September/October 2008 Vol. 1 No. 4

O ncology pharmacy is anincreasingly sophisticatedfield, and oncology phar-

macists are involved in directpatient care as well as research,teaching, and drug preparationand handling. Siu-Fun Wong,PharmD, FASHP, FCSHP, ofWestern University College ofPharmacy, has the distinction ofhaving served as principal inves-

tigator in clinical trials. She dis-cusses her research activities aswell as her teaching philosophy inthis interview.

Could you please describeyour background?

I was born and raised in HongKong and came to the UnitedStates when I started my collegeeducation. I received my Bachelor

of Science degree in biochemistryat the University of California,Los Angeles, and my Doctor ofPharmacy degree at the Universityof California, San Francisco.Afterwards, I did 1 year of clinicalpharmacy residency at theUniversity of California, Irvine.

OncologyTheOncologyPharmacist

The

PharmacistThe Official Newspaper of Record for the

Hem/Onc Pharmacist™

MEDICAL MINUTESDo sleeping pills increase cancer risk?

page 1

SEPTEMBER/OCTOBER 2008 • VOL. 1, NO. 4 www.theoncologypharmacist.com

ONCOLOGYTRENDS

Gene expression identifies high-risk prostate neoplasia

page 7

INTERVIEWLaura Boehnke Michaud, PharmD

page 12

© 2008 Green Hill Healthcare Communications, LLC

PRESORTED STANDARD

U.S. POSTAGE PAID

LEBANON JUNCTION, KY

PERMIT #651

HEMATOLOGIC CANCERS18-month response and survival ratesfor nilotinib in CP-CML

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CANCER CENTERPROFILEUniversity of Texas M.D.Anderson Cancer Center

page 12

PHARMACY CAREERS

Continued on page 7

Program #CIK 9944: Treatment of Cancer Anemiawith Erythropoiesis-stimulating Agents and IV Iron Supplementation

page 15

Oral ChemotherapyAdherence Enhanced by

Multiple Strategies

PHARMACY PRACTICE

Continued on page 8

Complimentary CE Credit

CONFERENCE NEWS

ANAHEIM—Compliance with new Centers ofMedicare and Medicaid Services (CMS) guidelines onthe use of erythropoiesis-stimulating agents (ESAs) inpatients with chemotherapy-induced anemia (CIA) mayresult in decreased utilization of ESAs and increased useof red blood cell (RBC) transfusions and other resources.

HOPA: CMS Regulations Impact ESAUtilization, Patient Outcomes

ANAHEIM—Oncology pharmacists can enhancepatient adherence with oral chemotherapy througha combination of educational interventions, med-ication reconciliation, and other strategies, saidGary Yee, PharmD, University of Nebraska MedicalCenter, Omaha.

Nearly one third of oncology drugs currently inContinued on page 10

GASTROINTESTINAL CANCERS

CHICAGO—A retrospective analysis indicates thatthe KRAS mutation status of tumors has a significantimpact on response rate and progression-free survival(PFS) in patients receiving first-line treatment formetastatic colorectal cancer (mCRC). The Oxaliplatinand Cetuximab in First-line Treatment of MetastaticColorectal Cancer (OPUS) study, reported by CarstenBokemeyer, MD, Universitätsklinikum Eppendorf,Hamburg, Germany, at the 2008 Annual Meeting of

KRAS Status Has Major Impact on Response in

Colorectal Cancer

Continued on page 13

Advancing OncologyPharmacy to a New LevelAn interview with Siu-Fun Wong, PharmD, FASHP, FCSHP

TOP September 2008_v5 9/19/08 12:31 PM Page Cov1

Advanced RCC: A Path Forward

Novartis Oncology—A commitment to clinical research

A rapidly changing environment The potential for progressOver the past several years there have been significantadvances made in the management of renal cell carcinoma (RCC). Targeted therapies have provided newoptions for oncologists treating this disease. Through thedevelopment of tumor-specific programs, Novartis Oncology continues to conduct clinical research with the goal of advancing our understanding of RCC.

The fast pace of emerging data within this dynamicenvironment is changing the landscape of RCC. There is a clear need to harness the potential of these recentadvances by establishing a clear path forward.

Novartis Oncology has built a strong history of furthering the development of cancer therapies. As we bring newresearch to the forefront of cancer care, our aim is to better address the outstanding issues in RCC, a disease we are dedicated to combating.

©2008 Novartis 7/08 C-ONC-100070

TOP September 2008_v5 9/19/08 9:16 AM Page Cov2

Seeking to improve on nature, scientists are now using spice-based compounds as a starting point, and they have developedsynthetic pharmaceutical compounds that may be able to killcancer cells and stop the cells from spreading. Investigators arecombining organic chemistry, computer-aided design, andmolecular biology techniques for developing compounds thatcan fight breast cancer and prostate cancer. The synthetic mol-ecules are derived from curcumin, a naturally occurring com-pound found in the spice turmeric.

Centuries of anecdotal evidence and recent scientific researchsuggest that curcumin has multiple disease-fighting features,including antitumor properties. However, when eaten, curcuminis not absorbed well by the body. Instead, most digested curcu-min in food or supplement form remains in the gastrointestinalsystem and is eliminated before it is able to enter the blood-stream or tissues.

“Newer evidence describes how curcumin interacts with cer-tain proteins to generate anticanceractivity inside the body. We’re focusingon the pathways that are most involvedin cancer and trying to optimize forthose properties,” said James Fuchs,PhD, assistant professor of medicinalchemistry and pharmacognosy at OhioState University, Columbus.

Fuchs, who is the principal investiga-tor for this study, said a selection of 40compounds appear to have the mostpotential to date to serve as the basis foranticancer drug development. He andhis colleagues are continuing to refinecompounds that are best structured tointeract with a few overactive proteinsthat are associated with cell activity inbreast and prostate cancers. Blocking

these molecular targets can initiate cell death or stop cell migra-tion in the cancers.

A major component of their strategy is called structure-based,computer-aided design. This is a relatively new technology inthe drug discovery field. Before working with an actual com-pound, scientists can manipulate computer-designed moleculesand observe simulated interactions between molecules and pro-teins to predict which structural changes will make the mostsense to pursue.

“Most of the interaction between our compound and the over-active protein comes from what are called hot spots on the pro-tein’s surface,” said Chenglong Li, PhD, an assistant professor ofmedicinal chemistry and pharmacognosy and an expert in com-putational chemistry at Ohio State University. “For each spot,we can design small chemical fragments and link them togetherto make a molecule. This is what computer-aided design andmodeling can do.”

The next time you consider popping a pill when you have troublesleeping, it might be worth counting sheep instead. A senior psychi-atrist at the Scripps Clinic Sleep Center in San Diego, California, hasfound evidence that taking sleeping pills on a regu-lar basis may increase the risk of skin cancer.

Daniel Kripke, MD, and his colleagues have pub-lished a study in the Journal of Sleep Research(Kripke DF, et al. J Sleep Res. 2008;17:245-250.)that is based on a compilation of studies involvingsleeping pills and cancer. The researchers assessedthe effects of 556 person-years of taking zaleplon,eszopiclone, ramelteon, or zolpidem compared witha control group who took placebo more than 230person-years. They found eight nonmelanoma skincancers and four tumors of uncertain malignancy in the groups thattook sleeping pills compared with none in the placebo groups.

Laboratory animals given high doses of hypnotic drugs have

developed kidney, thyroid, and testicular cancers and suffered chro-mosome damage, a sign of carcinogenicity. Although a direct causallink between cancer and sleeping pills has still not been proved,

Kripke is now urging additional studies. He said thisissue is critical today given the fact that sleeping pilluse has been steadily rising in the United States andthree new types have been approved for commercialuse in addition to zolpidem, which is the most popu-lar sleep-aid drug used in the United States.

“Because the compilation mixes diverse studies ofseveral drugs, and the number of cancers observedduring controlled hypnotics trials remains small,”writes Kripke, “this preliminary analysis should beviewed as an investigative step, rather than sufficient

proof that modern hypnotics cause cancer.”He is urging regulatory bodies and the US National Institutes of

Health to keep an eye on cancer cases reported by sleeping pill users.

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Medical MinutesBY JOHN SCHIESZER

John Schieszer is anaward-winning nationaljournalist and radiobroadcaster of TheMedical Minute.He can be reached at [email protected].

Researchers at Mount Sinai School ofMedicine in New York have found thatsorafenib may prolong the lives ofpatients with advanced liver cancer byabout 44% compared with patients whoreceived placebo. Liver cancer is current-ly the third leading cause of cancer deathglobally, often resulting in death within 1year of diagnosis.

“This is the first time that we’ve had aneffective systemic treatment for liver cancer,”said lead study investigator Josep Llovet, MD,who is director of research in Liver Cancer atMount Sinai School of Medicine. “Our find-ings demonstrated survival advantages thatare both statistically significant and clinicallymeaningful.”

Taken orally, sorafenib is approved inthe United States for treatment ofadvanced kidney cancer, but it is current-ly being evaluated in patients with othercancers. Llovet and his associates exam-

ined overall survival and the time it tookfor cancer to progress in patients withpreviously untreated liver cancer. All thesubjects were randomly assigned toreceive either 400 mg of sorafenib twicedaily (229 patients) or a placebo (303patients).

Patients who received sorafenib lived amedian of 10.7 months compared with7.9 months for those who received aplacebo. Time to radiologic progressionwas significantly longer in the treatmentgroup: 5.5 months versus 2.8 months.Llovet said because the findings were sopositive the trial was stopped early.

The incidence of adverse effects wassimilar in the two groups (52% in thesorafenib group and 54% in the placebogroup). The most common moderate-to-serious side effects were diarrhea, skinreactions on the hands and feet, fatigue,and bleeding.

