherapy-induced Peripheral NeuropathyBy Virginia Sun, RN, PhD(c) Senior Research Specialist, Division of Nursing Research & Education, Department of Population Sciences, City of Hope, Duarte, California

Virginia Sun, RN, PhD(c)

• Symmetrical, distal, length-dependentglove-and-stocking distribution

• Sensory symptoms (frequency and severity) predominant

• Mild or no motor symptoms

• Onset after administration of chemotherapy

• Dose-dependent

• Onset that is either progressive, rapid, or“coasting”

Table 1. Diagnostic Features ofCIPN

CIPN indicates chemotherapy-induced peripheralneuropathy.



A new tool, the Total Neuro pathy Score, was recentlyreported to be more sensitive in detecting changes inCIPN compared with the NCI-CTCAE.


neurotrophic agent, show a lower inci-dence of grade 3 neuropathy in patientstreated with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4), but withoutreductions in overall neurotoxicity inci-dence.25 A double-blind, multicentertrial, NEUROXA, is currently randomiz-ing patients on a FOLFOX4 regimen.1

Vitamin E has been tested as a neuro-protectant in patients receiving cis-platin-based chemotherapy. Three small,open-label studies randomized patientsreceiving cisplatin-based chemo therapyto vitamin E or control. The incidenceof CIPN was significantly lower in the

active arms (21%-31%) than in thecontrol group (69%-86%). Toxicityseverity scores were also reduced in theactive arms.26-28 An interim report froman ongoing double-blind, randomized,placebo-controlled trial of patientsreceiving cisplatin therapy showed asignificantly reduced median toxicityscore in the active arm. At the 2009annual meeting of the American Societyof Clinical Oncology, Kotts chade andcolleagues presented findings from aphase 3 double-blind, placebo-con-trolled study, N05C3, of vitamin E inthe prevention of CIPN in patientsreceiving therapy with taxanes and/orplatinum compounds.29 The primaryend point was incidence of grade 2+sensory neuropathy as measured byNCI-CTCAE. Although vitamin E waswell-tolerated, it did not appear toreduce the incidence of sensory neu-ropathy. Other agents, such as amifos-tine, nimodipine, and rHuLIF, did notshow clinical benefits in randomized trials.30-32 Newer agents, such as gluta-mine, acetyl L-carnitine, alpha-lipoicacid, and vitamins B12/B6, are currentlybeing tested in large-scale, phase 3, ran-domized trials.33-35

TreatmentDespite the growing number of clini-

cal trials testing various therapeuticoptions, currently there is no standard,evidence-based treatment to specificallymanage CIPN.36 Numerous pharmaco-logic agents have been tested to elimi-nate symptomatic neuropathy associat-ed with chemotherapy. Table 3 listspharmacologic agents being used as off-label treatments for symptomatic CIPN.Gabapentin, an antiepileptic agent, isprobably one of the most widely useddrugs for neuropathic pain. In severalrandomized trials involving mixed dis-ease populations, gabapentin was effec-tive in relieving pain and improvingQOL.37-39 In a double-blind, controlled,crossover trial, however, gabapentin wasno better than placebo for treatment ofCIPN.32 Pregabalin, another antiepilep-tic agent with similar mechanisms ofaction as gabapentin, is approved fordiabetic neuropathy and postherpeticneuralgia.40-44 Lamotrigine was tested ina multicenter, double-blind, placebo-controlled, randomized trial for thetreatment of pain and other neuropath-ic symptoms due to CIPN. However,there were no differences in averagepain scores for the lamotrigine andplacebo arms.45

Antidepressants have also been test-ed for the treatment of CIPN. Dulo x -etine, a serotonin and norepinephrinereuptake inhibitor (SNRI), has beenshown to reduce pain associated withdiabetic neuropathy.46 Another SNRI,

venlafaxine, was recently shown toreduce the incidence of acute oxali-platin-induced neuropathic pain com-pared with placebo (35% vs 67%).47

SNRIs, however, have contraindica-tions for patients taking tamoxifen aswell as other drugs that affect serotoninreuptake.48,49 Tricyclic antidepressants(TCAs) such as amitriptyline, nor-triptyline, and desipramine also arecommonly used for the treatment ofdiabetic neuropathy. Negative resultswere reported in two small randomized,placebo-controlled trials that testedthe efficacy of amitriptyline and nor-triptyline for CIPN.30,31 TCAs havesubstantial side effects (anticholiner-gic, cardiac) as well as pharmacologic in -teractions with drugs metabolized bycytochrome P450, further limiting theirpotential use. As a rule, TCAs are notrecommended for the first-line treat-ment of CIPN.1

Recently, a topical gel formulation ofbaclofen, amitriptyline, and ketamine(BAK-PLO) yielded moderate improve-ments in CIPN symptoms in a random-ized trial in patients with CIPN.50

Opioids such as tramadol, morphine,and oxycodone (in combination withgabapentin) have shown efficacy in dia-betic neuropathy.51-53 The lidocainepatch (5%) was shown to alleviate allo-dynia in patients with postherpetic neu-ralgia, but it did not have a significantimpact for postsurgical pain in cancerpatients.54,55 Complementary and alter-native therapies such as acupuncturehave also been tested for CIPN,56,57 andpreliminary results are encouraging, withpain intensity decreased by 36% withacupuncture versus 2% with placebo.56

Quality of lifeUnderstanding the relationship be -

tween CIPN and QOL in cancer isimportant not only for patients but alsofor healthcare practitioners caring forindividuals with cancer. To thoroughlyunderstand how CIPN affects the QOLof patients, it is necessary to capture theoverall experience of living with CIPNfrom the patient’s perspective. Fewqualitative studies have been conductedin recent years that attempted to under-stand CIPN from the subjective per-spective. Bakitas conducted an excel-lent qualitative study that described theCIPN symptom experience and theeffect of symptoms on everyday life.58

Patients described CIPN as “back-

ground noise” that can be overshad-owed by other treatment- and disease-related issues, but the unpleasantness ofCIPN can interfere with daily activitiesand socialization.58 Patients’ awarenessof CIPN was often inaccurate and itsoccurrence surprising, because most didnot recall being educated about CIPNor advised to anticipate the symptoms.When monitoring CIPN, clinicians pri-marily focused on how the symptomsaffected motor functionality (dexterity,gait) but rarely asked about the effect ondaily living.58 CIPN caused disruptionsin daily living, leisure, work, and familyroles.58 Patients who reported a paincomponent to their CIPN often experi-enced functional difficulties, fatigue,sleep disturbance, and mood distur-bances.58 Patients also described the useof multiple processes in learning to livewith CIPN.58

Similar results have been described inanother qualitative study conducted byCloss and colleagues59 as well as in ourwork at City of Hope, where weexplored the impact of CIPN on QOLin a cohort (n = 53) of CRC patients.60

In our study, significant differences inQOL were found after initiation oftreatment with an oxaliplatin-basedregimen. Patterns for neuropathy andtoxicity grading also suggested thatpatients may notice symptoms of neu-ropathy as early as 24 hours after treat-ment initiation, with temporary relief at1 week, and then noticeable symptomsagain at the 1- and 2-month assess-ments. By 2 months after treatment ini-tiation, more grade 2 and 3 neurotoxic-ities were observed.60 Although subjectsdid not find the dysesthesias and cold-related allodynia distressing, they foundthe acute sensations surprising whenfirst experienced, and made adjustmentsin eating and drinking habits related tocold foods and beverages to cope withthese neuropathic symptoms.60

Clinical and scientific implicationsBased on the current evidence avail-

able in the literature, it is clear thatmuch work needs to be done to deter-mine the most effective methods forassessment and treatment of CIPN. Theprompt assessment of symptoms relatedto CIPN is essential for determiningappropriate and effective managementstrategies. The assessment of CIPNshould continue throughout treatmentand beyond, because chronic CIPN can


Supportive Care

Management of Chemotherapy-induced Peripheral Neuropathy Continued from page 41



• Calcium and magnesium infusions

• Xaliproden

• Vitamin E

• Glutamine/glutathione

• Acetyl L-carnitine

• Amifostine

• Nimodipine

• rHuLIF

• Alpha-lipoic acid

• Vitamins B12/B6

Table 2. Agents Tested forPrevention of CIPN

Antiepileptics• Gabapentin• Pregabalin• Lamotrigine

AntidepressantsSerotonin and norepinephrine reuptakeinhibitors

• Duloxetine• Venlafaxine

Tricyclic antidepressants• Amitriptyline• Nortriptyline• Desipramine

Opioids• Tramadol• Morphine (alone or with gabapentin)• Oxycodone (alone or with gabapentin)• Methadone

Other agents/procedures• Local anesthetics (5% lidocaine patch)• 0.75% capsaicin• Intravenous lidocaine• Acupuncture


Sources: References 1 and 3.

Table 3. Agents Used Off-labelfor Treatment of CIPN

Patients’ awareness of CIPN was often inaccurateand its occurrence surprising, because most did notrecall being educated about CIPN or advised toanticipate the symptoms.



Supportive Care

occur months and years beyond treat-ment.4 It is important to understandthat many agents may be needed foradequate treatment of CIPN and thatthe clinical context should be used toguide the choice of medications.1 Thegeneral approach should be to choosean agent based on clinical context, effi-cacy, and safety, and to titrate the agentto maximum tolerated dose.1

Patients need to be educated on whatto expect with CIPN. It is evident from

some of the current evidence that clini-cians are not doing an optimal job ofproviding patients with timely informa-tion on CIPN. Beyond pharmacologictreatments, it may also be helpful to dis-cuss nonpharmacologic supportive carestrategies to cope with CIPN, such aspersonal safety measures to preventburns or falls that may be related to sen-sory motor deficits.10 Functional deficits,such as decreased balance, gait abnor-malities, and muscle weakness, can occurwith CIPN.61,62 Rehabilitation experts,such as physical and occupational thera-pists if available, should be included inthe interdisciplinary care of cancerpatients with CIPN. When functionaldeficits are a concern, patient and familycaregivers should be educated on poten-tial environmental hazards and the needfor home and environmental modifica-tions. These include installing adequatelight, removing hazardous items such asthrow rugs, modifying tasks, providingadaptive equipment, ensuring protectionagainst extreme temperatures (hot andcold), and wearing proper foot wear.1Finally, studies that characterize the timeof onset, duration, and resolution or per-sistence of symptoms are needed todevelop a more comprehensive and sub-jective understanding of CIPN.63 !

References1. Stubblefield MD, Burstein HJ, Burton AW, et

al. NCCN task force report: management ofneuropathy in cancer. J Natl Compr Canc Netw.2009;7(suppl 5):S1-S28.

2. Kaley TJ, DeAngelis LM. Therapy of chemo -therapy-induced peripheral neuropathy. Br JHaematol. 2009;145:3-14.

3. Wolf S, Barton D, Kottschade L, et al.Chemotherapy-induced peripheral neuropathy:prevention and treatment strategies. Eur JCancer. 2008;44:1507-1515.

4. Windebank AJ, Grisold W. Chemotherapy-

induced neuropathy. J Peripher Nerv Syst.2008;13:27-46.

5. Park SB, Goldstein D, Lin CS, et al. Acuteabnormalities of sensory nerve function associ-ated with oxaliplatin-induced neurotoxicity. JClin Oncol. 2009;27:1243-1249.

6. Siegal T, Haim N. Cisplatin-induced peripher-al neuropathy. Frequent off-therapy deteriora-tion, demyelinating syndromes, and musclecramps. Cancer. 1990;66:1117-1123.

7. Grothey A. Oxaliplatin—safety profile: neuro-toxicity. Semin Oncol. 2003;30(4 suppl 15):5-13.

8. Lehky TJ, Leonard GD, Wilson RH, et al.Oxaliplatin-induced neurotoxicity: acutehyperexcitability and chronic neuropathy.Muscle Nerve. 2004;29:387-392.

9. Wilson RH, Lehky T, Thomas RR, et al. Acuteoxaliplatin-induced peripheral nerve hyperex-citability. J Clin Oncol. 2002;20:1767-1774.

10. Wickham R. Chemotherapy-induced peripher-al neuropathy: a review and implications foroncology nursing practice. Clin J Oncol Nurs.2007;11:361-376.

11. Ajani JA, Welch SR, Raber MN, et al.Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest. 1990;8:147-159.

12. Oken MM, Creech RH, Tormey DC, et al.Toxicity and response criteria of the EasternCooperative Oncology Group. Am J Clin Oncol.1982;5:649-655.

13. Postma TJ, Heimans JJ, Muller MJ, et al.Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol.1998;9:739-744.

14. Cavaletti G, Frigeni B, Lanzani F, et al. TheTotal Neuropathy Score as an assessment toolfor grading the course of chemotherapy-induced peripheral neurotoxicity: comparisonwith the National Cancer Institute-CommonToxicity Scale; for the Italian NETox Group. JPeripher Nerv Syst. 2007;12:210-215.

15. Cavaletti G, Jann S, Pace A, et al; for theItalian NETox Group. Multi-center assessmentof the Total Neuropathy Score for chemothera-py-induced peripheral neurotoxicity. J PeripherNerv Syst. 2006;11:135-141.

16. CI-PERINOMS Sudy Group. CI-PERINOMS:chemotherapy-induced peripheral neuropathyoutcome measures study. J Peripher Nerv Syst.2009;14:69-71.

17. Sioka C, Kyritsis AP. Central and peripheralnervous system toxicity of common chemother-apeutic agents. Cancer Chemother Pharmacol.2009;63:761-767.

