april 2010, vol 3, no 2

CANCER CENTERPROFILE

Desert RegionalComprehensive CancerCenter Provides Varietyof Services Under One RoofBy Karen Rosenberg

The Leader

in News and

Meeting

Coverage

DRUG THERAPY

New Treatments for Chronic IdiopathicThrombocytopenic Purpura. Part 1.RomiplostimBy Michael S. Mathisen, PharmD; and Laura Boehnke Michaud, PharmD, BCOP, FASHPClinical Pharmacy Services, The University of Texas M. D. Anderson Cancer Center, Houston

©2010 Green Hill Healthcare Communications, LLC

Although thrombocytopenia is acommon problem in patientswith cancer, idiopathic throm-

bocytopenic purpura (ITP) is relativelyrare and is difficult to treat when dura-tion exceeds 6 months. ITP can beeither acute (duration ≤6 months) orchronic, can occur in both adults andchildren, and can be primary or sec-ondary to another disorder, includingthe malignancy.Primary chronic ITP is an autoimmune

condition occurring more frequently inadults, which results from antibody-medi-ated platelet destruction and is character-ized by a depressed platelet count andmucocutaneous bleeding.1,2 Althoughthe stimulus for these antiplatelet anti-bodies in primary chronic ITP remainslargely unknown, the goals of therapyinclude maintaining a platelet countabove 50,000/mm3 to avoid life-threaten-ing hemorrhagic complications. Cortico steroids are a mainstay of ther-

apy and are generally used as first-linetherapy. Re sponse rates range from 50%to 75%, but continued remission rangesfrom only 5% to 30%.2 Other optionsavailable for the management of ITPinclude rituximab, intravenous immuno-globulin, danazol, cyclophosphamide,immunosuppressive agents (eg, azathio-prine, cyclosporine), and splenectomy,which all elicit varying degrees of respon-siveness and have significant adverse

Continued on page 6

APRIL 2010 www.TheOncologyPharmacist.com VOL 3, NO 2

Chemotherapy appears tobe associated with a statis-tically significant decrease

in the relative risk of prostatecancer—specific mortality amongolder men with stage IV prostatecancer who are receiving andro-gen-deprivation therapy (ADT),according to a new study.

The findings, based on datafrom the Surveillance, Epide -miology and End Results (SEER)and Medicare databases, may helppharmacists better counsel theirolder male patients about thepotential benefits from chemo -therapy. The survival benefit,

Chemotherapy May SignificantlyBenefit Stage IV Prostate CancerPatients on Androgen-deprivation TherapyBy John Schieszer

Continued on page 12

Regist

er To

day f

or

Your

Free C

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www.coexm.com


Breast CancerTrastuzumab best givenalong with chemotherapyBased on a presentationby Edith Perez, MD

page 22

CE CreditAspirin therapy and survival in patients with colorectal cancer

page 14

Conference NewsWork-at-home pharmacist program confers multiple benefitsBased on a presentation by Sam Calabrese, RPh, MBA

page 8

Opened in 1989, the Com -prehensive Cancer Center(CCC) at Desert Regional

Medical Center was the first multidisci-plinary outpatient cancer program inthe Palm Springs, California, area. TheCCC represents the collaboration of themultispecialty regional medical centerwith Aptium Oncology, a nationalprovider of oncology management andconsulting services. The CCC nowemploys 120 healthcare professionalsand provides a full range of services,including screening, diagnosis, treat-ment, and follow-up care under oneroof. The 60,000-square-foot centerhouses a medical oncology infusioncenter, physician offices and examina-tion rooms, a radiation oncology treat-ment area, outpatient surgery facilities,a laboratory, a pharmacy, a researchdepartment, a comprehensive breastcenter, and a patient resource center.

ASCO GUThe following articles are based on presentations at the 2010ASCO Genitourinary Cancers Symposium in San Francisco.

Novel Treatment withMicrospheres ShowingPromise for Patientswith Liver CancerBy John Schieszer

GASTROINTESTINAL CANCERS

TAMPA, FLORIDA—A new interventional radiolo-gy treatment that utilizes intra-arterial yttrium-90 (Y-90) microspheres may prolong the lives of manypatients with hepatocellular carcinoma. New datapresented at the Society of Interventional Radiology’s35th annual scientific meeting showed this approachmay extend life for the more than three fourths ofhepatocellular carcinoma patients who are not eligiblefor surgery.“This is encouraging news for liver cancer patients,

especially those who have blockage in the portalvein. While patients aren’t cured, their lives are being


InsideCOMPLIMENTARY

TOP_April2010_TON 4/12/10 10:36 AM Page Cov1

You prepare anthracyclines, but are you prepared for an anthracycline extravasation?

1 Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. All images and captions are copyright © Photo Researchers, Inc. They may not be copied, reproduced or used in any way without permission from Photo Researchers, Inc. Use without permission is a breach of copyright under national and international laws.

© TopoTarget USA. All rights reserved. TOT0075/3-09 Totect and its logo mark are registered trademarks of TopoTarget USA, Inc., Rockaway, NJ, USA.

NEW LOWER PRICE OPTION Now Available Totect® (dexrazoxane for injection)

is indicated for the treatment of

extravasation resulting from

IV anthracycline chemotherapy.

ASD Healthcare (800) 746-6273

Cardinal Specialty (866) 677-4844

McKesson/OTN(800) 482-6700

Oncology Supply (800) 633-7555

US Oncology (888) 987-6679

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

First and only FDA approved treatment for anthracycline extravasation.

Supplied as a convenient and accessible complete three day emergency treatment kit, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation.

Demonstrates 98% overall e�cacy based on two biopsy-con�rmed clinical trials1,2 in preventing the need for:

o Surgical debridement, plastic surgery and related healthcare costso Postponement of a patient’s chemotherapy treatmentso Rehabilitation, follow-up and avoidance of long-term consequences

TOP_April2010_TON 4/12/10 10:36 AM Page Cov2

Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazox-ane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and admin-istration: Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the a�ected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent, supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administra-tion. Contraindications: None known. Warnings: Pregnancy Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/m2 basis) and embryotoxic and teratogenic at 8 mg/kg when given daily during the period of organogenesis. Teratogenic e�ects in the rat included imperforate anus, microphthalmia, and anophthalmia. In o�spring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg daily during the pe-riod of organogenesis caused maternal toxicity and doses of 20 mg/kg were embryotoxic and teratogenic. Terato-

genic e�ects in the rabbit included several skeletal mal-formations such as short tail, rib and thoracic malforma-tions, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-con-taining cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect is associated with leukopenia, neu-tropenia, and thrombocytopenia. Reversible elevations of liver enzymes may occur. Blood counts and liver enzymes should be monitored. Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation. Women who have the potential to become pregnant should be advised that Totect might cause fetal harm. There are no known drug interactions. No carcino-genicity studies have been done with Totect in animals. The carcinogenic potential of dexrazoxane has not been investigated. Long term dosing with razoxane (the race-mic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malig-nancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused signi�cant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Dexrazoxane is mu-

tagenic and clastogenic. The possible adverse e�ects of Totect on the fertility of humans and experimental ani-mals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administra-tion at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs. The e�ect of dexrazoxane on labor and delivery in humans has not been studied. It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The safety and e�ectiveness of Totect in pediatric patients have not been established. No di�erences in safety or e�-cacy were observed between older and younger patients, and other reported clinical experience has not identi�ed di�erences in responses between the elderly and younger patients, but greater sensitivity of some older patients has been observed. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal func-tion. Adverse reactions: Adverse reactions of nausea/vomiting, diarrhea, stomatitis, bone marrow suppression (neutropenia, thrombocytopenia), altered liver function (increased AST/ALT), and infusion site burning have been observed. These adverse reactions have been reversible.

Rx onlyTotect® is a registered trademark ofTopoTarget A/SUS Patent No. 6,727,253B2 NDC 38423-110-01

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

Hameln Pharmaceuticals GmbH31789 HamelnGermany

Manufactured for:TopoTarget A/SSymbionScience ParkFruebjergvej 3DK-2 100 CopenhagenDenmark

Marketed by:TopoTarget USA Inc.100 Enterprise DriveRockaway, New Jersey07866(866) 478-8274

www.totect.com

TOT0075/03-09©2009 TopoTarget USA

TOP_April2010_TON 4/12/10 10:36 AM Page 1

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

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

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

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

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

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

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

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

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

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

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

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

Dwight Kloth,PharmD, FCCP,BCOPFox Chase CancerCenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDNovant HealthWinston-Salem, NC

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

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

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

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

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

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

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

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

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

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

Editorial Board

2 APril 2010 I VOl 3, NO 2 www.TheOncologyPharmacist.com


FEATURE ARTICLES8 Conference News: ASHP Midyear

Clinical MeetingWork-at-home pharmacist program confers multiple benefits

Pharmacists can play important role in overseas medical mission

Chemotherapy-induced visual disturbancesoften ignored

12 Conference News: ASCO GUAdverse reactions to targeted therapies formetastatic renal cell carcinoma are reversible

14 Continuing EducationAspirin therapy and survival in patients with colorectal cancer

18 Clinical Pharmacy ReviewOptimizing dasatinib therapy for patients with chronic-phase CML

22 Breast CancerTrastuzumab best given along withchemotherapy

To protect bone, denosumab outperformszoledronic acid in breast cancer patients

24 Hematologic CancersStrong responses seen with bortezomib-basedtherapy after relapse in multiple myeloma

Bendamustine–rituximab combo an effectivefirst-line therapy for CLL

32 Pharmacy LifeCompounding in the kitchen

What you need to know about your creditscore

DEPARTMENTS

26 Oncology Drug CodesLymphomas

33 International Oncology News

APril 2010 • VOl 3, NO 2

The annual Hematology/Oncology Pharmacy As -sociation (HOPA) conference is always a reminderof the energy and enthusiasm the new genera-

tion of oncology pharmacists bring to their work andhow dynamic this field has become. The keynoteaddress at this year’s meeting by Joseph Bailes on whathealthcare reform will mean for oncology was particu-larly timely, coming just days after the President signedinto law the long-awaited Patient Protection andAffordable Care Act. As one attendee pointed out,this may have been the first major medical meeting atwhich the implications for practitioners of newlyenacted legislation were addressed. Bailes’ remarks andother reports from the meeting will be featured in theJune issue.This issue includes reports of exciting new advances

from several other recent meetings, including the recentAmerican Society of Clinical Oncology’s Gastro -intestinal Cancers and Genitourinary Cancers confer-ences, and the Society of Interventional Radiology as

well as continuing coverage of the annual mid-year meet-ing of the American Society of Health-System Pharmacists,the American Society of Hematology annual meeting, andthe San Antonio Breast Cancer Symposium. Other articles provide a more in-depth look at new

therapies for idiopathic thrombocytopenic purpura andchronic myeloid leukemia. With the requirement for RiskEvaluation and Mitigation Strategies for drugs common-ly used in oncology, such as for the erythropoiesis-stimu-lating agents darbepoetin and epoetin alfa announcedjust prior to the HOPA meeting, pharmacists will haveadditional responsibilities for educating colleagues andpatients about safe and effective use of these agents.In view of the increasing sophistication of oncology

pharmacy and the involvement of pharmacists in clinicalresearch and trials, we are planning the launch of a newpeer-reviewed journal, which will feature originalresearch by oncology pharmacists. We invite our readersto submit CVs for advisory board positions and manu-scripts to [email protected]. �

PUBLISHING STAFF

PublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Associate EditorDawn [email protected]

Director, Client ServicesJohn W. [email protected]

Production ManagerStephanie Laudien

Business ManagerBlanche [email protected]

Executive AdministratorAndrea Boylston

Circulation [email protected]

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

EDITORIAL CORRESPONDENCE should 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 manufactur-er of each drug to be administered to verify the dosage, themethod and duration of administration, or contraindica-tions. 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. ISSN #1944-9607.

The Oncology Pharmacist® is published 8 times a year byGreen Hill Healthcare Communications, LLC, 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831.Telephone: 732.656.7935. Fax: 732.656.7938. Copyright©2010 by Green Hill Healthcare Communications LLC.All rights reserved. The Oncology Pharmacist® logo is a reg-istered trademark of Green Hill Healthcare Com -munications, LLC. No part of this publication may bereproduced or transmitted in any form or by any meansnow or hereafter known, electronic or mechanical, includ-ing photocopy, recording, or any informational storage andretrieval system, without written permission from thePublisher. Printed in the United States of America.

Susan Goodin,PharmD, FCCP, BCOP

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

™

241 Forsgate Drive, Suite 205CMonroe Twp, NJ 08831

FROM THE EDITORS


CONTENTS

Patrick Medina,PharmD, BCOP


effects limiting quality of life. Whereassplenectomy is regarded as the singlebest treatment approach for refractorypatients, 30% to 40% of patients haveplatelet counts <50,000 ¥ 109/L afterthe procedure, necessitating new optionsfor salvage treatment with the goal ofmaintaining hemostasis.2Traditional therapies for ITP have

aimed at inhibiting the production ofantiplatelet antibodies; however, themajority of patients with chronic ITPalso have impaired platelet productionin the presence of normal thrombopoi-etin (TPO) levels.3 Therefore, second-generation thrombopoiesis-stimulatingagents have focused on methods tostimulate the TPO receptor, with min-imal im munogenicity and no structuralsimilarities to endogenous TPO. Romi -plostim is the first US Food and DrugAd ministration (FDA)-approved throm-bo poiesis-stimulating agent and is in dicated in patients who have had in ad-equate response to corticoste roids, im - munoglobulins, or splenectomy.4 Rom -i plostim is a recombinant protein thatbinds to the TPO receptor, stimulatingplatelet production. It bears no structur-al resemblance to endogenous TPO, thusescaping im mune recognition.

Supporting evidenceResults of two prospective, multina-

tional, double-blind, phase 3 studies wererecently published in a single manu-script, and serve as the foundation forwhich the approval of romiplostim wasgranted.3 The trials were of similardesign, and data were combined foranalysis. Both trials compared the effica-cy of romiplostim with placebo (random-

ized 2:1) in patients with ITP. One trialenrolled patients after splenectomy, andthe other enrolled nonsplenectomizedpatients; otherwise the eligibility wasidentical and included a mean plateletcount <30 ¥ 109/L, no active malignancyor history of stem-cell disorder, normalorgan function, and a hemoglobin level>9 g/dL. Continuation of concurrenttherapies for ITP was permitted at a con-stant dose and schedule, and other “res-cue” medications were allowed at anypoint of the study if needed. The startingdose of romiplostim was 1 µg/kg adminis-tered subcutaneously once weekly andwas titrated to maintain a platelet countof 50 ¥ 109/L to 200 ¥ 109/L. Plateletresponse was defined as a platelet countof ≥50 ¥ 109/L at a weekly study visit.The primary efficacy measure for thestudy was a durable response, defined asweekly platelet responses during 6 ormore of the final 8 weeks of evaluation. At the end of 24 weeks, more

patients randomized to romiplostimthan to placebo experienced a durableresponse to therapy (splenectomizedpatients, 38% vs 0%, P = .0013; non-splenectomized patients, 61% vs 4.8%,P <.0001; all patients, 49% vs 2%, Pvalue not stated; respectively). Also,significantly more patients in theplacebo group required rescue medica-tions for persistent thrombocytopenia(59.5% vs 21.7%, P <.0001). Insplenectomized and nonsplenecto mizedpatients, the median dose of romiplostimduring the study was 2 µg/kg (1 µg/kg-3µg/kg) and 3 µg/kg (2 µg/kg-7 µg/kg),respectively. However, doses required tomaintain platelet counts varied widelybetween patients in both studies.3

Dosage, administration, and toxicityIt is recommended that the lowest

possible dose of romiplostim be em -ployed to maintain a platelet count of50 ¥ 109/L; the agent should not be usedto try to normalize a patient’s plateletcount.4 The initial dose of romiplostimis 1 µg/kg based on actual body weight,administered subcutaneously onceweekly. Monitoring parameters andstrategies for dose modification can befound in the Table.Romiplostim is supplied as 250-µg or

500-µg single-use vials of powder forreconstitution. After it is adequatelymixed with preservative-free sterilewater, a clear, colorless solution contain-ing 500 µg/mL romiplostim should result.Because the final volume for injectionmay be very small, only syringes withgraduations to 0.01 mL should be used.4The most common adverse events

associated with romiplostim (occurringmore frequently than placebo) werearthralgia (26% vs 20%), dizziness (17%vs 0%), insomnia (16% vs 7%), andmyalgia (14% vs 2%).3,4 The most seri-ous adverse event noted with romi-plostim thus far is reticulin fiber deposi-tion within the bone marrow. Of 271patients, reticulin was observed on bonemarrow biopsy in 10 patients. Onepatient treated for an extended periodprogressed to bone marrow fibrosis dur-ing therapy. The manufacturer advisesthat the peripheral blood smear shouldbe closely scrutinized before startingromiplostim to establish a baseline levelof cellular abnormality.4 Worseningthrombocytopenia after discontinuationof romiplostim has been documented,and in several cases, platelet counts have

fallen below baseline levels. Thromboticcomplications and carcinogenesis arealso potentially serious complicationsassociated with romiplostim. As with allnew drugs, the true incidence of thesesevere adverse events cannot be precise-ly quantified until more experience isgained with the agent.

