march/april 2011,vol 4, no 2

For Payers, Purchasers, & Oncology P&T Committees

©2011 Green Hill Healthcare Communications, LLC

MARCH/APRIL 2011 www.TheOncologyPharmacist.com VOL 4, NO 2

COMPLIMENTARY CE . . . . . . . . . . . 22Maintenance Therapy for Non–SmallCell Lung Cancer, Part II

CONFERENCE NEWS . . . . . . . . . . . . 7Making Cancer Drugs Worth theCostAre You Talking to Patients AboutSmoking Cessation?

DRUG SHORTAGES . . . . . . . . . . . . 16A Growing Crisis in Oncology

NEWS IN REVIEW . . . . . . . . . . . . . . 20FDA Panel Recommends StricterProcess of Accelerated Approval

FDA Approves Ipilimumab forMelanoma

Medicare Plans to Cover Provenge

Variation in Prescribing InstructionsConfuses Patients

THE WHOLE PATIENT . . . . . . . . . . 28Cancer Treatment–Induced Diarrhea

Managing Comorbidities

I N S I D E

Clockwise from top left: Walter M. Sahijdak, MD; Philip J. Stella, MD; Lara Blair, RN; and Vita McCabe, MD; of the multidisciplinary lung clinic at St. Joseph Mercy Cancer Care Center.

St. Joseph Mercy Cancer Care CenterA Cancer Hospital in a Small Community Has Big PlansBy Dawn Lagrosa

Following a lung cancer diagnosis, patients typically embark on adizzying journey that takes them from one waiting room to anoth-er, as they follow their treatment plan from the medical oncologist

to the surgical oncologist to the radiation oncologist and back again.Coordinating these visits imposes yet another burden on the patientand often leads to delays in care. Six years ago, St. Joseph MercyCancer Care Center in Ypsilanti, Michigan, decided to simplify life fortheir patients by opening a multidisciplinary lung cancer clinic.

CANCER CENTER PROFILE

Continued on page 30

For more CE Opportunities and to take the posttest for

the CE article in this issue, visit

www.TheOncologyPharmacist.com

VISIT US

In a “Technical Issues” session at theHematology/Oncology Pharmacist As -sociation annual meeting, Bhavesh

Shah, RPh, BCOP, a clinical pharmacyspecialist in hematology/oncology withBoston Medical Center, in Mass -achusetts, discussed dose-rounding, rapidinfusion, and other strategies his centerhas adopted to reduce costs. Prior toestablishing measures your oncologypractice can implement to lower expens-es, you need to review your physicians’prescribing habits, identify causes of drug

waste at your facility, and look for outlaysin time or product that are not capturedin reimbursement channels.

Dose-RoundingA cost-saving measure that some inpa-

tient pharmacies have implemented isrounding the dose of certain biologicanticancer drugs to within 10% of theamount ordered. The purpose of dose-rounding strategies is threefold, saidShah: (1) to ensure the drug is measured

CONFERENCE NEWS

Cost-ContainmentStrategiesBy Christin Melton

CONFERENCE NEWS

Review of New OncologyDrugs at HOPABy Christin Melton

Continued on page 6

In a review of new drugs to hit the mar-ket, speaker Maribel Pereiras, PharmD,BCOP, BCPS, referred to 2010 as

“quite the year for prostate and breastcancer.” Pereiras, a clinical assistant professor at Ernest Mario School ofPharmacy, Rutgers University, and a clin-ical oncology pharmacist with Hacken -sack University Medical Center, NewJersey, reviewed newly approved anti-cancer agents sipuleucel-T (Provenge),

cabazitaxel (Jevtana), eribulin (Halaven),and denosumab (Xgeva) for pharmacistsattending the annual meeting of theHematology/Oncology Pharmacy As -sociation. She also discussed dabigatranetexilate (Pradaxa), an anticoagulantrecently approved to prevent stroke andembolism in patients with atrial fibrilla-tion, which she included because sheanticipates some oncologists using it off-

Continued on page 8

TOP_April 2011_v2_TOP 4/20/11 9:28 AM Page Cov1

Stephen F. Eckel, Pharm.D., M.H.A., BCPS

Melissa A. McDiarmid, MD, MPH, DABT

Kristie Howlett, RN, MS, CNS, AOCNS

National Safe Handling Awareness Day:

SAFE HANDLING BOOT CAMP

www.carmelpharmausa.com/aware5

Learning Objectives:At the completion of this activity, the participant will be able to:- Describe the evidence for the genotoxicity of anti-cancer chemotherapy in patients;- Relate the specific chromosomal targets that have been associated with various chemotherapy drug classes;- Discuss the sufficiency of current safe-handling policies in light of recent evidence of worker exposure;- Identify the concerns associated with handling hazardous medications;- Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications;- Review future research opportunities around hazardous medications;- List ONS guidelines for safe handling;- Describe nursing basics for safe handling;- Describe proper donning of personal protective equipment (PPE).

STAT Educational Services, a division of National Pharmacy Technician Association Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

This knowledge-based program has been accredited for 1.0 contact hours of continuing education for pharmacists, pharmacy technicians, nurses, and risk managers.

Activity Type: KnowledgeTarget Audience: Pharmacists, Pharmacy Technicians, Nurses, & Risk ManagersUniversal Activity Number (UAN): 0384-9999-11-002-C05-P 0384-9999-11-002-C05-T

The University of Nebraska Medical Center College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Provided under Iowa Provider #78. Provider approved by the California Board of Registered Nursing, Provider #13699.

SA S

B B OOT BO T AF E H AFE HA

BOOT CAMPSAFE HANDLING

BOOT CAMPSAFE HANDLING

anoitaN

e dnaHefSaSlla

erawAAwgnild

:yaDssene

ADM

TBA,.ssile MdimraiDcMAa

MtS e,HP, MDM

,.

CN SNCOOA,

,SNCr lwtsirK ttelwoHei

,, SMNR

plemrac.www

moc.asuamrah

5erawa/m

This knowledge-based program has been accredited for 1.0 contact hours of continuing education for pharmacists, pharmacy techni

dudeh ycamrahptacudETAATTTAS


i .noittaa

cunoitaNfonoisivida,secivrrveSlanoi


nInoitaicossAnaicinhceTTeycamrahPla


noitatiderccAehtybdetiderccasi,.cn

cians, nurses, and risk managers.

A


(noitacudEycamrahProflicnuoCn

cians, nurses, and risk managers.

gniunitnocforedivorpasa)EPCA

- Describe proper donning of personal protective equipment (PPE).

pecific chromo

- Describe nursing basics for safe handling;- List ONS guidelines for safe handling;- Review future research opportunities around hazardous medications;- Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications;- Identify the concerns associated with handling hazardous medications;

ficiency of c - Discuss the suf fficiency of current safe-handling policies in light of recent evidence of worker exposure;- Relate the sp - Describe the e evidence for At the comple tion of this actLearning Obj ectives:


osomal targets that have been assoc

- Describe nursing basics for safe handling;- List ONS guidelines for safe handling;- Review future research opportunities around hazardous medications;- Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications;- Identify the concerns associated with handling hazardous medications;

ficiency of current safe-handling policies in light of recent evidence of worker exposure; g

- Describe the evidence for the genotoxicity of anti-cancer chemotherapy in patients;, the participant will be able to:At the completion of this activity


ciated with various chemotherapy dr

- Review future research opportunities around hazardous medications;- Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications;- Identify the concerns associated with handling hazardous medications;

ficiency of current safe-handling policies in light of recent evidence of worker exposure; py

- Describe the evidence for the genotoxicity of anti-cancer chemotherapy in patients;

- Discuss pertinent aspects of the policy and procedure UNC Hospitals utilizes for handling hazardous medications;

ug classes;ficiency of current safe-handling policies in light of recent evidence of worker exposure;

g

Registered Nursing, Provider #13699.

0384-9999-1

Provided under Iowa Provider #78. Provider approved by the California Board of

American Nurses Credentialing CenterEducation is accredited as a provider of continuing nursing education by the The University of Nebraska Medical Center College of Nursing Continuing Nursing

Universal Audience:arget TTarget

Activity T

Registered Nursing, Provider #13699.

1-002-C05-T


s Commission on ’American Nurses Credentialing CenterEducation is accredited as a provider of continuing nursing education by the The University of Nebraska Medical Center College of Nursing Continuing Nursing

0384-9999-1 0384-9999-1Activity Number (UAN):Universal

T Pharmacists, Pharmacy Audience: Knowledgeype: T Type:


1-002-C05-P

Accreditation. s Commission on Education is accredited as a provider of continuing nursing education by the The University of Nebraska Medical Center College of Nursing Continuing Nursing

Managers 0384-9999-1

echnicians, Nurses, & Risk ManagersTTechnicians, Nurses, & Risk Managers


The University of Nebraska Medical Center College of Nursing Continuing Nursing

echnicians, Nurses, & Risk Managers

TOP_April 2011_v2_TOP 4/19/11 2:59 PM Page Cov2

March/aPril 2011 I VOl 4, NO 2 3www.TheOncologyPharmacist.com

Editorial Board

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 InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

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

David C.Gammon, BSPhOncologyPharmacist.net Warwick, RI

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, PharmDIndiana UniversityHospitalIndianapolis, IN

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

Burt 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

TOP_April 2011_v2_TOP 4/19/11 2:59 PM

PUBLISHING STAFF

Senior Vice President, Sales & MarketingPhilip [email protected]

PublisherJohn W. [email protected]

Editorial DirectorChristin [email protected]

Associate EditorDawn [email protected]

Quality Control DirectorBarbara Marino

Director, Client ServicesJoe [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

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2011 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

EDITORIAL CORRESPONDENCE should beaddressed to EDITORIAL DIRECTOR, The OncologyPharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp,NJ 08831. E-mail: [email protected]. YEARLYSUBSCRIPTION RATES: United States and posses-sions: individuals, $105.00; institutions, $135.00; singleissues, $17.00. Orders will be billed at individual rate untilproof of status is confirmed. Prices are subject to changewithout notice. Correspondence regarding permission toreprint all or part of any article published in this journalshould be addressed to REPRINT PERMISSIONSDEPARTMENT, Green Hill Healthcare Commun i -cations, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist® do not necessarily reflect those of theEditorial Board, the Editorial Director, or the Publisher.Publication of an advertisement or other product mentionin The 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 topersons or property arising out of or related to any use ofthe material contained in this periodical. The reader isadvised to check the appropriate medical literature and theproduct information currently provided by the manufac-turer of each drug to be administered to verify the dosage,the method and duration of administration, or contraindi-cations. It is the responsibility of the treating physician orother healthcare professional, relying on independent expe-rience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every efforthas been made to check generic and trade names, and toverify dosages. The ultimate responsibility, however, lieswith the prescribing physician. Please convey any errors tothe Editorial Director. BPA Worldwide membershipapplied for April 2011.

For Payers, Purchasers, & Oncology P&T Committees

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

™

241 Forsgate Drive, Suite 205C

Monroe Twp, NJ 08831

4 March/aPril 2011 I VOl 4, NO 2 www.TheOncologyPharmacist.com

New HOPA president MoeSchwartz, PharmD, BCOP,welcomed oncology phar-

macists to this year’s conference,where we had the chance to learnabout new therapies and new oncol-ogy pharmacy practice managementstrategies. Our roundup of new drugsand management strategies presentedshould provide a quick referenceguide for those of you looking toimplement what you learned.We also continue to publish the

latest research and evidence-basedpractical information to help you

provide care throughout the continuum of cancer. To thisend, we introduce The Whole Patient, a department that

will help you help your patients with all the things that leadto quality of life—be it lifestyle issues such as smoking cessa-tion, polypharmacy and comorbidities among the elderly orsupportive issues like treatment-induced diarrhea. Our feature highlights one of our biggest ongoing chal-

lenges—the oncology drug shortage—by illuminating ourinterconnectedness with our partners in care, various gov-ernment agencies and multiple drug manufacturers. In read-ing this article, I am reminded that we are all in this togeth-er and need to work as a team to solve problems and providethe best care to patients.I remind you to vote for one of our four finalists for the

T.O.P Pharmacist award. And as you read this issue, I hopeit provides you with information that helps you in your prac-tice, in your career, and in meeting the ever-changing chal-lenges of today’s healthcare environment. We look forwardto your feedback. �

Patrick Medina,PharmD, BCOPEditor-in-Chief

Vandetanib Approved for Medullary ThyroidCancerVandetanib (Zactima) received full approval from theUS Food and Drug Administration (FDA) for patientswith nonresectable or metastatic medullary thyroid can-cer (MTC). Vandetanib was initially approved under theFDA’s orphan drug program, becoming the first medicaltreatment for MTC.Approval was based on data from the phase 3 ZETA

trial comparing vandetanib with placebo. Vandetanibdid not improve overall survival (OS), but progression-free survival (PFS) for patients in this arm was signifi-cantly better compared with the placebo group (22.6 movs 16.4 mo, respectively; P < .0001), resulting in a 65%reduction in risk of disease progression. Commonadverse effects include diarrhea, rash, acne, nausea,hypertension, headache, fatigue, decreased appetite, andabdominal pain.Vandetanib’s label features a black-box warning about

the risks of treatment-related QT prolongation, torsadesde points, and sudden death, and notes that the drug’s19-day half-life could delay resolution of adverse reac-tions. To distribute vandetanib, prescribers and pharma-cies must be certified with AstraZeneca’s RiskEvaluation and Mitigation Strategies program.

ASCO Calls for EGFR Mutation Testing inSome Patients with Lung Cancer A provisional clinical opinion (PCO) by the AmericanSociety of Clinical Oncology (ASCO) recommends patientswith newly diagnosed advanced non–small cell lung cancer(NSCLC) be tested for an EGFR mutation prior to first-linetherapy with an EGFR tyrosine kinase inhibitor (TKI). Thedecision was made after 5 randomized, controlled trialsdemonstrated better PFS for patients with an EGFR muta-tion who took gefitinib (Iressa) or erlotinib (Tarceva). Nostudy has linked targeting EGFR TKI therapy to an activat-ing EGFR mutation with improvement in OS. Nearly 15%of patients with NSCLC have an activating EGFR mutation.Testing is available at most academic medical centers andsome community practices.The 5 trials reviewed compared standard platinum-

based chemotherapy with an EGFR TKI. The phase 3IPASS trial reported a median PFS of 9.5 months forEGFR-positive patients receiving gefitinib comparedwith 6.3 months for EGFR-positive patients given

chemotherapy. In EGFR-negative patients, gefitinib wasassociated with significantly worse PFS than chemother-apy, underscoring the need for testing prior to EGFR TKIuse. In second- and third-line studies of erlotinib, whichis more commonly available in the United States thangefitinib, EGFR-positive patients experienced longerPFS than EGFR-negative patients.The PCO notes that the FDA has not approved gefi-

tinib or erlotinib as a first-line treatment for advancedNSCLC, nor has the FDA given clearance to any EGFRmutation test. ASCO says results from fluorescence insitu hybridization and immunohistochemistry testing forEGFR are not sufficiently reliable to guide treatment.

Novartis Halts Trial of Nilotinib in GISTNovartis has discontinued a phase 3 trial assessingwhether its TKI nilotinib (Tasigna) might be a moreeffective first-line therapy than imatinib (Gleevec) inpatients with unresectable or metastatic gastrointestinalstromal tumors (GISTs). Nilotinib has shown better effi-cacy than imatinib in patients with newly diagnosedchronic myeloid leukemia and is approved for this indi-cation. Investigators were disappointed that nilotinibdid not similarly outperform imatinib in GIST.

Soy Foods Safe for Breast CancerSurvivorsIsoflavones from soy foods do not increase breast cancerrecurrence risks said researchers at the AmericanAssociation for Cancer Research annual meeting.Isoflavones have estrogen-like properties, promptingsome survivors to avoid soy foods. The study reviewedquestionnaires on the eating habits of 9515 women intrials of breast cancer survivors. At a median follow-upof 7.4 years, recurrence risk was 35% lower and overallmortality was reduced 17% in the 10% of women whoate the most soy foods. Investigators did not examine theeffects of isoflavones from soy supplementation.

Many Patients Still Smoke After LungCancer DiagnosisA study by the National Cancer Institute reports thatapproximately 1 in 5 patients with lung cancer continueto smoke after diagnosis. The authors say more needs tobe done to counsel these patients on how and why toquit smoking. �

News Notes

From the Editor

TOP_April 2011_v2_TOP 4/20/11 9:29 AM

TOP_April 2011_v2_TOP 4/19/11 3:00 PM

accurately; (2) to minimize drug waste;and (3) to maximize cost avoidance.He listed the 10 drugs most amenableto dose-rounding (Table).

“For any order that comes throughthe pharmacy, the pharmacist canround the dose to the nearest vile sizefor the concentration,” said Shah.There are exceptions, such as whenthe difference between the ordereddose and the nearest vile size exceeds10%. “That’s when we try to round itto the nearest concentration sizeavailable.”

A dose-rounding program is only aseffective as the level of adherence bypharmacy clinicians. A retrospectivestudy published in 2010 by Wingerand associates found that a 3-monthpilot program in 2005 to round dosesfor orders of 7 biologic anticanceragents would have produced a 42%reduction in drug wastage and $24,434in savings had there been 100% com-pliance with the program. Because 29of the 126 orders were not filledaccording to the dose-rounding pro- tocol, savings only amounted to$15,922. A dose-rounding programshould include measures for monitor-ing adherence.

Chemotherapy InfusionShah said changing how the facilityhandles chemotherapy infusion offersseveral opportunities for cost-contain-ment. He outlined Boston MedicalCenter measures enacted to save thou-sands of dollars annually.

Shift from Inpatient Administrationto Outpatient AdministrationEncourage your physicians to shift frominpatient chemotherapy administrationto outpatient chemotherapy administra-tion. Shah said Boston Medical Centerdid this after observing a marked increasein the number of inpatient chemothera-py sessions.

“We developed this because a lot ofchemotherapy was being administeredin the hospital, primarily due to con-venience, where we got reimbursed by DRGs [diagnostic-related groups]but not based on what the patient wasactually receiving,” Shah explained.Medicare allows only 1 DRG for inpa-tient claims, whereas outpatient claimscan use multiple ambulatory paymentclassifications (APCs). Chemotherapydrugs are not bundled under APCs,allowing higher reimbursement.

“Now, we always push our physiciansto do it on the day of or the day afterhospital release so we can capture thatcost,” he said. Shah said implementingthis program decreased orders for in-hospital chemotherapy administrationby 50%.