18. Berger T, Malayeri R, Doppelbauer A, et al.Neurological monitoring of neurotoxicityinduced by paclitaxel/cisplatin chemotherapy.Eur J Cancer. 1997;33:1393-1399.

19. Chaudhry V, Rowinsky EK, Sartorius SE, et al.Peripheral neuropathy from taxol and cisplatincombination chemotherapy: clinical and elec-trophysiological studies. Ann Neurol. 1994;35:304-311.

20. du Bois A, Neijt JP, Thigpen JT. First linechemotherapy with carboplatin plus paclitaxelin advanced ovarian cancer—a new standard ofcare? Ann Oncol. 1999;10(suppl):35-41.

21. Forsyth PA, Balmaceda C, Peterson K, et al.Prospective study of paclitaxel-induced periph-eral neuropathy with quantitative sensory test-ing. J Neurooncol. 1997;35:47-53.

22. Hochster HS, Grothey A, Childs BH. Use ofcalcium and magnesium salts to reduce oxali-platin-related neurotoxicity. J Clin Oncol.2007;25:4028-4029.

23. Hochster HS, Grothey A, Shpilsky A, ChildsB. Effect of intravenous calcium and magne-sium versus placebo on response to FOLFOX4+ bevacizumab in the CONcePT trial. ASCOGastrointestinal Cancer Symposium. 2008:Abstract 280.

24. Nikcevich DA, Grothey A, Sloan JA, et al.Effect of intravenous calcium and magneisum(IV CaMg) on oxaliplatin-induced sensoryneurotoxicity (sNT) in adjuvant colon cancer:results from a phase III placebo-controlled,double-blind NCCTG trial N04C7. J ClinOncol. 2008;26(18S):Abstract 4009.

25. Cassidy J, Bjarnason G, Hickish T, et al.Randomized double-blind (DB) placebo (Plcb)

controlled phase III study assessing the efficacyof xaliproden (X) in reducing the cumulativeperipheral sensory neuropathy (PSN) induced bythe oxaliplatin (Ox) and 5-FU/LV combination(FOLFOX4) in first line treatment of patients(pts) with metastatic colorectal cancer (MCRC).J Clin Oncol. 2006;24(18S):Abstract 3507.

26. Bove L, Picardo M, Maresca V, et al. A pilotstudy on the relation between cisplatin neu-ropathy and vitamin E. J Exper Clin Cancer Res.2001;20:277-280.

27. Pace A, Savarese A, Picardo M, et al.Neuroprotective effect of vitamin E supplemen-tation in patients treated with cisplatinchemotherapy. J Clin Oncol. 2003;21:927-931.

28. Argyriou AA, Chroni E, Koutras A, et al.Vitamin E for prophylaxis against chemothera-py-induced neuropathy: a randomized con-trolled trial. Neurology. 2005:64:26-31.

29. Kottschade L, Sloan JA, Mazurczak M, et al.The use of vitamin E for protection ofchemotherapy-induced peripheral neuropathy:a phase III double-blind, placebo controlledstudy-N05C3. J Clin Oncol. 2009;27(15S):Abstract 9532.

30. Hammack JE, Michalak JC, Loprinzi CL, et al.Phase III evaluation of nortriptyline for allevia-tion of symptoms of cis-platinum-inducedperipheral neuropathy. Pain. 2002;98:195-203.

31. Kautio AL, Haanpaa M, Saarto T, Kalso E.Amitriptyline in the treatment of chemothera-py-induced neuropathic symptoms. J PainSymptom Manage. 2008;35:31-39.

32. Rao RD, Michalak JC, Sloan JA, et al; for theNorth Central Cancer Treatment Group.Efficacy of gabapentin in the management ofchemotherapy-induced peripheral neuropathy:a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer.2007;110:2110-2118.

33. Cascinu S, Catalano V, Cordella L, et al.Neuroprotective effect of reduced glutathioneon oxaliplatin-based chemotherapy in ad -vanced colorectal cancer: a randomized, dou-ble-blind, placebo-controlled trial. J Clin Oncol.2002;20:3478-3483.

34. Lin PC, Lee MY, Wang WS, et al. N-acetylcys-teine has neuroprotective effects against oxali-platin-based adjuvant chemotherapy in coloncancer patients: preliminary data. Support CareCancer. 2006;14:484-487.

35. Wang WS, Lin JK, Lin TC, et al. Oral gluta-mine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancerpatients. Oncologist. 2007;12:312-319.

36. Visovsky C, Collins M, Abbott L, et al. Puttingevidence into practice: evidence-based interven-tions for chemotherapy-induced peripheral neu-ropathy. Clin J Oncol Nurs. 2007;11:901-913.

37. Backonja M, Beydoun A, Edwards KR, et al.Gabapentin for the symptomatic treatmentof painful neuropathy in patients with dia-betes mellitus: a randomized controlled trial.JAMA. 1998;280:1831-1836.

38. Baillie JK, Power I. Morphine, gabapentin, ortheir combination for neuropathic pain [authorreply]. N Engl J Med. 2005;352:2650-2651.

39. Ho TW, Backonja M, Ma J, et al. Efficientassessment of neuropathic pain drugs inpatients with small fiber sensory neuropathies.Pain. 2009;141:19-24.

40. Freynhagen R, Strojek K, Griesing T, et al.Efficacy of pregabalin in neuropathic pain eval-uated in a 12-week, randomised, double-blind,multicentre, placebo-controlled trial of flexi-ble- and fixed-dose regimens. Pain. 2005;115:254-263.

41. Lesser H, Sharma U, LaMoreaux L, Poole RM.Pregabalin relieves symptoms of painful diabet-ic neuropathy: a randomized controlled trial.Neurology. 2004;63:2104-2110.

42. Richter RW, Portenoy R, Sharma U, et al.Relief of painful diabetic peripheral neuropathywith pregabalin: a randomized, placebo-con-trolled trial. J Pain. 2005;6:253-260.

43. Rosenstock J, Tuchman M, LaMoreaux L,Sharma U. Pregabalin for the treatment ofpainful diabetic peripheral neuropathy: a dou-ble-blind, placebo-controlled trial. Pain. 2004;

110:628-638.44. Tolle T, Freynhagen R, Versavel M, et al.

Pregabalin for relief of neuropathic pain associ-ated with diabetic neuropathy: a randomized,double-blind study. Eur J Pain. 2008;12:203-213.

45. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy oflamotrigine in the management of chemother-apy-induced peripheral neuropathy: a phase 3randomized, double-blind, placebo-controlledtrial, N01C3. Cancer. 2008;112:2802-2808.

46. Quilici S, Chancellor J, Lothgren M, et al.Meta-analysis of duloxetine vs. pregabalin andgabapentin in the treatment of diabetic periph-eral neuropathic pain. BMC Neurol. 2009;9:6.

47. Durand JP, Deplanque G, Gorent J. Efficacy ofvenlafaxine for the prevention and relief ofacute neurotoxicity of oxaliplatin: results ofEFFOX, a randomized, double-blinded, place-bo-controlled prospective study. J Clin Oncol.2009;27(15S):Abstract 9533.

48. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparingduloxetine with placebo in the management ofdiabetic peripheral neuropathic pain. Pain Med.2005;6:346-356.

49. Wernicke JF, Pritchett YL, D’Souza DN, et al. Arandomized controlled trial of duloxetine in dia-betic peripheral neuropathic pain. Neurology.2006;67:1411-1420.

50. Barton D, Wos E, Qin R, et al. A randomizedcontrolled trial evaluating a topical treatment forchemotherapy-induced neuropathy: NCCTGtrial N06CA. J Clin Oncol. 2009;27(15S):Abstract 9531.

51. Gimbel JS, Richards P, Portenoy RK.Controlled-release oxycodone for pain in dia-betic neuropathy: a randomized controlled trial.Neurology. 2003;60:927-934.

52. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of exist-ing gabapentin therapy in painful diabetic neu-ropathy patients. Eur J Pain. 2008;12:804-813.

53. Watson CP, Moulin D, Watt-Watson J, et al.Controlled-release oxycodone relieves neuro-pathic pain: a randomized controlled trial inpainful diabetic neuropathy. Pain. 2003;105:71-78.

54. Cheville AL, Sloan JA, Northfelt DW, et al. Useof a lidocaine patch in the management of post-surgical neuropathic pain in patients with cancer:a phase III double-blind crossover study(N01CB). Support Care Cancer. 2009;17:451-460.

55. Meier T, Wasner G, Faust M, et al. Efficacy oflidocaine patch 5% in the treatment of focalperipheral neuropathic pain syndromes: a ran-domized, double-blind, placebo-controlledstudy. Pain. 2003;106:151-158.

56. Alimi D, Rubino C, Pichard-Leandri E, et al.Analgesic effect of auricular acupuncture forcancer pain: a randomized, blinded, controlledtrial. J Clin Oncol. 2003;21:4120-4126.

57. Wong R, Sagar S. Acupuncture treatment forchemotherapy-induced peripheral neuropathy—acase series. Acupunct Med. 2006;24:87-91.

58. Bakitas MA. Background noise: the experienceof chemotherapy-induced peripheral neuropa-thy. Nurs Res. 2007;56:323-331.

59. Closs SJ, Staples V, Reid I, et al. Managing thesymptoms of neuropathic pain: an explorationof patients’ experiences. J Pain SymptomManage. 2007;34:422-433.

60. Sun V, Otis-Green S, Shibata S, et al. Symptomconcerns and QOL in oxaliplatin-inducedperipheral neuropathy. ASCO GastrointestinalCancers Symposium. 2008:Abstract 503.

61. Visovsky C, Daly BJ. Clinical evaluation andpatterns of chemotherapy-induced peripheralneuropathy. J Am Acad Nurse Pract. 2004;16:353-359.

62. Wampler MA, Hamolsky D, Hamel K, et al.Case report: painful peripheral neuropathy fol-lowing treatment with docetaxel for breast can-cer. Clin J Oncol Nurs. 2005;9:189-193.

63. Hausheer FH, Schilsky RL, Bain S, et al.Diagnosis, management, and evaluation ofchemotherapy-induced peripheral neuropathy.Semin Oncol. 2006;33:15-49.

Rehabilitation experts,such as physical andoccupational therapists if available, should beincluded in the inter -disciplinary care of cancerpatients with CIPN.



Supportive Care

Chemotherapy-induced nauseaand vomiting (CINV) remainscommon despite the availability

of new antiemetic agents and the devel-opment of clinical guidelines by theAmerican Society of Clinical Oncology,the National Comprehensive CancerNetwork, and the Multinational As -sociation of Supportive Care in On -cology.1-3 It is estimated that 70% to 80%

of patients who receive chemotherapyexperience CINV; approximately 10% to44% experience anticipatory nausea andvomiting. Nausea is reported more fre-quently than vomiting by patientsreceiving chemotherapy and appears tobe more bothersome.1-4

If the evidenced-based guidelines forthe prevention and treatment of CINVwere followed, it is estimated that themajority of these episodes could beeffectively prevented or controlled.Several suggested potential reasons forthe failure to control CINV adequatelyinclude lack of familiarity with thephysiology of CINV and mechanism ofaction of antiemetics; reimbursementpolicies and expense of new agents;availability of agents based on formula-

ries; underestimation of the magnitudeof CINV; and the failure of patients andproviders to communicate the symp-toms adequately using common termi-nology.5 CINV can significantly affect apatient’s quality of life as well as theability or desire to continue treatment,and is associated with several poten-tially serious clinical consequences,including nutritional deficits, elec-trolyte abnormalities, and emotionaldistress.6 Familiarity with the risk fac-tors, physiology, and evidenced-basedprophylaxis of CINV will promoteeffective management.

Pathways and patternsNausea and vomiting is a complex

process regulated by key pathways medi-ated by neurotransmitters. The primarypathways involved in CINV include thecentral pattern generator, located in themedulla and activated by neurologicinput from sensory centers; the cerebralcortex and limbic system that respondto sights, smells, situations, and emo-tions; and the vagal and sympathetic/visceral pathways located in the uppersmall intestine and mediated by neuro-transmitters that affect the dorsal vagalcomplex, resulting in activation of thecentral pattern generator and the emet-ic reflex.1 The most common neuro-transmitters known to play roles inCINV include 5-hydroxytryptaminetype 3 (5-HT3), neurokinin 1 (NK1),dopamine, and substance P.1 Commonlyused antiemetic agents inhibit one ormore of these neurotransmitters, reduc-ing the stimulation of the emetic reflex,and are assigned either a high or lowtherapeutic index (Table 1).1,3,6

CINV can be further categorized

based on the time of onset. There arefour recognized patterns of CINV, eachwith distinct characteristics, proposedmediators, and strategies for preven-tion (Figure). These include acuteCINV, delayed CINV, anticipatoryCINV, and refractory/breakthroughCINV. Similarly, chemotherapeuticagents are associated with high, moder-ate, or low potential for nausea andvomiting (Table 2).2,4 Effective man-agement of CINV requires considera-tion of the emetogenic potential ofeach agent, the duration of effect (half-life), and number of days for each regi-men. Moderately emetogenic chemo -therapy (MEC) to highly emetogenicchemotherapy (HEC) generally re -quires a combination of antiemeticagents with a high therapeutic indexand varied mechanism of action (Table 3).7 The risk of CINV lasts upto 2 days after the last dose of treat-ment with MEC and up to 3 days afterthe last dose of treatment with HEC.7Drugs with a longer half-life or regi-mens given over several days willrequire dosing of antiemetic agentsover multiple days or use of long-actingantiemetic agents. Familiarity with thepathways and patterns of CINV,knowledge of the emetogenic potentialof individual agents or regimens, and arisk analysis of the individual patientwill provide the best opportunity foreffective management.