Restricted distribution program andmedication guideTo assure the appropriate use and safe-

ty of romiplostim, the agent is availableonly via the Network of Experts Under -standing and Supporting Nplate andPatients (NEXUS) Program. NEXUS isconsidered a risk evaluation and mitiga-tion strategy and was a condition thatthe manufacturer agreed to for the drugto gain FDA approval.5 Twice yearly,healthcare providers are contacted by aNEXUS specialist to verify the patientenrollment roster, collect safety informa-tion, and discuss whether it is appropri-ate for each enrolled patient to continuereceiving romiplostim. Pre scribers whoare enrolled must complete enrollmentand baseline data forms for each newpatient prescribed romiplostim. Theappropriate forms can be found on theNEXUS website.6 Healthcare institu-tions must enroll separately.The manufacturer of romiplostim,

Amgen, has also incorporated a manda-tory medication guide into the risk man-agement program, which is to be distrib-uted to patients along with propercounseling prior to each dose of romi-plostim. The most updated medicationguide can be downloaded from theNEXUS website.7 Serious adverseevents resulting from romiplostim ther-apy should immediately be reported toAmgen (877-675-2831) or the FDA(800-FDA-1088).

ConclusionRomiplostim is a novel, throm-

bopoiesis-stimulating agent that hasdemonstrated substantial efficacy inpatients with refractory chronic ITP.Although the long-term safety of romi-plostim has not been clearly established,this agent appears to be relatively well-tolerated in the majority of patients, butserious complications do occur and care-ful monitoring is necessary. The NEXUSrisk management program should bebeneficial in facilitating consistent mon-itoring and establishing the romiplostimrisk-benefit profile. Favorable results inpatients with ITP have encouragedinvestigation of use of romiplostim inother forms of thrombocytopenia, in -cluding thrombocytopenia secondary tomyelo dysplastic syndrome or chemo -therapy.8 The safety of romiplostim mustfirst be established in these groups of

www.TheOncologypharmacist.com6 April 2010 I VOl 3, NO 2

Drug Therapy

New Treatments for Chronic Idiopathic... Continued from cover

Table. Monitoring and Dosing Romiplostim Therapy

Monitoring parameters

Laboratory values Recommendation

Complete blood count (including Weekly until platelet count stabilizes (>50 ¥ 109/L for 4 platelet count), peripheral blood smear consecutive weeks without adjusting the dose); monthly

once stable

Dosing modificationsPlatelet count Recommendation<50 x 109/L Increase dose by 1 µg/kg

>200 x 109/L for 2 consecutive weeks Reduce dose by 1 µg/kg

>400 x 109/L Hold dose, continue to assess platelet count weekly; when platelet count is <200 x 109/L, may resume at a reduced dose by 1 µg/kg

Insufficient response If platelet count fails to increase to a level considered to avoid important bleeding after 4 weeks of the maximum recommendeddose (10 µg/kg), discontinue therapy; monitor complete blood count for at least 2 weeks after stopping romiplostim

Source: Reference 4. Continued on page 24


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

Important Safety Information• ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components

• Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%)

Please see the following brief summary of prescribing information.

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

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

ALOXI®:

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

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

Can be used with multiple-day chemotherapy regimens6†

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE

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

Distributed and marketed by Eisai Inc.

© 2009 Eisai Inc.

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

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

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

www.ALOXI.com

y-eir

mmmmeeeennnnssss6†6†6†6†


Investigators are reporting favorableresults with a program that allows ahospital pharmacy to employ phar-

macists who are not able to work on-site in the hospital.

“The program has been a ‘win-win’

for all parties involved,” said SamCalabrese, RPh, MBA, director ofinpatient pharmacy services at the

Cleveland Clinic inCleveland, Ohio.

The program hasdecreased the need foron-site pharmacists towork overtime and al -lowed them to work onpatient-care floors. Ithas also increased theamount of orders beingprocessed.

The program has also provided for thefirst time an opportunity for pharmaciststo practice their profession even whenthey are unable to work on-site at thehospital. “Other hospitals offer the sameopportunity to a much smaller degree,and there are companies that do remoteorder entry for those hospitals that don’thave third shifts. However, to my knowl-edge, we are the sole institution with anon-site pharmacy 24/7 that additionallyemploys pharmacists at home,” he said.

“When we were examining ourstaffing patterns, we tried to determinehow best to capture pharmacists in theworkforce who were not able to workon-site in the hospital setting but whononetheless had the skills required tosafely verify and process pharmacyorders,” Calabrese pointed out.

At the same time, the ClevelandClinic was experiencing a “double-digit” shortage in pharmacists. “Theshortage was so acute that our pharma-cists often had to work mandatoryextra shifts,” he added.

Pharmacists who wish to participate inthe off-site program undergo on-sitetraining that lasts about 3 months, afterwhich they are required to complete allstandard pharmacist competence assess-ments. Pharmacists who qualify for theprogram are provided with computers,cell phones, and reference materials.They typically communicate with on-sitestaff using instant messaging and the tele-phone. Order clarifications are pro cessedelectronically, using electronic signaturesand assistance from on-site pharmacists.

Calabrese said that work-at-homepharmacists are very satisfied with theprogram, and only one of 12 who signedup for the program has dropped out.

Finally, he noted that the at-homepharmacist’s ability to track orders is oneaspect of the program he would like toimprove. “If a nurse calls and says a doseis missing and wants to know if the orderis still being prepared in the IV room oris out on delivery, the at-home pharma-cist can’t answer that question,” he said.He added that an Internet-based track-ing system will soon be installed, whichshould be helpful. �


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ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

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

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

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

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

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

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

EventALOXI

0.25 mg (N=633)

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

Dolasetron 100 mg I.V.

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

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

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

Work-at-home Pharmacist Program Confers Multiple BenefitsBy Jill Stein

Sam Calabrese,RPh, MBA

ASHP MIDYEAR CLINICAL MEETING

The following articles are based on presentations at the 44th American Society of Health-System Pharmacists Midyear Clinical Meeting in Las Vegas, Nevada.


Researchers are calling for in -creased awareness of the potentialfor chemotherapy-induced visual

disturbances.“Although multiple chemotherapyagents can produce visual disturbances incancer patients, such incidents are rarelyreported,” said Bruce Wong, MS, RPh,assistant director of pharmacy for clinicalservices at Newton-Wellesley Hospitalin Newton, Massachusetts. “As a result,patients who are visually impaired due tochemotherapy are often excluded from avariety of treatments and resources thatare routinely available to patients whoare visually impaired from other causes,such as primary eye tumors, ocularmetastases, and age.”Wong and colleagues examined clini-cal trials, package inserts, and casereports in the medical literature to deter-mine which chemotherapy agents cancause visual disturbances. Next, theyreviewed their pharmacy database todetermine which of the offendingchemotherapy agents were on formularyat their hospital.

The investigators identi-fied 42 chemotherapy agentson formulary during the 12-month study period that mayinduce visual disturbances,19 of which had beenadministered. Over all, 175patients re ceived one ormore of the 19 chemothera-py agents. “These numbersdemonstrate the need forawareness, education, andvigilant tracking of these potential sideeffects,” Wong said.Some of the most commonly usedagents include anastrozole, bicalu-tamide, methotrexate, and tamoxifen.According to the medical literature,visual disturbances caused by theseagents include cataracts, conjunctivi-tis, dry eye, lacrimation, and blurredvision. Side effects may develop, de -pending on the agent, immediately,gradually, or even several years aftertreatment.About 25% of patients receivingchemotherapy agents (in cluding those

known to cause visual prob-lems) were 65 years of age orolder, and this percentage isexpected to increase, Wong ob -served. “As the populationages, many diseases affectingthe elderly such as cancer willin crease,” he said. “In fact,cancer incidence exponential-ly in creases with advancingage, and a surge in the numberof older cancer pa tients is

expected,” he added. Currently, per-sons 65 years of age and older accountfor 60% of newly diagnosed malignan-cies and 70% of all cancer deaths.Wong recommends that all health-care professionals be “keenly aware” of the potential for chemotherapy-induced visual disturbances and take amore active role in preventing them or,at the very least, informing patientsabout strategies that may improve theirquality of life.A comprehensive eye examination, forexample, should be done in cancer pa -tients before, during, and after chemo -

therapy, he said. Pharmacists, at leastthose who have contact with patients,may want to remind patients of theimportance of such an examination.It may also be helpful to make alldocuments (in cluding prescriptions)in tended for pa tients on chemothera-py ag ents known to cause visual dis-turbances available in large print oron audiotapes.Finally, he said that pharmacistsshould also consider providing infor-mation on public services such asstate-supported transportation at a re -duced rate for handicapped people;computer software that facilitateslarger font, character size, and speechcapabilities; and home aids, such astalking watches and calculators.“About 12% of patients who under-go chemotherapy develop visual prob-lems as a result,” Wong said. “It isimportant to educate our colleagues asa first step in improving the quality oflife of affected patients.” �

—Jill Stein

Chemotherapy-induced Visual Disturbances OftenIgnored

APril 2010 I VOl 3, NO 2 9www.TheOncologyPharmacist.com

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Pharmacists can make a significantcontribution to an overseas med-ical mission. In fact, the participa-

tion of a pharmacist on a recent missionto rural Kenya led by a California-basedhospital proved to be so invaluable thatall future missions to that region plan tohave a pharmacist onboard.

Bhavi Shah, PharmD, clinical phar-macist and pharmacy educator at HoagMemorial Hospital Presbyterian inNewport Beach, said, “My pharmacytraining allowed me to work as a clini-cian, educator, and dispenser.”For the past few years, the HoagHospital has been involved in an out-reach program that provides medicalresources to underserved communitiesboth locally and internationally.The medical personnel initially par-ticipating in the rural Kenya program

included physicians and registerednurses. However, the decision toinclude a dispensary as part of the serv-ices provided by the mission meantthat a pharmacist was needed. “Thedispensary serves as a laboratory, a clin-ic, and a pharmacy all rolled into one,and the first team visiting Kenya real-

ized that they couldn’t set up a dispen-sary properly without the expertise of apharmacist,” Shah said.Her responsibilities during the 10-dayprogram were highly varied. Followingmeetings with team members to assessmedical supply needs and determine dis-pensary conditions, she set up a completeformulary and worked alongside localpharmacists completing and dispensingprescriptions with assistance fromSwahili interpreters.She also helped develop lectures and

handouts on topics that had been identi-fied during prior missions as needingpharmacy education. Her “students”were pharmacists, nurses, and “clinicalofficers,” who are the equivalent ofphysicians assistants.“Sometimes we had to teach themreally simple things,” Shah noted. “Forexample, they would prescribe a babyaspirin for a child,” she said. “Theydidn’t understand that the ‘baby’ in‘baby aspirin’ did not mean that theproduct is intended for a baby.”Medical personnel in rural Kenya alsotended to overprescribe antibiotics andwere unable to distinguish between viraland bacterial infections.Shah also noted that she occasionallyfound herself working as a clinician. “Ifelt that with my clinical background, Iwas more credentialed than some of thelocal clinical officers,” she said.She cited the case of a young girlwhose eczema she diagnosed. “The localmedical personnel had not been able todiagnose her and had kept throwing [sic]antibacterials and antibiotics at herwhen all she needed was hydrocortisoneand a moisturizer,” she said.

Shah acknowledged that the pro-gram was fraught with some insur-mountable challenges. For example,most of the Kenyans in the area wherethey were working could not read orwrite so they were unlikely to retainwhat was explained to them by med-ical personnel. “So this made it diffi-cult to deliver quality care,” she said.Polygamy also led to potential prob-lems, she observed. “Men had multi-ple wives who had multiple kids,” shesaid. “And when we give out antibi-otics in varying doses to multiple fam-ily members who are all illiterate, it’seasy to see how problems may result,”she said.Another problem is that antibioticand antimalarial medications are avail-able over-the-counter, which has led tooveruse and escalating resistance.Finally, Shah said that although herresponsibilities included teaching, shealso had the opportunity to learn first-hand about clinical problems she hadnever encountered, including brucel-losis, typhoid fever, and malaria. �

—Jill Stein

Pharmacists Can Play Important Role in OverseasMedical Mission

Bruce Wong, MS, RPh

She set up a complete formulary and worked alongsidelocal pharmacists completing and dispensingprescriptions with assistance from Swahili interpreters.



extended and their quality of life isimproving with Y-90 microsphere treat-ment,” said study investigator RiadSalem, MD, MBA, who is director ofinterventional oncology at North -western Memorial Hospital, Chicago.“This is a unique interventional radiol-ogy treatment, which combines theradioactive isotope Y-90 into micro -spheres that deliver radiation directlyto a tumor. It is a particularly elegantway to give patients a cancer treatmentthat doesn’t harm the healthy cells.

Patients don’t feel sick or have any ofthe side effects that happen with stan-dard cancer treatments.”Combining the radioactive isotope

Y-90 into microspheres to deliver radia-tion directly to a tumor allows for ahigher, local dose of radiation to beused without subjecting healthy tissue

in the body to the radiation. Eachmicrosphere is about the size of five redblood cells in width. These beads areinjected through a catheter from thegroin into the liver artery supplying thetumor. The beads become lodged with-in the tumor vessels, where they exerttheir local radiation, causing cell death.Y-90 radiates from within and, becauseit is administered via the hepatic artery,it can be viewed as “internal” radiation,Salem explained. Y-90 treatment isapproved by the US Food and Drug

Administration for the treatment ofunresectable hepatocellular carcinoma.He presented data from a study

involving 291 patients with hepatocel-lular carcinoma, all of whom weretreated with intra-arterial Y-90 micro -spheres as part of a single-centerprospective study. The researchers

administered 526 Y-90 treatments(average, 1.8 per patient). They re -viewed 1250 scans to assess responseand time to progression. Survival bystage also was assessed. Overall, timeto progression was 7.9 months. Salemsaid that, in oncologic standards forthis disease, these were extremelypromising findings.The survival times differed by the

cancer staging system used: Child-Pugh A (17.2 months), Child-Pugh B(7.7 months), and Barcelona ClinicLiver Cancer staging (A, 26.9 months;B, 17.2 months). Toxicities includedfatigue (57%), transient pain (23%),nausea/vomiting (20%), and bilirubintoxicity (5%).“We take the approach that this is

definitive therapy,” said Salem in aninterview with The Oncology Phar m acist.“The trend is to move away from exter-nal beam and move to this kind of ther-apy for the liver, given the significantadvantages and the limitations of exter-nal beam.”He noted that liver cancer treatment

options are limited. Although surgicalremoval of liver tumors offers the bestcancer for a cure, it is not possible formore than three fourths of primary livercancer patients. Liver tumors are ofteninoperable because the tumor may be

too large or may have grown into majorblood vessels or other vital structures.Sometimes many small tumors arespread throughout the liver, making sur-gery too risky or impractical, Salemexplained. Historically, chemotherapydrugs and external radiation therapyhave been ineffective at curing inopera-ble liver cancer.“These are early promising results.

This information can be used to designfuture Y-90 trials and to describe Y-90 asa potential treatment option to livercancer patients,” Salem said. He notedthat this approach adds to intervention-al radiology’s nonsurgical advances forliver cancer, which in clude deliveringchemotherapy directly to the affectedorgan (chemo embolization), killing thetumor with heat (radiofrequency abla-tion), or freezing the tumor (cryoabla-tion) to treat cancer locally. �

Novel Treatment with Microspheres... Continued from cover

Gastrointestinal Cancers

“While patients aren’t cured, their livesare being extended and their quality oflife is improving with Y-90 microspheretreatment.”

—Riad Salem, MD, MBA

Medicare covers only 56% of the costs ofadministering chemotherapy and providinginfusion room services to elderly patients,according to a study of cancer care incommunity practices.

Did You Know?