Test Rituximab Before InfusionAnother new policy at Boston Medicalis to administer a test dose of rituximabprior to infusion. Shah said 80% ofpatients on rituximab have a reaction totheir first infusion that leads to discon-tinuation and drug waste. In 2009, infu-sion reactions led to $50,000 in wastedrituximab.

Now a 100-mg dose is administered toall patients scheduled for rituximab infu-sion who have not received the drug for≥6 months. In fiscal year 2010, BostonMedical Center saved approximately$2000 per patient prescribed rituximab.

Follow Guidelines for PegfilgrastimWhen Shah and his colleagues wereseeking ways to reduce costs, they sawthat orders for pegfilgrastim had in -creased. Based on data from a study bySugarman and colleagues in the 2009issue of Breast Cancer Research andTreatment, they concluded it might besafe to delay administration of whiteblood cell growth factor support forpatients treated with paclitaxel and test-ed the theory in a small group of patients.

For 10 patients prescribed 4 cycles ofpaclitaxel (175 mg/m2 every 2 weeks),the center administered a single dose ofpegfilgrastim with the first dose of thesecond cycle of paclitaxel. All patientscompleted therapy without delay, withno neutropenic events or hospitaliza-tions observed. Shah speculated thatdelaying pefilgrastim led to less bonepain from paclitaxel-induced arthral-gia. It also produced $60,000 in savings.

Shah and his colleagues found pegfil-grastim was sometimes administered asprimary prophylaxis in situations incon-sistent with National Comp rehensiveCancer Center and American Society ofClinical Oncology guidelines. “There wasa lot of inappropriate utilization, inmetastatic prostate cancer, stage IV non–small cell lung cancer [NSCLC], andmetastatic colon cancer,” said Shah.They requested that physicians stop using

growth factor support when the intentwas not curative and they could use dosereductions or delays. Physicians werealso told to stop giving it to patientsreceiving chemotherapy with curativeintent and an associated incidence offebrile neutropenia <20%.

In requesting that physicians adhereto evidence-based guidelines for pegfil-grastim use, Shah said they requiredadministering it in the adjuvant settingfor patients with colorectal cancer andNSCLC, the neoadjuvant setting forpatients with solid tumors whose oper-ative procedure had curative intent,and for patients with a malignancyrelated to acquired immunodeficiencysyndrome (AIDS). Even with requiringpegfilgrastim use in these circum-

stances, Shah said they decreasedexpenditures for the drug by $250,000annually. This does not factor in cost-savings that might have occurred as aresult of ensuring that patients whoshould get the drug received it.

Rapid InfusionShah described himself as a fan of rapidinfusion where appropriate, but he notedthat no formal economic analysis hasever been presented on its cost-effective-ness. Agents to consider for rapid infu-sion are the monoclonal antibodies ri tuximab, bevacizumab, trastuzumab,cetuximab, and low-molecular-weight(LMW) iron dextran. “This can increaseyour resource utilization,” said Shah.

A 2007 study published in Blood bySehn and associates tested a 90-minuterituximab infusion in >1200 patients.They reported a 0% rate of grade 3/4toxicity related to the faster infusion.Other studies have found 30-minuteinfusions of trastuzumab (6 mg/kg) andbevacizumab (0.5 mg/kg/min) and 60-minute infusions of cetuximab (500mg/m2) and LMW iron dextran (1 g) tobe relatively safe. A higher rate ofadverse events was observed in patientsallergic to >2 drugs who received LMWiron dextran; several patients in thebevacizumab study who received 15mg/kg over 30 minutes experiencedhypersensitivity reactions. Shah cau-tioned that Dexferrum—another formof iron dextran—“shouldn’t be used in arapid fashion.”

“I think rapid infusions are great. Ittotally increases the volume for yourclinic and decreases the absentees, andyou can get your patients out faster.”Shah said it also increases satisfactionamong patients and nurses.

Cetuximab versus PanitumumabAt Boston Medical Center, Shah said itwas decided to switch from cetuximab tothe lower-cost panitumumab for colo -rectal cancer based on studies showing

little difference in overall response rate,progression-free survival, or overall sur-vival. Shah said although the cost per100 mg is higher for panitumumab thanfor cetuximab ($618.81 vs $367.83,respectively), cetuximab requires an 8-vial loading dose. A cost analysisfound that the cost for 4 weeks of pani-tumumab averaged $5953.70 comparedwith $8460.09 for cetuximab. In addi-tion, reimbursement from the Centersfor Medicare & Medicaid Services(CMS) was higher for panitumumabthan for cetuximab ($49.737/10 mg vs$87.326/10 mg). Other savings wererealized with panitumumab in reducedchair time, because it can be adminis-tered every 2 weeks, and in significantlyless expense to treat febrile neutropenia.

Handling WasteAny number of events can lead to drugwaste. “There was a technician who putour cetuximab into the freezer and thathad to be wasted,” said Shah. “Therewas a physician who decided not to treatthe patient after it was mixed.” He relat-ed an occasion when a nurse spiked thebag. “We also see a lot of single-dose vialwaste because you can’t round to thenearest vial size, like with oxaliplatin.”

Shah said Boston Medical Centertakes advantage of biooncology spoilageprograms offered by pharmaceuticalcompanies. “They’re not well known,and you have to actually call, but onceyou find the forms, it’s pretty easy,” hesaid. If the cause of the waste is not list-ed, most forms provide a space to add it.Shah said the companies evaluate therequests on a case-by-case basis.

“We had about $20,000 in waste thatwe saved last year using these programs.Fill out a form and they send you acheck for the drug that’s been wasted,”said Shah.

Adopting programs to minimizewaste allows you to request reimburse-ment from CMS for “discarded drug/biological remaining in a single-useproduct after administering what is rea-sonable and necessary for the patient’scondition,” per Pub. 100-04, Chapter17, Section 40 in the Medicare ClaimsProcessing Manual.

Shah said, “There’s a JW code thatmirrors the J code you’re billing for.” TheCMS policy requires documenting thecause of waste in the patient’s medicalrecord, and that is another policy BostonMedical Center has implemented toensure that those costs can be recovered.

The most important considerationwhen looking for ways to save costs ispatient safety. Shah recommendedensuring that all the changes youdecide to implement align with evi-dence-based national guidelines forcancer care. �

Conference News

6 March/aPril 2011 I VOl 4, NO 2 www.TheOncologyPharmacist.com

Table The Top 10 Anticancer AgentsAmenable to Dose-Rounding

Drug Rounding Amount

Infliximab Nearest 100 mg

Bevacizumab Nearest 100 mg

Rituximab Nearest 100 mg

Docetaxel Nearest 20 mg

Pemetrexed Nearest 100 mg

Cetuximab Nearest 100 mg

Oxaliplatin Nearest 5 mg or 50 mg

Gemcitabine Nearest 200 mg

Panitumumab Nearest 20 mg or 100 mg

Bendamustine Nearest 25 mg

Cost-Containment Strategies Continued from cover

TOP_April 2011_v2_TOP 4/20/11 9:29 AM


Conference News

As nations around the globe strug-gle to afford the growing cost ofcare for their citizens, more peo-

ple are asking, “How much is too much?”when it comes to cancer. Although theJohn G. Kuhn Keynote Lecture deliveredat the annual meeting of the Hematology/Oncology Pharmacy Association wastitled “The Cost of Cancer Therapy,”speaker Tito Fojo, MD, PhD, with themedical oncology branch of the NationalCancer Institute (NCI), says cost is notthe real issue. “If you frame the argumentin terms of cost, you’re going to lose it,”he told the audience of pharmacists. Fojosaid the real issues are “how effectivedrugs are and how toxic drugs are.”Fojo offered examples of drugs used in

clinical practice that he believes notonly fail to improve survival but actuallyharm patients, including cetuximab(Erbitux) in metastatic colorectal cancer(mCRC) and bevacizumab (Avastin) in breast cancer. He noted that contro-versy surrounds these examples and noteveryone shares his views—includingGiuseppe Giaccone, his supervisor at theNCI and a member of the AmericanSociety of Clinical Oncology (ASCO)panel responsible for adding the combi-nation of cetuximab and paclitaxel tothe ASCO guidelines for first-line therapyof mCRC. The examples Fojo cites are alsofound in the National ComprehensiveCancer Network (NCCN) treatmentguidelines. Even if one disagrees with Fojo’s con-

clusions, his review of the pivotal trialsused to support approval of cetuximab inmCRC and bevacizumab in breast can-cer underscores important considerationsfor stakeholders when deciding howanticancer drugs should be developed,evaluated, and used. “Our drug develop-ment, drug approval, and drug consump-tion strategies need better focus,” saidFojo, who lamented that despite thedecade that has elapsed since imatinib(Gleevec) ushered in the “targeted ther-apy revolution,” too many treatments arestill used indiscriminately in broadpatient populations. Fojo sees room for improvement at all

levels: academia, the pharmaceuticalindustry, government agencies like theUS Food and Drug Administration, andclinicians caring for patients with cancer.All are responsible for “our failure todeliver on the promise of personalizedmedicine.” The experience with cetuximab in

mCRC supports Fojo’s contention thatresearchers need to analyze drugsprospectively, identifying predictivemarkers before initiating trials. Fouryears after cetuximab’s 2004 approval,

investigators reported in the NewEngland Journal of Medicine that it wasineffective in patients with mutatedKRAS. In 2009 ASCO issued itsProvisional Clinical Opinion recom-mending KRAS testing before prescrib-ing cetuximab but called compliancewith the opinion voluntary.

Fojo said a prospective investigationmight have uncovered the KRAS issuebefore trials were initiated. Cetuximabinhibits epidermal growth factor receptor(EGFR), and Fojo said, “As early as1990, Bert Vogelstein at Hopkins hadreported that as many as 50% of colorec-tal patients harbored KRAS.” In 1998,KRAS was reported to be in the EGFRsignaling pathway. “Despite this, wewent ahead and conducted studies with-out looking at this prospectively.” Continued investigation into the

causes of poor response to cetuximabamong some patients with wild-typeKRAS will likely whittle the viablepatient population down even further.“Eventually, we’ll be able to identify the80% of patients that do not benefit andgive it only to the 20% who benefit sub-stantially, and a drug that was marginalto begin with will become highly effec-tive,” explained Fojo.Fojo said he is concerned that “in -

creasingly, therapies that demonstrate atbest marginal improvement are beingused in the treatment of cancer.” Withbreast cancer, we might even be goingbackwards he said, pointing to the con-troversy over bevacizumab. He empha-sized that his views did not representthose of the NCI or anyone else. Fojo faulted the decision to approve

bevacizumab based on data from theEastern Cooperative Oncology Group(ECOG) 2100 study, which suggestedadding it to paclitaxel significantly pro-longed progression-free survival (PFS)but not overall survival (OS). Althoughthe study showed nonsignificant im -provement in OS favoring bevacizumab,Fojo said, “Nonsignificant improvement

is no improvement.” He added that itwas unusual for a study to reflect majordiscordance between PFS and OS. Fojo and other researchers published a

report in Lancet Oncology last year thatreviewed major studies published since1996 with a statistically significant PFSor OS and found “tight correlationbetween the two.” He therefore believesECOG 2100 is an outlier.Even if bevacizumab does improve PFS,

in Fojo’s opinion, PFS on its own is not animportant end point. “Delaying symptomsis a worthwhile goal, but delaying PFS doesnot equal delaying symptoms,” he said.Studies need to focus more on whether

the regimens used are harming patients.Fojo noted that in ECOG 2100, patientstreated with bevacizumab experiencedmore than twice as many adverse events asthe control group. Given its failure toimprove OS and its cost, Fojo said the tox-icity is unacceptable, but he acknowledgedthat many breast cancer specialists dis-agree. The FLEX trial, investigating cetux-imab in mCRC, also found high rates ofserious grade 3 and 4 toxicities related tocetuximab, particularly skin reactions thatare sometimes disfiguring.

With the growing use of oral treat-ments, Fojo said it is important that stud-ies not overlook the grade 1 and 2 toxic-ities. “The scale was developed forchemotherapy, but when you are taking adrug every day for months on end, agrade 1 or 2 event can be very difficult.”While cost is relevant for drugs that

cause serious adverse effects but demon-strate minimal efficacy, Fojo said itcomes down to the notion that you donot harm patients for little improve-ment in survival. Various attempts tocombine therapies have hurt patientswithout helping them, and Fojo calledfor an end to this “incrementalapproach” to treatment.Finding better treatments requires

determining the settings in which thedrugs work best but also the ones in whichthey do not work. Fojo said this wouldrequire major journals to give greaterweight to negative studies, which areoften relegated to second- and third-tierjournals. It also requires expanding incen-tives for pharmaceutical companies totake a more personalized approach to drugdevelopment, where rewards are likely tobe less lucrative. �

Making Cancer Drugs Worth the Cost By Christin Melton

“Delaying symptoms is aworthwhile goal, butdelaying PFS does not equal delayingsymptoms.”

—Tito Fojo, MD, PhD

How Costly Is Cancer Care in theUnited States?

The National Cancer Institute set out to answer this question last year andpublished results of their investigation in the January 2011 issue of the

Journal of the National Cancer Institute. The study’s authors point to flaws in previ-ous cancer cost estimates, many of which did little more than take figures from15 years ago and adjust them for inflation. When one considers the major transformations in cancer care in just the past

decade, it is not hard to see why these earlier estimates are unreliable. Using theSurveillence, Epidemiology, and End Results database to obtain incidence ratesand Medicare records for medical expenses, Mariotto and colleagues estimatedthe following:

US Cancer Care Costs in 2010: $124.57 billion

Projected US Cancer Costs in 2020:$157.77 billion-$207 billion**Lowest figure assumes constant incidence, survival, and cost; highest figure assumes increase for greater use of targeted therapies.

Most expensive cancers in 2010 (in billions):Breast: $16.50 Colorectal: $14.14 Lymphoma: $12.14 Lung: $12.12 Prostate: $11.85

For men and women whose deaths were caused by cancer in 2010, costs werehighest in the first 12 months after diagnosis and the last 12 months of life acrossall malignancies. The greatest increase in cost from the first year to the last yearwas for melanoma. For example, a woman aged <65 years accumulated $6057 inmedical costs in the year of diagnosis and $85,175 in the final year of life.Source: Mariotto AB, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl CancerInst. 2011;103(2):117-128.

TOP_April 2011_v2_TOP 4/20/11 9:30 AM

www.TheOncologypharmacist.com8 March/april 2011 I VOl 4, NO 2

Conference News

label. Ipilimumab (Yervoy) had not yetbeen approved at the time of the meet-ing and was included in a discussion ofinvestigational drugs, which we willpresent in an upcoming issue.

Sipuleucel-T (Provenge)Sipuleucel-T is the first approved thera-peutic vaccine in oncology and is indi-cated for men with asymptomatic orminimally symptomatic castration-resis-tant prostate cancer (CRPC). The drugis an autologous cellular immune thera-py, manufactured for each individualpatient in a process that involves train-ing the patient’s T cells to attackprostate cancer cells. Approval wasbased on data from the randomizedIMPACT trial, which reported a 4.1-month improvement in overall survival(OS) for men treated with sipuleucel-Tcompared with those given placebo (25.8vs 21.7 mo, respectively; P = .032).

The process for treating patients withsipuleucel-T requires coordinationamong multiple individuals. To assistclinicians, Dendreon announced theON Call program. After a physicianorders the drug, Dendreon returns atreatment schedule. Once the patientconfirms availability for the proposeddates, Dendreon approves the order.

Sipuleucel-T is administered in three1-hour infusions spaced 2 weeks apart.For each cycle, the patient undergoesleukapheresis to procure antigen-pre-senting cells (APCs) from his immunesystem, which are shipped to aDendreon facility. The laboratory com-bines the APCs with prostatic acidphosphatase, found in 95% of prostatecancer cells, and granulocyte-macro -phage colony-stimulating factor. In 2 to3 days, the APC is considered active andshipped back to the institution foradministration at the designated time.

The drug arrives at the time of theappointment in a special insulated con-tainer within a cardboard box. Uponreceipt, the pharmacist can open thebox and remove the container to verifyproduct and patient information butPereiras said not to open the inside con-tainer until Dendreon has issued a CellProduct Disposition Form and thepatient has been prepped. Universal pre-cautions should be taken when handlingthe drug, which normally appears slight-ly pink and cloudy.

Pereiras said 70% of patients havemild infusion reactions, consisting ofchills, fatigue, fever, and pain. To miti-gate adverse effects, she recommendedgiving patients acetaminophen anddiphenhydramine ~30 minutes prior toinfusion. Most reactions occur within 1day of treatment and typically last nolonger than 2 days. If a patient reacts dur-ing the infusion, Pereiras said the treat-

ment can be stopped and resumed if thereaction is not serious. She said to “thinktwice” before using steroids. “There havebeen some serious events reported,including a cerebrovascular accident.”

Formal data are not available on pos-sible drug interactions with sipuleucel-T. Because it works by boosting theimmune system, Pereiras said, “Any -thing given to suppress the immunesystem could counteract that, likechemotherapy or corticosteroids.”

Due to the time-consuming andcomplicated manufacturing process,sipuleucel-T is currently available onlyat the 50 centers involved in the origi-nal clinical trials. No more than 2000patients were expected to receive sip-uleucel-T in 2010, but Pereiras saidDendreon plans to expand its manufac-turing capacity soon.

Cabazitaxel (Jevtana)In the summer of 2010, the FDAapproved cabazitaxel, a microtubuleinhibitor, for patients with metastaticCRPC that has progressed on or follow-ing treatment with a docetaxel-contain-ing regimen. “Cabazitaxel works to bindfree tubulin to promote their assemblyinto stable microtubules but theninhibits the disassembly, so [that] it ulti-mately freezes the cell within mitosis,”Pereiras explained. The patient receivesa 25-mg/m2 injection of cabazitaxelevery 3 weeks and takes 10 mg of oralprednisone daily throughout treatment.

In the phase 3 TROPIC study,patients randomly assigned to receive

cabazitaxel plus prednisone demonstrat-ed superior median OS, progression-freesurvival, and response compared withpatients given mitoxantrone and pred-nisone (Table 1). Although cabazitaxelis a taxane, Pereiras said it has low affin-ity for P-glycoprotein –mediated effluxpumps associated with multidrug resist-ance and might be a means of overcom-ing taxane resistance in some patients.