Treatment of underlying conditionssuch as constipation, gastroparesis, gas-trointestinal reflux disease, esophagitis,or mucositis should be approachedaggressively as these factors will con-tribute to nausea and vomiting. Patientswith a history of nausea related to othermedications, younger patients, patientswith low alcohol use, women with a his-tory of morning sickness, and patientswho are prone to motion sickness aremore likely to experience CINV.6

Nausea and vomiting that does notrespond to aggressive interventionsshould be evaluated for other causes,such as bowel obstruction, lepto -meningeal disease, or other medica-tions. Patient education about diet,effective use of antiemetic agents, ade-quate hydration, avoidance of aggravat-ing factors, a regular bowel regimen, andreportable signs and symptoms mayreduce the incidence of severe nauseaand vomiting.

Chemotherapy-induced Nausea andVomiting: Clinical UpdatesBy Sandra E. Kurtin, RN, MS, AOCN, ANP-CClinical Assistant Professor of Medicine and Nursing, University of ArizonaNurse Practitioner, Arizona Cancer Center, Tucson

Sandra E. Kurtin, RN, MS, AOCN, ANP-C

5-HT3 indicates 5-hydroxytryptamine type 3; IV, intravenous; NK1, neurokinin 1; TI, therapeutic index.Sources: References 1, 3, and 6.

5-HT3 receptor antagonists, high TI

NK1 receptor antagonists, high TI

Dopamine receptor antagonists,low TI Other

• Dolasetron, oral or IV • Aprepitant, oral • Substitute benzamides: ! metoclopramide, oral or IV

• Corticosteroids, high TI, oral or IV

• Granisetron, oral, IV, transdermal • Fosaprepitant, IV • Phenothiazines: ! prochlorperazine, oral or IV! promethazine, oral or IV

• Cannabinoids, low TI:! dronabinol oral

• Ondansetron, oral or IV • Butophenones: ! haloperidol, oral or

intramuscular

• Benzodiazepines, high TI:! lorazepam, oral or IV

• Palonosetron, IV

Table 1. Commonly Prescribed Antiemetics

Figure. Patterns of Chemotherapy-induced Nausea and Vomiting

• Mediated primarily by serotonin• Related to emetogenic potential of the regimen• Intensity peaks at 5–6 hours• Pharmacologic management is primary strategy

• Substance P plays the primary role• Effective management of acute CINV will reduce the severity• More common with long half-life• Cisplatin is the most common drug with peak intensity at 48–72 hours

• Experiential—More difficult to control, ongoing• Nausea is more common than vomiting• Effective treatment of acute and delayed CINV is key

• Ongoing—May be a result of underlying processes

Refractory and breakthroughRef ghRefractory and breakthrough

Anticipatory – Occurs before drug administration

Delayed 24 hours to 7 days

AcuteFirst 24 hours

CH

EM

OT

HE

RA

PY


Serotonin receptor antagonistsIntegration of the 5-HT3 receptor

agonists (RAs) into the treatment ofCINV has improved the management ofCINV. The Cochrane Pain, Palliativeand Supportive Care Group7 reviewed16 randomized trials (n = 7808) evaluat-ing 5-HT3 RA in adult populations. Themajority (nine) of the trials comparedgranisetron with ondansetron. In thesestudies, granisetron and ondansetronshowed similar benefits in controllingacute and chronic CINV and had similartoxicity profiles, the most commonadverse events being headache and diar-rhea, with the possible exception of lessconstipation with ondansetron. Changesin electrocardiogram readings, includingprolongation of the PR, QRS, QT, andQTc intervals, have been reported.Cases of atrial fibrillation, myocardialischemia, and ventricular tachycardiahave been reported with ondansetronused in the postoperative setting.7

A small number of trials evaluated thenewer agents; however, none of thesetrials included tropisetron, dolasetron,ramosetron, or palonosetron, thus limit-ing any comparison with other agents. Asingle study (n = 1114) comparingpalonosetron plus dexamethasone withgranisetron plus dexamethasone sug-gested improved control of delayed nau-sea and vomiting with palonosetronplus dexamethasone; however, a subse-quent study comparing ondansetronplus dexamethasone to palonosetronplus dexamethasone showed no differ-ence.7 Palonosetron plus dexametha-

sone has shown benefit in preventingacute and delayed CINV, thus providingan option for patients who may benefitfrom a single dose or intravenous (IV)administration. But additional compar-ative trials will be necessary before itcan be stated that palonsetron is superi-or to the other 5-HT3 RAs.

It is important to consider the equiv-alent dosing of the 5-HT3 RA to pro-vide effective coverage. A single doseof a short-acting 5-HT3 RA is notequivalent to a single dose of a long-acting 5-HT3 RA because of the differ-ence in half-life. For example, a singledose of granisetron 2 mg given orally or1 g intravenously has a half-life of 9hours. In comparison, a single 0.25-mgdose of palonosetron given intra-venously has a half-life of 40 hours. Ifthe granisetron is given as a single dose

for HEC, it is not likely to provide ade-quate coverage of delayed CINV; how-ever, if given daily for 3 to 4 days, theseagents would likely provide equal bene-fit. Granisetron is now available in atransdermal patch, delivering 3.1 mg/day of medication. The patch must beapplied between 24 and 48 hours beforeexposure to the MEC or HEC to beeffective and must remain in place atleast 24 hours after exposure to thetreatment. It can be left in place for upto 7 days.8

Although the 5-HT3 RAs are con-sidered the gold standard for the treat-ment of MEC or HEC and are thoughtto be similar in efficacy, they differ intheir potential for interaction withcytochrome (CYP) P450 enzymes. Gran -isetron does not appear to require the

CYP pathways for metabolism anddoes not interfere with any of the CYPenzymes involved in metabolism.Ondansetron, tropisetron, dolasetron,and palonosetron involve the CYP2D6pathway, increasing the potential fordrug–drug interactions.9

NK1 inhibitionThe most recent development in

understanding CINV has been identifi-cation of the tachykinin pathway medi-ated by substance P, a neurotransmitterthat acts on both peripheral and centralNK1 receptor sites. NK1 receptor sites aremost abundant in the nucleus tractis soli-taires of the mid-brain and the vagalafferent pathways located in the enter-chromafin cells of the gut.10 Two multi-center, parallel, double-blind studiesusing a HEC regimen (cisplatin >50mg/m2) evaluated the efficacy of aprepi-

tant, the only US Food and DrugAdministration–approved NK1 in hib -itor, in combination with ondan setronand dexamethasone compared with stan-dard 5-HT3 and dexamethasone.Patients (n = 1105) were evaluated foracute and delayed CINV. The combina-tion of aprepitant, ondan setron, and dex-amethasone eliminated emesis and theneed for any breakthrough medication in73% of the patients compared with 52%receiving a 5-HT3 RA and dexametha-sone alone.11 Aprepitant is both aninhibitor (CYP3A4) and an inducer(CYP29A) of CYP450 pathways.9

Inhibition of CYP3A4 results in a dou-bling of plasma glucocorticoid levels,and induction of the CYP2A results in a33% reduction of warfarin concentra-tions with as much as a 10% drop in

international normalized ratio levels 7to 10 days after exposure to aprepitant.11

Reduction of the dexamethasone doseby 50% is recommended when given incombination with aprepitant.

Unique needs of the elderlyCancer is predominantly a disease of

older people, with 75% of cases in per-sons older than 65 years of age. One oftwo men and one of three women willdevelop cancer during their lifetime.12

Approximately 12 million people willbe diagnosed with cancer worldwideeach year, and it is estimated this num-ber will increase to 25 million in theyear 2030, primarily because of an agingpopulation.13 Therefore, the number ofolder patients receiving cancer treat-ment including chemotherapy is likelyto increase.


Supportive Care


5-HT3 indicates 5-hydroxytryptamine type 3; H2, histamine-2; PPI, proton pump inhibitor.Source: Reference 7.

High risk Moderate risk Low risk Minimal risk

• 5-HT3 receptor antagonist on day 1

• 5-HT3 receptor antagonist ondays 1 to 3

• Dexamethasone 12 mg oral/IV daily

• No routine prophylaxis, prescribeas needed

• Dexamethasone 12 mg on days 1 to 4

• Dexamethasone 12 mg on days 1 to 3

• Prochlorperazine or metoclo-pramide oral or IV every 4 to 6 hours, as needed

• Aprepitant 125 mg oral on day 1and 80 mg oral on days 2 to 3

• Aprepitant 125 mg oral on day 1and 80 mg oral on days 2 to 3

• H2 blocker or PPI

• Lorazepam oral, IV, or sublingualon days 1 to 4 and every 4 to 6hours, as needed

• Lorazepam oral, IV, or sublingualevery 4 to 6 hours, as needed

• Lorazepam oral or IV every 4 to 6hours, as needed

• H2 blocker or PPI • H2 blocker or PPI

Table 3. Risk-based Antiemetic Regimens

Highly emetogenic chemotherapy Moderately emetogenic chemotherapy

Carmustine >250 mg/m2, oral Carboplatin

Cisplatin >50 mg/m2 Azacitidine

Cyclophosphamide 1500 mg/m2 Epirubicin

Dacarbazine Etoposide, oral

Dactinomycin Cytarabine >1 g/m2

Lomustine, oral Cyclophosphamide <1500 mg/m2

Mechlorethamine Cyclophosphamide, oral

Pentostatin Daunorubicin

Procarbazine, oral Decitabine

Streptozotocin Doxorubicin

AC combination: doxorubicin or daunorubicinwith cyclophosphamide

Idarubicin

Ifosfamide

Imatinib

Irinotecan

Oxaliplatin >75 mg/m2

Temozolomide, oral

Vinorelbine

Table 2. Highly or Moderately Emetogenic Chemotherapy Agents

Sources: References 2, 4, and 5.

Nausea and vomiting that does not respond toaggressive interventions should be evaluated for othercauses, such as bowel obstruction, leptomeningealdisease, or other medications.



Supportive Care

Severe hypersensitivity reactionsto antineoplastic agents are quiterare, occurring 5% of the time

across all agents.1 Despite this, theimpact to the patient can be quite sig-nificant, resulting in discomfort anddistress, hospitalization, treatment dis-continuation, and even death. Unlikemost adverse reactions, which oftencan be predicted, infusion reactions areunexpected and variable. Althoughrare, nearly every antineoplastic drughas been associated with a hypersensi-tivity reaction.

It is estimated that an average of$177.4 billion is spent annually in theUnited States on managing adverse

drug reactions.2 Although infusion-related reactions make up a small per-centage of adverse drug reactions, theystill carry a significant economic im -pact. Infusion-related reactions maylead to prolonged infusion times, dosereductions, dose delays, and/or discon-tinuation of the drug.3,4 They also canlead to hospitalizations and compro-mise optimal cancer therapy outcome.For this reason, it is important for alloncologists, nurses, and pharmacists tohave a fundamental background in theprevention and management of infu-sion reactions.

Classification of hypersensitivityreactions

Hypersensitivity reactions are classi-fied into two categories: type A andtype B. Type-A reactions are adverseside effects caused by drug properties.For example, the use of vincristine maycause constipation. In contrast, type-Breactions are considered immune medi-ated. The classic mechanism of im -mune-mediated hypersensitivity reac-tions involves the formation ofim munoglobulin E (IgE) antibodiesfrom drug exposure. Subsequently, IgEbinds to mast cells, which can lead tothe release of numerous cytokines.5

Hypersensitivity reactions may also benon-IgE mediated, but the manifesta-tions are identical.6 An infusion reac-tion is a type of hypersensitivity reac-tion that develops during or shortlyafter administration of a drug. Signs and symptoms may include pruritus,urticaria, fever, rigors/chills, diaphoresis,bronchospasms, and cardiovascular col-lapse. The Cancer Therapy EvaluationProgram has developed grading criteriabased on presentation (Table 1).7

Incidence of infusion-relatedreactions

Severe hypersensitivity reactions arerare occurrences with the use of properpreventive measures. The overall inci-dence varies across drug classes andagents. In addition, incidence rateshave been variable across time andstudies. For example, earlier reports ofcisplatin infusion reactions cite a 10%to 27% overall incidence.1 Moderninfusion techniques with slower infu-

sion rates and improved premedicationwith dexamethasone have resulted in amuch lower rate of infusion reactions.

Historically, the most common drugclasses associated with hypersensitivityreactions were the taxanes, platinumcompounds, and monoclonal antibod-ies.8 Specific antineoplastics reported tocarry a significant risk include denileukindiftitox, liposomal doxorubicin, etopo-side, ixabepilone, teniposide, and L-asparaginase. Anti neo plastics that rarelyresult in hyper sensitivity reactions in -clude the anthracyclines, bleomycin, 6-mercaptopurine, azathioprine, and var-ious alkylating agents, including dacarb -azine and melphalan.9 Table 2 lists theagents by class with overall reported ratesof hypersensitivity reactions.

Exact mechanisms of hypersensitivi-ty reactions with antineoplastic agentsremain unclear. They can be immune-or nonimmune-mediated reactions.The cause may be related to the drugcompound, the drug vehicle, orpatient-related risk factors (ie, diseasesite, tumor burden). This article willfocus on three chemotherapy classescommonly associated with infusionreactions: taxanes, platinum com-pounds, and monoclonal antibodies.