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however, applied to men with stage IVprostate cancer who had metastaticdisease, but not to men with stage IVnonmetastatic disease.“Essentially what we found was that

there was about a 20% reduction in mor-tality for the people receiving chemo -therapy compared with those who didnot receive chemotherapy. Further more,what we found was that this benefit wasonly apparent in the group that hasmetastatic disease. We found no suchbenefit in the group with nonmetastaticdisease,” said lead study investigatorMichael Grabner, PhD, a postdoctoralfellow in pharmaceutical health servicesresearch at the University of MarylandSchool of Pharmacy, Baltimore.He said recent clinical trials have

demonstrated a survival benefit forchemotherapy in men with castration-resistant prostate cancer. However,this study is unique because of itsdesign and sample size. In this study,all the patients were 66 years old orolder and were diagnosed with pro -state cancer between 2000 and 2005.All the subjects were followed until

death or the end of the study period(December 31, 2007). The investiga-tors restricted the cohort to men withincident stage IV disease who hadreceived ADT. They were able toovercome observable selection bias bybalancing covariates across the treat-

ment and control groups using propensi-ty-score matching. The analysis was con-ducted for the entire cohort as well as fortwo subsets (men with metastatic diseaseand men without metastatic disease).Grabner told The Oncology Phar -

m acist that after applying inclusionand exclusion criteria, the total sam-

ple size was 4905 men. The mean ageof the men was 77 years, and 84% werewhite. This group included 1252 menwith nonmetastatic disease (mean age,73.7 years; 86.5% white) and 3653men with metastatic disease (meanage, 78 years; 83.2% white). Of the

total cohort, 23.4% received chemo -therapy (20.9% of those with non-metastatic disease and 24.2 of thosewith metastatic disease).The researchers found that for the

full unmatched sample, chemothera-py was associated with a 14% reduc-tion in the hazard of prostate cancer–

specific mortality compared with nochemo therapy. “The take-home mes-sage for oncology pharmacists is thatit is crucial to differentiate be tweenmen with stage IV prostate cancerwho have metastatic disease from themen who don’t have metastatic dis-ease,” Grabner said. “It appears thatthe ability of chemotherapy to bene-fit these patients may depend on thatdifference.”Study coinvestigator C. Daniel

Mullins, PhD, a professor of pharmacolo-gy at the University of Maryland Schoolof Pharmacy, said the study findings weresomewhat surprising since no benefit wasseen in the men with nonmetastatic dis-ease. “Our study shows that choosing theright patient to treat is important,” hetold The Oncology Pharmacist. “The phar-macist has always been the person who isin the best position to communicatewith the patient about their medicine.The physician will diagnose the disease,but the responsibility of explaining to thepatients why it is so important to takethe prescribed medicines gets transferredto the pharmacist.” �

ASCO GU

Chemotherapy May Significantly Benefit... Continued from cover

Most cases of severe treatment-related adverse reactions to thetargeted therapies for kidney

cancer appear to be reversible and re -solve after dose reduction or treatmentin terruption, according to ThomasHutson, DO, PharmD, director of geni-tourinary oncology at Baylor SammonsCancer Center, Dallas, Texas.He said optimal treatment with these

targeted agents requires proactive mon-itoring, early intervention, and appro-priate management of adverse effects.Taking these steps can help avoid un -necessary dose reductions, dose inter-ruptions, or even early treatment dis-continuation.The rapid increase in agents for

renal cell carcinoma has changed thetreatment paradigm. Sunitinib, sora -fenib, pazopanib, and bevacizumab(vascular endothelial growth factor[VEGF] targeted therapies) and tem-sirolimus and everolimus (mammaliantarget of rapamycin [mTOR] in -hibitors) have dramatically improvedoutcomes for patients with advanceddisease. Hutson pointed out, however,that these therapies are not curativeand are associated with mild-to-moder-

ate toxicity. In addition, they must beadministered long-term.“We have two main classes of agents.

We have VEGF inhibitors and we havethe mTOR inhibitors, and each class hasits own unique set of toxicities. The take-home message is that the toxicities arereadily manageable, with supportive care

or medical treatment,” he said in aninterview with The Oncology Pharm acist.“Some patients may have to have doseinterruptions, dose holidays, or dosereductions. However, we can generallymanage toxicities in most patients,allowing them to stay on therapy.”He said hypertension is the most rec-

ognized cardiovascular effect of the

VEGF inhibitors. It usually occurs earlyin the course of treatment, often withinthe first 8 to 12 weeks. Therefore, bloodpressure monitoring, and treatmentwhen necessary are recommended.Skin changes associated with both the

mTOR inhibitors and VEGF inhibitorsare very common, with an incidence as

high as 50% according to published stud-ies. The most common problems arehand-foot syndrome (VEGF in hibitors),changes in hair color and skin depig-mentation (most commonly reportedwith the VEGF inhibitors sunitinib andpazopanib), skin rashes, acral erythema,subungual splinter hemorrhages, andmucositis/functional stomatitis.

Changes in glucose and cholesterolmetabolism are expected toxicities ofmTOR inhibitors (temsirolimus andeverolimus), and close monitoring offasting blood glucose and hemoglobinA1C in patients treated with mTOR inhibitors is required, Hutson advised. “One of the concepts that has

emerged from our pharmacokineticstudies of the drugs is the concept thatmore is better. We really need to try tomaintain dose intensity, keep the doseas high as possible with managing tox-icity to allow the best quality of life forpatients,” Hutson said. Pharmacists need to play a key role in

educating patients about the expectedtoxicities and making sure the patientsare aware of the importance of earlyrecognition of the toxicities. “This hasbeen an explosive time for renal cell car-cinoma, with a number of new drugsapproved. We essentially have had sixnew drugs approved in a little over 3years, and with that is a steep learningcurve for physicians, pharmacists, nurses,and others involved in supportive care,Hutson noted. �

—John Schieszer

“We really need to try to maintaindose intensity, keep the dose as highas possible with managing toxicity toallow the best quality of life forpatients.”

—Thomas Hutson, DO, PharmD

Adverse Reactions to Targeted Therapies forMetastatic Renal Cell Carcinoma Are Reversible

“Essentially what we found was thatthere was about a 20% reduction inmortality for the people receivingchemotherapy compared with thosewho did not receive chemotherapy.”

—Michael Grabner, PhD

TOP_April2010_TON 4/12/10 1:17 PM Page 12

CONTINUING EDUCATION

Although aspirin is best known for itsuses as an analgesic, antiinflamma-tory, or cardiovascular prophylactic,

regular aspirin use also may prevent co l-orectal adenoma and colorectal cancer(CRC).1 Aspirin’s ability to inhibit colorec-

tal tumor growth is probably due, in part, toits inhibition of cyclooxygenase-2 (COX-2).2,3 The COX-2 enzyme is overexpressedin most colorectal cancer, and is known toinhibit natural cell death, encouragegrowth of tumor blood vessels, and increasetumor invasiveness.4-6Despite aspirin’s protective effect against

colorectal neoplasia, it is not recommended asa CRC chemopreventive agent due to con-cern over its potential harmful effects, includ-ing an increased risk for hemorrhagic strokeand gastrointestinal bleeding. However, theremay be a role for aspirin use in colorectal can-cer prevention among those at extremelyhigh risk of dying from the disease. One suchsubgroup is patients diagnosed with non-metastatic colorectal cancer. Although theirprognosis is generally more favorable co m- pared with patients who present withmetastatic disease, patients with, for example,stage III disease have as high as a 40% chanceof recurrent cancer and death.7 Thus, if an inexpensive, widely used med-

ication such as aspirin could improve survivalwhen added to conventional surgery andchemotherapy, it would represent a significantadvance in the treatment of CRC. CRC is thethird most common type of cancer in menand women. It is also the second most com-mon cause of cancer-related death in men andthe third most common cause of cancer-relat-ed death in women. According to estimatesfrom the National Cancer Institute, almost50,000 patients will die of CRC in 2009.8

Study analyzes data from two largeprospective cohortsAlthough a role for aspirin in reducing

CRC incidence is well-established, it is notclear whether aspirin can influence progno-sis in patients with confirmed CRC. Todetermine the effect of aspirin use after diag-nosis of CRC on survival, my colleagues andI conducted a prospective cohort study of1279 patients with nonmetastatic (stage I, II,and III) CRC.9 Our patients were drawnfrom two large, ongoing prospective stud-ies—the Nurses’ Health Study and theHealth Professionals Follow-up Study. Atthe time of enrollment in these two studies,no patient had been diagnosed with colorec-tal cancer. Of the 1279 patients, 560 usedaspirin regularly before the diagnosis of CRCand 549 used it after the diagnosis.Because patients were asked to provide

information on their use of aspirin every 2years, we were able to determine the effect ofprediagnosis and postdiagnosis aspirin use onsurvival in patients with established CRC.We also assessed whether the effect of aspirinvaried according to levels of tumoral expres-sion of COX-2.

Results show reduced mortality withaspirinAfter a median follow-up of 11.8 years,

there were 193 (35%) total deaths and 81(15%) deaths due to CRC among the 549patients who took aspirin regularly afterbeing diagnosed with CRC. Among aspirinnonusers, there were 287 (39%) totaldeaths and 141(19%) deaths due to CRC.Overall 5-year survival for the entire cohortwas 88% for aspirin users compared with83% for nonusers; 10-year survival rateswere 74% and 69%, respectively. Multi -variate analysis showed that patients who

Aspirin Therapy and Survival in Patientswith Colorectal CancerBy Andrew T. Chan, MD, MPH Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

PROGRAM TOP2 • RELEASE DATE: APRIL 15, 2010 • EXPIRATION DATE: APRIL 15, 2011

ESTIMATED TIME TO COMPLETE: 1.0 HOUR EDITORIAL BOARDAndrew T. Chan, MD,MPHGastrointestinal UnitMassachusetts GeneralHospital55 Fruit StreetGRJ 724Boston, MA 02114

Betty M. Chan, PharmD,BCOPAssistant Professor ofClinical Pharmacy andPharmaceutical Economics& PolicyUniversity of SouthernCalifornia

Clinical ProfessorUSC/Norris ComprehensiveCancer Center1441 Eastlake AvenueLos Angeles, CA 90033

PLANNING COMMITTEEGloria MuiMedical DirectorVeritas Institute for MedicalEducation, Inc.611 Route 46 West Hasbrouck Heights, NJ07604

Julie Ann TagliareniCME DirectorVeritas Institute for MedicalEducation, Inc.611 Route 46 West Hasbrouck Heights, NJ07604

Anne L. FingerPresidentVeritas Institute for MedicalEducation, Inc.611 Route 46 West Hasbrouck Heights, NJ07604

Dawn LagrosaAssociate EditorGreen Hill HealthcareCommunications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Karen RosenbergEditorial DirectorGreen Hill HealthcareCommunications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Jill Stein22 rue MalherParis, France 75004

STATEMENT OF NEEDBecause colorectal cancer (CRC) remains the thirdmost frequently diagnosed cancer in both men andwomen and the third leading cause of cancer-relat-ed death for both sexes, there is great interest inreducing both the incidence and mortality associat-ed with this disease. However, data regardingaspirin use and survival after a diagnosis of CRCare unknown. Therefore, the most recent data re -garding aspirin and CRC are met with great inter-est. Oncology pharmacists should be aware of themost recent data in order to be able to discussresults with patients diagnosed with CRC.

TARGET AUDIENCERegistered pharmacists, and other interested health-care professionals, especially those caring for cancerpatients

LEARNING OBJECTIVESAfter completing this activity, the reader should bebetter able to:• Explain the rationale for use of aspirin to protectagainst colorectal cancer

• Describe the effects of prediagnosis and postdiagnosis use of aspirin on survival in patientswith diagnosed colorectal cancer

• Discuss potential indications and contraindica-tions for aspirin use in patients at risk for co lo rectalcancer

CONTINUING PHARMACY EDUCATION ACCREDITATIONAND CONTACT HOURS STATEMENTVeritas Institute for Medical Education, Inc is accredited by the Accreditation Council forPharmacy Education as a provider of continuing pharmacy education. This program(UPN 0394-0000-10-003-H01-P) is acceptable for 1.0 Contact Hours. Initial releasedate: April 15, 2010. A statement of credit will be available online to participants whosuccessfully complete the program, learning assessment (>70%), and program evalu-ation form. There is no registration or processing fees.

METHOD OF PARTICIPATION1. Read the article in its entirety2. Log on to www.TheOncologyPharmacist.com3. Click on “CE Credits”4. Click on “Click here to complete the posttest and obtain a CE certificate online”5. Register to participate6. Enter program number TOP27. Complete and submit the CE posttest and CE Activity Evaluation and Request forCredit Form online

8. Print your statement of credit

This activity is provided free of charge to participants.

FINANCIAL DISCLOSURESVeritas Institute for Medical Education, Inc. is required to dis-close to the activity audience the relevant financial relation-

ships of the planners and faculty involved in the development of CE content. An indi-vidual has a relevant financial relationship if he or she has a financial relationship in anyamount occurring in the last 12 months with a commercial interest whose products orservices are discussed in the CE activity content over which the individual has control.In addition, all faculty are expected to openly disclose any unlabeled/unapproved/inves-tigational uses of drugs or devices discussed in this activity. Disclosures are as follows:• Andrew T. Chan, MD, MPH, has nothing to disclose.• Betty M. Chan, PharmD, BCOP, has received research/grant support from Merck & Co.The staff of Veritas Institute for Medical Education, Inc. and Green Hill HealthcareCommunications, LLC have nothing to disclose.

DISCLAIMERThe opinions expressed in this activity are those of the presenters and do not necessar-ily reflect the opinions or recommendation of Veritas Institute for Medical Education, Inc.

Copyright © 2010 Veritas Institute for Medical Education, Inc. All rights reserved.



used aspirin regularly after being diag-nosed with CRC had a 29% lower riskof death from CRC than those who didnot take aspirin (multivariate hazardratio [HR], 0.71; 95% confidence inter-val [CI], 0.53-0.95) and a 21% lowerrisk of overall mortality (multivariateHR, 0.79; 95% CI, 0.65-0.97). Pre -diagnosis use of aspirin, in contrast, wasnot associated with either CRC-specificor overall mortality.Aspirin’s benefit was most pro-

nounced in patients whose primarytumors overexpressed COX-2; thesepatients were 61% less likely to die ofCRC if they took aspirin after their diag-nosis than patients with similar COX-2levels who did not take aspirin (multi-

variate HR, 39; 95%CI, 0.20-0.76).Patients with COX-2–positive tumorsalso had a 38% lower risk of overall mor-tality (multivariate HR, 0.62; 95% CI,0.42-0.93). The findings, which are con-sistent with those of other human andexperimental data, suggest that COX-2–positive tumors may be relatively sensi-tive to the effects of aspirin whereasCOX-2–negative tumors may be rela-tively aspirin-resistant.Among study subjects who had not

used aspirin regularly before diagnosis,the association between postdiagnosisaspirin use and survival was found to bemodestly dose-responsive. Comparedwith subjects who used any aspirin, themultivariate-adjusted HR for CRC-spe-

cific mortality was 0.57 (95% CI, 0.32-0.99) for those who used 0.5 to 5 standardaspirin tablets and 0.49 (95% CI, 0.18-1.35) for those who used six or moretablets per week (P for trend = .04).