Cabazitaxel contains polysorbate 80and the diluent contains ~13% ethanol.As a result, severe hypersensitivity reac-tions are possible, and patients should bepremedicated with an antihistamine,corticosteroid, and a histamine-2 antag-onist approximately half an hour beforeadministration. The prescribing instruc-tions also recommend antiemetic pro-phylaxis as needed.

“It is really nice that we have some-thing efficacious, but from an adverseevent perspective, there really are somethings to be concerned about,” shewarned. In TROPIC, high rates of neu-tropenia, myelosuppression, and anemiawere observed in the cabazitaxel arm.

Gastrointestinal symptoms are com-mon, with ~6% of patients experiencingdiarrhea. Deaths have been reportedfrom severe treatment-related diarrhea,and doses should be reduced for anypatient with ≥grade 3 diarrhea. “This isan important counseling point topatients,” said Pereiras. “They need toknow to stay hydrated, use antidiar-rheals, and not go the whole weekendbefore contacting us.”

In TROPIC, nearly 30% of patients

treated with cabazitaxel suffered grade3/4 neutropenia and 7% developed neu-tropenic fevers, which might have beendose-related. Cabazitaxel is thereforecontraindicated in patients with neu-trophil counts ≤1500 cells/mm3. Pereirassaid it is important for clinicians to stayon top of monitoring blood counts dur-ing therapy. Patients aged ≥65 yearsappear more prone to neutropenia-relat-ed fevers and deaths, and some clini-cians recommend primary prophylaxiswith granulocyte colony-stimulatingfactor for any patient with an elevatedrisk of febrile neutropenia.

Some patients in TROPIC’s cabazi-taxel arm experienced neurotoxicities orsuffered cardiac-related events. A clini-cal trial is under way to investigate theeffect of cabazitaxel on QTc intervals.

Cabazitaxel is extensively metabo-lized by the liver via CYP 3A4/5 and, toa lesser extent, CYP 2C8. CYP 3Ainhibitors or inducers might affect areaunder the curve concentrations and areto be avoided. A phase 1 trial is evaluat-ing cabazitaxel in patients with hepaticimpairment. “Some dose-adjustmentmay be needed in patients with hepaticdysfunction,” Pereiras cautioned. Ex -cretion via the renal pathway is mini-mal, but because no data are availableon patients with creatinine clearance<30 mL/min, she said patients withrenal dysfunction should be monitored.

A 2-step dilution process is used forcabazitaxel. Pereiras cautioned that inpreparing the drug, it is essential to use apolyvinyl chloride–free bag and an in-line filter.

Eribulin Mesylate (Halaven)Eribulin is from a novel class of agentscalled halichondrins. “It is approved formetastatic breast cancer, specifically inthose patients that have already had atleast 2 chemotherapy regimens, whichshould have included an anthracyclineand a taxane,” said Pereiras.

Eribulin, a synthetic analogue of asea sponge chemical, is a nontaxane,microtubule dynamics inhibitor. “But

Review of New Oncology Drugs at HOPA Continued from cover

Table 1 Efficacy End Points for TROPIC

End Point Cabazitaxel Mitoxantrone P Value

Median OS, mo 15.1 12.7 <.0001

Median PFS, mo 2.8 1.4 <.0001

ORR, % 14.4 4.4 .0005

PSA response, % 39.2 17.8 .0002

ORR indicates overall response rate; OS, overall survival; PFS, progression-free survival;PSA, prostate-specific antigen.Source: de Bono J et al. Lancet. 2010;376(9747):1147-1154.

Table 2 Denosumab Efficacy Outcomes

mBC Solid Tumors/MM mCRPCDenosumab ZA Denosumab ZA Denosumab ZA

Patients, N 1026 1020 886 890 950 951

First On-Study SREPatients, n (%) 315 (30.7) 372 (36.5) 278 (31.4) 323 (36.3) 341 (35.9) 386 (40.6)

Median time to SRE, mo NR 26.4 20.5 16.3 20.7 17.1

First and Subsequent SREMean No./Patient 0.46 0.60 0.44 0.49 0.52 0.61mBC indicates metastatic breast cancer; mCRPC, metastatic castration-resistant prostate cancer; MM, multiple myeloma; NR, none reported;SRE, skeletal-related event; ZA, zoledronic acid.Sources: Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139; Fizazi K, et al. Lancet. 2011;377:813-822; Henry DH, et al. J Clin Oncol. 2011;29:1125-1132.

TOP_April 2011_v2_TOP 4/20/11 9:31 AM

when you get down to the basics, it’sjust like any other taxane—it works onthe microtubules,” she said. Unlike tra-ditional microtubule inhibitors thathalt cell division by stabilizing themicrotubules, eribulin achieves cellcycle arrest by preventing microtubulegrowth without affecting microtubuleshortening.In the EMBRACE study, a phase 3

randomized trial that compared eribulinwith the physician’s choice of chemo -therapy, OS was significantly improvedfor women who received eribulin (13.1 vs10.6 mo, respectively; P = .041). MedianPFS and the overall response rate werealso better for the eribulin arm, butwomen taking eribulin had a shorterduration of response. The recommended dose for eribulin is

1.4 mg/m2 administered via intravenouspush over 2 to 5 minutes on days 1 and 8of a 21-day cycle. No premedications arerequired. “It can be given as straight drugor can be further diluted in normal saline.It is not compatible with dextrose,” sheemphasized. Eribulin is minimally metabolized by

CYP enzymes. “[There is] some inhibitoreffect on CYP 3A4 and on P-glycopro-tein, but this is thought to be minimal,”she said. No formal studies have evalu-ated eribulin in patients with renal dys-function, but one pharmacokineticstudy looked at patients with mild tomoderate hepatic dysfunction. Pereirasdirected clinicians to the package insertfor specific recommendations on adjust-ing the eribulin dose for patients withhepatic or renal problems.At least one-quarter of patients in

EMBRACE experienced anemia, weak-ness/tiredness, alopecia, nausea, and con-stitution. Most (82%) patients developedneutropenia, with 4% experiencing grade3/4 febrile neutropenia. “Blood countsshould be closely monitored and doseadjustments should be made if a patientexperiences neutropenic fever or grade 4neutropenia,” said Pereiras. Eribulin extends the QT interval, and

she recommended monitoring in patientsat risk of cardiovascular events, especiallypatients with a wider QT interval at base-line. She also advised clinicians to checkmagnesium potassium levels and correctany deficiencies prior to therapy.Grade 3/4 peripheral neuropathy,

observed in several patients, was cited asthe most common reason for discontin-uation. For these patients, Pereiras sug-gested withholding eribulin and reintro-ducing once neuropathy falls to grade 2.

Denosumab (Xgeva)“Oncology is not just about thechemotherapy agents we work with dayin and day out. It’s also about supportivecare,” said Pereiras, as she moved on todenosumab, a drug recently ap proved toprevent skeletal-related events (SREs) in

patients with solid tumors and bonemetastases. It is marketed as Prolia totreat osteoporosis in postmenopausalwomen.Denosumab is a human monoclonal

antibody with affinity for the receptoractivator of nuclear factor kappa-β ligand(RANKL), a protein expressed by

osteoblasts that is critical to osteoclastformation. Denosumab binds to RANKL,interrupting osteoclast formation andthus preventing bone resorption. In 3 large, randomized trials, denosu -

mab was compared with zoledronic acid(ZA), a bisphosphonate commonly usedto prevent SREs. One trial enrolled 2046

patients with breast cancer; another,1901 men with prostate cancer; and thethird, 1776 patients with various solidtumors and multiple myeloma. In eachstudy, a smaller percentage of patients inthe denosumab arm experienced an on-study SRE, and denosumab delayed thetime to first on-site SRE (Table 2).


Conference News

ERBITUX Indications

Head and Neck Cancer� ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally

or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer� ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer

after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens

� Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS� Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately

3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions

� Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX

EGFR=epidermal growth factor receptor; RT=radiation therapy.

ERBITUX Increased Overall Survival in Both:

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

ERBITUX Indications

Head and Neck Cancer

EGFR-Expressing Recurrent Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure

as a Single Agent

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

in Combination With RT in Locoregionally Advanced Disease

TOP_April 2011_v2_TOP 4/19/11 3:00 PM

Xgeva is administered subcuta-neously at a 120-mg dose every 4weeks. Pereiras warned against con-fusing this with the dose for Prolia,which is 60 mg every 6 months.Obviously, Xgeva and Prolia shouldnot be administered concurrently

because they are the same drug. Xgevadoes not need to be reconstituted, andno dose adjustment is required forpatients with renal dysfunction.

“It is generally well tolerated, butthere are a few things to be aware of,”said Pereiras. “It can cause more elec-

trolyte disturbances than ZA, particu-larly with regard to calcium creatinineclearance <30 mL/min.” These patientsand those on dialysis were more likely todevelop severe hypocalcemia, and shesaid electrolytes should be monitored.For all patients, she recommended eval-

uating calcium levels and correcting, ifnecessary, before treatment, as well ashaving patients take calcium and vita-min D supplements.

Osteonecrosis of the jaw occurs in an estimated 2.2% of patients treatedwith denosumab. “It’s very important to


Conference News

ERBITUX (cetuximab) + RT vs RT alone(n=211) (n=213)

Median overall survival49.0 months vs 29.3 months HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate55% vs 45%P=0.05

Survival in Combination With RT (N=424)*1,2

RT=radiation therapy; HR=hazard ratio; CI=confi dence interval.* A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration

of locoregional control. Secondary endpoints included overall survival.1,2

Median follow-up=54 months.2

� Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN

� The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%)

� ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

� Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

19.7month

improvement

ERBITUX Signifi cantly IncreasedSCCHN

in Combination With RT in Locoregionally Advanced Disease

The most

The most

TOP_April 2011_v2_TOP 4/19/11 3:00 PM

counsel our patients on good oral hygieneand avoiding extensive dental procedureswhile on denosu mab,” Pereiras said.Other adverse events include dermatitis,eczema, rash, limb pain, cataracts, andhypercholesterolemia.

Pereiras said researchers are keen to

study whether denosumab has anti-cancer properties. She noted that dur-ing bone resorption, growth factorsbelieved to spur tumor growth arereleased, so preventing bone resorptionmight theoretically contribute to bet-ter outcomes. This is only a hypothe-

sis, however, and denosumab is onlyapproved to prevent bone loss.

Dabigatran Etexilate (Pradaxa)Dabigatran, an oral direct thrombininhibitor, is approved to prevent strokeand systemic embolism in pa tients with

nonvascular fibrillation. Pereiras said cli-nicians who treat cancer are increasinglylikely to en counter patients already tak-ing it. “It may get another indicationwhich would open it up to some of ouroncology patients,” she said.

In explaining its mechanism of


Conference News

T

The most f

E

L

6.14 months vs 4.57 monthsERBITUX + BSC BSC alone(n=287) (n=285) HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. † NCIC CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome measure of the trial was overall survival.1

� The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted

� Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC

� The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Median Overall Survival, All Patients (N=572)†1

34%improvement

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

Overall Survival in Both:EGFR-Expressing Recurrent mCRC after Irinotecan and Oxaliplatin Failure

as a Single Agent

TOP_April 2011_v2_TOP 4/19/11 3:00 PM


Conference News

action, Pereiras said, “We have anintrinsic pathway and an extrinsic path-way. Thrombin is affected by both path-ways and works to convert fibrinogen tofibrin, which results in and aids thrombusformation. Dabigatran inhibits thrombinand therefore thrombus formation.”

While the drug is not yet indicated toprevent deep-vein thrombosis (DVT) orpulmonary embolism (PE)—thrombo -embolic events common in patients withcancer—the RECOVER study conclud-ed that dabigatran (n = 1274) was non-inferior to warfarin (n = 1265) at pre-

venting recurrent DVT/PE. RECOVERenrolled patients aged ~55 years withgood renal function and found that,although dose adjustments were requiredfor patients with renal impairment, dabi-gatran had a good safety profile.

Adverse effects included bleeding

events and gastrointestinal effects, suchas dyspepsia and gastritis-like symptoms.Nearly 17% of patients in the dabigatranarm experienced a bleeding event, and1.5% of bleeding events were consideredlife-threatening. Only 5% of patients ineach arm had cancer, however, and

Important Safety Information Including Boxed WARNINGS

Infusion Reactions� Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in

clinical trials, with fatal outcome reported in less than 1 in 1000

— Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest

— Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions

� Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines

— Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions

— Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest� Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell

carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment

— Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks

— Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity� Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving

ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities� In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring,

paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients

— Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days

— Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae

— Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin� The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established

— Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck

— Two of 21 patients died, one as a result of pneumonia and one of an unknown cause

— Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

H

— M

— R

T

T

I

I

T

T

12/10

TOP_April 2011_v2_TOP 4/20/11 9:33 AM


Conference News

Pereiras said, “It’s going to be hard tosay if right now we can carry that infor-mation over to our oncology patients.” Dabigatran is not an inhibitor or

inducer of the CYP 450 enzyme systembut is a substrate of P-glycoprotein.Data suggest drug–drug interactions

with rifampin, ketoconazole, verap -amil, amiodarone, and clopidogrel.Pereiras noted that the package insertincludes special instructions for con-verting patients to and from warfarintherapy and to or from parenteral anti-coagulation.

“A very interesting tidbit that cameout a short time ago is that once a bot-tle is opened, it’s only good for 30 days,so make sure you use your blisterpacks,” said Pereiras. She said the man-ufacturer has not explained what hap-pens “between day 29 and day 30” and

expressed concern as to whether thedrug is slowly losing efficacy over the30-day period. �

Pereiras disclosed that she has received consultingfees from EUSA Pharma and fees for non–contin-uing education services from Sancusco.

— Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation o

— Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions

� Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite p

— Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their f

— Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment a

c

I

I

— A

— M

— S

T

— D

— T

— F

Electrolyte Depletion� Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe

(NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy

— Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy

— Replete electrolytes as necessary

Late Radiation Toxicities� The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation

therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone

and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing� In women of childbearing potential, appropriate contraceptive measures must be used during treatment

with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

� It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events� The most serious adverse reactions associated with ERBITUX across all studies were infusion

reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

� The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%)

� The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

©2010 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US10AB12704 12/10

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

TOP_April 2011_v2_TOP 4/19/11 3:01 PM

ERBITUX® (cetuximab)injection, for intravenous infusionBrief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGESquamous Cell Carcinoma of the Head and Neck (SCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressingmetastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a singleagent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who areintolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warningsand Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies(14.2) in Full Prescribing Information and Warnings and Precautions.]Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatmentbenefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is notrecommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) andClinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux,included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See BoxedWarning and Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes,including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis,cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88%of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17%of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of Erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin(100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and Electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Infusion reactions [See Boxed Warning and Warnings and Precautions.]• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]• Pulmonary toxicity [See Warnings and Precautions.]• Dermatologic toxicity [See Warnings and Precautions.]• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologictoxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm,angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions(range 1–11).

Table 1: Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally AdvancedSCCHN

Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

Body System Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of PatientsBody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4Skin/AppendagesAcneform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 Infusion reaction is defined as any event described at any time during the clinical study as “allergic

reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as“allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

3 Based on laboratory measurements, not on reported adverse events, the number of subjects with testedsamples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

4 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustularrash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%),esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARRESTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]


Conference News

At the annual meeting of theHematology/Oncology Pharm -acy As sociation, Jane Pruemer,

PharmD, BCOP, FASHP, professor ofclinical pharmacy practice at theUniversity of Cincinnati’s James L.Winkle College of Pharmacy in Ohio,

said clinicians have an obligation toencourage patients with cancer whosmoke to give up the habit. “It is incon-sistent to provide healthcare and, at thesame time, remain silent about a majorhealth risk,” she said. Studies show inter-vention from a clinician nearly doubles

the chances of a patient succeeding anattempt to quit smoking compared withpharmacologic interventions alone orself-help materials. Although medical oncologists often

tell smokers they should quit, Pruemersaid they do not always explain why.

“Patients may think, ‘I’ve already gotcancer, what’s the reason to quit?’” Shesaid, smoking and nicotine exposuredecrease the effectiveness of certain anti-cancer therapies, tobacco use impairswound healing after surgery and increas-es the risk of infection, and smoking is

Are You Talking to Patients About Smoking Cessation?By Christin Melton

TOP_April 2011_v2_TOP 4/19/11 3:01 PM

associated with greater epithelial damagein irradiated tissue and a higher inci-dence of mucositis. Perhaps the mostimportant reason to quit is that patientswho continue smoking have a higher riskof second cancers, shorter survival, andworse quality of life.

The first step is finding out howmuch the patient smokes. “Do youknow that 1 in 6 smokers really doesn’ttell the truth about how much they

smoke?” Pruemer asked. Health careproviders need to be understandingwhen patients seem reluctant to discusstheir tobacco use. “And if you don’thave a [tobacco cessation] program,refer them to one you know about.They are out there.”

A successful program addresses thephysiological and behavioral aspects ofdependence.

People highly dependent on ciga-

rettes find it harder to quit. Thisincludes someone who smokes >1 packa day or who lights up within 30 min-utes of waking. People with psychiatricdisorders or a history of chemicaldependency also struggle.

Another component of behavioralmodification is identifying smoking trig-gers. “Make sure they understand the dif-ference between a physical craving andhabit.” Pruemer recommended working

with the patient to establish goals, such asrelieving withdrawal symptoms, control-ling urges, and abstinence. Pharm a -cologic options are essentially equal ineffectiveness. Nicotine replacement ther-apy (NRT) comes in various forms and isa popular option, but it should be usedwith caution in patients with underlyingcardiovascular disease. Pruemer said thestandard dose is equivalent to 1 pack ofnicotine and might not work for heaviersmokers. Although researchers have notfound an increase in adverse effects whenusing the dose equivalent of 2 patches,Pruemer said, “I would not do this unlesspatients are under the guidance of aphysician that you’re working with.”

Prescription options consist of bupro-pion SR (Zyban) and varenicline.“Bupropion works by increasing the cen-tral nervous system levels of dopamine,which makes patients feel better.” Thedrug is started 1 week prior to the sched-uled quit date. Patients take 150 mg oncedaily for 3 days and then increase totwice-daily dosing for the remaining 7 to10 weeks of therapy. The drug increasesthe risk of seizures, and Pruemer advisedextreme caution for patients with a histo-ry of brain surgery or trauma, patients tak-ing medications that increase seizure risk,and patients with severe cirrhosis.Bupropion is contraindicated in patientswith bulimia, anorexia nervosa, or seizuredisorders, and in those who are abruptlyquitting alcohol or sedatives.