Taxanes The two most frequently used tax-

anes are paclitaxel and docetaxel.Hypersensitivity to paclitaxel typicallyoccurs within 10 minutes of infusionbut may extend to 12 hours.27 It is notknown whether the cause of infusionreactions is the drug or the poly-oxyethylated castor oil solvent. Forthis reason, nanoparticle albumin-bound paclitaxel is manufactured withhuman albumin as the solvent.Docetaxel is suspended in a polysor-bate 80 vehicle.28 Hypersensitivityreactions to docetaxel are unpre-dictable. It is possible that polysorbate80 is the culprit. Newer formulationsare under development to maximizeantitumor activities and minimize therisk of hypersensitivity reactions.29

Platinum agentsOxaliplatin, carboplatin, and cis-

platin are the platinum compoundsavailable in the United States. Most of

the hypersensitivity reactions associat-ed with their use are IgE mediated and,as a result, reaction incidence increas-es with subsequent cycles.30 For oxali-platin, the average time between firstdrug exposure and reaction has beenreported as 217.7 days (cycles 9-10).31

The average time to reaction for car-boplatin has been found to be five tosix cycles.32 The cause and timing ofreactions for cisplatin have not beenelucidated.

Monoclonal antibodiesThe incidence of hypersensitivity

reactions to monoclonal antibodies isvariable. The immunogenicity of eachspecific agent is an important determi-nant of the overall risk of a patientexperiencing a hypersensitivity reac-tion. The murine antibodies containno human proteins, whereas chimericantibodies contain approximately 65%to 90% human amino acids, human-ized antibodies contain >90% humanamino acids, and fully humanized anti-bodies contain 100% human aminoacids. Murine antibodies carry thehighest risk of an immune reaction andthus are not used for solid tumors andonly in a limited capacity for hemato-logic malignancies.

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibodyagainst the epidermal growth factorreceptor, is used to treat a variety ofsolid tumors. A retrospective study sug-gested that infusion reactions to cetux-imab are mediated via IgE antibodiesdirected at the oligosaccharide, galac-tose--1,3-galactose, which is presenton the fragment antigen binding por-tion of the cetuximab molecule.33 Inphase 2 and 3 clinical trials, reactionsto cetuximab most commonly occurredduring the first infusion.15 The overallrisk of severe infusion reaction tocetuximab is reported at 3% innational and international studies, butfollow-up reports have described thisrate to be variable across demographicareas of the United States.8,34 Forexample, in Tennessee and NorthCarolina the risk of severe infusionreaction was found to be 22%, whereasin the Northeast it was <1%.14 It has

Infusion-related ReactionsBy Christopher Campen, PharmD, BCPSClinical Assistant Professor, University of Arizona College of Pharmacy, Arizona Cancer Center, Tucson

Nolan Ngo, PharmD, BCPSHematology/Oncology/Bone Marrow Transplant Clinical Pharmacist, Baylor University Medical Center, Dallas,Texas

Ali McBride, PharmD, MS, BCPSClinical Pharmacist, Hematologic Malignancies/Stem Cell Transplant, Barnes-Jewish Hospital, St. Louis,Missouri

Christopher Campen, PharmD, BCPS

Nolan Ngo, PharmD, BCPS

Ali McBride, PharmD, MS, BCPS



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been proposed that this is because indi-viduals in specific geographic areashave increased expose to mouse anti-gen and develop IgE antibodies againstcetuximab.33

Rituximab is a chimeric monoclon-al antibody indicated for hematologicmalignancies. The reported overallincidence of hypersensitivity reactionsto rituximab is 77% with the first infu-sion, but by the eighth infusion, therate decreases to only 14%.35 Ri -tuximab reactions appear to be posi-tively correlated with tumor necrosisfactor- and interleukin-6 serum con-centrations.36 Risk factors for thedevelopment of an infusion reactioninclude lymphocyte counts >50 109/L and high numbers of circulatingCD20+ cells.36 The most commonadverse effects include fever, chills,rash, and nausea occurring during thefirst infusion. Infusion reactions typi-cally occur within 30 to 120 minutesand resolve with discontinuation ofthe infusion and supportive care.19

Humanized monoclonal antibodies,such as trastuzumab and bevacizumab,have a lower rate of hypersensitivityreactions than murine and chimericmonoclonal antibodies, and premed-ication is often not required. The exactmechanism of infusion reactions totrastuzumab has not been elucidated.Signs and symptoms reported in clini-cal trials include fever, chills, nausea,vomiting, headache, dizziness, dysp-nea, hypotension, rash, and asthenia.No risk factors have been identified topredict which patients are likely todevelop reactions.21 Bevacizumab is amonoclonal antibody that targets thevascular endothelial growth factor.Patients may present with hyperten-sion rather than hypotension, as seen

with other monoclonal antibodies.18

Fully human panitumumab has anextremely low incidence of hypersen-sitivity reactions and is well tolerat-ed.8,34 Ofatumumab, a novel CD20monoclonal antibody, however, has ahigh incidence with the first twodoses because of cytokine release, butit appears from an interim analysisthat long-term administration is welltolerated.17

Prevention and treatmentPatients who are about to begin

treatment need to have their medicalhistory reviewed, which must includeanalysis of previous therapies and aller-gic reactions. A thorough evaluationmay reveal previous allergic reactionsthat can lead to an increased risk ofhypersensitivity reactions duringchemotherapy infusion. Obtaining acomplete assessment of a patient’sallergies beforehand may prompt ther-apeutic interventions to decrease therisk of infusion-related reactions.Other factors that may increase therisk of hypersensitivity reactions thatshould be reviewed before the initia-tion of chemotherapy include age,race, sex, geographic location, malig-nancy, and previous chemotherapyadministration.9,14,37 Counseling shouldalso be a mainstay of a patient’schemotherapy treatment. Patientsshould be educated on the drug’s possi-ble side effects and informed of infu-sion-related reactions that may occurduring their course of therapy.

Most infusion-related reactions totaxanes can be prevented by using pre-medications. Use of histamine H1- andH2-receptor antagonists and corticos-teroids can decrease the occurrence ofinfusion-related reactions to less than

10%.1 Dex amethasone is used to reducethe incidence and severity of fluidretention from docetaxel infusions.38

Pre medications for monoclonal anti-bodies vary. In most cases, antihista-mines are used as the mainstay of pre-medication regimens. However, aretrospective study evaluated the use ofantihistamines versus steroids and anti-histamines for premedication beforecetuximab administration and showed asubstantial decrease in infusion-relatedreactions.38 Mild-to-moderate infusionreactions may be managed by holdingthe drug and then restarting the infu-sion at a slower rate, adding antihista-mines for symptom management,and/or adding corticosteroids. Patientsshould be monitored during their infu-sion, with cessation of infusion if thepatient experiences noticeable chestpain, cardiac issues, or anaphylaxis.Appropriate supportive care should beinitiated.

AnaphylaxisThe incidence of anaphylaxis during

infusion of antineoplastic or biologicagents varies as does severity andsymptomatology. Anaphylaxis is a life-threatening reaction that can either begeneralized or systemic based on its eti-ology. It is characterized by an unex-pected onset of symptoms that mayinclude an increase in anxiety similarto a panic disorder as well as changes inthe patient’s airway status, breathing,and/or circulation.39 Other possiblesymptoms include throat or tongueswelling, stridor, hoarseness, wheezing,increased respiratory rate, fatigue,hypoxia, hypotension, dizziness, andloss of consciousness.40 Some patientsmay experience systemic allergy symp-toms such as angioedema and urticaria,

which are usually less severe. In allcases, prompt attention and an imme-diate response to the patient’s initialhypersensitivity reaction are essential.

In cases of severe anaphylaxis, deathcan occur within 30 minutes from thetime of the patient’s initial exposure tothe drug.41 Criteria for treatmentshould be available at each infusioncenter to expedite measures and anti-dotes for treatment. Guidelines for themanagement of anaphylaxis have beendeveloped by the American HeartAssociation and the Oncology NursingSociety (Table 3).39,40,42 At the firstsign of a reaction, the chemotherapyshould be stopped with prompt inter-vention by the medical and healthcarestaff:

• Recline the patient to a comfort-able position, leaving the legs ele-vated

• Administer oxygen at high flowrates

• Continue to evaluate vital signs

DesensitizationNumerous chemotherapy agents can

cause infusion-related reactions, withsome patients exhibiting severe reac-tions during chemotherapy. In somecases, the patient may require thechemotherapy, even after experiencinga reaction because of the limitedchoice of therapeutic alternatives. Theuse of desensitization protocols forthese patients provides an option tocontinue with their chemotherapy.Desensitization protocols have beenused to treat hypersensitivity reactionsto most chemotherapy agents, includ-ing taxanes, platinoids, anthracyclines(including doxorubicin), and, to a less-er extent, monoclonal antibodies. The


Supportive Care

Infusion-related Reactions Continued from page 46

Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Cytokine-release syndrome/acute infusion reaction

• Mild reaction • Infusion interruption not

indicated• Intervention not indicated

• Requires therapy or infusion interruption butresponds promptly to symptomatic treatment (eg, antihistamines, NSAIDs,narcotics, IV fluids)

• Prophylactic medications indicated for 24 hrs

• Prolonged (ie, not rapidlyresponsive to symptomatic medication and/or brief interruption of infusion)

• Recurrence of symptoms following initial improvement

• Hospitalization indicated for other clinical sequelae (eg, renal impairment, pulmonary infiltrates)

• Life-threatening• Pressor or ventilatory support

indicated

• Death

Allergic reaction, hypersensitivity (including drug fever)

• Transient flushing or rash• Drug fever <38ºC (100.4ºF)

• Rash• Flushing• Urticaria• Dyspnea• Drug fever 38ºC (100.4ºF)

• Symptomatic bronchospasm,with or without urticaria

• Parenteral medication(s) indicated

• Allergy-relatededema/angioedema

• Hypotension

• Anaphylaxis • Death

Table 1. Common Terminology Criteria for Adverse Events

IV indicates intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.




Beforethe research is published…

Beforethe guideline is issued…

Beforethe drug is approved…

www.TheOncologyPharmacist.com

CANCER CENTERPROFILEDesert RegionalComprehensive CancerCenter Provides Varietyof Services Under One RoofBy Karen Rosenberg

The Leader

in News andMeeting Coverage

DRUG THERAPYNew Treatments for Chronic Idiopathic

Thrombocytopenic Purpura. Part 1.

RomiplostimBy Michael S. Mathisen, PharmD; and Laura Boehnke Michaud, PharmD, BCOP, FASHP

©2010 Green Hill Healthcare Communications, LLC

A lthough thrombocytopenia is acommon problem in patientswith cancer, idiopathic throm-

bocytopenic purpura (ITP) is relatively

rare and is difficult to treat when dura-

tion exceeds 6 months. ITP can be

either acute (duration 6 months) or

chronic, can occur in both adults and

children, and can be primary or sec-

ondary to another disorder, including

the malignancy.Primary chronic ITP is an autoimmune

condition occurring more frequently in

adults, which results from antibody-medi-

ated platelet destruction and is character-

ized by a depressed platelet count and

mucocutaneous bleeding.1,2 Although

the stimulus for these antiplatelet anti-

bodies in primary chronic ITP remains

largely unknown, the goals of therapy

include maintaining a platelet count

above 50,000/mm3 to avoid life-threaten-

ing hemorrhagic complications. Cortico steroids are a mainstay of ther-

apy and are generally used as first-line

therapy. Re sponse rates range from 50%

to 75%, but continued remission ranges

from only 5% to 30%.2 Other options

available for the management of ITP

include rituximab, intravenous immuno-

globulin, danazol, cyclophosphamide,

immunosuppressive agents (eg, azathio-

prine, cyclosporine), and splenectomy,

which all elicit varying degrees of respon-

siveness and have significant adverseContinued on page 6

APRIL 2010

www.TheOncologyPharmacist.com

VOL 3, NO 2

C hemotherapy appears tobe associated with a statis-tically significant decrease

in the relative risk of prostatecancer—specific mortality amongolder men with stage IV prostatecancer who are receiving andro-gen-deprivation therapy (ADT),according to a new study.

The findings, based on datafrom the Surveillance, Epide -miology and End Results (SEER)and Medicare databases, may helppharmacists better counsel theirolder male patients about thepotential benefits from chemo -therapy. The survival benefit,

Chemotherapy May Significantly

Benefit Stage IV Prostate Cancer

Patients on Androgen-deprivation Therapy

By John Schieszer


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Breast CancerTrastuzumab best givenalong with chemotherapyBased on a presentationby Edith Perez, MDpage 22

CE CreditAspirin therapy and survival in patients with colorectal cancer

page 14

Conference NewsWork-at-home pharmacist program confers multiple benefitsBased on a presentation by

Sam Calabrese, RPh, MBApage 8

O pened in 1989, the Com -prehensive Cancer Center(CCC) at Desert Regional

Medical Center was the first multidisci-

plinary outpatient cancer program in

the Palm Springs, California, area. The

CCC represents the collaboration of the

multispecialty regional medical center

with Aptium Oncology, a national

provider of oncology management and

consulting services. The CCC now

employs 120 healthcare professionals

and provides a full range of services,

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ment, and follow-up care under one

roof. The 60,000-square-foot center

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center, physician offices and examina-

tion rooms, a radiation oncology treat-

ment area, outpatient surgery facilities,

a laboratory, a pharmacy, a research

department, a comprehensive breast

center, and a patient resource center.