Sorafenib Found to Have Benefits in the Treatment of Liver Cancer

Prescription Sleeping Pills May Be Associated with Increased Cancer Risk

Spicing Up the Fight Against Cancer

September/October 2008 GREEN HILL HEALTHCARE COMMUNICATIONS 1

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Feature Articles

12 Cancer Center ProfileM.D. Anderson Cancer Center

13 Gastrointestinal CancersKRAS status and skin toxicity predict response in colorectal cancer

14 Hematologic CancersSustained dasatinib benefits

15 Continuing EducationTreatment of Cancer Anemia with ESAs and IV Iron

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David Baribeault, RPh, BCOPBoston Medical CenterBoston, MA

Sylvia Bartel, RPh, MPHDana Farber Cancer InstituteBoston, MA

Deborah Blamble, PharmD, BCOPUniversity of Texas MD Anderson Cancer CenterHouston, TX

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove Research InstituteColumbus, OH

Bryna Delman Ewachiw, BS, PharmDJohns Hopkins Bayview Medical CenterBaltimore, MD

Anjana Elefante, PharmD, BSc, BScPhm,RPh

Roswell Park Cancer InstituteBuffalo, NY

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

Christopher Fausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley, PharmD, MSJefferson School of PharmacyPhiladelphia, PA

David C. Gammon, BSPharmUniversity of Massachusetts Memorial HospitalWorcester, MA

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

Sandra Horowitz, PharmD, RPh The University of Texas MD Anderson Cancer CenterHouston, TX

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

Andrea A. Iannucci, PharmD, BCOPUniversity of California Davis Medical CenterSacramento, CA

Cindy Ippoliti, PharmD New York Presbyterian Hospital/Weill Cornell

Medical SchoolNew York, NY

Jim Koeller, MSUniversity of Texas at AustinSan Antonio, TX

Helen L. Leather, BPharmUniversity of FloridaGainesville, FL

Christopher J. Lowe, PharmDNovant HealthWinston Salem, NC

Helen McFarland, PharmD, BCOPUnion Memorial HospitalBaltimore, MD

Emily Mackler, PharmD, BCOPUniversity of Michigan Health System &

College of PharmacyAnn Arbor, MI

Patrick Medina, PharmD, BCOPOklahoma University College of PharmacyTulsa, OK

Laura Boehnke Michaud, PharmD, BCOP,FASHP

The University of Texas MD Anderson Cancer CenterHouston, TX

Deborah Moradi, PharmDThe Angeles Clinic and Research InstituteLos Angeles, CA

LeAnn Best Norris, PharmD, BCPSSouth Carolina College of PharmacyColumbia, SC

Debra L. Phillips, PharmDEast Carolina UniversityGreenville, NC

Timothy G. Tyler, PharmD, FCSHPDesert Regional Medical CenterPalm Springs, CA

John M. Valgus, PharmD, BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCOPUniversity of Nebraska College of PharmacyOmaha, NE

PUBLISHING STAFF

PublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Managing EditorLara J. Reiman

Senior Production ManagerStephanie Laudien

Directors, Client ServicesJohn W. [email protected]

Russell [email protected]

Director of Human ResourcesBlanche [email protected]

[email protected]

241 Forsgate Drive, Suite 205CMonroe Twp, NJ 08831

Vol. 1, No. 4 September/October 2008

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

™

EDITORIAL BOARD

EDITOR-IN-CHIEF

Susan Goodin PharmD, FCCP, BCOPCancer Institute of NewJersey

New Brunswick, NJ

Departments

1 Medical Minutes

4 Editor’s Letter

6 News Notes

6 Cartoon

7 Oncology Trends

10 Recent FDA Approvals

2 GREEN HILL HEALTHCARE COMMUNICATIONS September/October 2008

www.theoncologypharmacist.comReach us online at


Our vision extends beyond science

…making today’s therapies more accessible and tomorrow’s breakthroughs more achievableSupporting today

The Genentech® Access to Care Foundation makes our marketed products available to qualified patients in need*

Genentech BioOncology™ Access Solutions™, formerly known as SPOC® (Single Point of Contact)— For patients and their healthcare providers, Genentech BioOncology

Access Solutions provides coverage and reimbursement support,patient assistance, and informational resources

Investing in tomorrowGenentech BioOncology invests deeply in research and developmentand is an industry leader in investing a percentage of annualrevenues back into R&D

Genentech BioOncology funds grant and fellowship programs to support medical education, partner with professional societies, and encourage independent research

*The Genentech Access to Care Foundation was established to help qualified patients with unmet medicalneeds who are uninsured or rendered uninsured by payer denial and who meet specific medical criteriato receive proper medical treatment. The Genentech Access to Care Foundation may be available to helpthose who are not able to obtain Genentech therapeutics for financial reasons.

© 2008 Genentech, Inc. All rights reserved. 8111602

www.BioOncology.com

TOP September 2008_v5 9/19/08 9:23 AM Page 3

A study published in the July 28 issue of Archives of InternalMedicine shows a dramatic 360.5% increase in the overalldeaths from fatal medication errors (FMEs) in the United

States from 1983 to 2004. The authors suggest that the increase islinked to “a shift in the location of medication consumption fromclinical to domestic settings” and that “it may now be possible toreduce FMEs by focusing not only on clinical settings but also ondomestic settings.” Although this study was not specifically aboutcancer drugs, it has important implications for oncology pharma-cists in view of the increasing use of oral chemotherapy agentsadministered at home rather than in the clinic.

A major concern for oncology pharmacists and other healthcareproviders is how to ensure adherence to oral chemotherapy regi-mens, avoid medication errors, and improve treatment outcomes.Nonadherence to treatments for chronic medical conditions is soprevalent, in fact, that it has been termed “America’s other drugproblem.” One observer wrote “Increasing the effectiveness ofadherence interventions may have a far greater impact on thehealth of a population than any improvement in specific medicaltreatments” (Haynes RB, et al. Cochrane Database Syst Rev.2002;CD000011). No matter how many new drugs are developedor how effective they are, if patients do not take their medicines asprescribed, they will not work, and we will fail as healthcare

providers. The impact of nonadherence on treatment outcomesand strategies for improving adherence to oral chemotherapy werepresented in a symposium held during the annual HOPA/ISOPPmeeting and summarized in an article in this issue.

Another issue that has generated much discussion in the pastyear has been the appropriate use of erythropoiesis-stimulatingagents (ESAs) for cancer-related anemia. The continuing educa-tion article this month discusses the use of intravenous iron sup-plementation to increase the efficacy of ESAs in cancer patientswith anemia. Use of ESAs was also addressed in several studies pre-sented at HOPA/ISOPP and the findings are reported here.

Also of note in this issue is the interview with Siu-Fun Wong,an oncology pharmacist who has served as prinicipal investigatorin a number of clinical trials, one of the many new roles oncologypharmacists are now playing in cancer care.

October is American Pharmacists Month, which recognizes themany contributions pharmacists make to healthcare whether theywork in a retail pharmacy, hospital or clinic, industry, managedcare, or other setting. The Oncology Pharmacist seeks to highlightthe accomplishments of pharmacists in this increasingly complexfield. Please write to us ([email protected]) and tell us aboutyour own experiences and thoughts on issues of importance to youand your colleagues.


EDIT

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A Letter from the Editor

SUSAN GOODIN,PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

EDITORIAL CORRESPONDENCE should be addressed to EDI-TORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive,Suite 205C, Monroe Twp, NJ 08831. E-mail: [email protected] SUBSCRIPTION RATES: United States and possessions:individuals, $105.00; institutions, $135.00; single issues $17.00. Orderswill be billed at individual rate until proof of status is confirmed. Pricesare subject to change without notice. Correspondence regarding permis-sion to reprint all or part of any article published in this journal should beaddressed to REPRINT PERMISSIONS DEPARTMENT, GreenHill Healthcare Communications, LLC, 241 Forsgate Drive, Suite205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist™, do not necessarily reflect those of the EditorialBoard, the Editorial Director, or the Publisher. Publication of an adver-tisement or other product mention in The Oncology Pharmacist™, shouldnot be construed as an endorsement of the product or the manufacturer’sclaims. Readers are encouraged to contact the manufacturer with ques-tions about the features or limitations of the products mentioned.Neither the Editorial Board nor the Publisher assumes any responsibili-ty for any injury and/or damage to persons or property arising out of orrelated to any use of the material contained in this periodical. The read-er is advised to check the appropriate medical literature and the productinformation currently provided by the manufacturer of each drug to beadministered to verify the dosage, the method and duration of adminis-tration, or contraindications. It is the responsibility of the treating physi-cian or other healthcare professional, relying on independent experienceand knowledge of the patient, to determine drug dosages and the besttreatment for the patient. Every effort has been made to check genericand trade names, and to verify dosages. The ultimate responsibility, how-ever, lies with the prescribing physician. Please convey any errors to theEditorial Director. ISSN #1944-9607.

The Oncology Pharmacist™, is published 5 times a year by Green HillHealthcare Communications, LLC, 241 Forsgate Drive, Suite 205C,Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax:732.656.7938. Copyright ©2008 by Green Hill HealthcareCommunications LLC. All rights reserved. The OncologyPharmacist™ logo is a trademark of Green Hill HealthcareCommunications, LLC. No part of this publication may be repro-duced or transmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy, recording, orany informational storage and retrieval system, without written per-mission from the Publisher. Printed in the United States of America.

Coming Soon

CE article: Does Finasteride Prevent Prostate Cancer?

“Growing Pains” of Oncology Specialty Pharmacy

Opportunities for Oncology Pharmacists at the FDA

Setting Up a Chemotherapy Prep Area in a Community Practice

Using Nanoparticles to Deliver Chemotherapy

Reports from ASCO Breast Cancer Symposium, European

Society for Medical Oncology

For a free subscription go to www.theoncologypharmacist.com


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� Link Between Smoking andBladder Cancer Not Well Known

Physicians need to educate patientsthat smoking increases the risk of blad-der cancer and direct them to smokingcessation programs, a new study sug-gests. Up to half of bladder cancer casesmay be attributed to cigarette smoking,but a recent study indicates most peopleare not aware of the relationshipbetween the two. Results showed littlemore than one third of adults wereaware smoking increased the risk ofbladder cancer; even among those withearly-stage bladder cancer, just 22%were aware of smoking’s contribution tothe disease. Smoking cessation decreas-es the risk, as well as the recurrence ofbladder cancer, by as much as 30%, butresearchers also found physicians arenot actively counseling their patients.Even smokers with bladder cancerclaimed their physicians had notadvised them to quit smoking. One USstudy found that only half of smokers,and in the United Kingdom only 7% ofsmokers, had been advised to quit.(Strope SA, Montie JE. J Urol.2008;180:31-37.)

� Topical Analgesic May EaseDiscomfort of Mammography

Pretreatment with lidocaine can sig-nificantly reduce the discomfort ofmammography according to a newstudy. A double-blind, placebo-con-trolled study of 418 women betweenthe ages of 32 and 89 years showedthat women who premedicated with a

4% lidocaine gel experienced signifi-cantly less discomfort than those whoused 1000 mg acetaminophen or 800mg ibuprofen, which had no beneficialeffect. Patient satisfaction was signifi-cantly lower in patients who reporteddiscomfort. Patient satisfaction signifi-cantly affected the women’s plans tohave another mammogram the follow-ing year. Positive interactions betweenthe patient and the nurse or technologistincreased patient satisfaction. The re-searchers noted that lidocaine has fewside effects, is available over the counter,and can be applied at home approxi-mately 1 hour before a mammogram isscheduled to take place. (Lambertz CK,et al. Radiology. 2008;248:765.)