Varenicline binds to nicotine recep-tors, blocking the usual dopaminergicboost patients get from smoking. It alsohelps alleviate withdrawal symptoms.As with bupropion, patients shouldstart the drug 1 week prior to their quitdate; it should be taken with food. Thedose is titrated to 1 mg twice daily bythe start of the second week. This dos-ing is continued for 10 weeks. Pruemercautioned that varenicline increasesthe risk of depression.

Patients unable to quit on a single-agent option might be candidates fortherapy that combines NRT agents oruses an NRT agent with bupropion.Varenicline should not be used as part ofa combination regimen. Another optionis to continue on pharmacologic therapybeyond the standard treatment period.

During the question and answer ses-sion, Pruemer was asked whether pa tientswith rapidly progressive disease or in pal-liative care should quit. “Even thosepatients are going to have a higher risk ofpneumonia and more complications atthe end of life, and their quality of life isgoing to be poorer. There’s plenty of datathat still recommends they should bequitting,” she responded.

The benefits of smoking cessation areimmediate and long-term for patientswith cancer, and Pruemer said, “It can beone of the single most effective strategiesto improve outcomes for our patients.” �

Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with AdvancedColorectal Carcinoma1 Treated with Erbitux Monotherapy

Erbitux plus BSC BSC alone(n=288) (n=274)

Body System Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0Body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <1

1 Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.2 Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest

tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus,sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusion-related.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneformrash (14%).

ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may beinfluenced by several factors including assay methodology, sample handling, timing of sample collection,concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reaction has been identified during post-approval use of Erbitux. Because this reactionwas reported from a population of uncertain size, it was not always possible to reliably estimate its frequency orestablish a causal relationship to drug exposure.

• Aseptic meningitis

DRUG INTERACTIONSA drug interaction study was performed in which Erbitux was administered in combination with irinotecan. Therewas no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose ofcetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).

Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted,based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information],nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics ofcetuximab have not been studied in pediatric populations.

Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OVERDOSAGEThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATIONAdvise patients:

• To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequatecontraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last doseof Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA

Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA

Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A7 ER-B0001A-09-10 Rev September 2010


Conference News

TOP_April 2011_v2_TOP 4/19/11 3:01 PM


Drug Shortages

Drug shortages continue to plaguethe United States, compromis-ing patient safety and placing

additional strain on healthcare re -sources. The shortages encompass com-mon drugs used to treat a range of con-ditions, from everyday infections toheart attacks. The problem has escalated in recent

years, with the number of drugsdeemed unavailable or scarce jumpingfrom 74 in 2005 to more than 240 in2010, according to the Drug Info r -mation Service (DIS) at the Uni -versity of Utah Hospitals & Clinics.DIS, which started tracking drug short-ages in January 2001, is among the firstgroups to recognize the problem. ErinFox, PharmD, manages DIS and said inan interview, “I believe the currentstate of shortages is a crisis for theUnited States.” The shortages have hit oncology

hard. “In so many cases there are nogood alternative agents, particularly forchemotherapy agents. We have seenover 20 different chemotherapy drugs inshort supply during 2010 and continu-ing into 2011,” Fox explained. Thenonprofit Institute for Safe MedicationPractices (ISMP) warns “there is littlerelief in sight.”

Providers See the Effects of Drug Shortages Local news reports from Alaska,California, Maryland, Pennsylvania,Texas, Tennessee, Virginia, and else-where show that hospitals in virtuallyevery state are struggling to managethe growing list of hard-to-get drugs.A hospital administrator in Tennesseetold her local paper that drug short-ages were “the new norm.” Small hos-pitals feel the burden more than largehospitals, which can use their pur-chasing power to stockpile drugs onthe shortage list. Many hospitals innetworks manage shortages by shiftingsupplies to whichever sister facilityneeds them. In 2010, ISMP surveyed 1800 phar-

macists, physicians, nurses, and health-care administrators at hospitals andlong-term care facilities and found thatnearly all had been affected by drugshortages. More than 80% complainedthat they were never warned of a loom-ing drug shortage nor told how long itmight last, and 82% said it requiredconsiderable resources to come up witha management plan. Shortages havealso affected providers on a personallevel, with 55% of physicians surveyedsaying they felt anger toward otherstaff or the hospital when a drug wasnot available.

Three-quarters of respondents toldISMP that drug shortages had costtheir facility money. This correspondswith results of a survey by Premier, Inc,an alliance of 200 hospitals and healthsystems in the United States. From Julyto December 2010, Premier questioned311 pharmacy experts about the effectof drug shortages on their practice. Atleast 98% acknowledged substituting amore expensive drug 1 or more times,and 40% said they had done so morethan 21 times. Premier estimates oncology providers

shelled out an additional $10.5 millionin 2010 for the generic equivalents ofdrugs on the shortage list. Not everydrug in short supply has a generic equiv-alent, and Premier says using the besttherapeutic alternative increases treat-ment costs an average of 11%. Acrossall areas of care, hospitals paid an extra$200 million in 2010 for therapeuticsubstitutions.

More than Dollars and CentsThe highest costs of drug shortageshave been borne by patients. Health -care providers have only a few optionswhen they are unable to give thepatient the drug he or she needs: theycan substitute an equivalent or near-equivalent agent, give nothing, ordelay treatment until the drugbecomes available. All these optionscould lead to worse outcomes.Respondents to the ISMP survey

reported “more than 1000 near misses,errors, and adverse outcomes” attrib-utable to drug shortages. Some errorsled to a patient’s death. At one facili-ty, hydromorphone was substituted formorphine, which was not availabledue to shortages. The provider admin-istered the hydromorphone at thedose originally indicated for the mor-phine prescription, leading to thedeaths of 2 patients and nonfataloverdose in another. Whenever a drughas been substituted for another, it isessential to ensure that the new drugis correctly dosed or that the correctinfusion rate is used.Other dosing errors occur when the

only way the hospital can get the drugis by ordering a different concentra-tion. For example, when preloadedsyringes of epinephrine were difficultto get, some hospitals ordered thedrug in vials. Because epinephrine istypically used in emergencies, thenurse is pressured to draw the dosefrom the vial quickly, increasing therisk of delivering an underdose oroverdose.Institutions might try to conserve

supplies of a hard-to-get drug by using

smaller doses. ISMP said attempts toconserve propofol by cutting the doseat some hospitals led to inadequatesedation or anesthesia awareness.Some hospitals are shortening theduration of therapy when prescribingmedications in short supply. Forpatients with cancer, both approachescould lead to worse outcomes. Substituting one drug for another

compromises outcomes if the replace-ment drug proves to be less effectiveor less tolerable. Not every drug has a suitable replacement, such asamikacin and acyclovir. As BethFaiman, RN, MSN, APRN, BC,AOCN, a nurse practitioner at theCleveland Clinic Taussig Cancer

Institute in Ohio and editor-in-chiefof The Oncology Nurse-APN/PA,explained, “Last year, acyclovir wasvirtually unavailable for a fewmonths, which put our patients at riskto develop viral infections.”In addition to the detrimental phys-

ical effects of drug shortages onpatients with cancer, CatherineBishop, DNP, NP, AOCNP, doctor ofnursing practice and an oncology nursepractitioner at Virginia Cancer Care,Inc, pointed out that there are also psy-chological considerations. “Some ofthe issues patients face are the likeli-hood or need to discontinue a certainmedication, such as leucovorin oretoposide. For patients in the metasta-

Drug Shortages: A Growing Crisis in OncologyBy Christin Melton

Common Cancer Drugs in Short SupplyThe following is a list of drugs commonly used for patients with cancer thatthe American Society of Health-System Pharmacists (ASHP) classified asbeing in short supply in March. For some drugs, only certain doses or prepara-tions are unavailable. Most shortages are attributable to manufacturing delaysand/or increased demand. In some cases, the manufacturer discontinued thedrug or offered no explanation for the short supply. A couple (ie, capecitabine[Xeloda] tablets and dexamethasone sodium phosphate) have been voluntarilyrecalled because of contamination concerns. To alleviate the shortage ofcapecitabine, the US Food and Drug Administration has granted the manufac-turer permission to import the drug from the European Union. The ASHPWebsite provides suggestions for managing care when your facility does nothave one of the products listed below.

• Acyclovir injection

• Acyclovir capsules and tablets

• Amikacin injection

• Capecitabine tablets

• Carboplatin

• Cisplatin injection

• Cytarabine

• Dacarbazine powder for injection

• Daunorubicin hydrochloride

• Dexamethasone sodium phosphate

• Doxorubicin injection

• Etoposide injection

• Fentanyl injection

• Fludarabine injection

• Granisetron hydrochloride injection

• Idarubicin hydrochloride injection

• Leucovorin calcium injection

• Melphalan injection

• Morphine injection

• Vancomycin hydrochloride injection

• Vincristine injection

“Last year, acyclovir was virtuallyunavailable for a few months,which put our patients at risk todevelop viral infections.”

—Beth Faiman, RN, MSN,

APRN, BC, AOCN

TOP_April 2011_v2_TOP 4/19/11 3:01 PM

ALOXI® provides powerful CINV prevention that can’t be ignored.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc.© 2010 Eisai Inc.All rights reserved. Printed in USA. ALO000083C 08/10

STARTS STRONG. LASTS LONG.

IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults 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

of its components

include headache (9%) and constipation (5%)

Please see the brief summary of the Full Prescribing Information on the adjacent page.References: 1. 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. 2. 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. 3. Data on fi le. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

ALOXI is the only IV 5-HT3 receptor antagonist specifi cally approved for the prevention of both acute and delayed CINV Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

Lasts long against nausea following moderately emetogenic chemotherapy3

Powerful acute CINV prevention following highly emetogenic chemotherapy 4

Eisai offers: Contracting opportunities Reimbursement resources

TOP_April 2011_v2_TOP 4/19/11 3:01 PM


Drug Shortages

tic setting, this can produce a great dealof anxiety,” she said. Talking to patientsabout drug shortages is also tough onthe practitioner. “For any provider totell a patient that the drug that maybenefit them the most is not currentlyavailable is difficult and almost impos-sible to explain,” she said.

Why Are So Many Drugs in Short Supply?The drug shortage crisis has emergedfrom a confluence of factors. “Ourcountry depends on just a few genericmanufacturers to make the majorityof the critical drugs we need in ourhospitals and operating rooms each

day,” said Fox. A problem at one facil-ity or a de cision by one manufacturer toreduce production is ultimately felt atthe clinic.

The Pharmaceutical Research andManufacturers of America (PhRMA)released a statement on drug shortages inMarch, noting that “according to the

FDA [US Food and Drug Administra -tion] and other experts, drug shortagescan occur for any number of reasons.”PhRMA cited “natural disasters; shifts inclinical practices; wholesaler and phar-macy inventory practices; raw materialshortages; changes in hospital andpharmacy contractual relationshipswith suppliers and wholesalers that cancause fluctuations in the availability ofcertain products; adherence to FDA-mandated distribution protocols, whichcan impact patients’ timely access tomedicines; individual company deci-sions to discontinue specific medicines;and manufacturing challenges” as someof the causes of the country’s drugshortage problem.

In 2010, the FDA reported that 40%of drug shortages were caused by manu-facturing issues, which includes diffi-culty obtaining the drug’s raw materialsor containers and quality control issues.Another 20% of shortages occurredwhen the manufacturer decided to stopmaking the drug, often because it wasno longer profitable, and 20% resultedfrom production delays. Premier notesthat foreign companies provide nearly80% of the raw materials for drug man-ufacture in the United States. In 2010,concerns over the integrity of ingredi-ents from China led some drug compa-nies to look for a new supplier, disrupt-ing production for some drugs andlanding them on the shortage list.

At the Drug Shortages Summit con-vened in November 2010 by theAmerican Society of Health-SystemPharmacists (ASHP), the AmericanSociety of Anesthesiologists, theAmerican Society of Clinical On -cology, and the ISMP, participants rec-ognized that regulatory issues cancause shortages. As part of the 2006Unapproved Drugs Initiative, theFDA is requiring manufacturers ofdrugs approved prior to the adoptionof stricter drug regulations in 1938 toconduct trials and file a New DrugApplication for their generic product.Some drug companies balked at theexpense of complying with the initia-tive and instead elected to stop mak-ing the drug. A drugmaker must also

“Our country depends onjust a few genericmanufacturers to makethe majority of the criticaldrugs we need in ourhospitals and operatingrooms each day.”

—Erin F. Fox, PharmD

TOP_April 2011_v2_TOP 4/19/11 3:01 PM


Drug Shortages

file an application with the FDAwhen it wants to change suppliers foractive ingredients, and several havecomplained that the agency is slow toapprove these applications. Complexpackaging re quirements and demandsfor risk evaluation and mitigationstrategies for certain drugs have alsocontributed to delays.Premier outlines other potential caus-

es for drug shortages. When the econo-my was in recession, many companies inthe drug production chain scaled downthe quantity of supplies kept on hand.Any disruption in one company’s abili-ty to restock supplies has a ripple effecton the manufacturer’s ability to get thedrug to market.Some pharmacists complain that

“gray market distributors” are causingartificial drug shortages by buying largequantities of important, inexpensivedrugs and reselling them at greatlyinflated prices once the drugs are diffi-cult to obtain. This is a bit like when aticket outlet purchases all the premiumtickets for a major rock concert or pop-ular Broadway show and offers them ata high markup once the show has soldout. Providers who stockpile drugs forfear that they might become hard to getalso contribute to artificial shortages.Temporary shortages occur when onedrug is discontinued, everyone switchesto the same alternative, and the manu-facturer cannot keep up with supply.

Is Anything Being Done?Fox expressed optimism about a fewrecent developments reguarding thedrug shortage. “I am hopeful the prob-lem may subside in part because 2 of thelargest generic companies with multipleshortages seem to be resolving theirmanufacturing problems,” she said. Ifthis happens, Fox said the number ofshortages might fall to 2009 levels,which she notes were still too high. Congressional legislators have intro-

duced US Senate Bill 296, thePreserving Access to Life-SavingsMedications Act. The bill requiresdrugmakers to notify the FDA at least6 months before stopping or delayingproduction for a drug. Many in themedical community support the bill.“There is widespread belief by many inthe medical community that thereneeds to be oversight and regulations,which should be strictly enforced, somanufacturers cannot just decide tostop the manufacturing of a drug with-out significant notice,” said Bishop.Bill 296 also requires the FDA to iden-tify drugs vulnerable to shortages andtake steps to ensure that the supply isnot interrupted.“The bill won’t solve all shortage

problems, but it is a great start,” said

Fox. She encouraged clinicians to con-tact their congressional officials andurge them to support the bill.Some patients are not waiting for leg-

islation to resolve the problem and havedecided to head to court. Genzyme,which has been plagued with problemsat its manufacturing facilities, has beennamed in a civil lawsuit by a group ofpatients with Fabry disease. Genzymemanufactures Fabrazyme, the primarydrug used to treat the genetic disor-der. In the past year, the companystarted rationing access to the drugand cutting dosages; the lawsuitclaims at least 3 patients have diedfrom this approach. Genzyme hadsimilar manufacturing problems withCerezyme, its drug for Gaucher dis-ease, but believes it will soon havethe situation corrected.As the Drug Shortages Summit

participants pointed out, the FDAcannot require a drug manufacturerto keep making a product. They saidCongress can and should, however,offer incentives to companies thatmanufacture life-saving generic medi -cations, such as tax breaks and ex -tended exclusivity rights.

Taking Steps to Protect PatientsFox listed a few steps hospitals can taketo minimize the effects of drug shortages

on their patients. “Phar macists candiscuss shortages with clinicians as farahead as possible.” She noted thatsometimes this is not possible, but “asmuch advance notice as possible canhelp when decisions about therapy arebeing made, particularly if anothertreatment choice is available and willwork well for the patient.”She recommended that clinicians

consider centralizing their supply ofmedications and tracking what theyneed based on their patient roster. “Thisstrategy is particularly helpful with

chemotherapy shortages,” Fox said.“Track out the needs of the patients andthen, if insufficient drug is available, thephysicians can decide the best action.”In some cases that might be not accept-ing a new patient, delaying treatment,or altering the treatment plan.ISMP recommends “establishing a

shortage network” with other health-

care providers. The organization alsosuggests adopting strategies to preventerrors when using substitutes and con-sulting the ethics committee about anydecisions to prioritize or place limits onmedications in short supply.Several online resources are avail-

able to identify ongoing and poten-tial shortages and ways to manage adrug shortage. Fox recommended vis-iting www.ashp.org/shortage, whichmaintains a list of current shortages,resolved shortages, and drugs no longeravailable. The site also contains severalresources on managing drug shortagesand encourages clinicians to report pos-sible shortages to ASHP.Because the vast majority of drugs in

short supply or no longer available areinjectables, nurses often have the finalopportunity to ensure that the substi-tute drug provided is being used at thecorrect dose. The ASHP Website offershelp with this, by highlighting the pos-sibility of confusion or dosing errorswith some substitute medications. Forexample, ASHP warns providers of the“potential for dosing errors when inter- changing leucovorin and levoleuco- vorin (Fusilev),” noting that the levo -leucovorin dose should be one-half theracemic leucovorin injection dose. Etoposide for injection is another

drug in short supply, and many hospi-tals are substituting oral etoposide. Theoral version has only half the bioavail-ability of the injectable. This meansthat the oral dose needs to be doublethat of the intravenous dose. As the ISMP study indicates, problems

have also occurred with epinephrine dos-ing. Miscalculations have been madewhen switching be tween the 1-mg/mLstrength of epinephrine and the 0.1-mg/mL dose. In addition, some hos-pitals are using the 1-mg/mL syringe thathas an intracardiac needle permanentlyaffixed. The ISMP warns providers notto attempt to remove this needle.To prevent errors due to confusion

about differences in dosing, activity,adverse effects, etc, between the intend-ed drug and its substitution, ASHP rec-ommends updating automated systemsand order-entry systems. Pharmacy staffshould also communicate with nursingstaff about alternative therapies and anyspecial considerations.Talking to patients or caregivers

about why you have to delay their sur-gery, interrupt their treatment, or can-not give them the most effective drugfor their disease is probably one of thegreatest difficulties providers face indealing with the shortages. It is also oneproblem for which the organizationsadvising hospitals on how to managedrug shortages have few suggestions. �

“Some of the issues patientsface are the likelihood or needto discontinue a certainmedication, such as leucovorinor etoposide. For patients in themetastatic setting, this canproduce a great deal of anxiety.”—Catherine Bishop, DNP, NP, AOCNP

175

150

125

100

75

50

25

02005

Year

Num

ber

2006 2007 2008 2009

Total drugshortages

Drug shortagesinvolving sterileinjectables

Figure. Drug shortages per year.