ASCO GUThe following articles are based on presentations at the 2010

ASCO Genitourinary Cancers Symposium in San Francisco. Novel Treatment withMicrospheres ShowingPromise for Patientswith Liver CancerBy John Schieszer

GASTROINTESTINAL CANCERS

TAMPA, FLORIDA—A new interventional radiolo-

gy treatment that utilizes intra-arterial yttrium-90 (Y-

90) microspheres may prolong the lives of many

patients with hepatocellular carcinoma. New data

presented at the Society of Interventional Radiology’s

35th annual scientific meeting showed this approach

may extend life for the more than three fourths of

hepatocellular carcinoma patients who are not eligible

for surgery.“This is encouraging news for liver cancer patients,

especially those who have blockage in the portal

vein. While patients aren’t cured, their lives are beingContinued on page 11

Inside

COMPLIMENTARY

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Supportive Care

general principle is gradual reintroduc-tion of small amounts of drug antigens.Rapid desensitization induces tempo-rary clinical toleration and is achievedby administering small incrementaldiluted doses of the drug to the full ther-apeutic dose within several hours.43,44

Initial rapid desensitization should be

performed only in settings under theguidance of a physician, with one-on-one nurse –patient care and where resus-citation personnel and resources arereadily available. Repeated desensitiza-tion can be safely performed in outpa-tient settings with similar conditions,which allow patients to continue their

treatment schedule without a changein the efficacy of treatment.45

SummaryInfusion-related reactions occur

with numerous chemotherapy agentsin a wide variety of treatment regi-mens. Hypersensitivity reactions maybe specific to drug classes and biologicagents. Most patients who exhibit infu-sion-related reactions are able to berechallenged either by changes to pre-medications or through desensitizationpro tocols. The next decade shouldbring new biologic and antineoplasticoncology agents that will need to be con-tinually evaluated for infusion reactions.The expected increase in patients beingdiagnosed with cancer will likelyincrease the number of patients beingtreated with chemotherapy. Developinga plan that prevents infusion-relatedreactions at your institution requiresdeveloping a process that educateshealthcare staff to the signs and symp-toms of these reactions, counselingpatients on the adverse effects of therapy,and creating protocol guidelines for managing reactions when they occur.Implementation of these procedures forinfusion centers can provide proper man-agement to prevent and treat reactionsin a timely manner. !

References1. Syrigou E, Makrilia N, Koti I, et al. Hyper -

sensitivity reactions to antineoplastic agents:an overview. Anticancer Drugs. 2009; 20:1-6.

2. Ernst FR, Grizzle AJ. Drug-related morbidityand mortality: updating the cost-of-illnessmodel. J Am Pharm Assoc (Wash). 2001;41:192-199.

3. Schwartzberg LS, Stepanski EJ, Fortner BV,Houts AC. Retrospective chart review of severeinfusion reactions with rituximab, cetuximab,and bevacizumab in community oncology prac-tices: assessment of clinical consequences.

Support Care Cancer. 2008;16:393-398.4. Schwartzberg LS, Stepanski EJ, Walker MS, et

al. Implications of IV monoclonal antibodyinfusion reaction for the patient, caregiver, andpractice: results of a multicenter study. SupportCare Cancer. 2009;17:91-98.

5. Schnyder B, Pichler WJ. Mechanisms of drug-induced allergy. Mayo Clin Proc. 2009;84:268-272.

6. Castells MC. Hypersensitivity to antineoplasticagents. Curr Pharm Des. 2008;14:2892-2901.

7. Cancer Therapy Evaluation Program, CommonTerminology, Division of Cancer Treatmentand Diagnosis, National Cancer Institute,National Institutes of Health, Dept of Healthand Human Services. Common terminologycriteria for adverse events (CTCAE) and com-mon toxicity criteria (CTC). August 9, 2006.http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.Assessed February 23, 2010.

8. Lenz HJ. Management and preparedness forinfusion and hypersensitivity reactions.Oncologist. 2007;12:601-609.

9. Gobel BH. Chemotherapy-induced hypersensi-tivity reactions. Oncol Nurs Forum. 2005;32:1027-1035.

10. Taxotere [package insert]. Bridgewater, NJ:sanofi-aventis; 2008.

11. Paclitaxel [package insert]. Princeton, NJ:Bristol-Myers Squibb; 2007.

12. Gradishar WJ, Krasnojon D, Cheporov S, et al.Significantly longer progression-free survivalwith nab-paclitaxel compared with docetaxelas first-line therapy for metastatic breast cancer.J Clin Oncol. 2009;27:3611-3619.

13. Wendtner CM, Ritgen M, Schweighofer CD, et al; for the German CLL Study Group(GCLLSG). Consolidation with alemtuzumabin patients with chronic lymphocytic leukemia(CLL) in first remission—experience on safetyand efficacy within a randomized phase III trialof the German CLL Study Group (GCLLSG).Leukemia. 2004;18:1093-1101.

14. O’Neil BH, Allen R, Spigel DR, et al. Highincidence of cetuximab-related infusion reac-tions in Tennessee and North Carolina and theassociation of atopic history. J Clin Oncol.2007;25:3644-3648.

15. Erbitux [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2010.

Taxanes

Mild/moderate (grade 1/2) Severe (grade 3/4)

Recommended premedication

Docetaxel8,10 N/A 2% Steroids

Paclitaxel8,11 N/A 2% to 4% H1/H2-receptor blockers, steroids

Nanoparticle albumin-bound paclitaxel12

N/A Rare None

Platinum agents

Carboplatin8 N/A 2% None

Cisplatin N/A N/A None

Oxaliplatin8 N/A 2% to 3% None

Monoclonal antibodies

Alemtuzumab, intravenous13

65% N/A Acetaminophen, H1-receptor blocker

Bevacizumab8,14 <3% (overall) 0.2% (all infusions) None

Cetuximab8,14,15 16% to 19% 3% (all infusions) H1-receptor blocker

Gemtuzumab N/A N/A H1-receptor blocker,acetaminophen

Ibritumomab16 N/A N/A Acetaminophen, H1-receptor blocker priorto rituximab portion

Ofatumumab17 41% (overall, firstinfusion)

4% (overall, firstinfusion)

Acetaminophen, H1-receptor blocker,steroids

Panitumumab8,14,18 3% (overall) 0.1% None

Rituximab19 77% (overall, first infusion)

<10% (all infusions) Acetaminophen, H1-receptor blocker

Tositumomab20 29% (overall, dosimetric dose)

N/A Acetaminophen, H1-receptor blocker

Trastuzumab8,14,21 40% (overall, first infusion)

<1% (all infusions) None

Other agents with a moderate to high potential for infusion reaction

Denileukin diftitox22,23

69% (overall) N/A Acetaminophen, H1-receptor blocker

Liposomal doxorubicin24

9% (overall) N/A None

Ixabepilone25 N/A 0.6% H1- and H2-receptorblockers

L-asparaginase26 25% (overall) N/A None

Etoposide9,14 6% to 34% (overall) N/A None

Teniposide9,14 6% to 25% (overall) N/A None

Table 2. Incidence of Mild/Moderate and Severe InfusionReaction of Antineoplastic and Monoclonal Antibodies


• Cessation of chemotherapy

• Administer high-flow oxygen (>10 L/min)

• Administer epinephrine 1:1000 (weight-based) (adults: 0.01 mL/kg, up to a maximum of0.2 mL to 0.5 mL every 10 to 15 minutes as needed; children: 0.01 mL/kg, up to a maximum dose of 0.2 mL to 0.5 mL) by SC or IM route and, if necessary, repeat every 15 minutes, up to two doses.

• Administer fluid hydration (adults 500 mL to 1000 mL; children crystalloid 20 mL/kg). Colloids should be stopped as they may be the triggers for the reaction.

• Administer H1/H2 slowly by IV/IM injection. These can counteract some of the activity of circulating histamine from the mast cells.

• Administer inhaled albuterol/ipratropium for bronchospasms.

• Give hydrocortisone sodium succinate 100 mg to 200 mg by slow IV injection (choose thelower dose if steroid has already been given as antiemetic or premedication). Hydrocortisonehas an onset of action that is delayed for up to 4 to 6 hours. However, it may shorten or prevent a protracted reaction.

IM indicates intramuscular; IV, intravenous; SC, subcutaneous.


Table 3. Summary of Treatment Medications Used inAnaphylactic Reactions



Multiple myeloma (MM), al -though currently incurable,has seen significantly im -

proved response and overall survival(OS) rates with the inclusion of target-ed therapy in its treatment schema. MMtherapy has evolved greatly over thepast several years and, with innovativeresearch and medications, this diseasemay soon be curable. This article willfocus on the novel agents revolutioniz-ing therapy of MM.

BackgroundPrimarily a disease of the elderly,

MM is the second most commonhematologic malignancy in the United

States, second only to non-Hodgkin’slymphoma.1 The median average ageat diagnosis is 62 years for men and 61years for women, with fewer than 2%of cases occurring in patients youngerthan 40 years.1 The number of MMcases in 2009 was an estimated 20,580,and the disease is more prevalent inmen and blacks.2 Patients receivingstandard therapy have a median sur-vival of 3 to 4 years after diagnosis,whereas those who receive an autolo-gous stem cell transplant may survive 5to 7 years; survival ranges from weeksto >10 years.1

MM is a clonal B-cell disease; malig-nant plasma cells accumulate in thebone marrow and ultimately causecytopenias, bone resorption, and mono-clonal protein production.3 The clinicalpicture of MM can range from asympto-matic monoclonal gammopathy ofunknown significance (MGUS) to smol-dering MM (SMM) and ultimately tosymptomatic disease. Patients withMGUS have a 1% per year chance ofadvancing to MM, and those with SMMhave an even higher risk of progression(10% per year for the first 5 years).4Improved therapy has begged the ques-tion of whether to treat MM in these ear-lier clinical states, but currently therapyis reserved for patients who have sympto-matic disease. Typically, treatment is ini-tiated when evidence of at least one ofthe following criteria are met: hypercal-

cemia, anemia, renal insufficiency, orbone lesions (CRAB criteria).5

Diagnosis, staging, and prognosisThe MM diagnosis is confirmed by

obtaining quantitative serum im -munoglobulins, serum and urine proteinelectrophoresis, and immunofixation orserum immunoglobulin free light chainassay, skeletal survey, and bone marrowbiopsy.2 The presence of monoclonalgammopathy on electrophoresis andplasmacytosis (10% plasma cells in thebone marrow) indicates MM. In addi-tion, measuring beta-2-microglobulinlevels is standardly performed to assesstumor burden. Of note, fewer than 3%

of patients may present with nonsecre-tory myeloma, and thus may have littleto no monoclonal protein in the serumor urine.2

Historically, the Durie-Salmon stag-ing system has been used to categorizeMM patients into stage I, II, or III,depending on the level of anemia,hypercalcemia, presence of bonelesions, and levels of monoclonal pro-tein in the serum and urine.2 Morerecently, the International StagingSystem (ISS) has been widely em -

ployed. The ISS classifies MM usingserum values of beta-2-microglobulinand albumin, tests that are easily repro-ducible and highly prognostic.2 The ISScannot distinguish MGUS and SMMfrom active myeloma, however, andcannot be used for therapeutic riskstratification given that beta-2-micro -globulin levels may be increasedbecause of either myeloma tumor bur-den or renal failure.6 The ability of theISS to determine prognosis will contin-ue to evolve as the effect of the targetedtherapies becomes more apparent.

The role of cytogenetics in MM prog-nosis is becoming ever more important.It is recommended that both conven-tional cytogenetic testing as well as fluo-rescence in situ hybridization (FISH) beused to capture the characteristics thatplace patients in standard- or high-riskcategories.6 Conventional cytogeneticstudies may reveal chromosomal abnor-malities in only one third of patientswith MM, whereas FISH may showabnormalities in more than 90%.6 Poorprognosis has been associated witht(4;14), t(14;16), t(14;20), del(17) (p13),or del(13). In contrast, the presence oft(11;14), t(6;14), or hyperdiploidy hasconferred a more favorable prognosis.Again, the novel agents used in MMtreatment today may change the prog-nostic ability of these abnormalities.For example, bortezomib has beenshown to overcome the poor prognosisgarnered by del(13), t(4;14), anddel(17)(p13).5 Future study will eluci-date how cytogenetics or FISH willaffect risk stratification.

Novel agentsThalidomide, lenalidomide, and

bortezomib have significantly changedthe landscape of MM therapy. Theseagents now play a huge role in the treat-ment of newly diagnosed (both in trans-plant-eligible and -ineligible patients)and relapsed/refractory disease, and arealso being evaluated in the mainte-nance setting.

Thalidomide. The proposed mecha-nisms of action for thalidomide includeantiangiogenesis effects, inhibition oftumor necrosis factor-alpha, and in -creased cell-mediated cytotoxicity.7

How ever, its mechanism of action inMM therapy is not fully explained.Thalidomide’s teratogenicity is wellknown, and thus it is obtained solelythrough the System for ThalidomideEducation and Prescribing Safety(S.T.E.P.S.) programs.

Thalidomide dosing varies, but typi-cally ranges from 200 mg to 400 mg oraldaily.7 Lower doses may be used whenthalidomide is taken in combinationwith other chemotherapy or in elderlypatients unable to tolerate the sideeffects. Bedtime is the preferable admin-



Stephanie S. Taber, PharmD, BCOP



Multiple Myeloma: A ReviewBy Stephanie S. Taber, PharmD, BCOPClinical Assistant Professor, University of Michigan College of Pharmacy and Health System, Ann Arbor

Drug Grade of toxicity Dose modification Pharmaceutical intervention?