� Exercise Testing Not Adheringto National and InternationalGuidelines

Exercise testing is used increasinglyin both cancer care and research toevaluate either a patient’s presurgicalor cardiorespiratory fitness after a can-cer diagnosis. A new study indicates,however, that exercise tests are notadministered according to national andinternational guidelines. The re-searchers found that key physiologicaloutcomes that provide informationrapidly on a patient’s fitness level orthe validity of the test are frequentlynot reported. They recommend stan-dardizing exercise tests for oncologypatients to ensure safety and reliabletest results. (Jones LW, et al. LancetOncol. 2008;9:757-765.)

� Nurse-delivered PsychotherapyBeneficial for Depressed CancerPatients

One-on-one problem-solving therapywith an oncology nurse is more effectivethan usual care in helping patients withcancer cope with depression, Scottishresearchers report. In a study of 200 out-patients with cancer and depression, 99patients were assigned to usual care, and101 received usual care as well as psy-chotherapy. Patients participated inapproximately seven 45-minute sessionswith an oncology nurse, after which theyreceived monthly telephone calls for 3months to evaluate their depression. If itwas worsening, patients could have one

to two more therapy sessions. At 3months, the patients who received psy-chotherapy gained 0.34 points on theself-reported Symptom Checklist-20depression scale (range, 0-4) comparedwith those who received usual care,and this effect was sustained at 6 and12 months. The psychotherapy inter-vention was estimated to cost approxi-mately $10,556 per quality-adjustedlife-year gained. (Strong V, et al.Lancet. 2008;372:40-48.)

� Eliminating H Pylori ReducesRecurrence of Stomach Cancer

Prophylactic eradication of Heli-cobacter pylori after endoscopic resectionof early gastric cancer reduces the risk ofcancer recurrence, according to Japaneseresearchers. Results of a multicenter trialshowed that among 544 patients havingsurgery for early-stage cancer of thestomach, patients whose regimenincluded H pylori elimination had a twothirds lower risk of recurrence thanthose in the control group. After 3 years,stomach cancer had recurred in nine ofthe 272 patients given the regimen com-pared with 24 of 272 patients in the con-trol group, with an odds ratio for gastriccarcinoma of 0.353 (P = .009) and a haz-ard ratio of 0.339 (P = .003). The elimi-nation regimen included lansoprazole 30mg twice daily, amoxicillin 750 mg twicedaily, and clarithromycin 200 mg twicedaily for 1 week. The control groupreceived standard care only. Amongpatients receiving the H pylori regimen,adverse effects included diarrhea (in 19patients [7%]) and soft stools (in 32patients [12%]). (Fukase K, et al.Lancet. 2008;372:392-397.)

� Cancer Treatment’s Effects onSkin Affect Quality of Life

Skin-related side effects negativelyaffect cancer patients’ quality of life, aCancerCare survey shows. Of 345patients who were either undergoingor had recently completed treatmentfor breast, ovarian, lung, colorectal,prostate, bladder, or kidney cancer,63% believed the condition of theirskin had gotten worse as a result oftreatment, and one in three patientsbelieved these side effects had had anegative impact on their lives. Fewerthan two in five people had been con-cerned about skin-related side effectson beginning their cancer treatment,

but almost 80% became concernedabout the actual side effects they ulti-mately experienced. These side effectsincluded, in particular, irritation,rash, and dryness (which led the list ofcomplaints at 61%). Almost half(49%) complained of fingernail prob-lems and 34% complained of bothredness and itching. The findings ofthe survey indicate a need to educatepatients with cancer about their treat-ment’s possible effects on their skinand to assist them find ways to allevi-ate their symptoms. (http://www. cancercare.org/about_us/press_releases/pr_2008_05_27.php.)

� Triple-negative Breast Canceran Unmet Need

Among patients with metastaticbreast cancer, the biggest unmet needis for new treatments for those with“triple-negative” disease, whose tumorsdo not overexpress human epidermalgrowth factor receptor 2 (HER2), theestrogen receptor (ER), or the proges-terone receptor (PR), a survey of keyopinion leaders in oncology indicates.Respondents to the survey, conductedby The Mattson Jack Group, Inc,described the field as “wide open” forthese patients, who typically havemore aggressive disease and shorter sur-vival than breast cancer patients whooverexpress HER2, ER, or PR. It is esti-mated that about 18.5% of patientswith breast cancer are “triple nega-tive,” but no specific therapy otherthan traditional cytotoxic chemothera-py is currently available for thesepatients.(http://biz.yahoo.com/iw/080723/0418272.html).

News Notes

The findings of the survey indicate a need to

educate patients with cancer about their

treatment’s possible effects on their skin

and to assist them find ways to alleviate

their symptoms.

CARTOON

“These are the possible side effects.”



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How did you get involved inoncology pharmacy?

My interest in oncology pharmacybegan during my fourth year of clerkshiprotation in pharmacy school. I had agreat preceptor who was very active inoncology pharmacy, and my rotationwith him opened my eyes to the impor-tant role of the oncology pharmacist inpatient care. The pharmacy program atUC Irvine is multidisciplinary, and thereI learned to view patients in a compre-hensive manner. While fulfilling myclinical pharmacy residency require-ments, I made a special request to followtwo oncology patients for an entire year.That experience provided me withgreater insight into the challenges of car-ing for chronically ill patients on a long-term basis and secured my interest andcommitment to oncology pharmacy.

What do you find mostrewarding about working withoncology patients?

When faced with a life-threateningdisease, many oncology patients look atlife differently than others. In manycases, patients choose to avoid dwellingon their illness and instead focus on cel-ebrating life. I have had the privilege to

learn much from the oncology patients Ihave cared for. This is one of the uniqueaspects of oncology patient care.

Could you describe your cur-rent teaching activities?

I am a full-time associate professorat the Western University College ofPharmacy. My primary teachingresponsibilities used to be oncology.With the recruitment of a secondoncology faculty member, I teach lessoncology and am now teaching anintegrated course at the end of the sec-ond-year curriculum. I am also a clini-cal professor of medicine at UCIrvine, where I teach a pharmacologycourse for oncology fellows. This is an8-hour course, and the goal is to pro-vide knowledge on oncologic pharma-cology and related supportive care andto teach oncology fellows how to com-pose chemotherapy orders.

What are your teaching philosophies?

My teaching philosophy is toempower students with critical think-ing and integration skills. Anotherone of my major teaching philoso-phies in clinical rotation is theimportance of providing studentswith the experience of direct patientcare. My students have the opportu-nity to interact with patients on acontinual basis for 6 weeks. The stu-dents are required to document allpatient interventions and incorpo-rate these interactions into thepatient’s medical records. I think thisapproach gives students a sense ofresponsibility and helps emphasizethe connection between pharmacypractice and patient outcomes.

What are your clinicalresearch activities?

I serve as an advisor for the clinicalresearch program at St. JosephHospital Cancer Institute. My pri-mary role there is to develop strategicplans for clinical research in variousdisease management groups. I evalu-ate different disease and therapeuticcategories, determine the need andtargets for research, develop cost pro-jections, and identify potential inves-tigators. Frequently, I serve as a prin-cipal investigator or participate as asubinvestigator in the clinical trials. Ialso collaborate on research projectswith some of the scientists here atWestern University.

What types of treatment trialsare you participating in?

A majority of my research is in sup-portive care. Right now, my majorfocus is on therapeutic issues related tolung cancer.

What professional organiza-tions are you active in?

I have chaired the PharmacyCommittee of the SouthwestOncology Group (SWOG) since 1994and recently received an unprecedent-ed appointment as Leader of SWOGPharmaceutical Sciences, which Ihope brings more recognition of phar-macy practitioners in the area ofresearch. SWOG is one of the largestcooperative oncology groups focusingon clinical and translational research.I am also a member of the NorthAmerican Pharmacist LicensureExamination Review Committee andam involved in several of the nationalprofessional organizations, including

the Hematology/Oncology PharmacyAssociation (HOPA).

How has oncology pharmacychanged over the past fewyears?

I think oncology pharmacy hasbecome much better organized duringthe past several years. With the forma-tion and growth of HOPA, oncologypharmacists across the country havebeen provided an opportunity to meettheir colleagues, network, and fulfilltheir needs for continuing education.The quality of the annual meetingprogram has improved every year, andthis reflects the hard work of oncologypharmacists across the country.

How will oncology pharmacychange in the next fewyears?

I see a growing interest amongyounger practitioners in taking a sec-ond year of postdoctoral training andspecializing in oncology pharmacy. Ithink the practice of oncology phar-macy will grow exponentially over thenext few decades, due in part to theenthusiasm of these young practition-ers and the work of some of the greatleaders in our field. I am very encour-aged about the level of motivation Ihave seen among new practitioners inthis field. These newer oncology phar-macists have received sophisticatedtraining from some great educatorsand are highly capable of providingquality care to their patients. I thinkthe efforts of these newer graduateswill elevate the practice of oncologypharmacy to a new level.

—David S. MacDougall

SIU-FUN WONG Continued from cover

>>> Gene ExpressionIdentifies High-risk ProstateNeoplasia

PTOV1, a novel gene overexpressedin prostate cancer, is overexpressedin men with high-grade prostaticintraepithelial neoplasia (HG-PIN)and a potential marker for studyingthe carcinogenesis and progressionof prostate cancer. PTOV1 expres-sion was analyzed by semiquantita-tive immunohistochemistry (Histo-score) in HG-PIN lesions obtainedfrom 140 patients. The patientswere followed with a mean of 2.5repeat prostate needle biopsies dur-ing a mean period of 12.4 months.PTOV1 expression was significantlyhigher in HG-PIN lesions frompatients in whom cancer was detect-ed during follow-up than in lesionsfrom patients in whom it was notdetected (mean Histo-score, 151.4vs 94.6). PTOV1 expression in HG-PIN lesions was the only independ-

ent predictor of cancer in multivari-ate analysis. A threshold Histo-scoreof 100 for PTOV1 expression inHG-PIN lesions provided 90.9%sensitivity, 51.3% specificity, 34.5%positive predictive value, and 95.2%negative predictive value for thedevelopment of prostate cancer.(Morote J, et al. Clin Cancer Res.2008;14:2617-2622.)

>>> Pain Predicts Survival inMen with MetastaticCastration-RefractoryProstate Cancer

Pain is a significant predictor ofoverall survival in men with metastat-ic castration-refractory prostate can-cer (CRPC), according to an analysisof combined data from three ran-domized phase 3 multicenter trials.All patients had progressive CRPC,an Eastern Cooperative OncologyGroup performance status of 0 to 2,and adequate hematologic, renal,

and hepatic function. The impact ofpain on daily activities and qualityof life was measured using sevenitems from the Brief Pain Inventoryscale. Overall, 38% of the men usedopioid analgesics at baseline. Themedian survival times were 17.6months and 10.2 months in menwith low (<17) and high (≥17) painscores, respectively (P <.001). Painwas inversely associated with thelikelihood of prostate-specific anti-gen decline, objective therapeuticresponse, and time to bone progres-sion. (Halabi S, et al. J Clin Oncol.2008;26:2544-2549.)