Study strengths and limitationsWe believe that our study has sever-

al notable strengths. For example, weused prospective data on aspirin use,which allowed us to minimize the pos-sibility that patients would be inaccu-rate in their recollection of theiraspirin use. Also, we compiled data onaspirin use both before and after pa -tients had been diagnosed with CRC,which enabled us to clearly distinguishthe effect of aspirin use after diagnosis

from that of aspirin use be fore diagnosis.Notably, all study participants werehealth professionals, and health profes-sionals are presumably more likely to pro-vide an accurate report of aspirin use.Perhaps the key study limitation is its

observational design. We examinedaspirin use in individuals who hadeither decided on their own to takeaspirin or in whom aspirin had beenprescribed for some other condition.Observational studies are generally lessreliable than placebo-controlled stud-ies. Our results thus need to be con-firmed in placebo-controlled trials ofaspirin or associated agents as adjunctsto other standard CRC treatments.

www.TheOncologyPharmacist.com

COMMENTARY

The Use of Aspirin for Chemoprevention or asAdjuvant Therapy for Colorectal Cancer: WhereAre We Today?Betty M. Chan, PharmD, BCOP Assistant Professor of Clinical Pharmacy and Pharmaceutical Economics & Policy, University of Southern California, Los Angeles

Much is known about the use ofaspirin as a cardioprotectiveagent for prevention and

treatment of myocardial infarction andacute and transient ischemic stroke.Now studies are emerging regarding thepotential use of aspirin as primarychemoprevention of colorectal adeno-mas1 and as adjuvant therapy for co -lorectal cancer.2In a large cohort study conducted

by Chan and colleagues,2 the users ofaspirin had a 29% lower cancer-spe-cific mortality (hazard ratio [HR],0.71; 95% confidence interval [CI],0.53-0.95) and a 21% lower overallmortality (HR, 0.79; 95% CI, 0.65-0.97) among patients with colorectalcancer (stages I-III) compared withnonusers. When aspirin was initiatedin patients who were nonusers beforetheir colorectal cancer diagnosis,cancer-specific mortality was 47%lower (HR, 0.53; 95% CI, 0.33-0.86)and the benefit was greatly observedin patients with colorectal cancerthat overexpressed cyclooxygenase-2(COX-2) enzyme. For the entirecohort, the study reported an overall5-year survival rate of 88% for aspirinusers compared with 83% for non -users, and an overall 10-year survivalrate of 74% for aspirin users com-pared with 69% for nonusers. Theresults from this study further posethe question of the potential role ofaspirin as adjuvant therapy in co lorec-

tal cancer patients who overexpressthe COX-2 enzyme.About 80% to 85% of colorectal

cancers overexpress the COX-2 en -zyme, which promotes inflammationand cell proliferation. The overexpres-sion of the COX-2 enzyme has beenassociated with a poorer prognosisamong patients with colorectal can-cers.3,4 Although celecoxib, a selectiveCOX-2 enzyme inhibitor, is US Foodand Drug Administration–approved foruse to reduce the number of intestinalpolyps in patients with familial adeno-matous polyposis, its use has been asso-ciated with cardiovascular toxicity.5Aspirin, like nonsteroidal antiinflam-matory drugs, also has inhibition activ-ity against both the COX-1 and COX-2 enzymes; and although the use ofaspirin is widely used as a cardioprotec-tive agent, its use as primary chemopre-vention of colorectal cancer is current-ly not recommended by clinicalguidelines because of concern withadverse effects, primarily gastrointesti-nal irritation and bleeding and thepotential need for long-term therapy.6Although studies have demonstrated

the use of aspirin as effective in reduc-ing the incidence of colorectal adeno-ma and colorectal cancer, the potentialadverse effects from long-term aspirinuse remain a concern. Monitoringguidelines are needed. Co admin istra -tion of a proton pump inhibitor alongwith the use of aspirin has been pro-

posed as a treatment option and is cur-rently being investigated in a clinicaltrial. Until more safety and efficacydata are available, screening is still themost important step people can taketo protect themselves against colorec-tal cancer.Screening guidelines are available

for patients and healthcare profession-als from the National ComprehensiveCancer Network.7 In addition, newcolorectal cancer screening recommen-dations were also published in 2008from the US Preventive Services TaskForce.8,9 Joint guidelines from theAmerican Cancer Society, the USMultisociety Task Force on ColorectalCancer, and the American College ofRadiology are also available.10All guidelines recommend screening

to begin at age 50 for both men andwomen. Screening should start earlierin patients with:• Increased risk factors, such as a per-sonal history of adenoma/polyps,colorectal cancer, or in flammatorybowel disease, or a positive familyhistory of colorectal cancer

• Presence of Lynch syndrome/her -editary nonpolyposis colorectalcancer or polyposis syndromes

• Symptoms of colorectal cancer.

References1. Cole BF, Logan RF, Halabi S, et al. Aspirin for

the chemoprevention of colorectal adenomas:meta-analysis of the randomized trials. J NatlCancer Inst. 2009;101:256-266.

2. Chan AT, Ogino S, Fuchs CS. Aspirin use andsurvival after diagnosis of colorectal cancer.JAMA. 2009;302:649-659.

3. Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expressionin human colorectal adenomas and adenocarci-nomas. Gastroenterology. 1994;107:1183-1188.

4. Ogino S, Kirkner GJ, Nosho K, et al. Cyclo -oxygenase-2 expression is an independent pre-dictor of poor prognosis in colon cancer. ClinCancer Res. 2008;14:8221-8227.

5. Solomon SD, Wittes J, Finn PV, et al; for theCross Trial Safety Assessment Group. Cardio -vascular risk of celecoxib in 6 randomized place-bo-controlled trials: the cross trial safety analysis.Circulation. 2008;117:2104-2113.

6. Dubé C, Rostom A, Lewin G, et al; for the USPreventive Services Task Force. The use ofaspirin for primary prevention of colorectal can-cer: a systematic review prepared for the U.S.Preventive Services Task Force. Ann InternMed. 2007;146:365-375.

7. National Comprehensive Cancer Network.Clinical Practice Guidelines in Oncology: Co lorectalCancer Screening. V.1.2010. www. nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf. Accessed Jan uary 27, 2010.

8. US Preventive Services Task Force. Screeningfor colorectal cancer: U.S. Preventive ServicesTask Force Recommendation Statement. AnnIntern Med. 2008;149:627-637.

9. Whitlock EP, Lin JS, Liles E, et al. Screening forcolorectal cancer: a targeted, updated systemat-ic review for the U.S. Preventive Services TaskForce. Ann Intern Med. 2008;149:638-658.

10. Levin B, Lieberman DA, McFarland B, et al; forthe American Cancer Society ColorectalCancer Advisory Group; US Multi-SocietyTask Force; American College of RadiologyColon Cancer Committee. Screening and sur-veillance for the early detection of colorectalcancer and adenomatous polyps, 2008: a jointguideline from the American Cancer Society,the US Multi-Society Task Force on ColorectalCancer, and the American College ofRadiology. CA Cancer J Clin. 2008;58:130-160.




Summary and conclusionWhat we now know

• Patients with CRC who take aspirinmay reduce their risk of dying fromthe disease by nearly 30%.

• Aspirin use after rather than beforethe development of stage I, II, or IIIcancer is associated with improvedsurvival.

• Aspirin appears to primarily benefitonly those patients whose primarytumors test positive for the COX-2enzyme.

• Patients with stage III disease at thetime of diagnosis derive as much ben-efit from aspirin use as patients whohave stage I or II disease at diagnosis.

• Former aspirin users obtain lessbenefit from subsequent aspirin usethan former nonusers.

• Our data suggest that aspirin mayalter the biology of established co -lorectal tumors (ie, reduce the riskof recurrence among patients withcancer) in addition to preventingtheir occurrence (ie, reduce the riskof developing an initial cancer). At

this time, it is unclear exactly howaspirin interacts with the tumor toimprove survival.

• Our data demonstrate the potentialfor using COX-2 as a marker to tai-lor aspirin use in patients withnewly diagnosed CRC.

What we do not know• Because the study was observation-

al, we were not able to determinewhat roles factors other than aspirinmay have played in decreasing can-cer deaths.

• We do not know yet whether allpatients with CRC will benefit fromaspirin so we cannot make recom-mendations yet about who shouldtake it and how often and at whatdose. All these questions require ad -ditional research, including placebo-controlled trials of aspirin as adju-vant therapy for CRC. An ongoingstudy being conducted in Asia iscomparing aspirin with placebo inpatients with nonmetastatic CRC.10

At this time, we cannot make broad

recommendations about the use ofaspirin in patients with CRC. Somepatients may already be taking aspirin forother reasons, such as heart attack pre-vention. However, the risk of serious sideeffects with long-term exposure meansthat physicians should not prescribeaspirin to treat CRC until the evidencein favor of a significant benefit is defini-tive and until there is proof that its bene-fits outweigh its risks. For now, the besttreatments for CRC are surgery, chemo -therapy, and radiation therapy.

References1. Dubé C, Roston A, Lewin G, et al; for the U.S.

Preventive Services Task Force. The use ofaspirin for primary prevention of colorectal can-cer: a systematic review prepared for the U.S.Preventive Services Task Force. Ann Intern Med.2007;146:365-375.

2. Chan AT, Ogino S, Fuchs CS. Aspirin and therisk of colorectal cancer in relation to theexpression of COX-2. N Engl J Med. 2007;356:2131-2142.

3. Markowitz SD. Aspirin and colon cancer—tar-geting prevention? N Engl J Med. 2007;356:2195-2198.

4. Brown JR, DuBois RN. COX-2: a molecular tar-get for colorectal cancer prevention. J ClinOncol. 2005;23:2840-2855.

5. Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expressionin human colorectal adenomas and adenocarci-nomas. Gastroenterology. 1994;107:1183-1188.

6. Soumaoro LT, Uetake H, Higuchi T, et al.Cyclooxygenase-2 expression: a significantprognostic indicator for patients with colorectalcancer. Clin Cancer Res. 2004;10:8465-8471.

7. Goldberg RM. Intensive surveillance after stageII or III colorectal cancer: is it worth it? J ClinOncol. 2006;24:330-331.

8. Surveillance Epidemiology and End Results.SEER Stat Fact Sheets: colon and rectum. Basedon November 2008 SEER data submission, post-ed to the SEER website, 2009. http://seer.cancer.gov/statfacts/html/colorect.html. AccessedNovember 25, 2009.

9. Chan AT, Ogino S, Fuchs CS. Aspirin use andsurvival after diagnosis of colorectal cancer.JAMA. 2009;302:649-659.

10. National Cancer Institute. Clinical trials(PDQ): phase III randomized study of acetylsal-icylic acid (aspirin) in patients with completelyresected Dukes stage C colon or rectal cancer,Dukes stage B rectal cancer, or high-risk Dukesstage B colon cancer. January 30, 2009. http://www.cancer.gov/search/viewclinicaltrials.aspx?cdrid=577892&version=healthprof. AccessedNovember 25, 2009.

Jill Stein contributed to preparation of thismanuscript.

CONTINUING EDUCATION

Continued from page 15

Aspirin Therapy...


The center employs a multidisciplinaryteam of physicians with expertise in allthe major types of cancer and offers avariety of treatment options, includingchemotherapy, radiation therapy, genetherapy, and surgery. Patients haveaccess to on-site psychosocial, nutri-tional support, and financial counsel-ing services. In addition, the CCC pro-vides genetic testing for women at highrisk for breast or ovarian cancer, a hos-pice program, a pain management pro-gram, support groups, and volunteerservices. Because of its excellent repu-tation, patients come from far away tobe treated at Desert Regional CCC,and social workers help arrange hous-ing for patients and their families;translators are available to assist for-eign visitors.

Pharmacist plays many rolesThrough its affiliation with Aptium

Oncology–managed cancer centersthroughout the country, the CCCoffers patients the opportunity to par-ticipate in phase 1 to 4 clinical trials.Oncology pharmacist Craig Elg,PharmD, BCOP, coordinates clinicaltrials in addition to his other responsi-bilities. “At any given time, we have 40to 50 clinical trials open and running,”he says. “One of my responsibilities isto make sure that the pharmacy portionof those trials is running smoothly andcorrectly. I go to the site initiation vis-its and meet with the monitors to makesure that the protocol is being followedproperly, the drugs are being stored inthe correct manner, destruction poli-cies are being followed, and all the

paperwork is done. Since we implement-ed our electronic medical record (EMR),I’m also involved in building the proto-cols for all the new research trials. Oncewe sign on to do something, those ordersets are put into the EMR so that thephysicians have easy access to them.”

In addition to their more traditionalresponsibilities for counseling patientsand providing support to medical staff ona variety of supportive care issues, such asfatigue and pain management, Elg andhis fellow pharmacists at the center havethe ability through special California lawto prescribe controlled substances tohelp manage patients with cancer pain.

Desert Regional CCC provides anenvironment in which employees areencouraged to do new things and take onnew responsibilities, Elg has found. “You

get a lot of support from Administrationand the medical staff. It is a very collab-orative practice here and definitely anenjoyable place to work.”

Nurse appreciates range ofspecialties

Oncology nurse Kristin Rupp, RN,BSN, OCN, agrees, saying, “We feel as ifwe are a family here. Coming here as atransplant from Indiana, it has been verywelcoming.” Rupp previously worked onthe oncology floor of a local hospital inIndiana and in private oncology prac-tices in Indiana and California. In herprevious jobs, she says the nurses had totake on other responsibilities, such asmixing chemotherapy, in addition totheir nursing duties. “We wore all hats.We were the nurse; we administeredchemotherapy in our office; we ran thelab; we were the social worker; the dieti-tian, everything.” At the CCC, she says,“I can rely on all the different profes-sions—the pharmacists, the dietitians,social workers, and others—to add theirknowledge and expertise to taking careof the patient as a whole. This allows meto focus on my nursing role.” There arealso advantages for patients. “We haveeverything here under one roof,” makingit possible for patients to see differentspecialists in one visit, she notes. “Thelevel of expertise that I am surroundedby every day makes care of the patienttop notch.” �

CANCER CENTER PROFILE

Desert Regional Comprehensive Cancer Center... Continued from cover

Multidisciplinary staff of Desert Regional Comprehensive Cancer Center.


A Newsletter Series for Cancer Care Professionals

Center of Excellence Media, along with Editor-in-ChiefSagar Lonial, MD, of Emory University, are pleased tooffer your multidisciplinary cancer team this series ofnewsletters focusing on the challenges of treatingpatients with multiple myeloma.

SAGAR LONIAL, MDAssociate Professor of

Hematology and Oncology Emory University School of Medicine

� Earn Continuing Education Credits �

Each newsletter will feature:

These activities are supported by an educational grant from Millennium Pharmaceuticals, Inc.

• Front-line therapy• Maintenance Settings• Transplant Settings• Retreatment Settings

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• Contributions from thought-leadingphysicians, nurses, and pharmacists

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CASE STUDY DISCUSSIONS:

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

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Clinical Pharmacy Review

Chronic myeloid leukemia (CML)is characterized by the presenceof the Philadelphia chromo-

some (Ph), which is formed by geneticexchange between chromosomes 9 and22 and codes for the pathogenic tyrosinekinase BCR-ABL.1-3 Historically, thera-peutic interventions for CML haveincluded busulfan, hydroxyurea, interferon-a, and stem cell transplantation.4These therapies vary greatly in tolerabil-ity, toxicity, and efficacy. Current treat-ment options primarily comprise thetyrosine kinase inhibitors that targetBCR-ABL, which have revolutionized

the treatment of this disease. Imatinibwas the first BCR-ABL inhibitor to beapproved by the US Food and DrugAdministration (FDA) for CML. It iscurrently the standard first-line treat-ment, although its use is limited by resist-ance and/or intolerance. In the Inter -national Randomized Interferon andSTI-571 (IRIS) trial, 31% (171/553) ofpatients randomized to imatinib discon-tinued the study within 5 years of fol-low-up because of unsatisfactory thera-peutic effect, adverse events (AEs),switching to alternative treatment, orother reasons.5Subsequent BCR-ABL–targeted ag -

ents have been developed and ap proved:dasatinib and nilotinib. Pre clinical stud-ies have indicated that dasatinib was the

most potent inhibitor of native (unmu-tated) BCR-ABL. Indeed, both dasatiniband nilotinib were shown to be morepotent than imatinib (dasatinib, ~325-fold; nilotinib, ~20-fold).6Dasatinib was initially approved in

June 2006 based on data from the phase2 SRC/ABL Tyrosine Kinase InhibitionActivity: Research Trials of Dasatinib(START) study. START consisted of aseries of multicenter, open-label studiesof dasatinib 70 mg twice daily in chron-ic-phase (CP), accelerated-phase (AP),or myeloid or lymphoid blast crisis (BC)CML with resistance or intolerance toprior therapy, including imatinib.7-10Results from a recent dose-optimizationstudy (CA180-034) have led to a newlyapproved starting dose for dasatinib in

patients with CP CML: 100 mg admin-istered orally once daily in the morningor in the evening. For patients with APCML, BC CML, or Ph+ acute lym-phoblastic leukemia (ALL), the dosehas also recently changed to a oncedaily schedule of 140 mg.

Pharmacokinetic informationPharmacokinetic analysis demon-

strated that dasatinib reaches maximumplasma concentration between 0.5 and 6hours after oral administration. At adose range of 15 mg/day to 240 mg/day,elimination is linear, and increase inarea under the curve is proportional tothe dose. The overall mean terminalhalf-life is 3 to 5 hours. These resultswere, in part, the rationale for twice-daily dosing. Once-daily dosing hasproved to be at least as effective astwice-daily dosing, with an improvedtolerability profile.11,12 Binding of dasa-tinib and its active metabolite to humanplasma proteins in vitro was approxi-mately 96% and 93%, respectively, withno concentration dependence withinthe range of 100 ng/mL to 500 ng/mL.12Dasatinib is metabolized primarily to

its active metabolite by the cytochromeP450 enzyme 3A4 (CYP3A4). Theactive metabolite is unlikely to play amajor role in the observed pharmacolo-gy of the drug, because it represents only5% of the dasatinib area under thecurve. In the human liver, dasatinib is atime-dependent inhibitor of CYP3A4but does not induce human CYPenzymes. Elimination is primarily viathe feces (85%) and urine (4%).12

Drug interactionsBecause dasatinib is a CYP3A4 sub-

strate, the use of CYP3A4 inhibitorsmay increase exposure to dasatinib andshould be avoided. If CYP3A4 in -hibitors must be used, toxicity shouldbe monitored closely and dosages de -creased as needed (Table 1). Caution iswarranted any time azole antifungals,marcrolides, or antiretrovirals are usedconcurrently with dasatinib.Concurrent use of CYP3A4 inducers,

such as rifampin, may decrease dasatinibplasma concentrations. Agents with lessenzyme-induction potential would bepreferable in patients who requireCYP3A4 inducers; dasatinib dose escala-tion in 20-mg increments is recommend-ed if it is necessary to use CYP3A4

Optimizing Dasatinib Therapy forPatients with Chronic-phase CMLBy Timothy Tyler, PharmD, FCSHPDirector of Pharmacy Services, Comprehensive Cancer Center, Desert Regional Medical Center,

Palm Springs, California

Table 1. Recommendations for Concomitant Administration of Dasatinib with CYP3A4 Inhibitors orInducers

CYP3A4 Inhibitors CYP3A4 Inducers

Agents Ketoconazole, itraconazole, Dexamethasone, phenytoin,erythromycin, clarithromycin, carbamazepine, rifampin, phenobarbitalritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin

Actions Toxicity should be monitored closely CYP3A4 inducers with less enzyme and dasatinib dose reduction of 20 induction potential should be used if mg/day-40 mg/day should be considered possible; dose increases of dasatinib

in 20-mg increments is recommended

CYP3A4 indicates cytochrome P450 enzyme 3A4.Source: Reference 12.