Clinicians should considercentralizing their supplyof medications andtracking what they needbased on their patientroster.

TOP_April 2011_v2_TOP 4/19/11 3:01 PM


News in Review

The US Food and Drug Ad min -istration (FDA) held a publicmeeting in February to assess

whether stricter criteria are needed whenconsidering oncology drugs for accelerat-ed approval. Measures enacted in 1992allow the FDA to grant acceleratedapproval for drugs targeted at unmetneeds in cancer based solely on data fromsingle-arm studies and relying on endpoints other than the standard metric ofoverall survival. At the meeting, expertswith the FDA’s Oncologic DrugsAdvisory Committee (ODAC) criticizedthe FDA, with Silvana Martino, DO,who directs the Breast Cancer Programat the Angeles Clinic and ResearchInstitute in Santa Monica, California,calling its actions “ignorant.”Gary Lyman, MD, MPH, professor of

medicine and director of comparativeeffectiveness and outcomes research atDuke University School of Medicineand the Duke Comprehensive CancerCenter in Durham, North Carolina, saton the ODAC panel and discussed thehearing with The Oncology Nurse-APN/PA. “The major concern of theODAC is that accelerated approval hasbeen granted on the basis of a single-armstudy in more than half of instances,

which limits a full comparative look atefficacy and safety,” he explained.Lyman said relying on such limited

evidence might be appropriate in excep-tional cases, such as for drugs to treat raretumors or when a drug has very strong,observable treatment effects, but “thedefault recommendation is that this con-ditional approval be based on at least onewell-designed randomized, controlledtrial [RCT] reporting significant im -provement in an outcome measurementlikely to convey clinically meaningfulbenefit.” In every case, approval shouldbe “based on the robustness of the resultsin terms of a strong treatment effect anda very favorable risk-to-benefit ratio,”said Lyman.On the rare occasions when acceler-

ated approval is granted without datafrom an RCT, Lyman said ODAC rec-ommends that the FDA require thedrug’s maker to have an RCT under wayor imminent. The FDA should reviewplans for the trial to ensure that its designallows for reliable results, suitable to sup-port licensing approval.The review of the accelerated

approval process was prompted by theFDA’s controversial decision inDecember to withdraw approval of

bevacizumab (Avastin) in breast cancer,which Lyman said was the first time theagency had rescinded an approved indi-cation of a drug brought to market underthis mechanism. “There are a number ofothers—including 6 that we reviewedyesterday—that have not fulfilled theirpostmarketing requirements and may bevulnerable,” he added. The drugs inquestion include Erbitux by Eli Lilly,Bexxar and Arranon by GlaxoSmith -Kline, Clolar by Genzyme, Vectibix byAmgen, and Gleevec by Novartis forits indication in gastrointestinal stro-mal tumors.At the meeting, the panel ques-

tioned manufacturers about their fail-ure to submit requisite follow-up datafor these 6 drugs, but the FDA gave noindication that their approval status isin jeopardy. Most of the manufacturerscited difficulty recruiting enoughpatients for clinical trials to producemeaningful results as the primary rea-son for the delays. Amgen’s representa-tive told the committee the companywas confident it had complied with theFDA requirements.Whereas most companies that

receive accelerated approval for a drugshow due diligence in complying with

follow-up requirements, Lyman said afew have taken a decade or longer to sub-mit the requested data. “The ODACmembers [believe] that plans for morefrequent updates—perhaps annually—ofstudies with outstanding validation orpostmarketing requirements would helpshorten the time interval to completionand consideration for full approval.”Members of the ODAC panel also

voiced concern that the FDA hadoccasionally granted full approval to acancer drug without requiring soliddata from an RCT. “The ODACbelieves that, with few exceptions,such approval should be based on atleast 2 well-done RCTs with consistentor robust results,” said Lyman.Lyman acknowledged that patients

with cancer and advocacy groups havecomplained in the past that strictstandards delay access to lifesavingmedications. “It will be importantthat no unnecessary delays occur,” hesaid. If drug companies are pushed tofulfill their postmarketing require-ments more promptly, Lyman said heexpects it to shorten the time to fullapproval and decrease how long anineffective or unsafe drug remains onthe market. �

FDA Panel Recommends Stricter Process forAccelerated Approval of Cancer DrugsBy Christin Melton

Patients with inoperable metastat-ic melanoma now have anothertreatment option as ipilimumab

becomes the second immunotherapydrug approved by the US Food andDrug Administration (FDA) for thetreatment of cancer. Fortunately forclinicians, ipilimumab also has a new,easier-to-pronounce name—Yervoy.Specifically, Yervoy is indicated forpatients with unresectable metastaticmelanoma that is newly diagnosed orprogresses despite prior therapy.Ipilimumab is a recombinant, human

monoclonal antibody. It works by in -hibiting cytotoxic T-lymphocyte anti -gen-4 (CTLA-4), a protein that isinvolved in downregulating T-cells, tokeep the immune system from attackinghealthy tissue. Ipilimumab blocksCTLA-4 so that the T-cells remainactive and the patient’s immune systemcontinues to fight the cancer as long ashe or she is receiving treatment.Data from a pivotal phase 3 trial of

ipilimumab, which were published in

the New England Journal of Medicine in2010, show that patients who receivedipilimumab alone or in combinationwith gp100 had better survival out-comes than patients treated only withgp100. Median overall survival forpatients in the ipilimumab trial armsreached 10 months compared with 6months for patients in the gp100monotherapy arm.The rate of 1-year survival was 46%

for patients treated with ipilimumab versus 25% for patients on gp100monotherapy. Investigators estimatedthe 2-year survival rate at 24% for theipilimumab group and 14% for thegp100 arm. Ipilimumab was associatedwith a 34% reduction in risk of death(hazard ratio, 0.66; P = .0026).The overall response rate (ORR)

was only 10.9% for patients receivingipilimumab, but this was significantlyhigher than the ORR seen in the com-bination arm and the gp100 monother-apy group (5.7% vs 1.5%, respective-ly). The authors reported that the

mean duration of response was 11.5months for the group that receivedipilimumab and gp100 combined buthad not been reached in the othergroups because >50% of patients whoexperienced complete or partial re -sponses had not relapsed.Approximately 10% of patients dis-

continued ipilimumab because of treat-ment-related adverse events. Amongpatients receiving ipilimumab alone, themost common adverse events (allgrades) were fatigue (41%), diarrhea(32%), pruritus (31%), rash (29%), andcolitis (8%). Some patients treatedwith ipilimumab did have severe orfatal immune-mediated adverse reac-tions, including enterocolitis (7%),endocrinopathy (4%), dermatitis(2%), hepatitis (1%), neuropathy(1%), nephritis (1%), and eosinophilia(1%). Some of these can be treated withcorticosteroids, according to researcherspracticing at one of the institutions thatconducted phase 3 ipilimumab trials. In a review article on the drug, pub-

lished in Seminars in Oncology in 2010,Boasberg and colleagues warn that“colonic perforation can occur” andcall for patients who develop diarrheato be monitored carefully, “with strictadherence to treatment algorithms.”The researchers note that if adverseeffects are caught promptly and man-aged properly, “Ipilimumab is anextremely safe drug to administer.”Bristol-Myers Squibb, which manu-

factures the drug, has worked with theFDA to develop a Risk Evaluation andMitigation Strategy (REMS) for ipili-mu mab to help clinicians manage orprevent the most serious treatment-related adverse events. The companyannounced that it has launched acopayment program to assist “eligible,commercially insured patients whohave been prescribed ipilimumab” inline with its approved indication. Information on ipilimumab and

the REMS program is available atwww.yervoy.com.—CM �

Ipilimumab (Yervoy) Is First Melanoma Drug Approved in a Decade

News in Review continues on page 29

TOP_April 2011_v2_TOP 4/20/11 9:35 AM

��

��

To use 2D barcodes, download the ScanLife app:• Text “scan” to 43588• Go to www.getscanlife.com

on your smartphone’s web browser, and select “Download”

• Visit the app store for your smartphone

Scan Here to Register.

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

Current activities atwww.COEXM.com include:

Pushing Your Limits

COEKsize2711CE©iStockphoto.com/altaykaya

� �� TOP_April 2011_v2_TOP 4/20/11 10:39 AM

Improving outcomes for patients withnon–small cell lung cancer (NSCLC)is particularly relevant because

NSCLC accounts for 85% of all cases oflung cancer.1 In the appropriate patientswith advanced NSCLC, maintenancetherapy may help control the disease andextend patients’ lives. Maintenance ther-apy is relatively new in NSCLC treat-ment, representing a change from thepast approach of retreatment upon dis-ease progression.2 Two chemotherapyagents previously approved by the US Food and Drug Administration(FDA) for the treatment of advancedNSCLC—pemetrexed and erlotinib—recently received FDA ap proval for anew indication for maintenance therapyof advanced NSCLC. Pemetrexed, a folate analog metabolic

inhibitor, was granted FDA approval formaintenance therapy of advanced ormetastatic lung cancer in July 2009.3This new indication for pemetrexed isspecifically for patients with nonsqua-mous NSCLC that has not progressedafter 4 cycles of platinum-based first-linechemotherapy.4 Pem etrex ed is also indi-cated as initial treatment in pa tientswith locally advanced or meta static non-squamous NSCLC, in combination withcisplatin, and after prior chemotherapyas a single agent.4Erlotinib, an endothelial growth factor

receptor (EGFR) tyrosine kinase inhib -

itor (TKI), received FDA approval inApril 2010 for an expanded indication asa maintenance treatment in patientswith locally advanced or metastaticNSCLC whose disease has not pro-gressed after 4 cycles of platinum-basedfirst-line chemotherapy.5,6 Erlotinib isalso indicated to treat locally advancedor metastatic NSCLC after failure of atleast 1 prior chemotherapy regimen.6Identifying the appropriate patients

as characterized by histology (nonsqua-mous) or molecular (EGFR mutation)profile is an important considerationwhen selecting the appropriate main-tenance therapy.7 Using predictive bio-markers to target specific agents formaintenance therapy may helpimprove benefits and reduce risks bytailoring a specific treatment to theappropriate patient.7 For example,pemetrexed is an option for mainte-nance therapy in patients with non-squamous histology.1,4 In addition, amolecular-based strategy may be usefulin selecting the appropriate patientsbest suited for maintenance therapywith erlotinib.7 Progression-free sur-vival (PFS) was significantly longer inpatients with EGFR-positive immuno-histochemistry who were treated witherlotinib as maintenance therapy com-

pared with EGFR-positive patientswho received placebo, based on a ran-domized, placebo-controlled study.8In addition to histology and genetic

markers, maintenance therapy deci-sions involve a number of other impor-tant considerations, including the latest clinical data, evidence-basedclinical practice guidelines, and thepatient’s performance status and per-sonal preferences. Although mainte-nance therapy may slow the growth ofdisease and extend life, the benefits oftreatment must be weighed against thepotential toxicities and other sideeffects associated with extended treat-ment. Costs and resource utilizationassociated with maintenance therapymust also be considered.

NSCLC: Burden and EconomicImpactLung cancer claims the lives of moreAmericans than any other type of can-cer.1 Moreover, lung cancer imposes asubstantial economic burden on ourhealthcare system. The estimated annu-al costs to the American public as wellas lost productivity costs associated withlung cancer were previously outlined inthe first part of this article.9Treatment costs associated with lung

cancer, as well as treatment failure costs,are also substantial. A retrospective,case-control cohort study that followedpatients for 2 years from the first diagno-sis of lung cancer showed that themonthly cost per patient was $11,496 forinitial treatment, $3733 per month forsecondary treatment, and $9399 for ter-minal care treatment.10 Failure of initialtreatment was associated with increasedcosts: patients who experienced treat-ment failure incurred an additional$10,370/month in initial treatmentphase costs and $8779/month after start-ing the secondary and/or terminal carephase of treatment.10 Moreover, treat-ment failure was associated with incre-mental costs of $19,149/month and$74,697 across the study period.10 Thestudy authors concluded that improve-ments in prevention or treatment of lungcancer, including new therapies or adju-vant chemotherapy, might reducehealthcare resource utilization and costs,and that strategies aimed at reducinghospitalizations and preventing or delay-ing treatment failure may offset the asso-ciated cost burden.10More than 68% of all patients diag-

nosed with lung cancer are 65 years ofage or older.11 The burden and cost ofNSCLC may continue to grow as the


CONTINUING EDUCATION

Maintenance Therapy for Non–Small Cell Lung Cancer A Value-Based Approach to Improve Patient Care and Outcomes, Part II of II

PROGRAM P10068 • RELEASE DATE: NOVEMBER 19, 2010 • EXPIRATION DATE: NOVEMBER 19, 2011

ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

TARGET AUDIENCEThis activity was developed for oncologypharmacists and other healthcare profes-sionals practicing in oncology.

LEARNING OBJECTIVESAfter completing this activity, the readershould be able to:• Evaluate the benefits and risks of mainte-nance therapy compared with re-treatingupon disease progression in order torationalize maintenance in patients withstage IIIB or IV non–small cell lung cancer(NSCLC) who have responded to or arestable after induction therapy

• Identify molecular and histologic charac-teristics of NSCLC tumors that impactchoice of therapeutic agent for specificpatient populations and formulatestrategies for value-based care

• Develop optimal side effect managementstrategies for patients receiving mainte-nance therapy for NSCLC in order to pro-vide optimal care while considering theassociated costs.

SPONSORThis activity is jointly sponsored by MedicalLearning Institute, Inc. (a nonprofit medicalaccreditation company) and Center ofExcellence Media, LLC.

INSTRUCTIONS FOR CREDIT

1. Read the article in its entirety2. Log on to

www.TheOncologyPharmacist.com3. Select “Continuing Education”4. Click on this article’s title from the listshown

5. Select “Click here to complete the posttestand obtain a CE certificate online”

6. Complete and submit the CE posttest andCE Activity Evaluation

7. Print your Statement of Completion

PHARMACIST DESIGNATIONMedical Learning Institute, Inc., is ac cred-ited by the Accreditation Council for Phar m acy Education (ACPE) as a pro -

vider of continuing pharmacy education. Com -pletion of this activity provides for 1.0 contacthour (0.1 CEU) of continuing education credit.The universal activity number for this activity is0468-9999-10-059-H01-P.

This activity is provided free of charge to partici-pants. Upon completion of the evaluation andscoring 70% or better on the posttest, you willimmediately receive your certificate online. If youdo not achieve a score of 70% or better on theposttest, you will be asked to take it again. Pleaseretain a copy of the certificate for your records.

FACULTY DISCLOSURESBefore the activity, all faculty will disclose the exis-tence of any financial interest and/or relation-ship(s) they might have with the manufacturer(s)of any commercial product(s) to be discussed dur-ing their presentation(s): honoraria, expenses,grants, consulting roles, speaker’s bureau mem-bership, stock ownership, or other special rela-tionships. Presenters will inform participants ofany off-label discussions.

Beth Eaby-Sandy, CRNP, is on the speaker’sbureau for Genentech, Eli Lilly and Company, andMerck.

Corey J. Langer, MD, acknowledges grant/research support from Bristol-Myers Squibb,Genentech, ImClone, Eli Lilly and Company, OSI,and Pfizer. Dr Langer is on the speaker’s bureaufor Genentech, ImClone-BMS, Eli Lilly andCompany, and OSI, and is a scientific advisor toAbbott, Abraxis, Amgen, AstraZeneca, Bayer-Onyx,

Biodesix, Bristol-Myers Squibb, Caris DX, Clarient,Genentech, ImClone, Eli Lilly and Company,Morphotek, Novartis, Pfizer, and sanofi-aventis.

Loretta Fala participated in the development ofthis article. She has no financial relationships todisclose.

The associates of Medical Learning Institute, Inc.,the accredited provider for this activity, andCenter of Excellence Media, LLC, do not have anyfinancial relationships or relationships to prod-ucts or devices with any commercial interestrelated to the content of this CE activity for anyamount during the past 12 months.

DISCLAIMERThe information provided in this CE activity isfor continuing education purposes only and isnot meant to substitute for the independentmedical judgment of a healthcare provider rel-ative to diagnostic and treatment options of aspecific patient’s medical condition. Tradenames used in this supplement are for thelearner’s reference only. No promotion of orbias toward any product should be inferred.

CommerCial Support

aCknowledgment

This activity is supported by an educational grantfrom Eli Lilly and Company.