Bortezomib Grade 1 (mild) Continue therapy n/a

Grade 1 with pain or grade 2 Dose reduction to 1 mg/m2 Yes

Grade 3 Hold until resolution to baselineRestart 0.7 mg/m2

Consider once-weekly schedule

Yes

Grade 4 Discontinuation of therapy n/a

Thalidomide Grade 1 (mild) Continue therapy n/a

Grade 2 Intermittent symptoms: continuetherapyContinuous symptoms: hold andreduce dose upon resolution

Yes

Grade 3 Hold therapy until patient at baseline, restart at reduced dose

Yes

Grade 4 Discontinuation of therapy n/a

Table 1. Dose Modifications for Peripheral Neuropathy

Conventional cytogenetic studies may revealchromosomal abnormalities in only one third ofpatients with MM, whereas FISH may showabnormalities in more than 90%.


istration time due to the drug’s potentialto cause drowsiness; it should be takenwith water at least 1 hour after a meal.8

Thalidomide’s side effects may be dosedependent, and common adverse reac-tions include somnolence, fatigue, con-stipation, and rash. In addition, neu-tropenia, edema, and hypothyroidism arepossible. Peripheral neuropathy is alsoassociated with thalidomide, and doseadjustment or discontinuation of thedrug may be necessary8 (Table 1). Venousthromboembolism (VTE) is a significantcomplication of thalidomide treatment,particularly when the drug is used incombination with dexamethasone orother cytotoxic agents. Although a fulldiscussion of VTE in MM is beyond thescope of this article, VTE prophylaxis isan important step in the management ofthe patient with MM.

Lenalidomide. A more potent analogof thalidomide, lenalidomide wasdesigned to increase efficacy anddecrease nonhematologic toxicitiescompared with thalidomide. Likethalidomide, lenalidomide exerts itsactivity by inhibiting angiogenesis. Italso inhibits adhesion of myeloma cellsto bone marrow stromal cells and caus-es apoptosis of myeloma cells.7

The approved lenalidomide dose is25 mg orally daily on days 1 to 21 withdexamethasone 40 mg orally on days 1to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first four cycles. Fromthe fifth cycle and forward, thelenalidomide dose remains the same,but the dexamethasone dose decreasesto 40 mg daily on days 1 to 4 only. Thisagent is cleared renally, which may

necessitate dosage adjustments inpatients with renal dysfunction.10 Allpatients, prescribers, and pharmacistsmust register with the RevAssist pro-gram to obtain this medication.

Unfortunately, VTE is still a majorside effect with this agent, and patientsshould receive VTE prophylaxis if possi-ble. Lenalidomide does not cause thesame degree of somnolence, constipa-tion, or peripheral neuropathy asthalidomide. Myelosuppression (neu-tropenia and thrombocytopenia) is seenwith this drug and may lead to dosemodification10 (Table 2).

Bortezomib. Bortezomib is a first-in-class proteasome inhibitor that targetsthe 26S proteasome, ultimately leadingto cell death. Bortezomib not only tar-gets the myeloma cell, but also inhibitsthe binding of the myeloma cell to bonemarrow stromal cells.7

Bortezomib is administered as a 3- to5-second bolus intravenous injection, ata dose ranging from 0.7 mg/m2 to 1.3mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle. No dosage adjustments arenecessary for mild renal impairment(<1.5 upper limit of normal). Patientson dialysis, however, should receivebortezomib after dialysis because dialysismay reduce bortezomib concentrations.Patients with moderate or severe hepaticimpairment should be started at a dose of0.7 mg/m2; the dose may be titrated up ordown as necessary. Bortezomib under-goes hepatic metabolism throughcytochrome P450 enzymes 3A4, 2C19,and 1A2, and should be used cautiouslywith concomitant 3A4 inhibitors.11

The most common adverse reactions

reported with bortezomib include per -ipheral neuropathy), gastrointestinaldisorders, and thrombocytopenia. Bortez -omib-induced peripheral neuropathy isgenerally manageable and reversible,and often resolves or subsides followingdose reduction or after treatment hasended11 (Table 1).

TreatmentAfter a diagnosis of stage II or III

MM, patients are evaluated as candi-dates for high-dose therapy and stemcell transplantation based on age andcomorbidities. The National Com -

prehensive Cancer Network (NCCN)has established guidelines to addresstreatment in the various MM patientpopulations.2

Transplant-ineligible patients. Until theadvent of the immunomodulatingagents and proteosome inhibitors, themainstay of therapy for newly diagnosedpatients ineligible for transplant, wasmelphalan plus prednisone (MP).Several studies have compared MP withMP plus thalidomide (MPT) in elderlypatients with newly diagnosed diseasewho are unable to receive standardinduction therapy followed by autolo-gous bone marrow transplant. MPT hasproduced higher overall response rates(ORR), very good partial response

(VGPR), and longer progression-freesurvival (PFS) than MP.12-14 In addition,Facon and colleagues for IntergroupeFrancophone du Myélome (IFM) 99-06showed improved OS with MPT versusMP (51.6 vs 33.2 months).14 Suchresults have propelled MPT to become astandard of care in elderly patients withMM and those unable to receive atransplant. As expected, the MPT regi-men is associated with increased inci-dences of thromboembolism, infections,and neurologic toxicity as comparedwith MP.12-14 Elderly patients are oftenmore sensitive to thalidomide’s toxici-ties, and the recommended starting doseis 100 mg oral daily.

Likewise, the combination of MPplus bortezomib (VMP) has alsodemonstrated positive results in newlydiagnosed transplant-ineligible pa -tients. In the phase 3 internationalVISTA trial, San Miguel and colleaguescompared standard MP with VMP intransplant-ineligible patients withMM.15 Results of this study demonstrat-ed significant improvement in ORR,time to progression (TTP), and OSwith VMP compared with MP. A recentupdate of this study by Mateos and col-leagues confirmed this survival advan-tage. At a median follow-up of 3 years,69% of patients in the VMP group werealive, compared with 54% in the MPgroup.16 Per ipheral neuropathy, gastroin-testinal side effects, and herpes zosterinfection were more commonly reportedin the VMP arm. VMP, like MPT, is con-sidered a standard of care in the elderlypopulation.

Lenalidomide is also a valuable drugin the transplant-ineligible population.In a study by Zonder and associates,

lenalidomide plus high-dose dexa -methasone (LD) had a higher com-plete response (CR) rate and 1-yearPFS when compared with dexametha-sone alone.17 The combination oflenalidomide plus low-dose dexa -methasone (Ld) showed an OS advan-tage when compared with LD.18

Toxicities were fewer in the Ld arm,18

and thus Ld is considered a viableoption in patients who cannot receivea transplant.

Transplant-eligible patients. Primaryinduction therapy options for trans-plant-eligible patients include bortez -omib/dexamethasone (VD), bortez -omib/doxorubicin/dexamethasone




Multiple Myeloma: A Review Continued from page 51

G-CSF indicates granulocyte colony-stimulating factor.


Drug Condition Recommendation

Bortezomib Neutropenia (grade 4) Hold dose: once resolved, reduce dose by 25%

Thrombocytopenia (grade 4) Hold dose: once resolved, reduce dose by 25%

Thrombocytopenia (if falling <25 x 109/L) Hold dose: once resolved, reduce dose by 25%

Lenalidomide Neutropenia (first grade 3 episode) Hold dose: once resolved and neutropenia onlytoxicity, restart at 25 mg (or previous dose)Hold dose: once resolved and any other toxicity,restart at 15 mg or reduce dose from previous(do not dose <5 mg)Hold dose: consider adding G-CSF to next cycle

Neutropenia (subsequent grade 3 episode) Hold dose: once resolved, restart at 5 mg lessthan previous dose (do not dose <5 mg)

Thrombocytopenia (first episode <30 x 109/L) Hold dose: once resolved, restart at 15 mg orreduce dose 5 mg from previous (do not dose <5 mg)

Thrombocytopenia (each subsequent episode <30 x 109/L)

Hold dose: once resolved, reduce dose 5 mg from previous (do not dose <5 mg)

Thalidomide Neutropenia (<0.75 x 109/L) Consider withholding therapy if clinically appropriate

Table 2. Dose Modifications for Myelosuppression

The combination of MP plus bortezomib (VMP) hasalso demonstrated positive results in newlydiagnosed transplant-ineligible patients.


Current activities at www.COEXM.com include:

CONTINUING EDUCATION CREDITS

TON_May2010_v3:TON 5/4/10 11:11 AM Page 53

(PAD), bortezomib/thalidomide/dex-amethasone (VTD), and lenalido-mide/dexamthasone; all regimens areNCCN category I recommendations.2

Rajkumar and colleagues studied Ld(40 mg on days 1, 8, 15, and 22) versusLD (40 mg on days 1-4, 9-12, and 17-20) in a large randomized phase 3 trial.The results showed significantly betterPFS and OS at 1 and 2 years with Ldthan with LD.18

The IFM performed a large random-ized trial comparing VD induction ver-sus vincristine/doxorubicin/dexametha-sone (VAD), and found that the VDarm showed improved ORR and dura-tion of response. Data on PFS and OSare still needed, however.19

Likewise, VTD, when given beforetransplantation, led to a VGPR in 61%of patients compared with 30% of thosegiven thalidomide/dexamethasone (TD)(P <.001). In addition, 33% of patientsreceiving VTD achieved near-completeresponse or CR versus 12% in the TDarm (P <.001).20 Of interest, VTD over-came the adverse cytogenetics onresponse (del[13]), whereas TD did not.20

Lastly, Sonneveld and colleagues per-formed a phase 3 trial comparing PADwith VAD. Three hundred patientswith newly diagnosed stage II or III dis-ease were randomized to receive PAD orVAD. In the PAD arm, 41% of patientsachieved at least a VGPR, whereas only17% of patients in the VAD armachieved this result (P = .001). Aftertransplant, 15% of the PAD group re ached CR, versus 4% in the VADgroup (P = .05). Partial respose (PR) orbetter was seen after transplant in 92%and 77% of patients, respectively.21

Relapsed and relapsed/refractory. Thethree NCCN category I regimens thatare indicated for salvage therapy in therelapsed and relapsed/refractory pa -tient population include bortezomibalone, bortezomib plus liposomal dox-orubicin, and LD.2

Bortezomib was superior to high-dosedexamethasone in a phase 3 clinical trialconducted by Richardson and colleaguesfor the APEX Investigators. Bortezomibshowed an ORR of 38% compared with18% for the dexamethasone arm (P<.001). In addition, CR was seen in 6%of patients in the bortezomib group, withonly 1% in the dexamethasone arm

achieving the same result (P <.001).Median TTP and 1-year survival ratefavored the bortezomib arm (P <.001 andP = .003, respectively).22

The combination of bortezomib andliposomal doxorubicin has also gainedNCCN category I status as a result of aphase 3 trial in which bortezomib wascompared with bortezomib plus liposo-mal doxorubicin.23 Patients were bortez -omib-naïve with recurrent disease.Median TTP was 6.5 months in thebortezomib alone arm, and increased to9.3 months in the combination group (P= .000004). Survival rate at 15 monthswas also superior in the combinationgroup (76% vs 65%; P = .03), althoughresponse rates were similar between the

groups. The bortezomib plus liposomaldoxorubicin group did, however, experi-ence more grade 3 and 4 toxicities, suchas neutropenia, thrombocytopenia, diar-rhea, and hand-foot syndrome.23

Lenalidomide has also proved effec-tive in the relapsed and refractory MMpatient population. LD was comparedwith dexamethasone in two trials, whichshowed a significantly increased medianTTP in their combination arms (11 vs4.7 months, respectively). Median OS inboth studies, at approximately 30months, was also higher in the combina-tion group.24,25

Other regimens that may be consid-ered in the relapsed and relapsed/refractory population include VD, dexamethasone alone, dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide (DT-PACE), and TD; all are NCCN catego-ry IIA recommendations.2

[Tables summarizing induction trialsfor newly diagnosed patients who areineligible or eligible for transplant and forrelapsed/refractory MM are available atwww.TheOncologyPharmacist.com or bywriting to [email protected].]