Table 2. Adverse Reactions Reported in ≥20% of Patients in Dasatinib Clinical Studies of CML

100 mg once daily 140 mg once daily

Chronic phase Accelerated phase Myeloid blast crisis Lymphoid blast crisis(n = 165) (n = 157) (n = 74) (n = 33)

All grades Grades 3/4 All grades Grades 3/4 All grades Grades 3/4 All grades Grades 3/4

Fluid retention 34 4 35 8 34 7 21 6

Diarrhea 27 2 31 3 20 5 18 0

Headache 33 1 27 1 18 1 15 3

Skin rash 17 2 15 0 16 1 21 0

Nausea 18 1 19 1 23 1 21 3

Hemorrhage 11 1 26 8 19 9 24 9

Fatigue 24 2 19 2 20 1 9 3

Dyspnea 20 2 20 3 15 3 3 3

CML indicates chronic myeloid leukemia. Source: Reference 12.





inducers. Use of St. John’s wort should beavoided, because it may also decrease thedasatinib plasma concentrations.Because the solubility of dasatinib is

dependent on pH, concomitant adminis-tration of dasatinib and antacids candecrease the absorption of dasatinib;therefore, it is recommended that an t -acids be taken at least 2 hours before orafter dasatinib administration. Con -comitant use of proton pump in hibitorsmay reduce bioavailability of dasatiniband thus, ideally, should be avoided.Antacids would be the preferred therapyto use in place of proton pump in hibitors.Although not studied, the use of H2antagonists could also be a cause for con-cern, because their mechanisms of actionindirectly impact acid secretion in thegastrointestinal tract.

AEs and monitoringIn clinical studies, the most frequently

reported adverse reactions to dasatinib(reported in ≥20% of patients) are pre-sented in Table 2. The most frequentlyreported serious adverse reactions withclinical implications included pleuraleffusion (11%), pneumonia (3%), infec-tion (2%), febrile neutropenia (4%), gas-trointestinal bleeding (4%), dyspnea(3%), sepsis (1%), congestive heart fail-ure (2%), and pericardial effusion(1%).12 Of these, the incidence of pleu-ral effusion is particularly concerning.Patients who may develop symptomssuggestive of pleural effusion, such as dys-

pnea or dry cough, should be evaluatedby chest radiograph because early inter-vention is desirable. Fluid-retentionevents can usually be managed by sup-portive care mea sures that includediuretics or short courses of steroids.Severe pleural effusion (occurring in 2%of patients) may require thoracentesisand oxygen therapy. Fluid retentionevents were reported less frequently inpatients treated with 100 mg/day than inpatients treated with 70 mg twice daily,thus providing more than just conven-ience or compliance as an incentive forthe newly approved dosing schema.Treatment with dasatinib is also associ-

ated with cytopenias. Nearly half thepatients treated experienced neutropeniaand thrombocytopenia; 18% demonstrat-ed anemia. With this in mind, completeblood counts should be performed week-ly for the first 2 months then monthlythereafter (or as clinically indicated).Myelosuppression is generally reversibleand usually managed by dose reductionsor interruptions (Table 3).12 Myeloidgrowth factors and/or platelet transfu-sions may help lessen the risks of compli-cations associated with neutropenia andthrombocytopenia, respectively, and re -duce the need for dose modification.13,14Similar to fluid-retention events, throm-bocytopenia was reported less frequentlyin patients treated with 100 mg/day thanwith 70 mg twice daily.Cardiotoxicity has been described

infrequently in patients receiving dasa-

tinib, with an incidence of 3% in 911patients reported in the prescribinginformation.12 There is also in vitro evi-dence of prolonged cardiac ventricularrepolarization (QT interval) in patientsreceiving dasatinib. In clinical studies,these QTc interval changes from base-line were 3 millisecond to 6 millisecond.Nine patients had QTc prolongationreported as an AE, and three patients(<1%) experienced a QTc greater than500 millisecond. Cardio toxicity has alsobeen reported with imatinib15 and mostrecently with nilotinib, which has a blackbox warning included in the prescribinginformation highlighting the risk of QTprolongation and sudden death.16 Al -though the incidence of cardiotoxicitydiffers between agents, these AEs may berelated to BCR-ABL inhibition and,therefore, may be genuine class effects.Further research is needed to clarify themechanisms underlying these effects, andthe use of tyrosine kinase inhibitors ingeneral may benefit from closer monitor-ing of cardiac function.17

Clinical data supporting change todasatinib prescribing informationThe dasatinib 70-mg twice-daily regi-

men used in phase 2 studies and subse-quently FDA-approved was selectedbased on phase 1 study data, whichshowed that BCR-ABL kinase inhibitionwas more sustained across a 24-hour peri-od with the twice-daily schedule thanwith the once-daily schedule.18 However,

major cytogenetic response (MCyR) wasachieved regardless of treatment schedulein this phase 1 study, even in patientsreceiving the once-daily schedule whoachieved intermittent BCR-ABL inhibi-tion.18 The updated label for dasatinibincludes results from a phase 3 dose-opti-mization study11 and from a phase 2 studyof dasatinib versus high-dose imatinib.19

Phase 2 study of dasatinib versus high-dose imatinib in patients resistant to imatinib400 mg/day to 600 mg/day. High-doseimatinib has commonly been used as atreatment option for patients who experi-ence resistance to standard doses (400mg/day-600 mg/day) of imatinib in CML.Previous studies have shown that escalat-ing the dose of imatinib to 800 mg/daycan induce responses in some of thesepatients but that responses tend to beshort in duration and increased drugintolerance may be an issue.20-23 Hence, aphase 2 head-to-head randomized studyof dasatinib versus high-dose imat inib(START-R) was undertaken.19Dasatinib (70 mg twice daily) or high-

dose imatinib (800 mg/day) was adminis-tered to patients with CP CML who wereresistant to standard imatinib dosing.Crossover to the alternate treatment waspermitted after confirmed progression (ie,progression to AP or BC CML, loss ofcomplete hematologic response [CHR] orMCyR, or increasing white blood cellcount), lack of MCyR at the week 12cytogenetic evaluation, or intolerance(grade 3/4 nonhematologic toxicity orhematologic toxicity requiring multipledose modifications).With a 15-month follow-up, patients

treated with dasatinib experienced signif-icantly increased response rates comparedwith patients treated with high-dose ima-t inib (93% vs 82%, P = .034). Patients inthe dasatinib arm also had significantlygreater MCyR (52% vs 33%; P = .023)and complete cytogenetic response(CCyR; 40% vs 16%; P= .004) comparedwith the high-dose imat inib arm. MCyRrates were higher with dasatinib com-pared with the high-dose imatinib arm inthose who had no prior cytogeneticresponse and those who received priorimatinib doses of 600 mg/day. Molec ularresponse rates were also significantly high-er in the dasatinib arm versus the high-dose imatinib arm (16% vs 4%; P = .038).Responses were generally achieved inpatients with imatinib-resistant BCR-ABL kinase domain mutations.Dasatinib was also associated with a

significant prolongation in the time-to-treatment failure compared with high-dose imatinib (hazard ratio [HR], 0.16;95% confidence interval [CI], 0.10-0.26;P <.001).19 Rates of progression-free sur-vival showed a statistical difference infavor of the dasatinib arm, with a corre-sponding risk reduction of 86% com-

Optimizing Dasatinib Therapy... Continued from page 18

Table 3. Dose Adjustments of Dasatinib for the Management of Neutropenia and Thrombocytopenia

CP CML (starting ANC <0.5 ¥ 109/L and/or platelets <50 ¥ 109/L 1. Stop dasatinib until ANC ≥1.0 ¥ 109/L anddose, 100 mg/day) platelets ≥50 ¥ 109/L

2. Resume treatment at the original startingdose

3. If platelets <25 ¥ 109/L and/or recurrence ofANC <0.5 ¥ 109/L for >7 days, repeat step 1and resume dasatinib at a reduced dose of80 mg/day (second episode) or discontinue(third episode)

AP CML, BC CML, ANC <0.5 ¥ 109/L and/or platelets <10 ¥ 109/L 1. Check if cytopenia is related to leukemia(bone marrow aspirate or biopsy)

2. If cytopenia is unrelated to leukemia, stopdasatinib until ANC ≥1.0 ¥ 109/L and platelets≥20 ¥ 109/L and resume at the original starting dose

3. If recurrence of cytopenia, repeat step 1 andresume dasatinib at a reduced dose of 100mg once daily (second episode) or 80 mgonce daily (third episode)

4. If cytopenia is related to leukemia, considerdose escalation to 180 mg once daily

ALL indicates acute lymphoblastic leukemia; ANC, absolute neutrophil count; AP, accelerated phase; BC, blast crisis; CP, chronic phase; CML, chronic myeloidleukemia; Ph+, Philadelphia chromosome–positive.

Source: Reference 12.

and Ph+ ALL (startingdose, 140 mg twice daily)




pared with high-dose imatinib (HR,0.14; 95% CI, 0.05-0.40; P <.001).19These results suggest that when patientsdo not respond, or experience loss ofresponse to imatinib, treatment withdasatinib is more effective than escalat-ing the imat inib dose.19Phase 3 dose-optimization study. A

randomized, phase 3, open-label studywas conducted to optimize the dose andschedule of dasatinib in patients withCP CML. Dasatinib was administeredin once-daily and twice-daily schedulesat two total daily doses (100 mg and140 mg) in patients with CP CML afterimatinib resistance or intolerance. The100-mg daily dose was selected as themedian total daily dose across thephase 2 program in CP CML.11

Similar, marked hematologic andcytogenetic efficacy was seen across allfour treatment arms. Rates of CHR,MCyR, and CCyR were 90%, 59%, and41% for patients receiving 100 mg/dayand 87%, 55%, and 45% for patientsreceiving 70 mg twice daily.12 In thisnoninferiority trial design, the once-daily schedule demonstrated compara-ble efficacy with the twice-daily sched-ule on the primary efficacy end point(difference in MCyR, 2.8%; 95% CI,6.0-11.6). The main secondary endpoint of the study also showed compa-rable efficacy between the 100-mg totaldaily dose and the 140-mg total dailydose (difference in MCyR, –0.8%; 95%CI, 9.6-8.0). Because the minimum fol-low-up was only 6 months, too few pro-gressions were available to estimate theduration of MCyR. Compared with the70-mg twice-daily arm, 100 mg/day wasassociated with a reduced incidence ofcytopenia and pleural effusions.11,12

Severe AEs (grades 3/4) includedsuperficial localized edema (0%-1%),congestive heart failure (0%-2%), peri-cardial effusion (1%), pleural effusion(2%-3%), diarrhea (1%-4%), hemor-rhage (1%-2%), and gastrointestinalbleeding (0%-2%).12 The incidence ofall AEs (including grades 3/4) waslower in the 100-mg/day arm comparedwith the 70-mg twice-daily arm. Thereduced rate of pleural effusions in the100-mg/day arm is particularly en cour-aging. Grade 3/4 cytopenias occurred inall arms, but were less frequent in the100-mg/day arm compared with the 70-mg twice-daily arm.

The 100-mg/day arm was associatedwith fewer treatment interruptions anddiscontinuations compared with the 70-mg twice-daily arm. The rate of discon-tinuation for adverse reaction was 4%versus 12% in patients in the 70-mgtwice-daily arm.12

ConclusionsDasatinib has become a treatment

option for patients with all phases ofCML or Ph+ ALL who have failed on orare intolerant to imatinib. The newlyrecommended dose of 100 mg once dailyin patients with CP CML offers im -proved safety and compliance profiles—as evidenced by fewer treatment delaysand discontinuations—while main tain-ing efficacy compared with the previous70-mg twice-daily dose. The 70-mgtwice-daily dose remains the recom-mended regimen for patients withadvanced CML and Ph+ ALL. Newclinical data demonstrate greater efficacywith dasatinib compared with high-doseimatinib in CP CML patients resistant tostandard-dose imatinib.

From a practicing pharmacist’s stand- point, although clinical trial designsemploy logical dosing choices, it isinevitable that these original “calcu-lated guesses” (using preclinical andearly clinical data) on dosing will, onoccasion, require further investiga-tion. Less than optimal dosing proba-bly exists for multiple agents in cancercare, and is more likely with drugswhose clinical availability was acceler-ated because of unmet medical need.Clinicians wish to have the best avail-able treatments for their patients, butall parties, including the pharmaceuti-cal manufacturers, must be vigilant inthe management of these new agents.It is desirable for new published datato be rapidly incorporated into label-ing approval, as seen with the recentpackage change on dasatinib. Rapidlyinforming clinicians about dosagechanges ultimately benefits patients,not only in improved safety and toler-ability, but also potentially for im -proved clinical efficacy. �

AcknowledgmentsWriting and editorial support was pro-

vided by Kerrie Allen-O’Rourke, John -athan Maher, and Josh Collis and wasfunded by Bristol-Myers Squibb.

References1. Lugo TG, Pendergast AM, Muller AJ, Witte

ON. Tyrosine kinase activity and transforma-tion potency of bcr-abl oncogene products.Science. 1990;247:1079-1082.

2. Nowell PC, Hungerford DA. Chromosomestudies in human leukemia. II. Chronic granulo-cytic leukemia. J Natl Cancer Inst. 1961; 27:1013-1035.

3. Rowley JD. A new consistent chromosomalabnormality in chronic myelogenous leukaemiaidentified by quinacrine fluorescence and Giemsastaining [letter]. Nature. 1973;243:290-293.

4. Savona M, Talpaz M. Chronic myeloid leukemia:changing the treatment paradigms. Oncology(Williston Park). 2006;20:707-711.

5. Druker BJ, Guilhot F, O’Brien SG, et al; for theIRIS Investigators. Five-year follow-up of patientsreceiving imatinib for chronic myeloid leukemia.N Engl J Med. 2006;355:2408-2417.

6. O’Hare T, Walters DK, Stoffregen EP, et al. Invitro activity of Bcr-Abl inhibitors AMN107 andBMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res.2005;65:4500-4505.

7. Cortes J, Rousselot P, Kim DW, et al. Dasatinibinduces complete hematologic and cytogeneticresponses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast cri-sis. Blood. 2007;109:3207-3213.

8. Guilhot F, Apperley J, Kim DW, et al. Dasatinibinduces significant hematologic and cytogeneticresponses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerat-ed phase. Blood. 2007;109:4143-4150.

9. Hochhaus A, Kantarjian HM, Baccarani M, et al.Dasatinib induces notable hematologic and cyto-genetic responses in chronic-phase chronicmyeloid leukemia after failure of imatinib therapy.Blood. 2007;109:2303-2309.

10. Ottmann O, Dombret H, Martinelli G, et al.Dasatinib induces rapid hematologic and cytoge-netic responses in adult patients with Philadelphiachromosome positive acute lymphoblasticleukemia with resistance or intolerance to ima-tinib: interim results of a phase 2 study. Blood.2007;110:2309-2315.

11. Hochhaus A, Kim DW, Rousselot P, et al.Dasatinib dose and schedule optimization inchronic-phase CML resistant or intolerant to ima-tinib: results from a randomized Phase-III trial(CA180034). Haematologica. 2007;92 (suppl2):128. Abstract 0359.

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

13. National Comprehensive Cancer Network.Clinical Practice Guidelines in Oncology: ChronicMyelogenous Leukemia. V.3.2008. www.nccn.org/professionals/physician_gls/PDF/cml.pdf.Accessed March 4, 2008.

14. Quintas-Cardama A, Kantarjian H, O’Brien S, etal. Granulocyte-colony-stimulating factor (filgras-tim) may overcome imatinib-induced neutropeniain patients with chronic-phase chronic myeloge-nous leukemia. Cancer. 2004;100:2592-2597.