TOP_April 2011_v2_TOP 4/19/11 3:59 PM

baby boom generation (people bornbetween 1946 and 1964) reaches theage of 65 years and older over the next20 years.12

Maintenance Therapy Agents forthe Treatment of Advanced NSCLCMaintenance therapy, sometimes alsoreferred to as consolidation therapy orearly second-line therapy,7 is a relativelynew approach to improving outcomes inpatients whose disease either respondedto initial chemotherapy or was stablefollowing that, and is intended toimprove survival without adverselyaffecting quality of life.13 Aside fromimproving outcomes, the optimal main-tenance treatment should be well-toler-ated by patients and associated with fewor no cumulative toxicities.7The National Comprehensive Can -

cer Network (NCCN) has establishedspecific recommendations for the useof pemetrexed in maintenance thera-py, as well as for the use of erlotinib.1These guidelines also include recom-mendations for several other agents,including docetaxel, bevacizu mab,and cetuximab.1

Pemetrexed Based on phase 3 study results, patientswho received maintenance therapy withpemetrexed showed a significantlygreater PFS (1.7 months longer), com-pared with the placebo group, and a sig-nificantly greater overall survival (OS)duration (2.8 months longer), comparedwith the placebo group.14 Specific find-ings from the study were previouslyhighlighted in Part I of this article.9Moreover, in patients with nonsqua-mous histology treated with peme-trexed, the OS was 5.2 months longerthan in the placebo arm.14 The most common any-grade ad -

verse reactions associated with peme-trexed included nausea (19%) andanorexia (19%).14 The pemetrexedgroup had a greater frequency of grade3 or higher adverse events than theplacebo group, including fatigue (5%)and neutropenia (3%).14Another study that compared the

combination of cisplatin plus peme-trexed with cisplatin plus gemcitabinein chemotherapy-naïve patients withadvanced NSCLC demonstrated supe-rior efficacy and reduced toxicity inthe group receiving cisplatin pluspemetrexed.15

ErlotinibBased on a phase 3 study, patients whoreceived maintenance therapy witherlotinib showed a greater PFS (0.8weeks longer) and an improved OS (1month longer), compared with theplacebo group.6,8 In patients with EGFR-positive immunohistochemistry treatedwith erlotinib, compared with EGFR-positive patients receiving placebo, PFS

was significantly greater (1.2 monthslonger) in the erlotinib group, comparedwith the placebo group, in patients withEGFR-positive immunohistochemistrytreated with erlotinib.8 Specific studyresults were previously highlighted.9The most common any-grade ad -

verse reactions associated with erlo -tinib were rash (49.2%) and diarrhea(20.3%).6 The most common seriousadverse event was pneumonia (2%),and the most common grade 3 or high-er adverse events included rash (6%)and diarrhea (2%).8

Other Agents Included in ClinicalPractice Guidelines

DocetaxelAlthough docetaxel, a microtubuleinhibitor, does not have a specific FDAapproval for maintenance therapy inNSCLC, this agent is indicated as asingle agent for locally advanced ormetastatic NSCLC after failure onplatinum therapy; and with cisplatinfor unresectable, locally advanced, ormetastatic untreated NSCLC.16 Basedon a phase 3 randomized study thatassessed the efficacy and safety of do -cetaxel administered either immediate-ly after gemcitabine or at disease pro-gression, immediate docetaxel wasassociated with a significantly greaterPFS (5.7 months) compared withdelayed do cetaxel (2.7 months), andimmediate docetaxel was associatedwith a greater median OS (12.3months) compared with delayed do -cetaxel (9.7 months).17 However, thedifference in median OS was not statis-tically significant (P = .0853). Therewas no significant difference in qualityof life between the immediate anddelayed docetaxel groups.17Based on studies of docetaxel as

monotherapy for NSCLC patients pre-viously treated with platinum-basedchemotherapy (n = 176), the most com-mon grade 3/4 adverse reactions includ-ed neutropenia (65%), leuko penia(49%), and pulmonary effects (21%).16The most common any-grade adversereactions include neutropenia (84%);leukopenia (84%); anemia (91%);asthenia (53%); pulmonary effects(41%); infection (34%); nausea (34%);fluid retention (34%); neurosensoryeffects (34%); stomatitis (26%); diar-rhea (23%); and vomiting (22%).16In chemotherapy-naïve advanced

NSCLC patients receiving docetaxel incombination with cisplatin (n = 406),the most common grade 3/4 adversereaction was neutropenia (74%).16 Themost common any-grade adverse reac-tions included neutropenia (91%);anemia (89%); alopecia (75%); asthe-nia (74%); nausea (72%); vomiting(55%); fluid retention (54%); diarrhea(47%); neurosensory effects (47%);anorexia (42%); infection (35%);

peripheral edema (34%); andfever (33%).16

BevacizumabBevacizumab, a monoclonal anti-body that inhibits vascularendothelial growth factor, is indicat-ed for the treatment of nonsquamousNSCLC, with paclitaxel and carbo-platin for the first-line treatment ofunresectable, locally advanced, recur-rent, or metastatic disease.18 Accordingto the NCCN clinical practice guide-lines, the criteria for bevacizumab thera-py include a performance status of 0-1,nonsquamous histology, and no historyof hemoptysis.1Adding bevacizumab to chemo thera-

py with paclitaxel plus carboplatin hasshown a significant im provement inmedian OS (12.3 months), comparedwith chemotherapy alone (10.3months), based on a randomized 3-yearstudy of patients with recurrent oradvanced NSCLC (N = 878) conductedby the Eastern Cooperative OncologyGroup.19 An increased risk of treatment-related deaths were ob served in thegroup treated with bevacizumab pluspaclitaxel and carboplatin, and the rateof clinically significant bleeding was4.4% in this arm.19 Other adverse eventsincluded grade 4 neutropenia (24%),grade 3/4 hemorrhage (4.5%), hemopty-sis (1.9%), and hypertension (6%).1According to the NCCN guidelines,caution is advised when chemotherapyregimens with a high risk for thrombo-cytopenia and/or possible bleeding arecombined with bevacizumab.1Further studies are needed to deter-

mine whether bevacizumab mainte-nance is associated with a survival ben-efit compared with the combination ofchemotherapy and bevacizumab with-out maintenance bevacizumab.20

CetuximabCetuximab, a monoclonal antibody thattargets EGFR, is indicated for the treat-ment of specific head and neck cancersand colorectal cancers; however, thisagent does not have an indication for thetreatment of NSCLC.21 Cetuximab use isnot recommended for patients with col-orectal cancer whose tumors have KRASmutations in codon 12 or 13.21According to a study of patients (N =

1125) with advanced NSCLC (stageIIIB or IV; majority were stage IV),patients treated with cetuximab in com-

bination with vinorelbine and cisplatinshowed no difference in PFS and a sig-nificantly improved OS (11.3 months)compared with patients receivingvinorelbine and cisplatin alone (10.1months).1,22 Treatment-related deathswere similar in both groups.22 Patientsreceiving cetuximab had increased grade3/4 febrile neutropenia (22%) and grade3 acne-like rash (10%).1,22

Evidence-Based PracticeGuidelinesFor the NCCN NSCLC clinical prac-tice guidelines (updated in March2010), a new section with maintenancetherapy recommendations was added.1These recommendations categorizedmaintenance therapy into 2 types: con-tinuation maintenance therapy andswitch maintenance therapy. Con -tinuation maintenance therapy refers tothe use of at least 1 of the agents admin-istered as first-line therapy.1 Switchmaintenance therapy refers to the initi-ation of an agent that was not includedas part of the first-line treatment regi-men.1 Based on 2 recent studies demon-strating a benefit in PFS and OS, theguidelines now recommend initiationwith pemetrexed or erlotinib for switchmaintenance therapy in patients with-out disease progression (Category 2Brecommendation).1Highlights of the NCCN guideline

recommendations for continuationmaintenance therapy and switch main-tenance therapy were outlined previous-ly in the first part of this article.9Information about the AmericanSociety of Clinical Oncology (ASCO)guideline update, as well as recent guid-ance from the National Institute forHealth and Clinical Excellence are alsohighlighted in that article.

The Role of Histology andMolecular Biomarkers inMaintenance TherapyIt is important to identify the histologicsubtype of NSCLC (ie, squamous cell vsnonsquamous cell) when selectingmaintenance therapy.23 Histologic infor-mation may be particularly useful whenaugmented by molecular testing.23Detecting the bronchoalveolar subtypeof NSCLC adenocarcinoma may suggesta specific treatment approach, particu-larly if it is associated with specific muta-tions in the EGFR tyrosine kinasedomain, which indicates it may respond

maRch/apRil 2011 I vol 4, No 2 23www.Theoncologypharmacist.com

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

The optimal maintenancetreatment should be well-tolerated by patientsand associated with fewor no cumulative toxicities.

TOP_April 2011_v2_TOP 4/20/11 9:36 AM



COMMENTARY

Maintenance Therapy in NSCLC: PersonalizedPerspectivesBy Corey J. Langer, MDDirector of Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia

Maintenance therapy has be -gun to emerge as a treatmentstandard for patients with

non–small cell lung cancer (NSCLC)whose disease has not progressed after4 to 6 cycles of frontline chemo thera-py. But some caveats still apply.Although it may be suitable for fit,motivated patients who are highlysymptomatic at the time of presenta-tion, it is not yet clear if maintenancetherapy should be routine. Based on the phase 3 data, use of

pemetrexed is certainly justified inpatients whose advanced NSCLC hasstabilized or improved after 4 or morecycles of frontline therapy with a plati-nating agent, plus either gemcitabine ora taxane. Pemetrexed is particularly welltolerated and convenient, al though its“maintenance” benefits are confined tononsquamous histology and its utility isas yet unproven in patients who havereceived pemetrexed and/or bevacizu -mab as part of their first-line treatment.Similarly, erlotinib has yielded a sur-

vival advantage compared with placeboin the maintenance setting, althoughthe extent of its benefit seems less pro-nounced compared with pemetrexed.

Prolonged Initial ChemotherapyProlonged treatment with initialchemotherapy (eg, 6 vs 3 cycles or in -definite treatment vs 4 cycles) hasshown no overall survival (OS) bene-fit1-3; neither have prior maintenancestudies of attenuated dosing or singleagents yielded a survival benefit,although “intriguing trends” in time toprogression have been observed inunderpowered efforts.4,5 Switching to a new compound for

maintenance therapy demonstratedsome benefit in the well-designedstudy by Fidias and colleagues, whichevaluated immediate versus delayeddocetaxel upon disease progression afterfirst-line carboplatin/gem citabine.6 Pro -gres sion-free survival (PFS) im provedfrom 2.7 months in the delayed arm to5.7 months with maintenance (P<.001), and median OS trended better(12.3 vs 9.7 months; P = .085). Inaddition, a recent meta-analysis docu-mented a 30% reduction in diseaseprogression using maintenance thera-py with a third-generation regimen

compared with maintenance with olderregimens.7

Determining the OptimalMaintenance Therapy AgentThe study by Fidias and colleagues laidthe groundwork for pemetrexed asmaintenance after chemotherapy,6which was evaluated in a recent phase 3study by Ciuleanu and colleagues.8Patients were randomized 2:1 to peme-trexed or intravenous placebo. Diseaseprogression was reduced by 40% (P <.001) overall and by 53% inpatients with nonsquamous histology (P <.001), and deaths were reduced by21% (P = .012) and 30% (P = .002),respectively. Pemetre xed was reasonablywell-tolerated and devoid of cumulativetoxicity. Benefits were particularly pro-nounced in patients with nonsquamoushistology (they had a more than 5-month survival advantage); there wasno PFS or OS advantage in those withsquamous histology.8Although this was the first random-

ized, double-blind, placebo-controlledtrial to show a significant survival bene-fit for maintenance treatment, one stillneeds to exercise caution in basing clin-ical decisions on this study. Maintenance therapy is unrealistic

for many patients due to early diseaseprogression, comorbidities, and patientdesire to stop treatment. Pemetrexed isof no value to patients with squamoushistology and is unproven in patientswho have received first-line peme-trexed or bevacizu mab. Furthermore,the survival improvement in theCiuleanu study would be more impres-sive had there been mandatorycrossover to pemetrexed at the time ofdisease progression in the control arm;unlike the Fidias trial, mandatorycrossover was not instituted in thistrial. It is noteworthy that <20% ofenrollees in the control arm receivedpemetrexed at the time of disease pro-gression, although a majority receiveda standard second-line treatment.Many patients look forward to the

prospect of a therapeutic holiday. Ifpatients are closely monitored once theyhave completed first-line therapy, thereis often enough time to implement sec-ond-line treatment when disease pro-gresses before symptoms have taken

over. Finally, cost is the 800-lb gorilla inthe room. Recent analyses of peme-trexed maintenance suggest a minimumincremental cost of >$120,000 per life-year saved.9A recent phase 2 study evaluated

pemetrexed plus bevacizumab for main-tenance after 6 initial cycles of carbo-platin, pemetrexed, and bevacizu mab.9Median PFS was 9.3 months and medi-an OS was 14 months.10 Many practi-tioners are using this regimen increas-ingly in bevacizumab-eligible patients.These encouraging findings have led toa large, planned randomized phase 3trial in the Eastern CooperativeOncology Group (ECOG) 5508, whichjust opened and will randomize 1282patients to bevacizumab, pemetrexed, orto a combination of bevacizumab andpemetrexed after 4 cycles of initial ther-apy with paclitaxel/carboplatin/beva-cizumab. In addition, a separate phase 3trial, POINT-BREAK, will compare thisregimen to the “winning” arm of ECOG4599 (a combination of paclitaxel, car-boplatin, and bevacizumab), whichyielded a significant and clinicallymeaningful survival advantage in thissetting compared with chemo therapyalone. Finally, in Europe, pemetrexedmaintenance is being compared with“observation” in patients who have sta-bilized or responded to a “standard”pemetrexed/cisplatin regimen.

Erlotinib MaintenanceErlotinib has shown value as a mainte-nance agent in 2 key studies. TheSequential Tarceva® in UnresectableNSCLC (SATURN) trial found thaterlotinib reduced the risk of progressionby 29% (P <.001) and offered a 1-month OS benefit (P = .0088).11In the Assessment of Treatment withLisinopril And Survival (ATLAS) trial,maintenance therapy with erlotinib plusbevacizumab improved PFS by 39%, orby approximately 1 month (P = .0012),but no OS difference was shown.12Moreover, toxicity associated with thisapproach is not trivial.

ConclusionsDocetaxel, pemetrexed, and erlotinibare each approved in the second-linesetting, and all have shown a PFSbenefit as maintenance therapy and at

least a trend toward improved sur-vival, if not a statistically significantincrease in survival. To date, bothpemetrexed and erlotinib are US Foodand Drug Administration–approved formaintenance therapy. At the end of theday, treatment should be individualizedfor all patients, taking into account notonly clinical outcomes but patients’ per-sonal preferences, disease burden, andcomorbidities. �

References1. Socinski MA, Schell MJ, Peterman A, et al. PhaseIII trial comparing a defined duration of therapy ver-sus continuous therapy followed by second-line ther-apy in advanced-stage IIIB/IV non-small-cell lungcancer. J Clin Oncol. 2002;20:1335-1343.2. von Plessen C, Bergman B, Andresen O, et al.Palliative chemotherapy beyond three courses con-veys no survival or consistent quality-of-life benefitsin advanced non-small-cell lung cancer. Br J Cancer.2006;95:966-973.3. Smith IE, O’Brien ME, Talbot DC, et al. Durationof chemotherapy in advanced non-small-cell lungcancer: a randomized trial of three versus six coursesof mitomycin, vinblastine, and cisplatin. J Clin Oncol.2001;19:1336-1343.4. Belani CP, Barstis J, Perry MC, et al. Multicenter,randomized trial for stage IIIB or IV non-small-celllung cancer using weekly paclitaxel and carboplatinfollowed by maintenance weekly paclitaxel or obser-vation. J Clin Oncol. 2003;21:2933-2939.5. Brodowicz T, Krzakowski M, Zwitter M, et al.Cisplatin and gemcitabine first-line chemotherapyfollowed by maintenance gemcitabine or best sup-portive care in advanced non-small cell lung cancer:a phase III trial. Lung Cancer. 2006;52:155-163.6. Fidias P, Dakhil S, Lyss A, et al. Phase III study ofimmediate compared with delayed docetaxel afterfront-line therapy with gemcitabine plus carboplatinin advanced non-small cell lung cancer. J Clin Oncol.2009;27:591-598.7. Soon YY, Stockler MR, Askie LM, Boyer MJ.Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283.8. Ciuleanu T, Brodowicz T, Zielinski C, et al.Maintenance pemetrexed plus best supportive careversus placebo plus best supportive care for non–small-cell lung cancer: a randomized, double-blind,phase 3 study. Lancet. 2009;374:1432-1440.9. Klein R, Wielage R, Muehlenbein C, et al. Cost-effectiveness of pemetrexed as first-line maintenancetherapy for advanced nonsquamous non-small celllung cancer. J Thorac Oncol. 2010;5:1263-1272.10. Patel JD, Hensing TA, Rademaker F, et al. Phase IIstudy of pemetrexed and carboplatin plus bevacizu mabwith maintenance pemetrexed and bevacizumab asfirst-line therapy for nonsquamous non–small-cell lungcancer. J Clin Oncol. 2009;27:3284-3289.11. Capuzzo F, Ciuleanu T, Stelmakh L, et al.Erlotinib as maintenance treatment in advancednon–small-cell lung cancer: a multicentre, random-ized, placebo-controlled phase III study. Lancet Oncol.2010;11:521-529. 12. Miller VA, O’Connor P, Soh C, et al. A random-ized, double-blind, placebo-controlled, phase IIIbtrial (ATLAS) comparing bevacizumab (B) therapywith or without erlotinib after completion ofchemotherapy with B for first-line treatment of local-ly advanced, recurrent, or metastatic non-small celllung cancer (NSCLC). Presented at 2009 ASCOAnnual Meeting. J Clin Oncol. 2009;27(18 suppl):LBA8002.

TOP_April 2011_v2_TOP 4/19/11 4:15 PM

to treatment with an EGFR TKI.23However, it is important to point outwithin this NSCLC subtype, there arealso variabilities in histology and molec-ular information.23 Several predictive molecular bio-

markers play a key role in NSCLC treat-ment,1 and these biomarkers and associ-ated characteristics were summarized inPart I.9 Initial retrospective studies sug-gest that approximately 90% of patientswith a tumor response to erlotinib and

gefitinib (both EGFR TKI agents)had EGFR mutations E19 deletionand L858R mutation, whereaspatients without a response to these 2agents did not carry these mutations.1The NCCN guidelines recommend that

maRch/apRil 2011 I vol 4, No 2 25www.Theoncologypharmacist.com

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

COMMENTARY

Nursing and Patient ManagementConsiderations for Maintenance Therapy inNon–Small Cell Lung Cancer

By Beth Eaby-Sandy, CRNPOutpatient Thoracic Oncology Nurse Practitioner, University of Pennsylvania Health System, Philadelphia

Significant ad van ces in treat ingnon–small cell lung cancer(NSCLC) have been made over

the past 10 years; nevertheless, sur-vival im provement in this diseasepales compared with many other solidtumors. Because maintenance chemo -therapy offers improved survival inNSCLC, patients and doctors are jus-tifiably excited.

Nursing ConsiderationsIn my dealings with patients, thereseem to be 2 distinct responses tomaintenance treatment. On the onehand, patients are very happy thatthey can continue receiving some sortof therapy, because they feel that theyare continuing the fight. Before thedata supporting maintenance chemo -therapy for NSCLC, we would stoptherapy after 4 to 6 cycles and give atreatment break, and many patientswere worried that they weren’t doinganything to treat their disease duringthis time. Con versely, I have alsoencountered many patients who areyearning for a break in therapy.Suggesting maintenance chemothera-py, which promises more toxicity simi-lar to what the patient is already expe-riencing, leaves them bewildered. Butbecause the treatment offers a survivaladvantage, patients usually will contin-ue with it because they want to livelonger. However, they frequently askwhen there will be a break, and thisoften gives them the realization thatthey will be receiving this treatment forthe rest of their lives. It is important for oncology treat-

ment pro viders to have a detailed dis-cussion with patients about the prosand cons of maintenance therapy forNSCLC. These patients have a termi-nal illness with average survival ofaround a year. Doctors and nursesmust allow pa tients the autonomy to

make decisions about receiving main-tenance therapy, along with possiblebreaks to have a vacation or spendtime with family. Maintenance thera-py can continue indefinitely, whichcan leave a patient feeling thathis/her life is a constant schedule oftreatments and can cause tremendousemotional stress.