>>> Chemotherapy ProvidesNo Added Benefits inPatients with MalignantPleural Mesothelioma

The addition of chemotherapy toactive symptom control (ASC) pro-vides no significant survival or quali-ty-of-life benefits in patients with

malignant pleural mesothelioma(MPM). A group of 409 patients withMPM was randomized to ASC alone(treatment could include steroids,analgesic drugs, bronchodilators, andpalliative radiotherapy), ASC pluschemotherapy (mitomycin, vinblas-tine, and cisplatin), or ASC plusvinorelbine. Follow-up was every 3weeks to 21 weeks after randomiza-tion and every 8 weeks thereafter.Because of slow accrual, the twochemotherapy groups were combinedand compared with ASC alone forthe primary outcome of overall sur-vival. Median survival was 7.6months in the ASC alone group and8.5 months in the ASC pluschemotherapy group. Compared withASC alone, ASC plus chemotherapyprovided a small, nonsignificant sur-vival benefit (hazard ratio [HR],0.89; P = .29). Statistical analysisrevealed a small survival advantage


Oncology Trends

My teaching philoso-phy is to empowerstudents with criticalthinking and integra-tion skills.



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The findings emerged in studies pre-sented in poster sessions held during the2008 Hematology Oncology PharmacyAssociation/International Society ofOncology Pharmacy Practitioners jointannual conference.

In July 2007, CMS released aNational Coverage Decision (NCD)that defines criteria for reimbursementfor ESAs when used in the treatmentof patients with CIA (Table). TheNCD is designed to reduce costs asso-ciated with ESA use without compro-mising patient safety, but impact of theNCD on resource utilization and clini-

cal outcomes in patients with CIA hasnot been determined.

The clinical outcomes of 61 patientswith CIA who were treated with ESAsbefore or after the implementation ofthe CMS NCD were described byKenneth Utz, PharmD, and his col-leagues from the University ofColorado, Denver. The study groupwas treated at the University ofColorado Cancer Center betweenJanuary and December 2007 andincluded Medicare patients treatedbefore (Group A) or after (Group B)the release of the NCD and non-Medicare patients with other primarypayer sources (Group C).

Patients who were treated before

the release of the NCD received ESAtherapy according to an algorithm forthe management of CIA that wasbased on guidelines developed by theNational Comprehensive CancerNetwork.

The proportion of patients receivingRBC transfusion was higher in Group B(56%) than in Group A (33%) or GroupC (24%). The mean number of ESAdoses was lower in Group B (2.67) thanin Group A (3.67) or Group C (3.92).

Overall, fewer Medicare patientsachieved their target hemoglobin (Hb)level (Group A, 40%; Group B, 44%)compared with non-Medicare patients(65%). None of the differences in out-comes between the groups were statistically significant. A trend towards

decreased use of ESAs throughout 2007was observed.

Resource utilization may be increasedin patients with CIA who are classifiedas nonresponders to ESA therapyaccording to the revised CMS criteria,reported Siu-Fun Wong, PharmD, andher colleagues from Western Universityof Health Sciences, Pomona, California.

CMS currently defines an Hbresponse to ESA therapy as Hb >10g/dL and a hematopoietic response asHb >10 g/dL and >1 g/dL from base-line. Previous CMS guidelines allowedthe use of ESAs in patients with CIAand Hb <12 g/dL.

To determine the impact of the newCMS NCD on resource utilization andclinical outcomes in patients withCIA, the researchers performed a ret-rospective chart review of 28 patientswith CIA who received ESAs afterimplementation of the revised CMSguidelines. The mean age of the studypopulation was 60 years, and breastcancer was the most common cancertype (43%).

A total of 22 patients (79%)achieved an Hb response, but only 14patients (50%) achieved a hematopoi-etic response according to CMS criteria.A total of 6 patients were Hb andhematopoietic nonresponders.

The total number of RBC units trans-fused was 8 in the responders and 22 inthe nonresponders (P = .23). The meanlength of hospitalization was 4 days inthe responders and 11 days in the non-responders (P = .016).

Total resource utilization (the costof RBC transfusions plus hospitaliza-tion) was $7800 in responders and$21,420 in nonresponders. The meanresource utilization cost per patientwas $354.50 in responders and $3570in nonresponders.

Implementation of the revised CMSguidelines did not compromise patientsafety, but may have resulted in higherresource utilization in the nonrespon-der group, the researchers concluded.They noted that the possible impact of ESA dose escalation performedaccording to approved package insertson resource utilization in nonrespon-ders remains unclear.

—DSM

OncologyNurse

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About Multidisciplinary Cancer Care

Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community.

Target AudienceThis educational publication is designed for physicians, nurses, and pharmacists who wish toenhance their knowledge concerning the management of patients with multiple myeloma andrenal dysfunction.

Learning ObjectivesAt the completion of this educational activity, you should be able to:• Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM)• Recognize the special challenges in pharmacologic treatment of the many patients with MM

who also have renal insufficiency, especially those requiring dialysis• Discuss the results of studies showing treatments that are active and safe in MM patients with

renal impairment, including those with advanced renal failure requiring dialysis

AccreditationPhysiciansThis activity has been planned and implemented in accordance with the Essential Areas andPolicies of the Accreditation Council for Continuing Medical Education (ACCME) through thejoint sponsorship of CME Consultants and Center of Excellence Media. CME Consultants isaccredited by the ACCME to provide continuing medical education for physicians.

CME Consultants designates this educational activity for a maximum of 1.0 AMA PRA Category1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their partici-pation in the activity.

PharmacistsCME Consultants is accredited by the Accreditation Council for Pharmacy Educationas a provider of continuing pharmacy education.

This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, allparticipants must complete an evaluation, request for credit form, and a posttest. Statements ofCredit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09.

Nurses CME Consultants is accredited as a provider of continuing nursing education by theAmerican Nurses Credentialing Center’s Commission on Accreditation.

CME Consultants designates this program for 1 contact hour. Participants should claim onlythose contact hours actually spent in the educational activity.

In order to receive credit for this program, each participant must complete the evaluation form,posttest, and certificate request form. Certificates will be mailed to program participants inapproximately four to six weeks after receipt of the completed evaluation form, posttest, and cer-tificate request form.

Supported by an educational grant from Millennium Pharmaceuticals, Inc.

Clinical Topics:

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To request free copiesTo request free copies

CMS REGULATIONS Continued from cover

Table. Highlights of the CMSNCD on the use of ESAsin patients with CIA

• Allows ESA administration only whenHb <10 g/dL (previous guidelinesallowed ESA usage at Hb <12 g/dL)

• Allows 25% dose adjustment afterweek 4 for each chemotherapy cycle(previous guidelines allowed 50%-100% dose adjustment)

• Limits duration of ESA treatment to 8weeks in patients who achieve an Hbincrease <1 g/dL (previous guidelinesallowed duration up to 12 weeks)


development are oral agents. The increasingavailability of oral oncology drugs and percentageof oral agents considered “targeted therapies”underscore the importance of maximizing patientadherence with oral chemotherapy regimens, Yeesaid during a symposium held at the 2008Hematology Oncology Pharmacy Association/International Society of Oncology PharmacyPractitioners joint annual conference.

According to Yee, no consensual standardexists for differentiating adherence fromnonadherence. Patients who take at least80% of the prescribed number of pills dailywithin the correct prescribed period are con-sidered adherent in most standard clinicalstudies, he explained, although rates as highas 95% have been used to establish adher-ence in studies of patients with HIV infec-tion and other populations.

“Nonadherence to oral chemotherapy canhave far-reaching negative consequences,” Yee

said. Adverse consequences of nonadherenceinclude misinterpretation of a patient’s worsen-ing condition as an absence of drug activity,increased physician visits, unnecessary diag-nostic testing, longer length of hospital stay,unnecessary changes in medication dose or reg-imen, and deterioration of the patient–provider relationship, he noted.

Medication adherence can be determineddirectly through continual observation orthe use of blood assays or physiologic mark-ers of drug activity. Indirect methods ofdetermining medication adherence includethe use of patient questionnaires, diaries,pill counts, refill rates, electronic monitors,and pharmacy record review.

The presence of psychological problems, par-ticularly depression, is a major predictor of med-ication nonadherence, Yee explained. Other fac-tors associated with nonadherence include cogni-tive impairment, treatment of asymptomatic dis-ease, adverse medication effects, patient’s lack ofbelief in treatment benefit, complexity and costsof treatment, and a poor provider–patient rela-tionship (Table 1).

Medication adherence can be enhancedthrough a combination of behavioral, education-al, and affective interventions, Yee said (Table 2).Such interventions are designed to influence spe-cific behavioral patterns, convey information,and appeal to emotions and social relations,respectively, in an effort to improve adherence.

Yee described the findings of a systematicreview of 37 randomized controlled trials ofinterventions intended to improve medicationadherence (JAMA. 2002;288:2868-2879). Alltrials were in patients with chronic medicalconditions and none of the trials enrolledpatients with cancer.

Of the 37 trials, 12 evaluated educationalinterventions, 10 evaluated behavioral interven-tions, and 15 evaluated combined interventions.Educational interventions typically includedcounseling by a physician, pharmacist, or healtheducator, and behavioral interventions includeddosage simplification, cognitive behavior therapy,and the use of specialized packaging and directlyobserved therapy.

Overall, 20 (54%) of the 37 studies reported asignificant increase in at least one adherencemeasure. The most consistent increases in adher-

ence were achieved with behavioral interven-tions that reduced dosing demands and thoseinvolving repeated monitoring of medication usewith feedback and reinforcement.

Patient adherence programsA review of patient adherence programs

implemented at leading sites across the UnitedStates was provided by Shauna Choi, PharmD,University of Texas M.D. Anderson CancerCenter, Houston. According to Choi, oralchemotherapy adherence initiatives at herinstitution include individualized patientcounseling, dispensing of one chemotherapycycle per pill bottle, and the use of patient edu-cation materials and industry-sponsored toolswritten in various languages.

A system designed to educate and monitorpatients starting new oral chemotherapy has beendeveloped by the Cincinnati Veterans Ad-ministration Medical Center. In this system,patients receive education and monitoring from ateam member who is assigned particular oralchemotherapy agents and are followed up weeklyfor adherence and adverse drug reactions(ADRs).

The incidence of ADRs in patients receivingoral chemotherapy agents decreased from 33% to26% during the first few months after implemen-tation of the program, Choi said, and the medica-tion adherence rate during the program has beendocumented at 94%.

At BioScrip, a specialty pharmaceuticalhealthcare organization, efforts to enhance oralchemotherapy adherence include the reductionof financial barriers to treatment availability.Such efforts involve the identification of eco-nomic reality and feasibility before the start oftreatment and helping patients navigate costassistance programs and organizations.