15. Kerkelä R, Grazette L, Yacobi R, et al. Cardio -toxicity of the cancer therapeutic agent imatinibmesylate. Nat Med. 2006;12:908-916.

16. Tasigna (nilotinib) [package insert]. East Hanover,NJ: Novartis Pharmaceuticals Corporation; 2007.

17. Xu Z, Cang Z, Yang T, Liu D. Cardiotoxicity oftyrosine kinase inhibitors in chronic myelogenousleukemia therapy. Haematol Revs. 2009;1(1):e4.

18. Talpaz M, Shah NP, Kantarjian H, et al.Dasatinib in imatinib-resistant Philadelphiachromosome-positive leukemias. N Engl J Med.2006;354:2531-2541.

19. Kantarjian H, Pasquini R, Hamerschlak N, et al.Dasatinib or high-dose imatinib for chronic-phasechronic myeloid leukemia after failure of first-lineimatinib: a randomized phase 2 trial. Blood.2007;109:5143-5150.

20. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diag-nosed Philadelphia chromosome-positive chron-ic phase chronic myeloid leukemia. Blood. 2004;103:2873-2878.

21. Kantarjian HM, Talpaz M, O’Brien S, et al. Doseescalation of imatinib mesylate can overcomeresistance to standard-dose therapy in patientswith chronic myelogenous leukemia. Blood.2003;101:473-475.

22. Marin D, Goldman JM, Olavarria E, Apperley JF.Transient benefit only from increasing the imat -inib dose in CML patients who do not achievecomplete cytogenetic remissions on conventionaldoses. Blood. 2003;102:2702-2703.

23. Zonder JA, Pemberton P, Brandt H, et al. Theeffect of dose increase of imatinib mesylate inpatients with chronic or accelerated phase chron-ic myelogenous leukemia with inadequate hema-tologic or cytogenetic response to initial treat-ment. Clin Cancer Res. 2003;9:2092-2097.

COMING SOON!

HEMATOLOGYONCOLOGYPHARMACY

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For women with human epidermalgrowth factor receptor type 2(HER2)-positive early breast can-

cer, delaying trastuzumab until chemo -therapy is completed may impair out-comes, according to findings from thelandmark N9831 trial. The findings werepresented by Edith Perez, MD, director ofthe Breast Cancer Program at the MayoClinic, Jacksonville, Florida.The addition of 52 weeks of tras -

tuzumab, either after standard chemo -therapy with doxorubicin/cyclo phos -phamide followed by paclitaxel (AC-T)or concurrently with the paclitaxel,reduced the risk of breast cancer recur-rence by 33% overall, but the benefit wassignificantly greater when trastuzumabwas given concurrently with the pacli-taxel portion of the chemotherapy, anapproach that can now be recommend-ed, Perez said.“Often, the research community con-

ducts studies that conclude with ‘thatwas interesting, but let’s do moreresearch,’” she noted. “This is an impor-tant finding on how we can help preventbreast cancer recurrence and improve

survival…. This will clearly informphysician decision-making.”The N9831 trial, by the North

Central Cooperative Trials Group, con-sisted of two comparisons. The first com-parison included 2448 women random-

ized to chemotherapy alone or chemo -therapy followed by trastuzumab. Theproportion of women remaining disease-free increased from 72% with chemo -therapy alone to 80% with the addition

of trastuzumab. The second comparison,which included 1903 women who wereanalyzed according to whether they re -ceived trastuzumab after chemo therapy(sequentially) or along with chemo ther-apy (concurrently with paclitaxel), con-

tinued for 52 weeks.The sequential use of trastuzumab

reduced recurrences by 33% overchemotherapy alone. At a median fol-low-up time of 5.3 years, 80% ofwomen receiving 52 weeks of tras -tuzumab after chemotherapy were aliveand disease-free, compared with 72%not receiving trastuzumab. But by giv-ing trastuzumab concurrently with thepaclitaxel portion of chemotherapy,the risk of recurrence was reduced byan additional 25%, compared with thesequential delivery of the drug. Withconcurrent trastuzumab, 84% ofwomen were alive and disease-freecompared with 80% of women treatedsequentially, Perez reported.“Based on a positive risk–benefit

ratio, we recommend that adjuvanttras tuzumab be incorporated in a con-current fashion with taxane chemo -therapy,” she said. �


Breast Cancer

“Based on a positive risk–benefit ratio,we recommend that adjuvanttrastuzumab be incorporated in aconcurrent fashion with taxanechemo therapy.”

—Edith Perez, MD

Trastuzumab Best Given Along with ChemotherapyBy Caroline Helwick

For the prevention of skeletal-relat-ed events (SREs) in breast cancerpatients with bone metastasis,

denosumab proved superior to zole-dronic acid (ZA) in a head-to-headrandomized comparison conducted in2048 women.“Denosumab prevented more events,

was better tolerated, and, as a subcuta-neous [SC] injection, was more conven-ient for patients in this randomized dou-ble-blind trial against what has been thestandard of care for treating bone metas-tasis,” said Alison Stopeck, MD, of theUniversity of Arizona Cancer Center,Tucson, who described the study at apress briefing.She told reporters that should deno-

sumab become US Food and DrugAdministration (FDA)-approved, shewill incorporate the drug “quickly” intoher care of patients with bone metas-tases, “because subcutaneous administra-tion is easy, you don’t need to monitorcreatinine, and it is less toxic, assumingthe price is not exorbitant.”Denosumab works by inhibiting

RANK ligand, which regulates osteo-clast activity and function. It is not yetFDA-approved for use in metastaticbreast cancer.Patients with bone metastases not pre-

viously treated with intravenous (IV)bisphosphonates were randomized totreatment with SC denosumab 120 mgevery 4 weeks and IV placebo, or SCplacebo and IV ZA 4 mg every 4 weeks.Patients also received supplemental cal-cium and vitamin D.During the 34-month study, 36.5% of

patients treated with ZA developedSREs compared with 30.7% receivingdenosumab, for a 6% absolute reductionin risk and a 16% relative risk reduction,Stopek announced.

The study’s primary end point, timeto first on-study SRE (pathologic frac-ture, radiation or surgery to bone, orspinal cord compression), was signifi-cantly shorter with ZA, at a median of26.5 months, whereas half the deno-sumab-treated group has not yet expe-rienced an SRE (ie, the end point hasnot been reached), Stopek reported.

“We also assessed whether staying ondenosumab was beneficial, since patientswho have an SRE are at risk for a secondone,” she said. Again, the benefit ofdenosumab was clear, as time to first-and-subsequent on-study SRE was reduced by23%, over ZA. At 30 months, 608 eventsoccurred with ZA compared with just474 events with denosumab, a highly sig-nificant difference.“Another encouraging observation

was that the curves continue to sepa-rate,” she added. “We expect the data to

continue to strengthen as patients are onthe drug longer.”Denosumab was also more protective

against hypercalcemia of malignancy,and was superior in an analysis of skeletalmorbidity rate.“Most importantly for patients,” she

said, denosumab was associated with adelay in the onset of moderate-to-severe

pain, from 64 days with ZA to 88 days.“What makes bone metastases so brutalis the pain, and patients on denosumabtook longer to develop moderate-to-severe pain,” she reported.Adverse events were similar, al -

though ZA was associated with higherincidence of acute-phase reactions(27.3% vs 10.4%). There was morerenal toxicity with ZA but more hyper-calcemia with denosumab. The occur-rence of osteo necrosis of the jaw(ONJ) was rare and was not signifi-cantly different between the groups,occurring in 14 patients (1.4%) withZA and 20 (2.0%) with denosumab.Importantly, 80% of subjects develop-ing ONJ had risk factors for the condi-tion, including dental extraction, poordental hygiene, or dental appliances.Theresa Guise, MD, professor of

medicine and Jerry W. and Peg S.Throg martin professor of oncology atIndiana University School of Med -icine, commented as moderator ofthe press briefing: “This study is veryimportant. It shows that by inhibit-ing bone resorption in different wayswe can get improved effects on pre-venting SREs.” �

—CH

“We expect the data to continue tostrengthen as patients are on the drug longer.”

—Alison Stopeck, MD

To Protect Bone, Denosumab OutperformsZoledronic Acid in Breast Cancer Patients

SABCSThe following articles are based on presentations at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS),

held in San Antonio, Texas, December 9-13, 2009.


FACULTY

Neal P. Christiansen, MDAssistant Professor of MedicineMedical University of South CarolinaDivision of Hematology/OncologyCharleston, South Carolina

TARGET AUDIENCEThis activity is intended for hematologists, oncologists, oncology nurses, oncology/specialtypharmacists, and others who are involved with the care of patients with metastatic colorectalcancer (mCRC).

STATEMENT OF NEEDColorectal cancer (CRC) is the third most commonly diagnosed malignancy and the secondleading cause of cancer death in the United States. Approximately 149,000 new cases are diag-nosed each year. At the time of presentation, about 20% of patients with CRC will havemetastatic disease. Cure at this stage is rarely possible, although some patients whose metastasesare limited (especially if to the liver or lung) may be “cured” by surgical means. For most suf-ferers of mCRC, however, treatment is palliative, offering prolonged survival, improvement insymptoms, and enhanced quality of life.

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

• Evaluate and assess current findings in the management of mCRC• Identify current first-line therapies, both chemotherapeutic and biologic agents, and practices in mCRC

• Tailor a therapeutic regimen to meet the needs of the individual patient with mCRC• Employ select strategies to minimize exposure to ineffective therapies and their toxicities

INSTRUCTIONSTo receive a statement of credit, you must:

• Review the content of the activity• Successfully complete the post-test (70% or higher)• Complete the evaluation at the end of the activity

Your statement of credit will be issued immediately upon successful completion of the post-testand submission of the evaluation

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the Essential Areas andpolicies of the Accreditation Council for Continuing Medical Education (ACCME) throughthe joint sponsorship of the University of California, Irvine School of Medicine (UCI) andCenter of Excellence Media, LLC. The University of California, Irvine School of Medicine isaccredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENTThe University of California, Irvine School of Medicine designates this educational activity fora maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit com-mensurate with the extent of their participation in the activity. This activity is complimentary.

Metastatic Colorectal Cancer:Sound Strategies for Selecting First-Line Therapies

FACULTY INFORMATION AND DISCLOSURESDr Christiansen has received consultancy fees

from sanofi-aventis and Genentech.Off-label use of cetuximab (in patients in whom

irinotecan has not failed) and bevacizumab (con-tinuing after first-line therapy) will be discussed inthis presentation.Conflict resolution: This presentation has been

peer reviewed for evidence base and fair balance.

GENERAL DISCLOSURE STATEMENTIt is the policy of the University of California, Irvine

School of Medicine and the University of CaliforniaCME Consortium to ensure balance, independence,objectivity, and scientific rigor in all CME activities. Fulldisclosure of conflict resolution will be made in writingvia handout materials or syllabus.

Bonnie Carroll, Director, CME, UC Irvine School ofMedicine, has no financial or other relationship to prod-ucts or devices with commercial interests related to thecontent of this CME/CE activity.

Center of Excellence Media, LLC: The planners andmanagers have nothing to disclose related to the contentof this activity.

Erica Johansson, RN, Astute CE, LLC, has nothing todisclose related to the content of this activity.

Dr. Randall F. Holcombe, University of California,Irvine School of Medicine, peer-reviewed the content forevidence base and fair balance. Dr Holcombe has no realor apparent conflicts of interest related to this activity.

Conflict resolution: This presentation has been peerreviewed for evidence base and fair balance.

This activity is in compliance with CaliforniaAssembly Bill 1195, which requires continuing medicaleducation components to include curriculum in the sub-jects of cultural and linguistic competency. For specificinformation regarding Bill 1195 and definitions of cultur-al and linguistic competency, please visit the CME website at http://www.cme.uci.edu.

This activity is supported by an educational grant fromGenentech BioOncology.

www.coexm.com/ace01.aspLOG ON TODAY TO PARTICIPATE

Release Date: November 25, 2009 Expiration Date: November 24, 2010

In collaboration with


For patients with relapsed or refrac-tory multiple myeloma (MM),bortezomib-based therapy is effec-

tive after lenalidomide plus dex a m-ethasone (LD), accordingto a Can a dian study thatevaluated sequencing ofnovel agents.

“The optimal sequenc-ing of novel agents inMM is not certain. Dueto limitations in provin-cial drug funding inOntario, Canada, we hada unique opportunity toevaluate the efficacy ofbortezomib in patients who progressedafter treatment with lenalidomide plusdexamethasone, provided through ex -panded access programs and clinical tri-als for relapsed or refractory disease,”said principal investigator DonnaReece, MD, associate professor and

director of the program for multiplemyeloma and related diseases atPrincess Margaret Hospital, Toronto.

Outcomes were analyzed for 49patients who received LD forrecurrent MM (first- to fourth-line), followed by bortezomib-based regimens for their nextrelapse, without any interim ther-apy. Thirty- nine (80%) patientshad also undergone autologousstem-cell transplantation. Patientsreceived bortezomib alone (33%),bortezomib plus steroids (47%),bortezomib plus prednisone andcyclophosphamide (8%), borte-

z omib plus thalidomide and dexamethasone (4%), or bor tezomib plusanother agent (8%).

The median treatment duration ofLD was 5.3 months. For that regimen,response included near-complete re -sponse (nCR) in 6%, very good partialresponse (VGPR) in 6%, partial re -sponse (PR) in 51%, minimal re -

sponse (MR) in 12%, stable disease(SD) in 19%, and progressive disease(PD) in 25%.

After relapse, when patients began abortezomib-based treatment, median fol-low-up was 6.5 months and the bestresponses to those regimens includedcomplete response or nCR in 2%, VGPRin 16%, PR in 26%, MR in 14%, SD in16%, and PD in 24%.

Median progression-free survival(PFS) was 4.0 months, with a 12%median 1-year PFS rate. Median over-all survival (OS) was 9.5 months, witha 31% median 1-year survival rate.

Investigators assessed a number offactors for their prognostic effects onPFS and OS, including age at diagnosis,gender, subtype, duration of initial ther-apy, and response to LD, but only thepatient’s response to the bortez omib-based therapy was significant (P <.0001for PFS and P = .002 for OS).

“The PFS and OS observed afterbortezomib-based therapy is not de -

pendent on the response to lenalido-mide plus dexamethasone,” Reece said.

Patients who achieved at least a PRto bortezomib had a median PFS of 7.3months, compared with 2.0 months forpatients with MR or less. One-year PFSwas 29% versus 13%, respectively.Similarly, for OS, a response of PR orbetter was associated with a median OSof 14.3 months, versus 3.9 months for alesser response, and 1-year OS wasobserved in 12% and 14%, respectively.

“We concluded that treatment ofsequential multiple myeloma relapseswith bortezomib-based therapy afterprogression on LD produces partialresponses or better in 44% of patients,results in a median PFS similar to the6.2 months seen with bortez omib in lessheavily pretreated patients in the APEXtrial [Richardson PG, et al. N Engl JMed. 2005;352(24):2487-2498], anddemonstrates the effectiveness of borte-zomib even after exposure to the potentLD combination,” Reece said. �

Strong Responses Seen with Bortezomib-basedTherapy after Relapse in Multiple MyelomaBy Caroline Helwick

One third of patients with newlydiagnosed, ad vanced chroniclymphocytic leukemia (CLL)

who received the combination of ben-damustine and rituximab achieved acomplete response, according to re -searchers from the German CLLStudy Group.

Another 56% of the patients treatedwith this combination had partialresponses, said principal investigatorKirsten Fischer, MD, Center of In -tegrated Oncology, University of Co -logne, Germany, at the annual meetingand exposition of the American Societyof Hematology.

Bendamustine had already beenshown to have considerable activity asmonotherapy in CLL and many otherlymphoid cancers, as well as in combi-nation with rituximab in patients withrelapsed or refractory CLL.

This new study examined bendamus-tine in combination with rituximab as

first-line therapy in 117 patients, 48% ofwhom had Binet stage C disease and41% of whom had Binet stage B.

Rituximab was given as four 6-weekcycles with two doses of bendamustinein each cycle. Some 72% of patients inthe study were treated with all six cyclesof therapy.

The median observation time was15.4 months, and the overall responserate was 90.9%. A complete responsewas observed in 32.7% and a partialresponse in 55.5%. All other patients(9.1%) had stable disease, and none ofthe patients had progressive disease.

With up to 26 months of follow-up,75.8% of the patients were still in remis-sion, and median progression-free sur-vival has not been reached.

Objective response rates of approxi-mately 90% were achieved among thedifferent genetic subgroups, except fordel(17p), a high-risk subgroup in whichthe partial response rate was 42.9%.

Complete responses occurred mostoften in patients with unmutatedimmunoglobulin variable region heavychain. The overall response rate in thisgroup was 88.9%.