Managing ToxicitiesAs maintenance therapy becomes amore widely used treatment option forpatients with NSCLC, it is importantto weigh its toxicities. Pemetrexed,which is US Food and Drug Ad -ministration (FDA)-approved in themaintenance setting, and docetaxel,which has a recommendation (al -though not an FDA approval) formaintenance therapy, are both cytotox-ic chemo therapy agents and pose con-cerns different from other approvedmaintenance therapies. Common sideeffects of chemotherapeutic agents,including risk for myelosuppression,fatigue, and nausea, are a concern forpatients receiving maintenance thera-py, especially be cause there is nodefined end date to it unless there is dis-ease progression or unacceptable toxic-ity. So patients may end up taking thesedrugs without a break for up to a year ormore.In the pemetrexed maintenance

study, anemia occurred in 15% ofpatients in the pemetrexed mainte-nance arm versus 6% in the placeboarm.1 Patients receiving pemetrexedmay therefore require more frequentblood transfusions and possibly colony-stimulating factors such as darbepoe tinor erythropoietin. Managing fatiguecan be come difficult for these patients,and considering that they are dealingwith a terminal illness, fatigue must betaken into serious account in terms ofits effect on the patient’s quality of life.

Nausea was also reported in 19% ofpatients in the pemetrexed arm versus6% in the placebo arm.1The targeted therapies erlotinib (in

the switch maintenance setting) andbevacizumab and cetuximab (in thecontinuation maintenance setting)do not typically induce the same sideeffects as chemotherapy but rathercarry their own set of unique toxici-ties. The toxicities from these agentscan also interfere with a patient’squality of life and must be consideredand addressed before embarking onmaintenance therapy.Rash was the most common side

effect in patients receiving erlotinibin the maintenance trial. Grade 3/4rash, causing interference with activ-ities of daily living, was 6%.2 Becausegood randomized data on treating thisrash have not emerged, managementstrategies have focused on best-prac-tice recommendations. Depending onseverity, papulopustular rash can betreated with topical steroids or antibi-otics, oral antibiotics, and even oralsteroids in severe cases.3 These med-ications can be used in combinationor separately depending on the gradeof rash. Although it is rarely life-threatening, rash can be uncomfort-able and disfiguring at times. In thecetuximab continuation trial, rashwas present in approximately 70%(382/548) of patients, with 10%experiencing grade 3/4 rash.Rates of grade 3/4 diarrhea in both

the cetuximab and erlotinib mainte-nance trials were 4% and 2%, respec-tively.2,4 It is usually easily controlledwith loperamide and sometimes re -quires a prescription-strength anti -diarrheal. Concern for dehydrationmay be an issue given that thispatient population is often elderly, soprompt assessment and ensuring fluidintake are important.

Bevacizumab is only approved forthe use of nonsquamous NSCLCbecause of bleeding risk. The mostcommon side effects of bevacizumabinclude hypertension and protein-uria,5 and assessing for these on eachvisit is recommended. Standard anti-hypertensives will usually controlbevacizumab-associated hyperten-sion; pro tein uria often improves onholding the bevacizumab dose. In rareNSCLC cases, bevacizumab has thepotential to cause fatal pulmonaryhemorrhage, so it is essential thatpractitioners assess for hemoptysisand permanently discontinue beva-cizumab if hemoptysis occurs. In summary, the improvement in

survival for metastatic NSCLC bycontinuing a maintenance therapyafter first-line treatment is modest,but it is certainly an advance.Conversations with patients aboutthe schedule, toxicities, and benefitsof therapy must be unbiased and thor-ough. Patients need to be able tovoice their concerns and have ampleopportunity to shape their treatmentregimen because of their limited prog-nosis and possible effect of mainte-nance treatment on quality of life. �

References1. Ciuleanu T, Brodowicz T, Zielinski C, et al.Maintenance pemetrexed plus best supportive careversus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind,phase 3 study. Lancet. 2009;74:1432-1440.2. Cappuzo F, Ciuleanu T, Stelmakh L, et al.Erlotinib as maintenance treatment in advancednon-small-cell lung cancer: a multi-center, random-ized, placebo-controlled phase 3 study. Lancet Oncol.2010;11:521-529.3. Lynch T, Kim E, Eaby B, et al. Epidermal growthfactor receptor (EGFR) inhibitor-associated rash: anevol ving paradigm in clinical management.Oncologist. 2007;12:610-621.4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximabplus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label random-ized phase III trial. Lancet. 2009;373:1525-1531.5. Sandler A, Gray R, Perry MC, et al. Paclitaxel–car-boplatin alone or with bevacizumab for non–small-celllung cancer. N Engl J Med. 2007;355:2542-2550.

TOP_April 2011_v2_TOP 4/19/11 4:19 PM



pathological evaluation be performed toclassify the lung cancer, determine itsextent of invasion, determine the statusof surgical margins, and identify molec-ular abnormalities that may predict thetreatment response, or resistance to,EGFR TKI therapy.1

Other Maintenance TherapyConsiderationsThe potential benefits of maintenancetherapy—preventing cancer recurrence,slowing disease growth, and prolonginglife—must be weighed against thepotential risks—increased side effectsand potential for toxicities, drug resist-ance, and more frequent doctor visits.Another consideration is that mainte-nance therapy does not provide thepatient with a chemotherapy break,also referred to as a wait-and-see peri-od.7 Data on the quality of life associat-ed with maintenance therapy are limit-ed, including data on cumulativetoxicity associated with extendedchemotherapy.7 Although mainte-nance therapy increases chemotherapycosts and may increase overall costs, itmay conversely decrease costs associat-ed with palliative radiotherapy andhospital admissions resulting from per-formance stat us deterioration.20 The value of maintenance therapy is

the subject of ongoing discussion amongclinicians, particularly in light of its costand potential toxicity.24 Pemetrexedadministered in 6 cycles at the averagewholesale price of $3000 per cyclewould total $18,000.24 The wholesaleacquisition cost for erlotinib mainte-nance treatment would be $4000 permonth ¥ a mean PFS of 3 months, for atotal treatment cost of $12,000.24 Some of the challenges surrounding

cost of added survival were presented atthe 2010 ASCO meeting by ScottRamsey, MD, PhD, of the FredHutchinson Cancer Research Center inSeattle.24,25 Ramsey asserted that main-tenance therapy was unlikely to be cost-effective, based on a ratio that considersboth the price over standard care andthe months of OS benefit. However, heacknowledged that pharmacogenomicstrategies may improve the cost-effec-tiveness of therapy and that the cost oftesting will be a factor. Ramsey claimedthat many new oncology agents do notmeet the criteria for cost-effectivenessand that many economic analyses donot meet the guidelines for economicevaluation.24,25 Guideline-driven phar-macoeconomic studies may shed lighton whether maintenance therapy is themost cost-effective. The rationale in favor of mainte-

nance therapy was presented at the 2010

ASCO meeting by Tracey Evans, MD,of the Abramson Cancer Center, Uni -versity of Pennsylvania, in Phila -delphia.26 According to Evans, “mainte-nance therapy for advanced NSCLC isabsolutely a standard of care” thatshould be considered for all patients,particularly based on clinical data show-ing prolonged survival and tolerability.26An opposing point of view was present-ed by Tom Stinchcombe, MD, of theLineberger Comprehensive CancerCenter, at the University of NorthCarolina at Chapel Hill.27 According toStinchcombe, maintenance therapy isnot necessarily a standard of care forevery patient but rather an option to beconsidered, which depends on toxicitiesas well as the patient’s disease burden,extent of symptoms, performance status,and preferences.27 He maintained that atreatment-free interval is still an optionin this incurable disease setting.27

ConclusionMaintenance therapy, a relatively newapproach in the treatment of patientswith advanced NSCLC, has the poten-tial to extend survival and improve out-comes. Key considerations for tailoringtreatment for the appropriate patientsinclude the histology of the carcinoma,genetic biomarkers, the extent of dis-ease invasion, and the patient’s per-formance status and preferences. Thebenefits of maintenance therapy mustbe weighed against the potential toxici-ties and other side effects associatedwith extended treatment. Selecting theappropriate therapy for the appropriatepatients and involving patients in thedecision process are important aspectsof the treatment plan. Strategies for

managing side effects warrant carefulconsideration. Optimally, the agentselected for maintenance therapyshould be well-tolerated by the patient,demonstrate improved patient out-comes, and have minimal side effects/cumulative toxicities.7Recent clinical data and evidence-

based guidelines are valuable decision-making tools for clinicians. However,data assessing quality of life, cost-effec-tiveness, and cumulative toxicity ofmaintenance therapy are lacking. Costsand resource utilization associated withmaintenance therapy must be balancedagainst the risks and costs of not treat-ing or of deteriorating performance sta-tus. A delay strategy may be associatedwith a shorter survival time and a fasterdisease progression than immediateadditional therapy.28,29 In any case, theprospect of extended survival of severalmonths, or even weeks, particularly iftreatment is well-tolerated, representsan important milestone for patientswith advanced NSCLC. �

References1. National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology™.Non-small cell lung cancer, V.2.2010. March 5, 2010.www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010.2. Peck P. Maintenance pemetrexed extends NSCLCsurvival by 3 months. Medpage Today. May 30, 2009.www.medpagetoday.com/tbprint.cfm?tbid=14437.Accessed September 22, 2010. 3. Riley K. FDA approves first maintenance drugtherapy for advanced lung cancer [press release].July 6, 2009. US Food and Drug Administration.www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170515.htm. Accessed Sep tember 22,2010.4. Alimta (pemetrexed disodium) [package insert].Indian apolis, IN: Eli Lilly and Company; 2010.5. Waknine Y. FDA approves use of erlotinib asmaintenance therapy for advanced non-small celllung cancer [press release]. April 20, 2010.www.medscape.com/viewarticle/720446. AccessedSeptember 22, 2010. 6. Tarceva (erlotinib) [package insert]. Melville, NY:OSI Pharm aceuticals Inc; and South San Francisco,CA: Genentech; 2010. 7. Owonikoko TK, Ramalingam SS, Belani CP.Maintenance therapy for advanced non-small celllung cancer: current status, controversies, and emerg-ing consensus. Clin Cancer Res. 2010;16:2496-2504.8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al.Erlotinib as maintenance treatment in advancednon-small-cell lung cancer: a multicentre, random-ized, placebo-controlled phase 3 study. LancetOncol. 2010;11:521-529. Epub May 20, 2010.9. Maintenance therapy for non-small-cell lung can-cer: a value-based approach to improve patient care

and outcomes, part I of II. Value-Based Cancer Care.2010;1:24-26.10. Kutikova L, Bowman L, Change S, et al. The eco-nomic burden of lung cancer and the associated costsof treatment failure in the Un ited States. Lung Cancer.2005;50:143-154. Epub August 19, 2005. 11. National Cancer Institute, US NationalInstitutes of Health. Surveillance, Epidemiology,and End Results. SEER stat fact sheets: lung andbronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed September 20, 2010.12. Vincent GK, Velkoff VA. The Next Four Decades,the Older Population in the United States: 2010 to 2050.Current Population Reports, P25-1138. Washington,DC: US Census Bureau; May 2010.13. American Society of Clinical Oncology.Explaining maintenance therapy. Cancer.net.Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/Cancer.Net+Feature+Articles/Treatments%2C+Tests%2C+and+Procedures/Explaning+Maintenance+Therapy. Accessed September20, 2010.14. Ciuleanu T, Brodowicz T, Zielinski C, et al.Maintenance pemetrexed plus best supportive careversus placebo plus best supportive care for non–small-cell lung cancer: a randomized, double-blind,phase 3 study. Lancet. 2009;374:1432-1440. EpubSeptember 18, 2009. 15. Scagliotti GV, Parikh P, von Pawel J, et al.Phase III study comparing cisplatin plus gem citabinewith cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J ClinOncol. 2008;26:3543-3551.16. Taxotere (docetaxel) [package insert].Bridgewater, NJ: sanofi-aventis US, LLC; 2010.17. Fidias PM, Dakhil SR, Lyss AP, et al. Phase IIIstudy of immediate compared with delayed docetaxelafter front-line therapy with gemcitabine plus carbo-platin in advanced non-small-cell lung cancer. J ClinOncol. 2009;27:591-598. Epub December 15, 2008.18. Avastin (bevacizumab) [package insert]. SouthSan Francisco, CA: Genentech, Inc; 2009. 19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542-2550. 20. Eaton KD. Maintenance chemotherapy in non-small cell lung cancer. J Natl Compr Canc Netw.2010;8:815-821.21.Erbitux (cetuximab) [package insert].Branchburg, NJ: ImClone Systems Inc; 2010; andPrinceton, NJ: Bristol-Myers Squibb Company;2010.22. Pirker R, Pereira JR, Szczesna A, et al.Cetuximab plus chemo therapy in patients withadvanced non–small-cell lung cancer (FLEX): anopen-label randomized phase III trial. Lancet.2009;373:1525-1531.23. Neal JW. Histology matters: individualizingtreatment in non-small cell lung cancer [editorial].Oncologist. 2010;15:3-5. Epub January 19, 2010.24. Hayes E. Will maintenance sell in NSCLC?Experts weigh costs against benefits. PharmaceuticalAp provals Monthly. August/September 2010. 25. Ramsey S. Cost effectiveness in lung cancer tri-als and treatment. Presented at the 2010 AmericanSociety of Clinical Oncology Meeting—EducationSession. June 4-8, 2010; Chicago, IL.26. Evans TL. Maintenance therapy for advancedNSCLC is standard of care. Presented at the 2010American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.27. Stinchcombe T. Maintenance therapy foradvanced NSCLC is not standard of care. Presentedat the 2010 American Society of Clinical OncologyMeeting—Education Session. June 4-8, 2010;Chicago, IL.28. Belani CP, Liao J. Maintenance therapy fornon-small cell lung cancer [comment]. Lancet.2010;375:281-282; comment on Stinchcombe T,West H comment in: Lancet. 2009;374:1398-1400.29. Soon YY, Stockler MR, Askie LM, Boyer MJ.Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol.2009;27:3277-3283. Epub May 26, 2009.

Although maintenance therapy increaseschemotherapy costs and may increase overall costs, it may conversely decrease costs associated withpalliative radiotherapy and hospital admissions resultingfrom performance stat us deterioration.

Maintenance therapy isnot necessarily a standardof care for every patientbut rather an option to beconsidered.

TOP_April 2011_v2_TOP 4/19/11 4:18 PM

THANK YOU FORMAKING US#1Source: © Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)

��

�� The Oncology Pharmacist��

The #1* Read

Oncology Pharmacy

Tabloid Publication

In a recent survey, oncology pharmacists said thatthey read The Oncology Pharmacist 1.5 times more*than its closest competitor in the pharmacy market.

� � � �� TOP_April 2011_v2_TOP 4/20/11 10:40 AM


The Whole Patient

Managing Elderly Patients Who Have Comorbidities

Cancer treatment–induced diar-rhea (CTID) occurs in 50% to 80% of patients receiving

chemo therapy and 50% of patientsundergoing radiotherapy. Older patients,women, patients on an irinotecan-con-taining regimen, and patients treated inthe adjuvant setting are at higher risk ofCTID, reported Kelly Markey, PharmD,BCOP. Markey is a clinical pharmacistwith the gastrointestinal tumor programat Moffitt Cancer Center in Tampa,Florida, and discussed CTID at the annu-al meeting of the Hematology/OncologyPharmacy Association.

“There are many different sourcesfor diarrhea in this patient popula-tion,” she said. It can be caused by sur-gery, nosocomial infection, treatment,graft-versus-host disease, and thepatient’s malignancy.

A diagnostic work-up for diarrhearequires obtaining a clinical history and adescription of the stool. “Stool descrip-tion is especially important, includingnot only the number of stools but thecomposition,” said Markey. “Are theywatery or bloody? Did they occur noctur-nally?” Patients should be checked forfever and asked if they have experienceddizziness, cramping, pain, or weakness.

“Sometimes fever can indicate infectionor even bowel obstruction,” she noted.Current medications or diet might alsocontribute to diarrhea.

Persistent diarrhea requires a stoolwork-up, complete blood count, andassessment of electrolyte levels. Markeysaid an abdominal examination is alsonecessary, as is an endoscopy in somecases, to check for Clostridium difficile orinflammatory bowel disease. “Noso -comial infections are most often associ-ated with C difficile,” she said. Otherculprits include Salmonella, Shigella,Campylobacter, and Escherichia coli. Fordiarrhea lasting >7 days, “You need tostart thinking about your protozoa.”

Patients meeting National CancerInstitute criteria for grade 1/2 persistentdiarrhea but who do not have fever,dehydration, neutropenia, or blood intheir stool can be seen at the office.Patients with grade 3/4 diarrhea requirehospital admittance, even if they haveno other symptoms. Markey said probiotics, which contain live bacteria oryeast, secrete acids that lower the pHlevel in the gastrointestinal (GI) tract,which thwarts the growth of pathogenicbacteria. “They also secrete toxins tothese bacteria, such as hydrogen perox-

ide, and they inhibit the binding of thesebacteria to the GI tract,” she explained.Caution is recommended when usingprobiotics in patients who are immuno-compromised or have central venousdevices. Probiotics should not be used inpatients on an antifungal agent. A con-cern with probiotics is that they are notquality controlled by the US Food andDrug Administration.

Several antimotility agents are used inthe initial treatment of CTID. “Manytimes I find my patients haven’t maxi-mized use of their first-line agents, suchas loperamide, and we prematurely movethem to a second-line agent,” saidMarkey. “You want to make sure you’remaximizing your dosing.”

For patients with persistent diarrhea,long-acting and short-acting octreotideare available. “Long-acting wouldn’t beused in the refractory-treatment popula-tion, but it is being investigated as a pro-phylactic, particularly in the radiation-induced population,” she said. One studyfound continuous octreotide infusioneffective in patients with colorectal can-cer who were receiving 5-fluorouracil.Diphenoxylate, opium tincture, budes-onide, and cholestyramine resin areother options for CTID.