Supportive careMyelosuppression. Although thalido-

mide, lenalidomide, and bortezomibhave greatly improved MM therapy,they all have the potential to causesome degree of myelosuppression;dosage adjustments for neutropeniaand/or thrombocytopenia may be nec-essary7,8,10,11,26 (Table 2). Neutropenia(all grades) is seen in 28% of patients

taking lenalidomide, and limited data inlenalidomide trials suggest growth fac-tor support may be helpful for thesepatients through the neutropenic peri-od.27 Bortezomib-related neutropenia ispredictable and usually self-limiting,thus dosage reductions are not recom-mended until the patient is experienc-ing grade 4 neutropenia.11 Likewise,severe neutropenia is not widely seenwith thalidomide use, and doses are typ-ically reduced solely for grade 4 neu-tropenia.8

Bortezomib-related thrombocytope-nia is usually transient and returns tobaseline in the rest period betweentreatment cycles. If a patient does de -velop grade 4 toxicity, current recom-mendations include holding the bortez -omib dose until the platelet countrecovers and then decreasing the doseby 25%.11 Likewise, lenalidomide’spackage insert calls for dose reductionby 5-mg increments when the plateletcount falls to less than 30 109/L.10

Peripheral neuropathy. Peripheral neu-ropathy is another potential toxicityassociated with bortezomib and thalido-mide use. Bortezomib-related peripheralneuropathy appears to occur at a dosethreshold, and incidence peaks aroundcycle five of therapy. Fortunately, theneuropathy is often reversible upondrug discontinuation. In the case ofthalidomide, peripheral neuropathymay be cumulative and therefore is fre-quently irreversible.9 Dosage reductionor cessation of therapy in severe casesmay be warranted; Table 1 lists poten-tial dose alterations. Pharmacologicinterventions such as tricyclic antide-pressants, gabapentin, pregabalin,duloxetine, and lidocaine patches havebeen used with some success in thetreatment of peripheral neuropathy, andmay be used along with dosage adjust-ments to allow continuation of therapyif at all possible.9

Venous thromboembolism. VTE is aserious complication of lenalidomideand thalidomide therapy. Factors thatcontribute to VTE include hyperviscos-ity, previous VTE, dexamethasone andother chemotherapy use in MM thera-py, immobility, other comorbid condi-tions (cardiac disease, diabetes mellitus,renal dysfunction, blood clotting disor-der), presence of a central catheter, sur-gery, and the use of erythropoiesis-stim-ulating agents.28 Thus, VTE prophylaxisis a major component of care for MMpatients. Aspirin, low-molecular-weightheparins (LMWHs), and warfarin haveall been used for VTE prophylaxis in thispatient population, but strong data illus-trating which agent is most effective inthe MM patient are lacking. Palumboand colleagues, with the IFM, suggestthat patients with zero or one of the

risk factors should receive aspirin asprophylaxis, whereas those with two ormore factors should use LMWH or full-dose warfarin.28 Patient-specific charac-teristics, degree of thrombocytopenia,renal im pairment, and contraindica-tions to anticoagulation must be con-sidered when choosing a method forVTE prophylaxis.28

Skeletal lesions. Bone disease is verycommon in patients with MM, and, asmentioned previously, is one of themarkers of active disease.29 Affectedpatients may have significant pain, andthe American Society of ClinicalOncology has created guidelines forthe prevention and management ofMM-related bone disease. It is recom-mended that intravenous bisphospho-nates such as pamidronate and zole-dronic acid be administered on amonthly basis to patients with lyticbone destruction or spine compressionfractures. Pamidronate is dosed at 90mg over 2 to 6 hours; the dose of zole-dronic acid is 4 mg over 15 minutes.Although there are no formal recom-mendations on pamidronate dosing inthe setting of renal dysfunction, it isoften recommended that the dose bedecreased to 60 mg monthly. Inpatients with a creatinine clearance ofless than 30 mL/min, zoledronic acidshould not be given. The starting dosefor zoledronic acid for patients with aclearance greater than 30 mL/minranges from 3 mg to 4 mg, dependingon the degree of renal impairment.29

A rare but serious complication ofintravenous bisphosphonate therapy isosteonecrosis of the jaw. In an effort toreduce the incidence or severity of thecondition, it is recommended that allMM patients receive a comprehensivedental examination as well as any pre-ventive dental procedures before initiat-ing bisphosphonate therapy. Oral infec-tions should be promptly treated, andmajor dental work should be avoided if atall possible while patients are receivingactive bisphosphonate therapy.29

ConclusionMM is a disease whose treatment is in

process. Novel therapeutic agents suchas thalidomide, lenalidomide, andbortezomib have dramatically improvedresponse and survival rates in patientswith this disease, but more research iscertainly needed to cure this cancer. !

References1. Raab MS, Podar K, Breitkreutz I, et al. Multiple

myeloma. Lancet. 2009;374:324-339.2. National Comprehensive Cancer Network.

Clinical Practice Guidelines in Oncology: MultipleMyeloma. V.3.2010. www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. AccessedFebruary 12, 2010.

3. Fonseca R, Bergsagel PL, Drach J, et al; for the

Palumbo and colleagues, with the IFM, suggest thatpatients with zero or one of the risk factors shouldreceive aspirin as prophylaxis, whereas those withtwo or more factors should use LMWH or full-dosewarfarin.






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International Myeloma Working Group.International Myeloma Working Group molec-ular classification of multiple myeloma: spot-light review. Leukemia. 2009;23:2210-2221.

4. Kumar SK, Mikhael JR, Buadi FK, et al.Management of newly diagnosed symptomaticmultiple myeloma: updated Mayo Stratificationof Myeloma and Risk-Adapted Therapy(mSMART) consensus guidelines. Mayo ClinProc. 2009;84:1095-1110.

5. Palumbo A, Rajkumar SV. Treatment of newlydiagnosed myeloma. Leukemia. 2009;23:449-456.

6. Kyle RA, Rajkumar SV. Criteria for diagnosis,staging, risk stratification and response assess-ment of multiple myeloma. Leukemia. 2009;23:3-9.

7. Schwartz RN, Vozniak M. Current and emerg-ing treatments for multiple myeloma. J ManagCare Pharm. 2008;14(7 suppl):12-19.

8. Thalomid [package insert]. Summit, NJ:Celgene Corporation; 2007.

9. Tariman JD, Love G, McCullagh E, Sandifer S;for the IMF Nurse Leadership Board. Peripheralneuropathy associated with novel therapies inpatients with multiple myeloma: consensusstatement of the IMF Nurse Leadership Board.Clin J Oncol Nurs. 2008;12(3 suppl):29-36.

10. Revlimid [package insert]. Summit, NJ:Celgene Corporation; 2009.

11. Velcade [package insert]. Cambridge, MA:Millennium Pharmaceuticals, Inc; 2009.

12. Palumbo A, Bringhen S, Caravita T, et al; forthe Italian Multiple Myeloma Network,GIMEMA. Oral melphalan and prednisonechemotherapy plus thalidomide compared withmelphalan and prednisone alone in elderly

patients with multiple myeloma: randomisedcontrolled trial. Lancet. 2006;367:825-831.

13. Palumbo A, Bringhen S, Liberati AM, et al.Oral melphalan, prednisone, and thalidomidein elderly patients with multiple myeloma:updated results of a randomized controlled trial.Blood. 2008;112:3107-3114.

14. Facon T, Mary JY, Hulin C, et al; for theIntergroupe Francophone du Myélome.Melphalan and prednisone plus thalidomideversus melphalan and prednisone alone orreduced-intensity autologous stem cell trans-plantation in elderly patients with multiplemyeloma (IFM 99-06): a randomised trial.Lancet. 2007;370:1209-1218.

15. San Miguel JF, Schlag R, Khuageva NK, et al;for the VISTA Trial Investigators. Bortezomibplus melphalan and prednisone for initial treat-ment of multiple myeloma. N Engl J Med.2008;359:906-917.

16. Mateos M-V, Richardson PG, Schlag R, et al.Bortezomib plus melphalan and prednisonecompared with melphalan and prednisone inpreviously untreated multiple myeloma: updat-ed follow-up and impact of subsequent therapyin the phase III VISTA trial. J Clin Oncol.2010;28:2259-2266.

17. Zonder JA, Crowley J, Hussein MA, et al.Superiority of lenalidomide (len) plus high-dose dexamethasone (HD) compared to HDalone as treatment of newly-diagnosed multiplemyeloma (NDMM): results of the randomized,double-blinded, placebo-controlled SWOGtrial S0232. Blood (ASH Annual MeetingAbstracts). 2007;110:Abstract 77.

18. Rajkumar SV, Jacobus S, Callander N, et al.

Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide pluslow-dose dexamethasone in newly diagnosedmyeloma (E4A03), a trial coordinated by theEastern Cooperative Oncology Group: analysisof response, survival, and outcome. J ClinOncol. 2008;26(May 20 suppl):Abstract 8504.

19. Harousseau JL, Mathiot C, Attal M, et al.Velcade/dexamethasone (Vel/D) versus VAD asinduction treatment prior to autologous stemcell transplantation (ASCT) in newly diag-nosed multiple myeloma (MM): updated resultsof the IFM 2005/01 trial. Blood (ASH AnnualMeeting Abstracts). 2007;110:Abstract 450.

20. Cavo M, Tacchetti P, Patriarca F, et al. Superiorcomplete response rate and progression-freesurvival after autologous transplantation withup-front Velcade-thalidomide-dexamethasonecompared with thalidomide-dexamethasone innewly diagnosed multiple myeloma. Blood(ASH Annual Meeting Abstracts). 2008;112:Abstract 158.

21. Sonneveld P, van der Holt B, Schmidt-WolfIGH, et al. First analysis of HOVON-65/GMMG-HD4 randomized phase III trial com-paring bortezomib, adriamycine, dexametha-sone (PAD) vs VAD as induction treatment priorto high dose melphalan (HDM) in patients withnewly diagnosed multiple myeloma (MM). Blood(ASH Annual Meeting Abstracts). 2008;112:Abstract 653.

22. Richardson PG, Sonneveld P, Schuster MW, et al;for the Assessment of Proteasome Inhibition forExtending Remissions (APEX) Investigators.Bortezomib or high-dose dexamethasone forrelapsed multiple myeloma. N Engl J Med.

2005;352:2487-2498.23. Orlowski RZ, Nagler A, Sonneveld P, et al.

Randomized phase III study of pegylated liposo-mal doxorubicin plus bortezomib compared withbortezomib alone in relapsed or refractory multi-ple myeloma: combination therapy improves timeto progression. J Clin Oncol. 2007;25:3892-3901.

24. Dimopoulos M, Spencer A, Attal M, et al; for theMultiple Myeloma (010) Study In vestigators.Lenalidomide plus dexamethasone for relapsed orrefractory multiple myeloma. N Engl J Med. 2007;357:2123-2132.

25. Weber DM, Chen C, Niesvizky R, et al; for theMultiple Myeloma (009) Study Investigators.Lenalidomide plus dexamethasone for relapsedmultiple myeloma in North America. N Engl JMed. 2007;357:2133-2142.

26. Kettle JK, Finnkbiner KL, Klenke SE, et al.Initial therapy in multiple myeloma: investigat-ing the new treatment paradigm. J Oncol PharmPract. 2009;15:131-141.

27. Mateos MV, Garcia-Sanz R, Colado E, et al.Should prophylactic granulocyte-colony stimulat-ing factor be used in multiple myeloma patientsdeveloping neutropenia under lenalidomide-based therapy? Br J Haematol. 2008;140:324-326.

28. Palumbo A, Rajkumar SV, Dimopoulos MA, etal; for the International Myeloma WorkingGroup. Prevention of thalidomide- andlenalidomide-associated thrombosis in myelo-ma. Leukemia. 2008;22:414-423.

29. Kyle RA, Yee GC, Somerfield MR, et al; for theAmerican Society of Clinical Oncology.American Society of Clinical Oncology 2007clinical practice guideline update on the role ofbisphosphonates in multiple myeloma. J ClinOncol. 2007;25:2464-2472.


Numerous chemotherapy regimenshave been found to be safe and effectivewithout dose modification in the elder-ly, which suggests that there is a similarrisk of CINV in this population as inyounger patients. Evaluating the risk of

CINV in the older adult requires con-sideration of comorbidities and poly -pharmacy, self-care capabilities, cost,and diminished renal and hepatic func-tion affecting drug metabolism andexcretion.13 Hypertension and cardio-vascular disease are common in the eld-erly, often requiring medications formanagement, thus increasing the riskfor drug–drug interactions. Carefulattention to agents that inhibit orinduce the CYP450 pathway or thosewith the potential for prolongation ofthe QT interval is necessary when con-sidering antiemetic regimens. Oralabsorption of drugs may be delayed bythe decreased intestinal motility com-mon in the elderly.13 The potential forimpaired vision, memory deficits, and

changes in dexterity in older patientsmay present problems for self-medica-tion. It may be more beneficial in thisinstance to administer long-acting IVmedication to ensure effective manage-ment of CINV.

Financial impactA retrospective analysis of 19,139

patients who received either HEC orMEC and at least one antiemetic agentevaluated the incidence and cost of out-patient and hospital visits associatedwith CINV-related ICD-9-CM diagnosiscodes.14 CINV prophylaxis included a 5-HT3 RA (85%), dexamethasone (76%),and an NK1 an tagonist (2%). Almost14% of the patients had a CINV-relatedvisit, most commonly associated withHEC and the majority occurring afterthe first 24 hours (delayed CINV). Thetreatment setting affected the costs:inpatient setting (64%, mean cost$7448), outpatient setting (26%, meancost $1494), and emergency department(10%, mean cost $918). Prevention

strategies that reduce CINV, particularlydelayed CINV, and allow effective out-patient management are critical toreducing the costs associated with CINV.

ConclusionCINV remains a common problem for

patients receiving chemotherapy de -spite the availability of newer an tiemet-ic agents and the establishment of treat-ment guidelines. Understanding thecomplex network of neurotransmitters,receptor sites, pathways, and patterns ofCINV is critical to developing effectivetreatment strategies. Con sideration ofthe unique needs of individual patientsbased on risk profiles, age, comorbidities,and medications is necessary to reducepotential toxicities. Evidence-basedmanagement of CINV can improvepatient outcomes, including cost andquality of life. !

References1. Hesketh PJ. Chemotherapy-induced nausea

and vomiting. N Engl J Med. 2008;358:2482-2494.

2. Kris M, Hesketh P, Somerfeld M, et al; for theAmerican Society of Clinical Oncology.American Society of Clinical Oncology guide-line for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24:2932-2947.

3. Jordan K, Sippel C, Schmoll HJ. Guidelines forantiemetic treatment of chemotherapy-inducednausea and vomiting: past, present and future rec-ommendations. Oncologist. 2007;12:1143-1150.

4. National Comprehensive Cancer Network.

Clinical Practice Guidelines in Oncology:Antiemesis. V.1.2010. www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. AccessedFebruary 19, 2010.