Hematologic toxicities were grade3/4 anemia in 4.9%, grade 3/4 leukope-nia in 14.6%, grade 3/4 neutropeniaand throm bocytopenia in 6.5% and6.1% of all given courses, respectively.Twenty-nine episodes of common tox-icity criteria grade ≥3 infections weredocumented (5.1% of all courses).

There were two treatment-relateddeaths during the study: one fatal pneu-monia and one case of sepsis related toneutropenia.

Based on these encouraging data, thegroup is now conducting a phase 3 trialin which the efficacy of bendamustine/rituximab is being compared with that offludarabine-based immunochemothera-py in the first-line treatment of CLL,said Fischer. �

Bendamustine-Rituximab Combo anEffective First-line Therapy for CLLBy Wayne Kuznar


Hematologic Cancers

DRUG THERAPY

New Treatments forChronic Idiopathic...Continued from page 6

patients, however, before widespread useis advocated, and reimbursement for thisnovel agent will be limited to FDA-approved indications. �

References1. Cines DB, Blanchette V. Immune thrombocy-

topenic purpura. N Engl J Med. 2002;346:995-1008.2. Cines DB, Bussel JB. How I treat idiopathic

thrombocytopenic purpura (ITP). Blood. 2005;106:2244-2251.

3. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy ofromiplostim in patients with chronic immunethrombocytopenic purpura: a double-blind ran-domised controlled trial. Lancet. 2008;371:395-403.

4. Nplate (romiplostim) [package insert]. ThousandOaks, CA: Amgen, Inc; 2008.

5. Thompson CA. FDA approves thrombopoiesis-stimulating agent. Am J Health Syst Pharm.2008;65:1788.

6. Enrollment. How do I enroll in the NplateNEXUS program? www.nplatenexus.com/enrollment.html. Accessed October 11, 2008.

7. Medication guide. Nplate (romiplostim). www.nplatenexus.com/pdfs/misc/nplate_mg.pdf.Accessed October 11, 2008.

8. Levy B, Arnason JE, Bussel JB. The use of second-generation thrombopoietic agents for chemother-apy-induced thrombocytopenia. Curr Opin Oncol.2008;20:690-696.

Part 2 of this article on eltrombopag willappear in the June issue.

ASH

The following articles are based on reports at the 51st Annual Meeting and Exposition of the American Society of Hematology (ASH), held in New Orleans, December 5-9, 2009.

Donna Reece, MD


Current activities at www.COEXM.com include:

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Medications Used for the Treatment of Lymphomas

NCCN Drugs Current MedicareFDA- & Biologics code price allowableapproved Compendium (AWP-based (ASP + 6%), CPT

generic (Brand) HCPCS code: for off-label use for pricing), effective effective administrationname code description lymphomas lymphomas 4/1/10 4/1/10-6/30/10 codes

alemtuzumab J9010: injection, � $680.73 $578.01 96413, 96415(Campath) alemtuzumab, 10 mgasparaginase J9020: injection, � $70.42 $60.94 96401, 96413(Elspar) asparaginase, 10,000 unitsbendamustine J9033: injection, � $21.60 $18.47 96413(Treanda) bendamustine HCl, 1 mgbetamethasone J0702: injection, � $6.85 $6.55 11900, 11901, 20600,(Celestone Soluspan) betamethasone acetate, 20605, 20610, 96372

3 mg and betamethasone sodium phosphate, 3 mg

O N C O L O G Y D R U G C O D E SSupplied by: RJ Health Systems

The following sections include:• Associated ICD-9-CM codes used for the classification of lymphomas

• Drugs that have been FDA-approved in the treatment of lymphomas. Please note: if a check mark appears in the FDA col-umn it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium

• Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in lymphomas. NCCN is recognized by the Centers for Medicare & Medicaid

Services (CMS) as a referencing source• Corresponding HCPCS/CPT codes and code descriptions

• Current Code Price (AWP-based pricing)• Most recent ASP plus 6% (Medicare allowable)

• Possible CPT Administration Codes for each medication

Associated ICD-9-CM Codes Used for LymphomasThe following fifth-digit subclassification is for use with categories 200-202:

0 unspecified site, extranodal and solid organ sites1 lymph nodes of head, face, and neck2 intrathoracic lymph nodes3 intra-abdominal lymph nodes4 lymph nodes of axilla and upper limb5 lymph nodes of inguinal region and lower limb6 intrapelvic lymph nodes7 spleen8 lymph nodes of multiple sites

200 Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue200.0 Reticulosarcoma200.1 Lymphosarcoma200.2 Burkitt’s tumor or lymphoma200.3 Marginal zone lymphoma200.4 Mantle cell lymphoma200.5 Primary central nervous system lymphoma200.6 Anaplastic large cell lymphoma200.7 Large cell lymphoma200.8 Other named variants

Lymphoma (malignant):lymphoplasmacytoid typemixed lymphocytic-histiocytic (diffuse)

Lymphosarcoma, mixed cell type (diffuse)Reticulolymphosarcoma (diffuse)

202 Other malignant neoplasms of lymphoid and histiocytic tissue202.0 Nodular lymphoma202.1 Mycosis fungoides202.2 Sézary’s disease202.3 Malignant histiocytosis202.4 Leukemic reticuloendotheliosis202.5 Letterer-Siwe disease202.6 Malignant mast cell tumors202.7 Peripheral T-cell lymphoma202.8 Other lymphomas

Lymphoma (malignant):not otherwise specifieddiffuse

Excludes: benign lymphoma (229.0)202.9 Other and unspecified malignant neoplasms of lymphoid and histiocytic tissue

Follicular dendritic cell sarcomaInterdigitating dendritic cell sarcomaLangerhans cell sarcomaMalignant neoplasm of bone marrow not otherwise specified



• Lenalidomide starting dose 25 mg po once dailyb

aLenalidomide will be dosed po once daily on days 1-21 of each 28-day cycle.bSubjects with creatinine clearance ≥30 mL/min but <60 mL/min will receive a lower starting dose of lenalidomide 10 mg po once daily. Dose may be escalated to 15 mg po once daily if no dose-limiting toxicities occur during the first 2 cycles.

Pretreatment Phase (4 Weeks)

• MCL diagnosis confirmed by local pathological review

EMERGETM is a trademark of Celgene Corporation. ©2008 Celgene Corporation 10/08 CELGO8010T

A Phase 2 Study for Patients With Relapsed/Refractory Mantle Cell Non-Hodgkin’s Lymphoma

Primary Investigator André Goy, MD

Primary ObjectiveTo determine the tumor response and duration of response of lenalidomide monotherapy in subjects with mantle cell lymphoma (MCL) who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib

Key Eligibility Criteria*• Individuals with MCL previously treated with all of the following (alone or in combination):

– Bortezomib† – An anthracycline or mitoxantrone– Rituximab – Cyclophosphamide

• Individuals must have documented relapse after bortezomib treatment or be refractory to bortezomib • Excluding individuals who are candidates for high-dose chemotherapy/allogeneic stem cell transplant*Additional criteria apply.†Note: When the agent bortezomib is mentioned this also includes ANY BORTEZOMIB-CONTAINING REGIMEN.

Study Design

Treatment Phasea (until disease progression)

Investigational use of lenalidomide.

For more information contact Deborah Ingenito, Celgene Study Manager [email protected] (908) 673-9581www.clinicaltrials.gov (NCT00737529)

N=133

NHL Mantle Cell TrialNow Recruiting Investigators and Enrolling Study ParticipantsCelgene CC-5013-MCL-001







bexarotene J8999a: prescription drug, � NDC NDC N/A(Targretin) oral, chemotherapeutic, level level

not otherwise specified pricing pricingbleomycin J9040: injection, � $45.30 $26.08 96401, 96409(Blenoxane) bleomycin sulfate, 15 unitsbortezomib J9041: injection, � $45.43 $38.24 96409(Velcade) bortezomib, 0.1 mgcarboplatin J9045: injection, � $48.55 $5.31 96409, 96413, 96415(Paraplatin) carboplatin, 50 mgcarmustine J9050: injection, � $205.69 $176.41 96413, 96415(BiCNU) carmustine, 100 mgchlorambucil J8999a: prescription drug, � NDC NDC N/A(Leukeran) oral, chemotherapeutic, level level

not otherwise specified pricing pricingcisplatin J9060: cisplatin, powder or � $4.33 $1.98 96409, 96413, 96415(Platinol-AQ) solution, per 10 mgcisplatin J9062: cisplatin, � $21.66 $9.91 96409, 96413, 96415(Platinol-AQ) 50 mgcladribine J9065: injection, cladribine, � $58.20 $28.22 96413, 96415(Leustatin) per 1 mgcyclophosphamide, J8530: cyclophosphamide, � $2.09 $0.84 N/Aoral oral, 25 mg(Cytoxan)cyclophosphamide, J9070: cyclophosphamide, � $7.55 $4.35 96409, 96413, 96419injection 100 mg(Cytoxan)cyclophosphamide, J9080: cyclophosphamide, � $15.10 $8.69 96409, 96413, 96415injection 200 mg(Cytoxan)cyclophosphamide, J9090: cyclophosphamide, � $37.76 $21.73 96409, 96413, 96415injection 500 mg(Cytoxan)cyclophosphamide, J9091: cyclophosphamide, � $68.00 $43.46 96409, 96413, 96415injection 1.0 gram(Cytoxan)cyclophosphamide, J9092: cyclophosphamide, � $122.39 $86.92 96409, 96413, 96415injection 2.0 grams(Cytoxan)cytarabine J9100: injection, � $2.31 $1.51 96409, 96413,(Cytosar-U) cytarabine, 100 mg 96415, 96450dacarbazine J9140: dacarbazine, � $22.21 $7.37 96409, 96413(DTIC-Dome) 200 mgdaunorubicin J9150: injection, � $25.20 $19.46 96409, 96413(Cerubidine) daunorubicin, 10 mgdenileukin diftitox J9160: injection, denileukin � $1,756.80 $1,494.82 96409, 96413, 96415(Ontak) diftitox, 300 microgramsdexamethasone J1100: injection, dexamethasone � $0.15 $0.09 11900, 11901, 20600,(Decadron) sodium phosphate, 1 mg 20605, 20610, 96372,

96374dexamethasone J8540: dexamethasone, � $0.09 $0.38 N/A(Decadron) oral, 0.25 mgdoxorubicin HCl J9000: injection, doxorubicin � $13.20 $3.04 96409(Adriamycin) hydrochloride, 10 mg






doxorubicin liposome J9001: injection, doxorubicin � $578.88 $472.01 96413(Doxil) hydrochloride, all lipid

formulations, 10 mgetoposide J9181: injection, � $0.53 $0.49 96413, 96415(Etopophos, Toposar) etoposide, 10 mgetoposide J8560: etoposide, � $47.64 $28.26 N/A(Vepesid) oral, 50 mgfludarabine J9185: injection, fludarabine � $309.70 $205.81 96413phosphate phosphate, 50 mg(Fludara)gemcitabine J9201: injection, gemcitabine � $173.83 $145.10 96413(Gemzar) hydrochloride, 200 mghydrocortisone J1720: injection, hydrocortisone � $2.46 $3.14 96365, 96366, (Solu-Cortef) sodium succinate, up to 100 mg 96372, 96374ibritumomab A9542: indium In-111 � $4,200.00 N/A 96374tiuxetan ibritumomab tiuxetan, diagnostic, (Zevalin) per study dose, up to 5 millicuriesibritumomab A9543: yttrium Y-90 ibritumomab � $37,800.00 N/A 79403tiuxetan tiuxetan, therapeutic, per (Zevalin) treatment dose, up to 40 millicuriesifosfamide J9208: injection, � $56.40 $30.76 96413, 96415(Ifex) ifosfamide, 1 graminterferon J9214: injection, interferon, � $21.90 $15.84 96372, 96401alfa-2b alfa-2b, recombinant, (Intron-A) 1 million unitsinterferon gamma 1-b J9216: injection, interferon, � $517.89 $430.93 96372(Actimmune) gamma 1-b, 3 million unitsisotretinoin J8499a: prescription drug, � NDC NDC N/A(Accutane) oral, non-chemotherapeutic, level level

not otherwise specified pricing pricinglenalidomide J8999a: prescription drug, � NDC NDC N/A(Revlimid) oral, chemotherapeutic, level level

not otherwise specified pricing pricinglomustine J8999a: prescription drug, � NDC NDC N/A (CeeNU) oral, chemotherapeutic, level level

not otherwise specified pricing pricinglomustine S0178: lomustine, � $10.59 S0178: not N/A(CeeNu) oral, 10 mg payable by

Medicaremechlorethamine J9230: injection, � $178.71 $154.50 96409(Mustargen) mechlorethamine hydrochloride

(nitrogen mustard), 10 mgmelphalan J8600: melphalan, � $5.68 $4.83 N/A(Alkeran) oral, 2 mgmelphalan J9245: injection, melphalan � $1,922.50 $1,500.32 96409, 96413(Alkeran) hydrochloride, 50 mgmesna J8999a: prescription drug, � NDC NDC N/A(Mesnex) oral, chemotherapeutic, level level

not otherwise specified pricing pricingmesna J9209: injection, � $10.44 $4.26 96409(Mesnex) mesna, 200 mgmethotrexate J8610: methotrexate, � $3.61 $0.16 N/A

oral, 2.5 mg







generic (Brand) HCPCS code: for off-label use for pricing), effective effective administrationname code description lymphomas lymphomas 4/1/10 4/1/10-6/30/10

methotrexate J9250: methotrexate sodium, � $0.29 $0.21 96372, 96374, 96401,sodium 5 mg 96409, 96450

methotrexate J9260: methotrexate sodium, � $2.86 $2.10 96372, 96374, 96401,sodium 50 mg 96409, 96450

methoxsalen J8499a: prescription drug, � NDC NDC N/A(Oxsoralen, 8-MOP, oral, non-chemotherapeutic, level levelOxsoralen Ultra) not otherwise specified pricing pricing

methylprednisolone J1030: injection, � $5.70 $3.40 11900, 11901, 20600,(Depo-Medrol) methylprednisolone 20605, 20610, 96372

acetate, 40 mg

methylprednisolone J1040: injection, � $10.20 $6.64 11900, 11901, 20600,(Depo-Medrol) methylprednisolone 20605, 20610, 96372

acetate, 80 mg

methylprednisolone J2920: injection, � $2.36 $2.28 96365, 96366, (Solu-Medrol) methylprednisolone sodium 96372, 96374

succinate, up to 40 mg

methylprednisolone J2930: injection, � $4.15 $3.06 96365, 96366, (Solu-Medrol) methylprednisolone sodium 96372, 96374

succinate, up to 125 mg

methylprednisolone J7509: methylprednisolone, � $0.61 $0.08 N/A(Medrol) oral, per 4 mg

mitoxantrone J9293: injection, mitoxantrone � $109.60 $45.27 96409, 96413(Novantrone) hydrochloride, per 5 mg

nelarabine J9261: injection, � $123.19 $105.91 96413, 96415(Arranon) nelarabine, 50 mg

ofatumumab C9260: injection, � $52.80 N/A 96413, 96415(Arzerra) ofatumumab, 10 mg

ofatumumab J9999a: not otherwise specified, � NDC NDC 96413, 96415(Arzerra): antineoplastic drugs level level

pricing pricing

oxaliplatin J9263: injection, � $8.25 $6.83 96413, 96415(Eloxatin) oxaliplatin, 0.5 mg

pentostatin J9268: injection, � $2,182.80 $1,246.38 96409, 96413(Nipent) pentostatin, per 10 mg

pralatrexate C9259: injection, � $187.50 N/A 96409(Folotyn) pralatrexate, 1 mg

pralatrexate J9999a: not otherwise � NDC NDC 96409(Folotyn) classified, antineoplastic drugs level level

pricing pricing

prednisolone J7510: prednisolone, � $0.66 $0.02 N/A(Millipred, Orapred, oral, per 5 mgVeripred)

prednisone J7506: prednisone, � $0.05 $0.04 N/Aoral, per 5 mg

procarbazine J8999a: prescription drug, � NDC NDC N/A(Matulane) oral, chemotherapeutic, level level

not otherwise specified pricing pricing

procarbazine S0182: procarbazine HCl, � $55.68 S0182: not N/A(Matulane) oral, 50 mg payable by

Medicare

rituximab J9310: injection, � $664.32 $578.40 96413, 96415(Rituxan) rituximab, 100 mg







romidepsin C9399a: unclassified drugs or � NDC NDC 96413, 96415(Istodax) biologicals (This code should only level level

be used for new drugs and pricing pricingbiologicals that are approved by the FDA on or after January 1, 2004)

romidepsin J9999a: not otherwise � NDC NDC 96413, 96415(Istodax) classified, antineoplastic drugs level level

pricing pricingtemozolomide, J9328: injection, temozolomide, � $5.66 $4.90 96413, 96415injection 1 mg (For billing prior to 1/1/10,(Temodar) use J9999 or C9253)temozolomide, oral J8700: temozolomide, � $10.65 $8.83 N/A(Temodar) oral, 5 mgtemsirolimus J9330: injection, � $58.72 $49.83 96413(Torisel) temsirolimus, 1 mgthalidomide J8999a: prescription drug, � NDC NDC N/A(Thalomid) oral, chemotherapeutic, level level

not otherwise specified pricing pricingthiotepa J9340: injection, � $138.00 $113.53 51720, 96409(Thioplex) thiotepa, 15 mgtositumomab A9545: iodine I-131 tositumomab, � $34,873.19 N/A 79403(Bexxar) therapeutic, per treatment dosetretinoin J8999a: prescription drug, � NDC NDC N/A(Vesanoid) oral, chemotherapeutic, level level

not otherwise specified pricing pricingvinBLAStine J9360: injection, � $3.18 $1.02 96409

vinblastine sulfate, 1 mgvinCRIStine J9370: vincristine sulfate, � $8.12 $4.31 96409(Vincasar PFS) 1 mgvinCRIStine J9375: vincristine sulfate, � $16.24 $8.62 96409(Vincasar PFS) 2 mgvinCRIStine J9380: vincristine sulfate, � $40.60 $21.54 96409(Vincasar PFS) 5 mgvorinostat J8999a: prescription drug, � NDC NDC N/A(Zolinza) oral, chemotherapeutic, level level

not otherwise specified pricing pricing

aWhen billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J9999 for Folotyn) in Column 24D and the drug name, strength, and National DrugCode (NDC) in Box 19 in order to ensure appropriate reimbursement.