If C difficile is the culprit, metronida-zole or vancomycin are standard first-lineoptions. “The problem with these agentsis they can be efficacious up front, but20% to 30% of patients are going torecur within 60 days...the majority recurwithin 2 weeks,” said Markey. Severalnew drugs for C difficile are on the mar-ket. In 2010, a small study by Basu andcolleagues reported that 73% of pa -tients who were refractory to metronida-zole responded to rifamycin (Xifaxan). A2011 study by Louie and associates deter-mined that fidaxomicin (not yet ap -proved) was noninferior to vancomycinas initial therapy for C difficile; it wasassociated with a lower rate of recur-rence. Nitazoxanide (Alinia) is usedagainst protozoa with similar effective-ness to vancomycin. It is also activeagainst norovirus and rotavirus.

Persistent diarrhea can be a life-threatening complication of anticancertherapy. Even low-grade persistent diar-rhea has a negative effect on quality oflife. Persistent diarrhea requires promptinvestigation, particularly when accom-panied by fever. It is important to letpatients with cancer know when diar-rhea warrants calling their healthcareprovider or seeking hospitalization. �

Considerations for Cancer Treatment–Induced DiarrheaBy Christin Melton

The median age for someone toreceive a cancer diagnosis is 67years according to the Sur -

veillance, Epidemiology, and End Resultsdatabase and even higher for certainmalignancies. For example, many gas-trointestinal cancers are diagnosed inseptuagenarians. With the advancing ageand expanding waistlines of the US pop-ulation, the number of patients seen atoncology clinics who have multiplechronic conditions is also expanding.Said Rowena Schwartz, PharmD,BCOP, director of oncology pharmacyat Johns Hopkins Hospital in Balti -more, Maryland, and president of theHematology/Oncology Pharmacy As -sociation, “We know that as patientsage, there are more comorbidities; andas patients age, the instance of cancerincreases, so it makes sense that thosego together.”

Schwartz said elderly patients withcomorbidities often have worse out-comes with anticancer therapies and saidno one is certain why. “Is it because theyhave high comorbidities and they don’ttolerate treatments, or is it because wedose-modify to deal with the comorbidi-ties? Is it because they don’t present untiltheir disease is advanced because their

cancer symptoms are confused with thecomorbidities?” she asked. “We don’tknow why. The data in comorbiditiesand the data in geriatrics are not reallyplentiful,” explained Schwartz.

The COPIT (Cancer in the Oldest:Prevalence, Related-Illnesses, and Treat -ment Modalities) study looked at recordsfor 194,797 US military veterans aged>70 years with cancer (99.6% were men)to assess the rates of various comorbidi-ties in this aged population. Theresearchers found that 70% had hyper-tension, >50% had hyperlipidemia, 40%had heart disease, 25% had diabetes,21% had osteoarthritis, 17% were med-ically frail, 10% had depression, and 6%had dementia. Some patients fell intomore than 1 of these categories.

A single-institution study byWedding and colleagues found a highrate of comorbidity in adult patients with

cancer in all age demographics. Com or -bidities were severe in approximatelythree-quarters of the elderly patientscompared with half of the youngerpatients. The rate of severe comorbidi-ties was similar in the cohort of elderlypatients without cancer (79%).

Schwartz said a 2010 literature re viewby Lee and associates looked at 34 stud-ies and concluded that clinicians usedchemotherapy less often or at lower dosesfor patients who had comorbidities,regardless of the type or stage of cancer.More than two-thirds (69%) of the 29studies to report on overall survivalfound it was diminished in patients withcancer who had comorbidities. Theprevalence, range of comorbid condi-tions, and their effects on treatment andoutcomes point to the need for cliniciansto consider comorbidities when caringfor patients with cancer. Schwartz

believes this is something that must bedone on an individual basis, but also atthe clinical trial level.

“There are no clinical trials that lookat comorbidities and look at treatment inindividual populations,” Schwartz said.“We may need to look at specific comor-bidities in specific populations with spe-cific types of disease.”

Monitoring patients with comor-bidities involves more than askingquestions at a follow-up visit. Schwartzprefers to telephone patients, particu-larly when prescribing anticoagulationtherapies. “I like to do phone follow-ups because you can do it every dayand get a better picture.” That dailyinteraction is important for some ofthe highest risk patients because “peo-ple’s memories just don’t jive withwhat actually happens,” she said. Thisis especially true for elderly patients,who, weeks later, might not rememberto tell their clinician about a symptomthat seemed important at the time.Schwartz said monitoring an elderlypatient with comorbidities also re -quires engaging the people in theirlives who provide support. “Figure outwhere they live and who provides thatoverview of care.”—CM �

“I like to do phone follow-upsbecause you can do it every dayand get a better picture.”

—Rowena Schwartz, PharmD, BCOP

TOP_April 2011_v2_TOP 4/19/11 3:02 PM


News in Review

The Centers for Medicare & Medi caid Services(CMS) has re leased a proposed decisionmemo that suggests it will cover the cost of

sipuleucel-T (Provenge), the immunotherapy vac-cine approved in April 2010 for men with asympto-matic or mildly symptomatic meta static castrate-resistant prostate cancer, for on-label use. CMScontractors will have discretion as to whether theywill cover it for off-label use.To date, no studies have been published that

support off-label use of sipuleucel-T, but CMSdecided to leave the coverage question open sothat patients in clinical trials investigating off-label indications might have access to the drug.The agency noted that it does not expect clini-cians to prescribe sipuleucel-T for indicationsunsupported by evidence, but if this occurs regu-larly, CMS said it would reconsider the ruling.When sipuleucel-T was first approved, CMS

took the unusual step having the MedicareEvidence De velopment and Coverage Ad visoryCommittee (MEDCAC) re view the clinical trialdata before agreeing to cover the drug’s estimated$93,000 cost. The committee completed its reviewin November 2010, and panel members rated the

drug an average of 3.6 for effectiveness despiteconcerns about flaws in the trials’ protocols andanalyses.CMS also asked the Blue Cross & Blue Shield

Technology Evaluation Center to conduct anindependent investigation of the evidence for itseffectiveness. The center concluded it had “mod-erate” efficacy.During an initial 30-day public comment period,

620 (94.4%) of the 657 comments received byCMS expressed support for covering sipuleucel-T.CMS also reviewed national guidelines and metwith officials from Dendreon to discuss the trials.In issuing its proposed coverage decision, CMS

noted the underrepresentation of nonwhite men inthe trials and “encourage[d] researchers to takeappropriate steps to assure that clinical trials enrollsubject populations that reflect the distribution ofpa tients affected by the disease.” Black men aremore than twice as likely to die from prostate can-cer as white men.CMS has initiated another call for public com-

ments on its proposed determination. The agencysays it will review these comments and issue itsfinal ruling by June 30, 2011. �

Medicare Plans to Cover ProvengeBy Christin Melton

APP Pharmaceuticals has issued a volun-tary recall of 5 lots of irinotecan hydro -chloride injection (Camptosar) as a pre-

cautionary measure. No adverse events related tothe recalled products have been reported. Thefollowing lots have been recalled:• 870DE00301• 870CZ00301• 870DE00101• 870DE00201• 870DE00401APP issued the recall after receiving customer

complaints associated with lot 870DE00301, inwhich particulates were observed in the productsolution. An investigation of the vials returned tothe manufacturer established that the particulatematter was a fungal microbial contaminant. Afterconsulting with the US Food and DrugAdministration, and as a precautionary measure,all lots produced immediately before and after lot870DE00301 are being recalled. For completedetails, visit www.apppharma.com. �

Voluntary Recall ofIrinotecan AnnouncedBy Dawn Lagrosa

Every physician has a preferred wayof writing prescription instruc-tions, and pharmacists differ in

how they translate those instructions tothe pill bottle. A study published in theAnnals of Internal Medicine by Wolf andassociates found that the lack of a uni-versal medication schedule (UMS) tostandardize how prescriptions are writ-ten and filled contributes to poorpatient adherence and increases safetyconcerns. Elderly patients or thosewith low health literacy are moreprone to confusion when trying to fol-low a multidrug regimen.In a 2008 report, “Standardizing

Medication Labels,” the Institute ofMedicine (IOM) recommended imple-menting a UMS to reduce misunder-standings related to medication use.Noting that 90% of prescriptions requireno more than 4 daily doses, the IOMcalled for delineating 4 standard dosagetimes—morning, noon, evening, andbedtime—to help patients taking multi-ple drugs to consolidate doses. Receptionto the proposal was mixed, with calls formore research.To determine whether a UMS was

needed, investigators assessed the abilityof 464 patients aged 55 to 74 years toadhere to a hypothetical 7-drug prescrip-tion regimen. The patients were part of abroader study that incorporated a 2-hourinterview to evaluate their adeptness at

performing everyday health tasks. Most(84%) had at least 1 chronic health con-dition; approximately 61% were collegeeducated and an equal proportion hadhousehold incomes >$50,000.Researchers gave every patient pre-

scription bottles containing fake pillsand mock labels for 7 retired drugs; dos-ing instructions varied between thedrugs. Patients also received a pill boxwith 24 slots marked with consecutive 1-hour intervals, going from 12:00 AM to11:00 PM. Each patient was verballyinstructed to “imagine that your doctorhas prescribed you these medications. Iwould like you to please show me whenyou would take these medicines over thecourse of 1 day,” and offered additionalinstruction as needed.Although the drugs could be neatly

consolidated into 4 dosing intervals,participants sorted them into an aver-age of 6 slots. Some consolidated theregimen into as few as 3 dosing periods,whereas others used as many as 14slots. One-third of patients indicated 7intervals each day for taking drugs;14.9% indicated 4 times or fewer.Labels for 3 drugs had identical dosing

instructions and could therefore havebeen taken simultaneously, yet one-thirdof patients failed to do so. Another 2drugs required thrice-daily dosing, with 1stipulating to take it with food and water.Only 50.5% of participants scheduled

them to be taken together. Another 2drugs needed to be taken twice a day; thelabel for one said “twice daily” and theother said “every 12 hours.” In all, 79%of patients failed to consolidate theminto concurrent dosing intervals.For drugs calling for twice-daily dos-

ing, an average of 10.3 hours elapsedbetween doses (range, 1 hour to 18hours). For thrice-daily dosing, a mean of5.4 hours elapsed between the first andsecond doses and 6.5 hours between thesecond and third doses.Low health literacy—ascribed to

20.7% of patients—was the only factorthat independently predicted a greaterlikelihood of taking medications more

than 7 times per day. Patients with lowhealth literacy and no chronic condi-tions had the worst rate of efficient consolidation.The authors said strategies are need-

ed to help patients understand how totake prescriptions and how to consoli-date multiple prescriptions. They saidadopting a UMS could “unite medicaland pharmacological practice” andsuggested that an electronic healthrecords system could be used to facili-tate standardization in prescribing.They also recommended educatingproviders on how to identify patientslikely to have trouble adhering to acomplicated regimen.—CM �

Variation in Prescribing Instructions Confuses Patients on Multidrug Regimens

©C

opyrigh

t B

igsto

ck.c

om

/th

esh

utt

er-

bu

g

TOP_April 2011_v2_TOP 4/19/11 3:02 PM


Cancer Center Profile

“They can come in the morning andsee everybody and come out with aplan,” explained Philip J. Stella, MD,the clinic’s medical director and med-ical oncologist. The multidisciplinaryapproach seems to be working. Notonly has the program shaved morethan two-thirds off the time betweenwhen lung cancer is suspected to initi-ation of a treatment plan, “We havevery high rates of satisfaction from thepatients and their families,” said Stella.Patients are not the only ones who

appreciate St. Joseph Mercy’s efforts.Primary care physicians in the regionhave shown their satisfaction with theprogram by referring more patients tothe lung cancer clinic. “We try to makeit easy for them, so [that] when theyhave a patient with lung cancer, theydon’t have to call 3 different offices…Just 1 call will get the patient seen in atimely fashion,” said Stella. The lung cancer clinic’s reputation

continues to spread. Stella said thepositive reception for the multidisci-plinary approach has led to patientreferrals from physicians outside theSt. Joseph Mercy system and the needto expand.

A Model in the MakingLike other multidisciplinary clinics at St.Joseph Mercy, the lung cancer clinic isspearheaded by an advisory committee,which consists of physicians and otherproviders who tend to patients at theclinic and participate in tumor boards.Vita McCabe, MD, a cardiothoracic sur-geon, chairs the committee and helpssteer the program. McCabe described her philosophy of

care: “When you are a cancer patient,you need to feel that you are in a high-end department store, that you are com-pletely cared for from every direction—[that] this is not a discount-shoppingsituation.” Department stores claim tooperate according to the principle thatthe “customer is always right.” Althoughthe patient might not always be right atSt. Joseph Mercy, the lung cancer clinic’s multidisciplinary team factors thepatient’s perspective into each decision.In developing the program from the

perspective of the patient, it becameclear that it would be important to assigneach patient to a nurse navigator. Thenavigator serves as the point person forarranging visits and facilitating commu-nication between the patient or thepatient’s caregivers and the individualson his or her care team. This is useful forcoordinating not only anticancer treat-ment, but also support services. Alongwith medical oncologists, surgeons, andradiologists, many patients meet withresearchers, social workers, and nutri-tionists at the clinic.

Lara Blair, RN, is one of the program’snurse navigators. “Even if someone justhas a small question, when you have ateam of 3 or 4 different doctors and otherspecialists, that can mean 20 phonecalls,” said Blair. “One of my biggest jobsis cutting that process down and stream-lining it for [the patients].”Benefits of this system are that

“patients don’t have to wait for care,nor are they confused,” said McCabe.The clinic strives to stay at the fore-

front of lung cancer care, offering anarray of advanced surgical and radio-therapy techniques. To handle growingdemand, a second surgeon was recentlyadded to the staff. With 2 surgeons on-board, the clinic has been able toexpand the number of minimally inva-sive approaches available, to includevideo-assisted and robotic surgery andthoracoscopic procedures. St. Joseph Mercy became the first

hospital in Michigan to offer theCyberKnife system for stereotacticbody radiation therapy. As a result,“Medically inoperable patients arebeing treated for their lung cancerswith a high degree of success and withminimal complications and sideeffects,” said Walter M. Sahijdak, MD,a radiation oncologist at the clinic. As a member of the Community

Clinical Oncology Program (CCOP)network for the past 20 years, St.Joseph Mercy has actively recruitedpatients with cancer for a number ofclinical trials. The CCOP affiliationallows patients treated at St. JosephMercy, including those seen in thelung cancer clinic, to enroll in trialsconducted by major national researchgroups, such as the Mayo Clinic andthe M. D. Anderson Cancer Center.The lung program currently haspatients enrolled in several innova-tive studies its researchers are con-ducting, including trials comparingoutcomes with CyberKnife versusstandard resection in patients withsolitary lung nodules.The lung cancer clinic recently

moved into new space, which houses anurse navigation office and the adviso-ry committees for each of St. JosephMercy’s multidisciplinary clinics. Stellasaid the lung cancer program has beenso successful he expects it to serve as amodel for future multidisciplinary clin-ics focused on other tumor types.

Success Paves the WayThe success of the lung cancer programno doubt factored into last year’s deci-sion by the National Cancer Institute’sCommunity Cancer Centers Program(NCCCP) to designate St. JosephMercy as one of only 30 NCCCP sitesin the nation. The NCCCP initiativeseeks to develop a network of commu-nity hospitals tasked with re searchingways to improve the quality of cancercare and prevention, as well as toreduce disparities in access to care andoutcomes.

An accompanying $2.5-million grantwill allow St. Joseph Mercy to add sever-al cancer specialists to its staff and devel-op new programs. In a press releaseannouncing the designation, Stella, the

grant’s principal investigator, said, “Thisprogram allows St. Joseph Mercy AnnArbor to accelerate the tempo of scien-tific research and advancement of cancercare… St. Joe’s is already recognized forour cancer research; this contract allowsus to take our program to the next leveland expand other areas of research andcare. It underscores our dedication toproviding our patients with the latestand most state-of-the-art care.” The NCCCP contract calls for St.

Joseph Mercy to develop a tissue bank.Stella said while St. Joseph Mercy typi-cally submits tissue from patients in itsclinical trials for translational research,the center will now be preserving tumortissue samples for all their patients withcancer. “We are going to…be able toprovide that to investigators at academiccenters around the country that wantaccess to fresh tissue or paraffin-embed-ded tissue to do their translational work,”said Stella. “This is a very important partof this grant and the network as awhole,” he explained. “So much of whatwe are going to be learning about canceris going to be through translationalresearch.” Other plans include hiring a geneti-

cist to counsel patients and evaluatethose considered high risk and expand-ing outreach efforts to underservedcommunities. This will require hiring aminority coordinator to reach out toethnic minority populations andadding a financial counselor to thestaff to help low-income and indigentpatients with obtaining oncologic care.“There is no way in this economic

environment that the hospital wouldever be able to provide these posi-tions,” Stella said. “If it had not beenfor this grant, we absolutely would notbe able to provide many of the servicesthat I think we should be doing as acancer program.” And had it not beenfor the stellar multidisciplinary lungcancer clinic at St. Joseph Mercy, itmight have taken the NCCCP longerto recognize just how determined thecenter is to ensure that people withcancer have the best care possible. �

St. Joseph Mercy Cancer Care Center... Continued from cover

“Medically inoperablepatients are being treatedfor their lung cancers witha high degree of successand with minimalcomplications and sideeffects.”

—Walter M. Sahijdak, MD

“They can come in the morning and seeeverybody and come out with a plan.”

—Philip J. Stella, MD

• Access daily news impacting you and your patients

• Easily share and post to social media sites

• Earn continuing education credits

Oncology News

YOUR Way

www.TheOncologyPharmacist.com©iStockphoto.com/Sean Locke

TOP_April 2011_v2_TOP 4/19/11 3:02 PM

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

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

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

Newsletter Series

��

��

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

��

��

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

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

This activity is jointly sponsored by Global Education Groupand Medical Learning Institute, Inc.

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

��

YOUR QUESTIONS ANSWERED

COEKsize40611MM

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

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

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

� �� TOP_April 2011_v2_TOP 4/19/11 3:02 PM

TOP_April 2011_v2_TOP 4/20/11 10:41 AM

march/april 2011,vol 4, no 2

Documents

cancer center profilecontinued

lung cancer diagnosis

nonsmallcell lung cancer

cancer drugs worth thecostare

joseph mercycancer care

multidisciplinary lung

purpose of dose

review of new drugs