A primary adherence enhancement initiativeunderway at BioScrip is the Refill AdherenceManagement Program (RAMP). The program isdesigned to prevent treatment interruptions byaddressing ADRs, resolving drug delivery issues,and partnering with physicians to ensure that pre-scriptions are sent in a timely manner.

In patients with HIV infection receiving anti-retroviral therapy, RAMP produced an overalladherence rate 20% greater than BioScrip’s cus-tomary pharmaceutical services program, Choisaid. The implementation of RAMP also led to a60% increase in the proportion of patientsachieving 85% or better adherence levels (96%vs 60%) and a nearly 200% increase in the pro-portion achieving 95% or better adherence(92% vs 32%).

—DSM


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ORAL CHEMOTHERAPY Continued from cover

• Expanded Approval for AzacitidineAzacitidine (Vidaza; Celgene) has

received expanded US Food and DrugAdministration (FDA) approval, reflectingnew overall survival achieved in theAZA-001 survival study, an internationalphase 3 trial in patients with higher-riskmyelodysplastic syndromes (MDS). In2004, the demethylation agent becamethe first therapy approved by the FDA fortreatment of MDS; it was approved forall five French American British subtypesof MDS, which include both low-risk andhigh-risk patients.

• New Indication for Bortezomib The FDA has approved bortezomib

(Velcade; Millenium, Takeda) for patientswith previously untreated multiplemyeloma based on the results of aninternational, open-label, active-controltrial. The agent was previously approvedas second- or third-line therapy for mul-tiple myeloma and is also approved forpatients with mantle cell lymphoma whohave received at least one prior therapy.

• Oral Formulation of PalonosetronAn oral formulation of palonosetron

hydrochloride (Aloxi; Eisai, Helsinn) hasbeen approved by the FDA for preventionof chemotherapy-induced nausea andvomiting. An injectable form wasapproved in 2003.

• Blood Test for Colorectal CancerThe AMDL-ELISA DR-70(R) (FDP) has

been cleared by the FDA for monitoringdisease progression in patients previous-ly diagnosed with colorectal cancer. Theblood test is the first monitoring productfor colorectal cancer cleared by the FDAsince 1982.

Recent FDAApprovals

Table 1. Major predictors of pooradherence

• Presence of psychological problems

• Presence of cognitive impairment

• Treatment of asymptomatic disease

• Inadequate follow-up or dischargeplanning

• Side effects of medications

• Patient’s lack of belief in benefit oftreatment

• Patient’s lack of insight into illness

• Poor provider–patient relationship

• Missed appointments

• Complexity of treatment

• Cost of medication, copayment, or both

Adapted with permission from Osterberg L, et al. N Engl J Med.2005;353:487-497.

Table 2. Types of Interventions

BehavioralDesigned to change adherence by targeting, shap-ing, or reinforcing specific behavioral patterns

Educational (informational or cognitive)Designed to convey information

Affective (social/environmental)Designed to change adherence through appeals tofeelings and emotions or social relationships andsocial supports

Source: Roter DL, et al. Med Care. 1998;36:1138-1161.


Other drug transfer devices claim to be closed, but they lack the independent, clinical evidence to prove it. They claim to offer affordability,but their incompatibility with all drugs and vial sizes means you’ll pay more with inadequate coverage and drug waste. They claim familiar ease of use, but their wet connections guarantee exposure, even with perfect user form.

Strip away the claims and see for yourself what others have already confirmed. Ordinary lemon juice and litmus strips are all you need to conduct a simple pH test to determine the leakproof integrity of today’s available transfer devices.So take the test—and then demand the facts.

Backed by 14+ years of experience devoted solely to the development of our closed-system drug transfer device (CSTD) and supported by more than 10 independent, peer-reviewed, published clinical studies, we can factually state that our product offers clinically-proven,full spectrum protection. Can they?

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Spiros™ & Clave® by ICU Medical Inc. (Same connections as Genie™) B. Braun OnGuard™ Vial Adaptor & Syringe Adaptor by Teva Medical Ltd.

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Leakproof Connection Integrity TestAuthor: James Jorgenson, RPh, MS, FASHP, Executive Director, Pharmacy Services, Clarian Health Partners, Methodist Hospital, Indianapolis, IN

RESULTS: No leakage was observed after 10 manipulations with the PhaSeal System.Visible leakage occurred outside of the ICU Medical System, the B. Braun OnGuard™ System and the Cardinal Health/Alaris System during all manipulations.

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Don’t have pH test supplies on hand? Request kit materials and find more evidence-based research at www.PhaSeal.com or call 866-487-9250



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M.D. Anderson Cancer Center

T he University of Texas M.D. AndersonCancer Center is a component of theUniversity of Texas System. Over its 66 years,

more than 700,000 patients have been treated with sur-gery, chemotherapy, radiation therapy, immunotherapy,or combinations of these and other leading treatments.

The stated mission of M.D. Anderson is to eliminatecancer through outstanding programs that integratepatient care, research, and prevention, and througheducation for undergraduate and graduate students,trainees, professionals, employees, and the public.

M.D. Anderson employs more than 17,000 people atfacilities that total more than 9 million square feet. Itnow has five satellite centers, four of which offer radia-tion therapy and one that offers radiation and a medicaloncology practice. Two to three additional satellites areplanned each year, and chemotherapy and linked surgi-cal services will be offered at some of these facilities.

Patient visits number nearly 85,000 annually, ofwhom 29,000 were newly registered in 2007. Morethan 11,000 patients per year participate in therapeu-tic clinical research exploring novel treatments, mak-ing it the largest such program in the nation.

M.D. Anderson earned the distinction of beingvoted the number one cancer center in the UnitedStates by U.S. News & World Report’s annual “BestHospitals” survey. The 2008 recognition was thefourth time in 6 years that M.D. Anderson has beenranked number one in this survey.

In his state-of-the-institution address delivered inOctober 2007, John Mendelsohn, MD, president ofM.D. Anderson, said, “We have articulated a visionof a cancer care cycle that includes a continuuminvolving prevention, early detection, treatment,and survivorship, and are planning expansion of ourprevention and survivorship programs both clinical-ly and in research.”

The survivorship program will provide moreappropriate, complete, and convenient services topatients who have responded well to therapy, he said.Such a program is needed as the number of cancer sur-vivors increases due to successes in early diagnosis andtreatment.

Over the past year, phase 1 clinical trials at M.D.Anderson have tested more than a dozen new anti-cancer agents for the first time in humans.

New laboratory facilities to support research activi-ties and centers of excellence are under construction,which will provide more than 500,000 gross square feetof new space for research when completed.

The increased emphasis on cancer prevention willinclude expanded clinical services in personalizedrisk assessment, genetic testing, counseling in behav-ior and lifestyle modification, and sophisticated can-cer screening that will incorporate evaluation ofmarkers and new imaging modalities.

The Clinical Cancer Genetics program comprises amultidisciplinary team of specially trained geneticcounselors and physicians working together to provideeducation, hereditary risk assessment, and individual-ized cancer screening and prevention to people whoare concerned about their personal and family historyof cancer.

The Division of Cancer Prevention andPopulation Sciences has more than 500 employees,69 faculty members, and an annual research budgetof $24 million, making it one of the largest programsof its kind in the world. Risk assessment models havebeen developed to predict an individual’s chance ofdeveloping lung and bladder cancer based on genet-ic, environmental, and lifestyle factors. The causes ofprimary brain tumors are also being explored in thedivision by studying biologically related members diag-nosed with primary brain tumors; the research will alsoattempt to identify a panel of genes that can predictwho will develop the disease.

A 300,000 square foot building will be devoted pri-marily to pathology and laboratory medicine, and thepharmacy will handle the increase in diagnostic testsand services and the growth in demand on the institu-tion’s pharmacy. The aim is to open this facility within4 years.

M.D. Anderson was designated a magnet nursingorganization by the American Nurses CredentialingCenter, a recognition held by fewer than 200 institu-tions worldwide. Formal training programs and aca-demic programs for nurses are expanding at M.D.Anderson. From 2005 to 2007, 209 registered nurseshave enrolled in the postbaccalaureate residency pro-grams, and 81% of graduates accept jobs at M.D.Anderson.

The Ben Love/El Paso Corporation Melanoma andSkin Center opened in 2006, and more than 4000 newpatients were among the more than 15,000 patientswith melanoma and other skin cancers treated there in2007. Research at the center is focusing on the devel-opment of blood markers to predict recurrence ofmelanoma. A clinical trial is testing a vaccine as adju-vant therapy for patients with melanoma who are athigh risk of recurrence.

Investigators in the Department of Neuro-oncologyare collaborating on Delta-24-RGD, a virus designed todestroy a highly-resistant and lethal form of glioblas-toma multiforme. Four brain tumor cell lines have beencharacterized from four specimens of glioblastoma mul-tiforme, and Delta-24-RGD was successful at killing allfour types. A clinical trial of the virus in patients isexpected soon.

Clinical trials in patients with low-grade lymphomahave started using a second-generation vaccine madewith a genetically engineered chemokine molecule thatwas developed at M.D. Anderson. Undergoing earlyclinical evaluation is a customized vaccine developed atM.D. Anderson for patients with relapsed myeloma.

In 2007, investigators in the Department ofGynecologic Oncology published research showing

that insulin resistance was an independent riskfactor for endometrial cancer. The next step tothe finding will be a chemoprevention study ofobese, insulin-resistant women to test the efficacyof metformin in preventing endometrial cancer.

—Wayne Kuznar

Clinical Pharmacy Services Manager

Laura Boehnke Michaud, PharmDExpanding pharmacy’s walls has been part of

the culture at M.D. Anderson during the 15-yeartenure of Laura Boehnke Michaud, PharmD. Shehas been manager of clinical pharmacy servic-es at M.D. Anderson since 2005; for the previous12 years she was a clinical pharmacy specialist.

During that time, she has witnessed the inte-gration of pharmacy into every aspect of care,“including the administrative side, which is abig part of what I do now in terms of guidelinedevelopment within the institution, developinginstitutional order sets for high-risk medica-tions and chemotherapy, and our chemothera-py policy,” she said.

“I like being involved in the institutional ini-tiative and driving quality care as a whole.That’s exciting to me because I know that I notonly affect the patients that I see on a day-in,day-out basis, but I can affect all patients in thatmanner.”

Because M.D. Anderson is not a traditionalteaching hospital, much of the patient care ismanaged by mid-level clinicians, including theclinical pharmacists.

The operations of M.D. Anderson are separat-ed into 13 care centers that have individual clin-ical care teams, each with its own set of clinicalpharmacists, the number of which depends onthe volume and acuity of patients in each par-ticular center.

“We’ve been integrated with the teams for solong that they rely on us to do even more thanjust day-to-day patient care,” said Michaud.Clinical pharmacists in Texas have prescriptiveauthority for inpatient medication orders, andthe clinical pharmacists at M.D. Anderson con-duct rounds with the clinical care team.