References• HCPCS Level II Expert 2010 • CPT 2010 • ICD-9-CM for Professionals Volumes 1 & 2; 2010 • The Drug Reimbursement Coding and Pricing Guide, Vol 7, No 2; RJ Health Systems International LLC;2nd Quarter 2010 • FDA-approved indication (from products’ prescribing information) • NCCN Drugs & Biologics Compendium; 2010. National Comprehensive Cancer Network, Inc. Available at:www.nccn.org. Accessed February 15, 2010. To view the most recent and complete version of the NCCN compendium, go online to www.nccn.org • www.ReimbursementCodes.com powered by RJHealth Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 2nd Quarter 2010 (effective dates 4/1/10-6/30/10).

Prices listed herein are effective as of April 1, 2010.

ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS,Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650

www.RJHealthSystems.com

This information was supplied by:



Pharmacy Life

From an early point in my life, I havehad two overriding passions: phar-macy and cooking. Pharmacy be -

came my chosen career and intellectualoutlet. Cooking is my hobby and ulti-mate stress reliever. Recently, I’ve beenable to blend my two loves together. I am currently a full-time pharmacist

at Rush University’s oncology/hematol-ogy clinic in Chicago. I also work part-time as a retail pharmacist for CVSPharmacy. As a pharmacist, I regularlymeasure, compound, pour, and check avariety of drugs. In my positions, I amable to talk to and help people from allwalks of life. The ability to help peoplewith their medical needs is an immense

responsibility and continually providesme with honor and satisfaction in myjob. But, I was still hungry for excite-ment, something outside my zone ofcomfort. Then, I realized that the profes-sional skills I had honed as a pharmacistcould be applied to my love of food—adelicious combination.My love of cooking started at an early

age. I acquired my cooking gene frommy mom and grandma, who are bothgreat cooks. As the demands of schoolmounted, however, I found myself drift-ing away from the kitchen. Committedto getting my hobby back, I began col-lecting new cookbooks from my favoritechefs. I also updated my cooking uten-sils, buying as much that would fit in mykitchen and help me whip up tasty dishafter tasty dish. I also dusted off familyrecipes from the “old” country.Then, I began to blend my two loves

together. I persuaded my colleagues thatwe should apply the same skills we usebehind the counter to the stovetops andovens. I like to call our culinary method“compounding in the kitchen.” Duringthe day, we measure, grind, and pour

chemicals for the benefit of our patients.We use those same skills to dazzle in thekitchen. The same patience and carenecessary for pharmacy also are necessaryfor precision (and taste) in the kitchen.By applying the care we give to pharma-ceutical compounding to any detailedrecipe, we are able to ensure great dishestime and again. In addition, the check-ing and double-checking we devote to afinal drug product can be used whencooking our favorite casserole or pastry.Cooking has become a natural outlet

and extension of my job. What’s more,cooking brings my coworkers closertogether and helps us create a betterworking environment. Making mistakes,sharing our successes, and tasting theresults is rewarding for both us and ourpatients (who often get to sample ourafter-hour masterpieces). As much as I love my pharmacy

career, I would like to take my cookinghobby to another level—catering to mypatients in and out of the pharmacy.Ideally, I could take my dual skill set andembark on a career behind both thecounter and the apron. �

Compounding in the KitchenBy Jill Drury

Jill’s BananaPuddingIngredients

1 box vanilla wafers (reduced fat,optional)

7 bananas, sliced

2 cups milk (skim milk, optional)

1 (5-oz) box instant French vanillapudding (sugar free, optional)

1 (8-oz) package cream cheese,softened (fat free, optional)

1 (14-oz) can sweetened con-densed milk (fat free, optional)

1 (12-oz) container frozenwhipped topping, thawed (fat free, optional)

Directions

Line the bottom of a 13" ¥ 9" ¥ 2"dish with cookies, and layer bananason top. In a bowl, combine the milkand pudding mix; blend well using ahandheld electric mixer. Using anoth-er bowl, combine the cream cheeseand condensed milk; mix until smooth.Fold the whipped topping into thecream cheese mixture. Add the creamcheese mixture to the pudding mixtureand stir until well blended. Pour themixture over the cookies and bananas;cover with the remaining cookies.Refrigerate until ready to serve.

How do you relieve stressafter a busy day?

Send your ideas and recipes to [email protected]

©iStockphoto.com/Steven Aja

The current economic crisis iscausing lenders and credit cardissuers to err on the side of cau-

tion as more borrowers default on theirloans and fall behind on credit card pay-ments. The days when a good creditscore was enough to qualify for the bestmortgage, loan, and credit card rates arebehind us.A few years ago, a credit score of 700

out of the maximum 850 ensured manypeople the most attractive mortgageand credit card rates. Now financialexperts are telling potential borrowersthey need a credit score of 720 or high-er to qualify for the best rates. You havethree credit scores: one each based onyour credit reports from Equifax,Experian, and TransUnion.A good credit score is more than just

paying your bills on time. Payment his-tory only accounts for about one third ofthe formula that makes up your creditscore. The credit-rating organizationFair Isaac Corporation breaks down acredit score into five variables: paymenthistory, 35%; available credit used,30%; length of credit history, 15%;types of credit used, 10%; new creditapplications, 10%.Nationally recognized credit expert

John Ulzheimer, president of consumereducation for Credit.com, offers thesetips on his website to help improveyour score:• Keep credit card balances low. Thepercentage of available credit that acardholder uses compromises aboutone third of a credit score. This vari-able is as important as paying billson time. Keep your total balance atno more than 10% of your totalcredit limits. If you plan to submit aloan or credit application, pay offyour credit cards completely andrefrain from using them for 60 daysbefore submitting the application.• Avoid too many applications fornew credit. Applying for any typeof credit can hurt your credit score.Almost 10% of your overall score isbased on how many credit applica-tions you have applied for in thepast 12 months. If you do not havea good credit history, refrain fromapplying for credit cards you do notneed. If you have a solid credit his-tory, a couple of credit applicationsover the course of 1 year will nothave a major impact on your score.Avoid filling out applications foranything that requires a credit

check until you have been ap -proved for the loan you want.• Vary your credit. Nearly 10% of yourtotal credit score is determined byyour types of present and past credit.Lenders prefer borrowers with diver-sified credit including credit cards,retail cards, and student and autoloans. It is important to show youhave had both major bank creditcards and installment debt, such asan auto loan. It does not matter ifthese accounts are active or havebeen paid off. Ulzheimer does notrecommend you take out a loan oropen a credit account to help yourcredit score. However, if you want toestablish credit of a type that youhave not previously used, such as anauto loan, you may want to considera loan instead of paying cash.• Keep accounts open for a longtime. Approximately 15% of yourcredit score is calculated by the ageof your oldest accounts. The longeryou have had the account the bet-ter. If you are just beginning toestablish a credit history, ask a par-ent, spouse, or sibling to add you totheir long-term credit account asan “authorized user.” �

What You Need to Know About YourCredit Score By Eileen Koutnik-Fotopoulos

@Copyright iStockphotos.com/Larry Sherer


Zoledronic Acid CutsFracture Risk in Men withAdvanced Prostate CancerBARCELONA—Men with prostatecancer and malignant bone metastaseswho are treated with intravenous (IV)zoledronic acid are significantly lesslikely to sustain bone fractures thanmen not receiving an IV bisphospho-nate, researchers announced at the 25thAnniversary European Association ofUrology Congress.Henry Henk, PhD, with i3 Innovus in

Eden Prairie, Minnesota, and colleaguespresented data in 4976 men withprostate cancer and bone metastases.“Prostate cancer patients with malig-

nant bone metastases frequently experi-ence skeletal-related events, includingpathologic fracture, spinal cord compres-sion, and hypercalcemia of malignancy,which are associated with significantmorbidity and mortality,” Henk said.Patients enrolled in the trial between

January 1, 2001, and December 31, 2006,and remained in the study until they diedor the study ended (December 31, 2007).Men treated with zoledronic acid

developed fewer fractures (vertebral,nonvertebral hip, and nonvertebral non-hip) than men who did not. Overall,there were 5.9 fractures per 100 person-years in patients treated with zoledronicacid compared with 8.5 per 100 person-years in the placebo group (P = .0003).In addition, longer treatment with thebisphosphonate was associated with alower fracture risk.

Disconnect Between Doctorand Patient Views on BreastCancer Treatment GoalsBARCELONA—Women with metasta-tic breast cancer and oncologists general-ly agree that overall survival is the mostimportant end point when selecting atreatment, Canadian researchers an -nounced at the 7th European BreastCancer Conference.However, the groups disagree on how

much improvement a treatment shouldprovide before it should be included inthe patient’s therapeutic strategy.Amir Sheik-Yousouf, MD, with the

University of Toronto, and colleaguesanalyzed responses to surveys completedby 52 women with breast cancer and 28oncologists. Their analysis revealed thatover half of patients and oncologistsalike considered overall survival to bethe most important end point in“accepting” a therapy.Physicians, however, tended to con-

sider much smaller improvements inoverall survival as significant enough toadopt therapies. In fact, 48% of physi-cians thought that a minimum mean-

ingful incremental improvement inoverall survival compared with first-linemetastatic breast cancer therapy was 4to 6 months, and 44% believed that 2 to4 months was meaningful. Forty-six per-

cent of patients required a greater than12-month improvement in overall sur-vival to consider a treatment.Sheik-Yousouf said that although the

findings are limited by the small number

of participants, the data “highlight dis-parities between patients and oncologistsin the relative ranking of defined thera-peutic end points and in metastaticbreast cancer treatment expectations.” �

Reports from International Meetings and ResearchersBy Jill Stein


International News

adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting,and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicity As with all therapeutic proteins, ythere is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have beenidentified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged :pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal:bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk.However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Amongpatients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic LeukemiaAmong patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. Patients 70 years or older received lower dose intensity of fludarabine andscyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicyor mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided theRituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Revised 02/2010 (4851501)

Jointly Marketed by:Biogen Idec Inc. 5200 Research Place San Diego, CA 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) isindicated for the treatment of patients with: Relapsed or refractory, low-grade orfollicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, afterfirst-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positiveNHL in combination with CHOP or other anthracycline-based chemotherapy regimens.Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patientswith previously untreated and previously treated CD20-positive CLL. Limitations of useRituxan is not recommended for use in patients with severe, active infections.WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe,including fatal, infusion reactions. Severe reactions typically occurred during the firstinfusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medicalmanagement (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusionreactions as needed. Depending on the severity of the infusion reaction and the requiredinterventions, temporarily or permanently discontinue Rituxan. Resume infusion at aminimum 50% reduction in rate after symptoms have resolved. Closely monitor thefollowing patients: those with pre-existing cardiac or pulmonary conditions, those whoexperienced prior cardiopulmonary adverse reactions, and those with high numbers ofcirculating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure,hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis,some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patientswith NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burdenconfers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. Thesereactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoiddermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety ofreadministration of Rituxan to patients with severe mucocutaneous reactions has notbeen determined. [See Boxed Warning, Adverse Reactions.] Progressive MultifocalLeukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases.The majority of patients with hematologic malignancies diagnosed with PML receivedRituxan in combination with chemotherapy or as part of a hematopoietic stem celltransplant. The patients with autoimmune diseases had prior or concurrentimmunosuppressive therapy. Most cases of PML were diagnosed within 12 months oftheir last infusion of Rituxan. Consider the diagnosis of PML in any patient presentingwith new-onset neurologic manifestations. Evaluation of PML includes, but is not limitedto, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxanand consider discontinuation or reduction of any concomitant chemotherapy orimmunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitis wasapproximately 4 months after the initiation of Rituxan and approximately one month afterthe last dose. Screen patients at high risk of HBV infection before initiation of Rituxan.Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBVinfection for several months following Rituxan therapy. Discontinue Rituxan and anyconcomitant chemotherapy in patients who develop viral hepatitis, and instituteappropriate treatment including antiviral therapy. Insufficient data exist regarding thesafety of resuming Rituxan in patients who develop hepatitis subsequent to HBVreactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial,fungal, and new or reactivated viral infections can occur during and up to one yearfollowing the completion of Rituxan-based therapy. New or reactivated viral infectionsincluded cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. [See Adverse Reactions.] CardiovascularDiscontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxanadministration in patients with NHL. Renal toxicity has occurred in patients whoexperience tumor lysis syndrome and in patients with NHL administered concomitantcisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not anapproved treatment regimen. Monitor closely for signs of renal failure and discontinueRituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leadingto death, can occur in patients receiving Rituxan in combination with chemotherapy. Inpostmarketing reports, the mean time to documented gastrointestinal perforation was 6(range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation andinstitute appropriate treatment for complaints of abdominal pain. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines followingRituxan therapy has not been studied and vaccination with live virus vaccines is notrecommended. Laboratory Monitoring In patients with lymphoid malignancies, duringtreatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. s Progressive Multifocal Leukoen cephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].s

counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy,obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias. [See Adverse Reactions]. The duration of cytopeniasscaused by Rituxan can extend months beyond the treatment period. ADVERSEREACTIONS The most common adverse reactions of Rituxan (incidence ≥25%)observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia. Clinical Trials Experience in Lymphoid MalignanciesBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1926). The population included 679 patients with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination withfludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, schills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxanwas administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL areceiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Previously Untreated Low-Grade NHL In Study 4,Lpatients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared to patients who received no furthertherapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan armcompared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCL In Studies 6 and 7, [L see Clinical Studies]s the following adverse reactions,regardless of severity, were reported more frequently (≥5%) in patients age ≥60 yearsreceiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). CLL The data below reflectexposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 9 or Study 10 [see Clinical Studies]. The age range was s30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Wholey 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic Systemy p y 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendagespp g 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory Systemp y y 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and NutritionalDisorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive Systemg y 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous Systemy 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal Systemy 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular Systemy 25 3Hypotension 10 1Hypertension 6 1


CLL8 TRIAL (N=817)

In relapsed/refractory* CLL2.1-year follow-up

In first-line CLL1.7-year follow-up

39.8 monthsR-FC

31.5 monthsFC

vs

REACH TRIAL (N=552)RITUXAN-NAIVE PATIENTS

26.7 monthsR-FC

21.7 monthsFC

vs

8.3month

improvementin median

PFS

5.0month

improvementin median

PFS

Indication RITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

RITUXAN is not recommended for use in patients with severe, active infections.

DRIVING BETTEROUTCOMESRITUXAN+FC improved median PFS in first-line and previously treated CLL1,2

In the CLL8 trial2

RITUXAN+FC more than doubled CR in first-line CLL compared with FC alone (36% vs 17%; p<0.0001)

In the REACH trial2

Patients who responded to RITUXAN+FC (n=167) maintained their responses for nearly 2 years longer (48 months vs 27 months; p=0.0294) than those treated with FC alone (n=134)

NOW IN THE TREATMENT OFCHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

BOXED WARNINGS and Additional Important Safety InformationRITUXAN therapy can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia. In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment.For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS.Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

* In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2

R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response.

Treatment considerationsThese trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1

©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved. 10021500 February 2010

References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc.

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