5. Herrstedt J. Antiemetics: an update and theMASCC guidelines applied in clinical practice.Nat Clin Pract Oncol. 2008;5:32-43.

6. Hawkins R, Grunberg S. Chemotherapy-induced nausea and vomiting: challenges andopportunities for improved patient outcomes.Clin J Oncol Nurs. 2009;13:54-64.

7. Billio A, Morello E, Clarke MJ. Serotoninreceptor antagonists for highly emetogenicchemotherapy in adults. Cochrane Database SystRev. 2010;(1):CD006272.

8. Sancuso (Granisetron Transdermal System)[package insert]. Bedminster, NJ: ProStrakanInc; 2008.

9. Blower P, deWit R, Goodin S, Aapro M. Drug-drug interactions in oncology: why are theyimportant and can they be minimized? Crit RevOncol Hematol. 2005;55:117-142.

10. Higa GM, Auber M, Altaha R, et al.Concordance between substance P levels andantiemetic guidelines. J Support Oncol. 2009;7:138-142.

11. Trigg ME, Higa GM. Chemotherapy-inducednausea and vomiting: anti-emetic trials thatimpact clinical practice. J Oncol Pharm Practice.January 19, 2010. Epub ahead of print.

12. Cancer Facts and Figures, 2009. American CancerSociety. www.cancer.org/downloads/ STT/500809web.pdf. Accessed February 19, 2010.

13. Jakobsen JN, Herrstedt J. Prevention ofchemotherapy-induced nausea and vomiting inelderly cancer patients. Crit Rev Oncol Hematol.2009;71:214-221.

14. Burke T, Wisniewski T, Ernst F. Resource uti-lization and costs associated with chemothera-py-induced nausea and vomiting (CINV) fol-lowing highly or moderately emetogenicchemotherapy administered in the US outpa-tient hospital setting. Support Care Cancer.January 26, 2010. Epub ahead of print.

SUPPORTIVE CARE

Chemotherapy-induced Nausea and Vomiting: Clinical Updates Continued from page 45

Prevention strategies that reduce CINV, particularlydelayed CINV, and allow effective outpatientmanagement are critical to reducing the costsassociated with CINV.


16. Zevalin [package insert]. Irvine, CA: SpectrumPharmaceuticals, Inc; 2009.

17. Osterborg A, Kipps TJ, Mayer J, et al.Ofatumumab (HuMax-CD20), a novel CD20monoclonal antibody, is an active treatmentfor patients with CLL refractory to both flu-darabine and alemtuzumab or bulky fludara-bine-refractory disease: results from thePlanned Interim Analysis of An InternationalPivotal Trial. Blood (ASH Annual MeetingAbstracts). 2008;112:Abstract 328.

18. Vectibix [package insert]. Thousand Oaks,CA: Amgen Inc; 2008.

19. Rituxan [package insert]. South San Francisco,CA: Biogen Idec Inc. and Genentech Inc; 2010.

20. Bexxar [package insert]. Research Triangle Park,NC: GlaxoSmithKline; 2005.

21. Herceptin [package insert]. South SanFrancisco, CA: Genetech Inc; 2009.

22. Olsen E, Duvic M, Frankel A, et al. Pivotalphase III trial of two dose levels of denileukindiftitox for the treatment of cutaneous T-celllymphoma. J Clin Oncol. 2001;19:376-388.

23. Foss FM, Bacha P, Osann KE, et al. Biological cor-relates of acute hypersensitivity events withDAB(389)IL-2 (denileukin diftitox, ONTAK) incutaneous T-cell lymphoma: decreased frequencyand severity with steroid premedication. ClinLymphoma. 2001;1:298-302.

24. Alberts DS, Garcia DJ. Safety aspects of pegy-lated liposomal doxorubicin in patients withcancer. Drugs. 1997;54:30-35.

25. Yardley DA. Proactive management of adverseevents maintains the clinical benefit ofixabepilone. Oncologist. 2009;14:448-455.

26. Billett AL, Carls A, Gelber RD, Sallan SE.Allergic reactions to Erwinia asparaginase in chil-dren with acute lymphoblastic leukemia who hadprevious allergic reactions to Escherichia coliasparaginase. Cancer. 1992;70:201-206.

27. Kintzel PE. Prophylaxis for paclitaxel hypersen-sitivity reactions. Ann Pharmacother. 2001;35:1114-1117.

28. Eisenhauer EA, Vernmorken JB. The taxoids.Comparative clinical pharmacology and ther-apeutic potential. Drugs. 1998;55:5-30.

29. Engels FK, Mathot RA, Verweij J. Alternativedrug formulations of docetaxel: a review.Anticancer Drugs. 2007;18:95-103.

30. Van Gerpen R. Chemotherapy and biothera-py-induced hypersensitivity reactions. J InfusNurs. 2009;32:157-165.

31. Brandi G, Pantaleo MA, Galli C, et al.Hypersensitivity reactions related to oxali-platin (OHP). Br J Cancer. 2003;89:477-481.

32. Markman M, Kennedy A, Webster K, et al.Clinical features of hypersensitivity reactionsto carboplatin. J Clin Oncol. 1999;17:1141.

33. Chung CH, Mirakhu B, Chan E, et al.Cetuximab-induced anaphylaxis and IgE spe-cific for galactose--1,3-galactose. N Engl JMed. 2008;358:1109-1117.

34. Carney PH, Ollom CL. Infusion reactions trig-gered by monoclonal antibodies treating solidtumors. J Infus Nurs. 2008;31:74-83.

35. Chung CH. Managing premedications and therisk for reactions to infusional monoclonal anti-body therapy. Oncologist. 2008;13:725-732.

36. Winkler U, Jensen M, Manzke O, et al.Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and highlymphocyte counts after treatment with ananti-CD20 monoclonal antibody (rituximab,IDEC-C2B8). Blood. 1999;94:2217-2224.

37. Azmi SS, Sachdev J, Kronsih L, et al. Hyper -sensitivity to cetuximab: is there an associationwith race, region, or both? J Clin Oncol.2008;26(May 20 suppl):Abstract 14002.

38. Chan S, Winterbottom L, Gardner S. Re -sponse to dexamethasone in patients withfluid retention after docetaxel. Lancet. 1996;347:1486-1487.

39. Sampson HA, Munoz-Furlong A, CampbellRL, et al. Second symposium on the definitionand management of anaphylaxis: summaryreport—second National Institute of Allergyand Infectious Disease/Food Allergy and

Anaphylaxis Network symposium. J AllergyClin Immunol. 2006;117:391-397.

40. American Heart Association. Guidelines forcardiopulmonary resuscitation and emergencycardiovascular care. Part 10.6: anaphylaxis.Circulation. 2005;112:IV-143–IV-145.

41. Drain KL, Volcheck GW. Preventing andmanaging drug-induced anaphylaxis. Drug Saf.2001;24:843-853.

42. Hypersensitivity and anaphylaxis. In: PolovichM, White JM, Kelleher LO, eds. Chemotherapyand Biotherapy Guidelines: Recommendations forPractice. 2nd ed. Pittsburgh, PA: OncologyNursing Society; 2005:83-87.

43. Castells M. Rapid desensitization for hypersensi-tivity reactions to chemotherapy agents. CurrOpin Allergy Clin Immunol. 2006;6:271-277.

44. Castells MC, Tennant NM, Sloane DE, et al.Hypersensitivity reactions to chemotherapy: out-comes and safety of rapid desensitization in 413cases. J Allergy Clin Immunol. 2008;122:574-580.

45. Lee CW, Matulonis UA, Castells MC. Rapidinpatient/outpatient desensitization for chemo -therapy hypersensitivity: standard protocoleffective in 57 patients for 255 courses. GynecolOncol. 2005;99:393-399.



Supportive Care

adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting,and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicity As with all therapeutic proteins, ythere is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have beenidentified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged :pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk.However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Amongpatients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic LeukemiaAmong patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. Patients 70 years or older received lower dose intensity of fludarabine andscyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicyor mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided theRituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Revised 02/2010 (4851501)Jointly Marketed by:Biogen Idec Inc. 5200 Research Place San Diego, CA 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) isindicated for the treatment of patients with: Relapsed or refractory, low-grade orfollicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, afterfirst-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positiveNHL in combination with CHOP or other anthracycline-based chemotherapy regimens.Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patientswith previously untreated and previously treated CD20-positive CLL. Limitations of useRituxan is not recommended for use in patients with severe, active infections.WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe,including fatal, infusion reactions. Severe reactions typically occurred during the firstinfusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medicalmanagement (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusionreactions as needed. Depending on the severity of the infusion reaction and the requiredinterventions, temporarily or permanently discontinue Rituxan. Resume infusion at aminimum 50% reduction in rate after symptoms have resolved. Closely monitor thefollowing patients: those with pre-existing cardiac or pulmonary conditions, those whoexperienced prior cardiopulmonary adverse reactions, and those with high numbers ofcirculating malignant cells (!25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure,hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis,some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patientswith NHL. A high number of circulating malignant cells (!25,000/mm3) or high tumor burdenconfers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. Thesereactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoiddermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety ofreadministration of Rituxan to patients with severe mucocutaneous reactions has notbeen determined. [See Boxed Warning, Adverse Reactions.] Progressive MultifocalLeukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases.The majority of patients with hematologic malignancies diagnosed with PML receivedRituxan in combination with chemotherapy or as part of a hematopoietic stem celltransplant. The patients with autoimmune diseases had prior or concurrentimmunosuppressive therapy. Most cases of PML were diagnosed within 12 months oftheir last infusion of Rituxan. Consider the diagnosis of PML in any patient presentingwith new-onset neurologic manifestations. Evaluation of PML includes, but is not limitedto, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxanand consider discontinuation or reduction of any concomitant chemotherapy orimmunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitis wasapproximately 4 months after the initiation of Rituxan and approximately one month afterthe last dose. Screen patients at high risk of HBV infection before initiation of Rituxan.Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBVinfection for several months following Rituxan therapy. Discontinue Rituxan and anyconcomitant chemotherapy in patients who develop viral hepatitis, and instituteappropriate treatment including antiviral therapy. Insufficient data exist regarding thesafety of resuming Rituxan in patients who develop hepatitis subsequent to HBVreactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial,fungal, and new or reactivated viral infections can occur during and up to one yearfollowing the completion of Rituxan-based therapy. New or reactivated viral infectionsincluded cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. [See Adverse Reactions.] CardiovascularDiscontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxanadministration in patients with NHL. Renal toxicity has occurred in patients whoexperience tumor lysis syndrome and in patients with NHL administered concomitantcisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not anapproved treatment regimen. Monitor closely for signs of renal failure and discontinueRituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leadingto death, can occur in patients receiving Rituxan in combination with chemotherapy. Inpostmarketing reports, the mean time to documented gastrointestinal perforation was 6(range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation andinstitute appropriate treatment for complaints of abdominal pain. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines followingRituxan therapy has not been studied and vaccination with live virus vaccines is notrecommended. Laboratory Monitoring In patients with lymphoid malignancies, duringtreatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. s Progressive Multifocal Leukoen cephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].s

counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy,obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias. [See Adverse Reactions]. The duration of cytopeniasscaused by Rituxan can extend months beyond the treatment period. ADVERSEREACTIONS The most common adverse reactions of Rituxan (incidence !25%)observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of Rituxan (incidence !25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia. Clinical Trials Experience in Lymphoid MalignanciesBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1926). The population included 679 patients with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination withfludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, schills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxanwas administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL areceiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Reactions in !5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Previously Untreated Low-Grade NHL In Study 4,Lpatients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (!5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (!5%) in patients receiving Rituxan following CVP compared to patients who received no furthertherapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (!2%) in the Rituxan armcompared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCL In Studies 6 and 7, [L see Clinical Studies]s the following adverse reactions,regardless of severity, were reported more frequently (!5%) in patients age !60 yearsreceiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). CLL The data below reflectLexposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 9 or Study 10 [see Clinical Studies]. The age range was s30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Wholey 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic Systemy p y 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendagespp g 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory Systemp y y 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and NutritionalDisorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive Systemg y 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous Systemy 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal Systemy 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular Systemy 25 3Hypotension 10 1Hypertension 6 1


CLL8 TRIAL (N=817)

In relapsed/refractory* CLL2.1-year follow-up

In first-line CLL1.7-year follow-up

39.8 monthsR-FC

31.5 monthsFC

vs

REACH TRIAL (N=552)RITUXAN-NAIVE PATIENTS

26.7 monthsR-FC

21.7 monthsFC

vs

8.3month

improvementin median

PFS

5.0month

improvementin median

PFS

Indication RITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.RITUXAN is not recommended for use in patients with severe, active infections.

DRIVING BETTEROUTCOMESRITUXAN+FC improved median PFS in first-line and previously treated CLL1,2

In the CLL8 trial2

RITUXAN+FC more than doubled CR in first-line CLL compared with FC alone (36% vs 17%; p<0.0001)

In the REACH trial2

Patients who responded to RITUXAN+FC (n=167) maintained their responses for nearly 2 years longer (48 months vs 27 months; p=0.0294) than those treated with FC alone (n=134)

NOW IN THE TREATMENT OFCHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

BOXED WARNINGS and Additional Important Safety InformationRITUXAN therapy can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence !25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia. In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment.For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS.Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

* In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2

R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response.

Treatment considerationsThese trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1

©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved. 10021500 February 2010

References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc.


May 2010 Vol 3, No 3

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