Of the 250 pharmacists employed in theDivision of Pharmacy, approximately 70 areclinical pharmacists. “At most institutionsyou’re trying to justify every single position andit’s difficult to get more clinical pharmacistsbecause often the medical staff doesn’t see thevalue. They see the pharmacists dispense thedrugs and review the orders; they don’t under-stand what they can do outside of the pharma-cy walls,” she said. “There’s a reason we have 70people in the clinical group; it’s purely fromphysician demand. They value our input toservice, not only patient care but research andeducation programs. It has been a benefit to theprofession of pharmacy to see us move in thisdirection and become independent practition-ers, having our own set of skills.”



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the American Society of Clinical Oncology,included 337 mCRC patients receivingeither FOLFOX4 (oxaliplatin 85 mg/m2 5-fluorouracil/folinic acid [+5FU/FA] every 2weeks) or cetuximab (400 mg/m2 initialintravenous infusion on day 1 then 250mg/m2 weekly) plus FOLFOX4.

Previous retrospective analyses haveshown KRAS gene mutations to be associ-ated with poor prognosis and have suggest-ed that KRAS mutations may explain lackof response to endothelial growth factorreceptor inhibitors like cetuximab and pan-itumumab in some patients. KRAS muta-tions are found in 40% to 50% of CRCpatients, Bokemeyer said.

The Initial OPUS efficacy analysisshowed a strong trend favoring the cetux-imab combination for response rate (35.7%FOLFOX4; 45.6% cetuximab plus FOL-FOX4, P = .064), but identical median PFS

(7.2 months each). The advantage forthe cetuximab + FOLFOX4 patients,when the researchers examined the134 KRAS wild-type and 99 KRASmutant patients separately, however,became significant.

The response rate in the KRASwild-type patients was 37% for FOL-FOX4 and 61% for the cetuximab +FOLFOX4 combination (P = .011).For those with the KRAS mutation,there was no significant differencebetween treatments, with FOLFOX4numerically favored (49% vs 33% forFOLFOX4 and cetuximab + FOL-FOX4, respectively; P = .106). “Thebenefit for patients with the wild-typeKRAS was clearly significantly differ-ent—with high significance,” Bokemeyer

said. With mutant KRAS, henoted, “It was somewhat theother way around.”

The pattern for median PFSwas similar. PFS was 7.2 monthsfor FOLFOX4 and 7.7 monthsfor the cetuximab + FOLFOX4combination (hazard ratio, 0.57;

P = .016) with wild-type, but actuallyreversed for KRAS mutation patients at8.6 months for FOLFOX4 and 5.5 monthsfor cetuximab plus FOLFOX4 (P = .019).

Neither duration of treatment nor rela-

tive dose intensity varied significantlybetween treatments. There were no differ-ences in the most common grade 3 to 4adverse events, and the safety profiles wereconsistent with those seen in earlier trials.

Adding cetuximab to FOLFOX4 result-ed in significant, relevant improvementsin response rates and in PFS amongpatients with KRAS wild-type tumors,Bokemeyer concluded. In patients withKRAS mutant tumors, adding cetuximabto FOLFOX had no apparent benefit.

—Walter Alexander

CHICAGO—In patients with metastatic colorectal cancer in theEVEREST trial, both skin toxicity and KRAS status independent-ly predicted response. Also, patients who had KRAS wild-typetumors benefited from treatment with irinotecan plus cetuximab,and escalating the cetuximab dose created a trend toward furtherincreased responses.

Sabine Tejpar, MD, University Hospital Gasthuisberg,Leuven, Belgium, noted that EVEREST investigators havealready shown that increasing the cetuximab dose in patientsalready receiving standard-regimen irinotecan (180 mg/m2

every 2 weeks) improves efficacy in patients with grade 0/1skin reactions. Her presentation at the American Society ofClinical Oncology 2008 Annual Meeting addressed whetherpatients with mutated KRAS status benefit when standard-dose cetuximab (250 mg/m2) is increased in 50 mg/m2 incre-ments up to 500 mg/m2 in combination with standard-doseirinotecan. Ras family members (genes that cause cancer

when mutated), such as KRAS, are important in growth sig-naling, differentiation, and cell division in normal cells.

KRAS mutation status was tested in tumors from 148 patients.In those with wild-type KRAS status (n = 54), the relative responserate was 30.4% among controls who received the standard cetux-imab dose and 41.9% among dose-escalated patients (P = .396).The response rate was 0% in KRAS mutant controls (n = 44) anddose-escalation patients (n = 45). Estimated progression-free sur-vival (PFS) was 173 days in KRAS wild-type patients and 83 daysin KRAS mutant patients (P <.0001). PFS in wild-type KRAS sta-tus patients was significantly better in the dose-escalation group (P<.0001), the control group (P = .014), and in a group of nonran-domized patients (n = 62, P = .020).

In the entire EVEREST population, PFS was longer amongthose with skin toxicity, with a general pattern of correlationbetween skin toxicity severity and PFS length. The pattern persist-ed among wild-type KRAS patients and less clearly in KRASmutant patients.

Tejpar concluded that patients with KRAS wild-typetumors benefited from irinotecan plus cetuximab treatment.In the dose-escalation arm, there was a trend towardincreased responses in patients with KRAS wild-type tumors,but dose escalation did not improve efficacy in KRASmutant tumors. She also pointed out that “skin toxicity andKRAS status are independent predictors of outcome.”

American Society of Clinical Oncology discussant MaceL. Rothenberg, MD, from the Vanderbilt-Ingram CancerCenter, Nashville, Tenn, underscored that no responses wereseen in KRAS mutant patients regardless of cetuximab dose,and that the rate of stable disease was actually lower in thedose-escalation arm than in the standard arm (33% vs 45%).The trend toward increased responses in the KRAS wild-typetumors, he added, was not matched in PFS. Lastly,Rothenberg noted that while both skin toxicity and KRASstatus were independent predictors of outcome, “KRAS wasthe much stronger of the two.”

—WA

KRAS Status and Skin Toxicity Predict Response in Colorectal Cancer

Adding cetuximab to FOLFOX4resulted in significant, relevantimprovements in response ratesand in PFS.

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CHICAGO—“This is a drug that candeal with resistance,” said Richard M.Stone, MD, who presented long-termresults of the phase 2 START-C trial ofdasatinib in patients with chronic-phase chronic myelogenous leukemia(CP-CML) who are resistant to orintolerant of imatinib at the AmericanSociety of Clinical Oncology 2008annual meeting.

Stone is clinical director of theAdult Leukemia Program at Dana-Farber Cancer Institute, Boston. The387 patients enrolled in the multicen-ter trial were treated with dasatinib 70mg twice daily. All patients were resist-ant to or intolerant to imatinib.

Before imatinib failure, 82% of par-ticipants had a complete hematologicresponse (CHR) to imatinib; 37%had a major cytogenetic response(MCyR); and 19% had a completecytogenetic response (CCyR). Tenpercent had prior stem cell transplan-tation. Forty percent of patients hadBCR-ABL mutations.

At 2 years, CCyRs were achievedby 53% of patients, and among these,79% had major molecular responses(defined as more than a 3-log reduc-tion in BCR-ABL burden). Overall,62% had MCyRs, and 91% hadCHRs. Looking separately at patientswith imatinib resistance, Stone said

that rates were similar to those in theoverall trial population (CHR, 87%;MCyR, 59%; CCyR, 52%). The samewas noted for progression-free sur-vival (PFS) (91% at 12 months; 80%at 24 months) and overall survival(OS) (97% at 12 months; 94% at 24months). Among imatinib-resistantpatients, whom Stone called “theworst of the worst,” PFS was 88% at12 months and 75% at 24 months.OS was 96% at 12 months and 94%at 24 months.

Dasatinib responses were found forall BCR-ABL mutations except forthe T3151 mutation. The likelihoodof response was similar regardless ofmutation status, with CCyRs in 52%

of those with mutations and 56% ofthose without. Also, PFS at 24months was 75% with any mutationand 83% without mutation.“Dasatinib efficacy was demonstratedacross subgroups, including all butone of 43 different baseline muta-tions,” Stone said.

Cytopenias did not worsen withlonger-term treatment. Rates ofleukopenia at 12 months and 24months were the same (27%), andboth neutropenia rates (49% and50%, respectively) and thrombocy-topenia rates (48% and 49%, respec-tively) were similar at 12 and 24months. Grade 3 to 4 nonhematolog-ic side effects also did not increase

substantially. Pleural effusions werereported in 9% and 11% of patientsfor the first and second years, respec-tively, with no grade 4 events.Furthermore, among those intolerantto imatinib, cross-intolerance todasatinib was not reported.

Stone noted that in a subsequentphase 3 dose-optimization study in CP-CML, 100 mg of dasatinib given oncedaily demonstrated similar efficacy toother doses, but with less frequent fluidretention and cytopenia and a morefavorable risk-benefit ratio. As a result,100 mg daily is the currently approvedCP-CML dasatinib dose.

—WA

CHICAGO—Updated 18-month re-sults for nilotinib in patients with ima-tinib-resistant or imatinib-intolerantchronic-phase chronic myelogenousleukemia (CP-CML) showed favorableresponse and survival rates with excel-lent tolerability according to Hagop M.Kantarjian, MD, M.D. AndersonCancer Center, Houston, Tex. Nilotinibwas approved by the US Food and DrugAdministration for patients with CP-CML resistant to or intolerant of priortherapy in October 2007. It is a highlyselective BCR-ABL inhibitor, binding

to ABL with higher affinity and greaterselectivity than imatinib. Nilotinibinhibits most imatinib-resistant BCR-ABL mutants (T3151 excluded),Kantarjian said.

In the phase 2 trial cohort, the ratioof imatinib-resistant to imatinib-intol-erant patients was 71% to 29%. Medianage was 58 years, median CML durationwas 58 months, and prior imatinib ther-apy ranged from 400 mg to >800 mg(72% had received ≥600 mg/day).Median duration of prior imatinib thera-py was 33 months, Kantarjian said at the

American Society ofClinical Oncology 2008annual meeting.

Patients received nilo-tinib at a dose of 400 mgorally twice daily (2hours from meals). Majorcytogenetic (MCyR) re-sponse rate was the pri-mary end point.

Among 321 patientsenrolled, the mediandose intensity was 788mg/day for a median of465 days. Dose reduc-

tions were required in 25% of patientsand dose interruptions in 55% for amedian of 19 days.

Median time to complete hemato-logic response (CHR) was 1 month,and median time to MCyR was 2.8months. CHRs were reported in 77%,with MCyR and complete cytogeneticresponse rates (CCyRs) of 58% and42%, respectively. The response ratesfor imatinib-resistant and imatinib-intolerant patients were 56% and 63%,respectively, for MCyR and 39% and50%, respectively, for CCyR. At 18months, MCyR responses were sus-tained in 84% of patients, and progres-sion-free survival was 67%. Ninety-fivepercent of patients were alive at 12months, and 91% were alive at 18months. These survival durationsexceeded those reported for other ther-apies and allogenetic stem cell trans-plant, Kantarjian pointed out(Kantarjian H, et al. Cancer. 2007;109:1556-1560).

The most common non-hematologic adverse eventswere rash (30%), pruritus(25%), and nausea (24%), butgrade 3 to 4 rates were 2% orless. Although biochemicalabnormalities were seen inmany patients, grade 3 to 4

events were uncommon (lipase eleva-tion, 16%; hypophosphatemia, 15%;hyperglycemia, 12%; total bilirubin 7%).Grade 3 to 4 anemia, neutropenia, andthrombocytopenia rates were 10%, 30%,and 28%, respectively. Median durationwas 9 days for anemia, 15 days for neu-tropenia, and 23 days for thrombocy-topenia. Peripheral edema (grades 1 to 2)was reported in 6% of patients, and peri-cardial and pleural effusion were seen in2% and 4%, respectively (all grades).

To date, Kantarjian said, nilotinibtherapy has been discontinued in 53% ofpatients (23% for disease progression,17% for adverse events).

Kantarjian concluded that nilotinibhas significant activity in patients withCP-CML after imatinib treatment fail-ure, and responses are durable.Tolerability is excellent, and grade 3 to 4adverse event occurrence is minimal.

—WA

High Response and Survival Rates at 18 Months for Nilotinib in CP-CML

�www.theoncologypharmacist.com

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Two-year Data Show Sustained Dasatinib Benefits in Imatinib-resistant, intolerant CP-CML




A nemia is frequent in patients with cancer, being an impor-tant contributor to morbidity in these patients.1 The eti-ology of cancer-related anemia is multifactorial, but, in

most cases, it is a result of the chronic disease process associatedwith cancer (anemia of chronic disease or, more recently, anemiaof inflammation).2 The mechanisms that lead to the anemiainclude impaired erythropoietin (Epo) production, an impairedresponse of the erythroid marrow to Epo, iron-restricted erythro-poiesis, and a diminished pool of Epo-responsive cells.Chemotherapy, which inhibits erythroid marrow proliferation andfurther impairs erythropoietin production, exacerbates anemia inpatients with cancer.

The recombinant erythropoiesis-stimulating agents (ESAs),epoetin alfa and beta and darbepoetin alfa (DA), given accordingto evidence-based clinical practice guidelines,3 can correct cancer/chemotherapy-related anemia (CRA), reduce the need for redblood cell transfusion, and provide clinically meaningful improve-ments in overall health in patients receiving chemotherapy.4,5

Although these agents represent a major advance in the treatmentof CRA, approximately 30% to 50% of patients do not achieve ameaningful response to ESAs.6,7

Data mostly derived from the dialysis population8 have clearly shownthat an important factor that seriously limits erythropoietic responseto ESA is functional iron deficiency (FID), which is an imbalancebetween iron needs in the erythropoietic marrow and iron supply.9

FID may be either pre-existing or may occur during ESA therapy,when red blood cells are produced at a rate that outstrips labile ironavailability. As a consequence, iron supplementation may still berequired to achieve or maintain an optimal response to ESAs. Inroutine clinical management of anemic cancer patients, transferrinsaturation (TSAT) between 10% and 20% with normal or increasedferritin, is an accepted indicator of FID.9

Surprisingly, the use of iron supplementation during treatment withESAs has not been as rigorously applied in anemic patients with canceras it has for dialysis patients. This underuse is at least in part due to: (1)the false perception that patients with cancer do not have decreasediron stores (as measured by serum ferritin) and are therefore thought notto require iron supplementation during ESA therapy; (2) misinforma-tion and misinterpretation of the incidence and clinical nature of serious adverse effects of intravenous (IV) iron.10 Parenteral iron is stillconsidered a poorly tolerated medication that not infrequently causes


Continuing EducationProgram #CIK 9944 • RELEASE DATE: September 30, 2008 • EXPIRATION DATE: September 29, 2009

FACULTY/PLANNER DISCLOSURESIt is the policy of the University of Nebraska MedicalCenter, Center for Continuing Education that all plannersand faculty participating in continuing education activitiesprovided by the University of Nebraska Medical Center,Center for Continuing Education are to disclose to theaudience any real or apparent conflicts of interest withproviders of commercial products and/or devices relatingto the topics of this educational activity and also disclosediscussion of labeled/unapproved uses of drugs or devicesdiscussed in their presentation. The planners and facultyhave been advised that this activity must be free fromcommercial bias and based upon all the available scientif-ically rigorous data from research that conforms toaccepted standards of experimental design, data collec-tion, and analysis.

The following authors, reviewers, and planning committeemembers listed below have stated they have no significant orsubstantial relationship with providers of commercial prod-ucts and/or devices discussed in this activity and/or with anycommercial supporter of this activity.

• Lisa Anzai, RN, MA• Catherine Bevil, Rn EdD• Cass Hammond, RN, MSN, CRNP• Lara J. Reiman• Karen Rosenberg• Manuel G. Afable II, RN, BSN• Silvia Mague, OCN• Paolo Pedrazzoli, MD• Elena Pelegatta, OCN• Gabriella Rassu, OCN• Ilaria Schiavetto, MD

The following author has stated that he has the followingfinancial relationships:

David Baribeault, RPh, BCOP, states that he is on thespeaker’s bureau for Amgen, Roche, and Valeant.

ACCREDITATION The University of Nebraska Medical Center,Center for Continuing Education is accredited bythe Accreditation Council for Pharmacy Educationas a provider of continuing pharmacy education.

The ACPE provider number is 447-000-08-451-H04-P. Toreceive the 1 contact hour of continuing education credit, phar-macists should complete the activity requirements and evalua-tion at the conclusion of the activity. Approval is valid from theinitial release date of September 30, 2008. The expiration dateis September 29, 2009. A statement of credit will be availablefor printing online upon completion of the post-test with ascore of 70% or better and the evaluation instrument.

Complimentary

Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents and Intravenous IronSupplementation

HOW TO RECEIVE CREDITTo receive continuing education credit, learners must:• Read the article in its entirety.• Take the CE self-assessment test and complete the evaluation test:

1. Log onto www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage.3. Register to participate. 4. Enter program number # CIK 9944.

• The learner must answer at least 70% of the questions on the post-test correctly.• The estimated time to complete this activity is 1 hour. Your continuing education

certificate can be printed by following the directions online after successful com-pletion of the post-test and evaluation.

TARGET AUDIENCERegistered pharmacists and other interested healthcare professionals, especially thosecaring for cancer patients receiving erythropoiesis-stimulating agents for anemia.

COSTThis program is complimentary for all learners.

DISCLAIMERSThe opinions or views expressed in this continuing education activity are those of thefaculty and do not necessarily reflect the opinions or recommendations of theUniversity of Nebraska Medical Center (UNMC), Center for Continuing Education.While the University of Nebraska Medical Center, Center for Continuing Education isan ACPE accredited organization, this does not imply endorsement by the UNMC orACPE of any commercial products affiliated with this activity.

LEARNING OBJECTIVESAfter completing this activity, the reader should be better able to:• Explain the how iron deficiency affects response to erythropoiesis-stimulating agents

(ESAs) in patients with cancer.• Describe differences in safety and efficacy of available oral and intravenous (IV) iron

preparations.• Discuss the potential benefits of concomitant use of IV iron supplements and ESAs

in patients with cancer and anemia.

EDITORIAL BOARDManuel G. Afable II, RN, BSNTaussig Cancer InstituteCleveland ClinicCleveland, OH 44195

David Baribeault, RPh, BCOPBoston Medical CenterBoston, MA 02118

Silvia Mague, OCNDivisione Oncologia Medica FalckOspedale Niguarda Ca’GrandaMilan, Italy 20162

Paolo Pedrazzoli, MDDivisione Oncologia Medica FalckOspedale Niguarda Ca’GrandaMilan, Italy 20162

Elena Pelegatta, OCNDivisione Oncologia Medica FalckOspedale Niguarda Ca’GrandaMilan, Italy 20162

Gabriella Rassu, OCNDivisione Oncologia Medica FalckOspedale Niguarda Ca’GrandaMilan, Italy 20162

Ilaria Schiavetto, MDDivisione Oncologia Medica FalckOspedale Niguarda Ca’GrandaMilan, Italy 20162

PLANNING COMMITTEELisa Anzai, RN, MANurse PlannerUniversity of Nebraska Medical CenterCollege of Nursing985330 Nebraska Medical CenterOmaha, Nebraska 68198-5330

Catherine Bevil, RN EdDDirector, Continuing Nursing Educationand EvaluationUniversity of Nebraska Medical CenterCollege of Nursing985330 Nebraska Medical CenterOmaha, Nebraska 68198-5330

Lara J. ReimanManaging EditorGreen Hill Healthcare Communications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Karen RosenbergEditorial DirectorGreen Hill Healthcare Communications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

REVIEWERCass Hammond, RN, MSN, CRNPAvid Education Partners18071 Crampton LaneSharpsburg, MD 21782

BY GABRIELLA RASSU, OCN; ILARIA SCHIAVETTO, MD; SILVIA MAGLIE, OCN; ELENA PELEGATTA, OCN; AND PAOLO PEDRAZZOLI, MDOncologia Medica Falck, Osperdale Niguarda Ca’Granda, Milano, Italy





anaphylatic reactions. This opinion is erroneous, how-evever. The currently available iron preparations(low-molecular-weight dextran, iron saccarate, ferricgluconate) are safe, as clearly demonstrated in patientsundergoing dialysis.11

Clinical studies of iron supplementation inESA-treated patients

Until recently, a limited number of studies on useof iron supplementation during treatment withESAs were available. A Swedish study12 demonstrat-ed the efficacy of IV iron in improving hematopoi-etic response to epoetin beta in 67 patients withlymphoproliferative malignancies not receivingconcurrent chemotherapy. Patients were enrolled ifthey had a positive stain for bone marrow hemo-siderin. Two large US studies13,14 included patientswith solid tumors undergoing chemotherapy, and

both examined different routes of iron administra-tion (IV or oral) versus none, in conjunction withepoetin alfa use. Both studies showed that patientswho received IV iron had a significant improve-

ment in hematopoietic response compared with no-iron controls; in contrast, no difference betweenthe no-iron and oral-iron groups were found.

Results of such studies cannot be interpreted

without a close look at the iron status of enrolledpatients. This crucial aspect is usually poorly dis-cussed in the literature, and the current guide-lines3,15 do not emphasize this point either. Both USstudies and the Swedish study included a proportionof patients with iron deficiency (functional in mostcases), and therefore did not provide a definitiveanswer on whether iron supplementation canincrease the percentage of iron-replete patients (themajority of CRA patients) who respond to ESAs.

Two recently published prospective trials havebetter clarified this issue. Bastit and colleagues16

randomized patients with nonmyeloid malignanciesreceiving DA to either IV iron 200 µg every 3 weeks(or the same dose within a 3-week period) or stan-dard practice for iron administration (no iron ororal iron). Iron parameters were not considered inpatient selection. Response, measured both astransfusion requirement and achievement of

Both studies showed that

patients who received IV iron

had a significant improvement

in hematopoietic response

compared with no-iron controls.

Continued from page 15

T he study by Rassu and colleagues dis-cussed in this issue is a long-overdueevaluation of the literature supporting

the use of parenteral iron supplementation inthe management of anemia in cancer patients.1

For many years, it has been well-establishedthat the successful management of anemia inpatients with chronic kidney disease (CKD),especially when erythropoiesis-stimulatingagents (ESAs) are used, requires the use of par-enteral iron supplementation.2,3 Rassu and col-leagues offer suggestions that potentiallyexplain the reticence of oncologists to adminis-ter parenteral iron to anemic cancer patients:the perception that patients with cancer are notiron-deficient, based almost universally on ele-vated serum ferritin levels that are more thanlikely a result of inflammatory cytokines, andthat parenteral iron administration carries withit unacceptable risks.

It is important that oncology pharmacistsinvolved in the management of anemia criti-cally evaluate the available literature on theuse of parenteral iron administration and edu-cate other practitioners about the benefits andrisks of this therapy. Although the data, whencompared with that on the CKD population,are sparse, they are, nonetheless, telling.

In the first trial evaluating the use of iron incombination with ESAs, two questions wereasked: (1) Does the response rate in anemiccancer patients increase when iron is adminis-tered concurrently with ESAs, and (2) If ironsupplementaton does help, does the route ormethod of administration make a difference inthat response.4 The answer to the first question,of course, was a resounding “yes.” This shouldhave been somewhat intuitive, however, be-

cause, by most definitions, patients had to beiron-deficient to be enrolled in the study. Theanswer to the second question sparked theinterest of many oncology pharmacistsinvolved in anemia management. It wouldseem from the results of this trial that it did notmatter whether total requirements were frac-tionated or given as a total dose, but the routeof administration was paramount to success.3

Not long after Auerbach’s original work waspublished, Henry and colleagues asked a simi-lar question.5 They hypothesized that if irondextran could improve response rates to ESAs,then so should ferric gluconate, which couldpotentially give physicians who feared irondextran reactions an alternative that theycould be comfortable with, and one that wouldimprove response rates. The study design wasvery similar to Auerbach’s original trial in thatpatients were randomized to either receiveparenteral iron (eight weekly doses of 125 mg),oral iron, or no iron at all. Not surprisingly, theresults were almost identical, with patientswith parenteral iron repletion having a muchbetter chance at a hematopoietic responsethan either the oral-iron or no-iron groups.Interestingly, overt iron deficiency was not astrict eligibility criterion in this study, and, assuch, there was a cohort of patients who werenot iron deficient by standard definitions. Thisfinding heralded for the first time that in can-cer patients, as well as in CKD patients, stimu-lated erythropoiesis requires iron supplemen-tation to be effective and that supplementa-tion should not be given orally.

This led to the recently published work ofRassu and colleagues, who set out to answerthis question definitively by enrolling only

iron-replete patients in a study of anemic can-cer patients receiving ESAs for chemotherapy-induced anemia.1 In this open-label trial, aheterogeneous population of anemic cancerpatients were randomized to receive eitherweekly darbepoetin alfa or weekly darbepoet-in alfa coupled with weekly intravenous ferricgluconate.5 Once again, the administration ofparenteral iron was shown to improveresponse rates and decrease transfusionrequirements, but this was the first time thatit was shown in patients who were not irondeficient.

Although it has taken quite some time to getto the realization that stimulated erythropoei-sis requires iron supplementation, clearly thedata that we have before us should point ustoward that conclusion. It is incumbent nowon oncology pharmacists to work with theirprovider colleagues to ensure that anemiamanagement for cancer patients includes theuse of parenteral iron compounds.

References1. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of

intravenous iron supplementation in patients with chemother-apy-related anemia without iron deficiency treated with darbe-poetin alfa. J Clin Oncol. 2008;26:1619-1625.

2. Fishbane S, Maesaka JK. Iron management in end-stage renaldisease. Am J Kidney Dis. 1997;29:319-333.

3. National Kidney Foundation. Kidney Disease Outcomes QualityInitiative clinical practice guidelines and clinical practice rec-ommendations for anemia in chronic kidney disease.http://www.kidney.org/professionals/KDOQI/guidelines_anemia/ped32.htm. Accessed August 11, 2008.

4. Auerbach M, Ballard H,Trout JR, et al. Intravenous iron optimizesthe response to recombinant human erythropoietin in cancerpatients with chemotherapy-related anemia: a multicenter, openlabel, randomized trial. J Clin Oncol. 2004;22:1301-1307.

5. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric glu-conate significantly improves response to epoetin alfa versusoral iron or no iron in anemic patients with cancer receivingchemotherapy. Oncologist. 2007;12:231-242.

Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents andIntravenous Iron Supplementation: A Pharmacist’s Perspective

C O M M E N TA RY

BY DAVID BARIBEAULT, RPH, BCOPBoston Medical Center, Massachusetts




hematopoietic response, significantly favored the IViron group. An Italian study,17 that included 149 iron-replete patients (defined as having a serum ferritinlevel of ≥100 ng/mL and TSAT ≥20%) demonstratedthat IV iron supplementation significantly reducestreatment failures to DA with no additional toxicity.The percentage of responders in the no-iron group wascomparable with rates reported in previous studiesusing DA.7 The Table summarizes published studies ofiron supplementation and ESAs.

ConclusionBased on the novel evidence from phase 3 trials, IV

(not oral) iron supplementation in conjunction withESA therapy should be considered a component of themanagement of CRA, both in patients with FID andin iron-replete patients. This issue is clinically rele-vant because appropriate iron supplementation, in

addition to allowing more patients to benefit fromESA therapy, may represent a strategy to improve thecost-effectiveness of ESAs in oncology.18

Case Report

A 51-year-old patient was referred to our hospitalwith a newly diagnosed metastatic breast carcino-

ma. One month earlier, a 3-cm mass in the upperouter quadrant of the right breast had been foundon physical examination. Pathologic evaluation ofa through-cut biopsy showed a grade 3, triple-nega-tive ductal carcinoma. Radiographs of the chest andfindings on abdominal ultrasound were unremark-able. A bone scan and a computed tomography scandetected osteolytic lesions in the right proximalfemur and dorsal column. Chemotherapy consistingof a combination of adriamycin 60 mg/m2 of bodysurface with paclitaxel at a dose of 175 mg/m2 ofbody surface was initiated. After two cycles ofchemotherapy, a hemoglobin (Hb) value that wasnear normal at baseline (11.9 g/dL) dropped to 9.1g/dL. At the same time, iron parameters were with-in normal ranges (TSAT, 24%; serum ferritin, 144ng/dL). Subcutaneous DA 150 µg/week was startedwith no response (Hb, 9.5 g/dL) after 4 weeks, but

IV (not oral) iron supplementa-

tion in conjunction with ESA

therapy should be considered

a component of the manage-

ment of CRA.

A nemia in cancer patients has beenreported in up to 75% of patients,1 anderythropoiesis-stimulating agents (ESAs)

have been used to manage this condition.Although the role of ESAs is well recognized, it isestimated that 30% to 50% of patients do notachieve a significant response to ESAs.2 Moreover,the use of ESAs is also associated with a consider-able cost. It is estimated that in the United Statesalone, $6 billion is spent per year on ESAs.3

The characterization of functional iron defi-ciency (FID) has helped explained why cancer-related anemia (CRA) does not always respond toESAs. It is believed that in various chronic dis-eases, including cancer, inflammatory cytokines,particularly interleukin 6 (IL-6), are released. IL-6upregulates hepcidin, a peptide secreted in theliver by the hepatocytes. Hepcidin inhibits therelease of absorbed iron into the circulation byinactivating ferroportin, a transmembrane pro-tein.3 This results in FID, a scenario in which anindividual actually has sufficient iron stores, buthas a limited amount of iron available at the siteof erythropoeisis. Similarly, this condition existswhen using ESAs without adequate iron sup-port.4 Hypererythropoiesis of the bone marrowexists, which outstrips the labile iron pool. Irondeficiency is diagnosed through laboratory test-ing for ferritin levels and transferrin saturation.

As discussed in the article by Rassu and associ-ates, at least six clinical trials have shown theeffectiveness of the combination of ESAs andintravenous (IV) iron in increasing hemoglobinlevels.This is indeed a welcome outcome if we areto encourage the concomitant use of IV iron withESAs. The latest two trials were published in theApril issue of the Journal of Clinical Oncology.2,5 It isinteresting to note that in the study by Bastit andcolleagues5 the addition of IV iron to ESAs result-ed in a statistically significant difference in blood

transfusion requirement between the IV irongroup (9%) and the standard group (20%) (P =.005). However, this study was not powered todetect a difference in the Functional As-sessment of Cancer Therapy: Fatigue results,which was the tool used for the quality of lifeassessment. In general, these trials did not onlyshow efficacy, but also safety when ESA and IViron are combined.

Despite the favorable responses seen with theESA and IV iron combination, health practitionerstreating CRA are still not routinely using it in theirpractice. The primary reason could be the percep-tion that IV iron is associated with anaphylacticshock. Auerbach and colleagues,3 however, havepointed out that the anaphylactic reactions werelargely caused by the high-molecular-weight irondextrans, which are no longer used today. The IViron preparations currently being used (ie, ironsucrose and iron gluconate) are less frequentlyassociated with adverse events. In fact, adversedrug events (ADEs) data from the US Food andDrug Administration (2001-2003) showed absoluterates of life-threatening ADEs for iron sucrose, irongluconate, and low-molecular-weight iron dextranof 0.6 per million doses, 0.9 per million doses, and3.3 per million doses, respectively.1

The risk of developing cardiovascular diseasedue to iron’s potential capacity to increase oxida-tive risk is also a concern. In hemodialysis patientsreceiving IV iron, however, no increase in mortali-ty was observed.1

For cancer patients being treated withchemotherapy, both iron sucrose and iron glu-conate are good options considering their ADEprofile. Both iron salts can be given as 200-mg, 2-minute IV bolus, and no test dose is required.6

Higher doses are not recommended because ofdose-dependent gastrointestinal reactions. Theiron salt preparations are also given without pre-

medication. When diphenhydramine is given as apremedication, it can potentially cause vasoactivereactions, which could mistakenly be attributed toIV iron. When IV iron dextran is being considered,however, administration of IV methylpredni-solone before and after IV infusion helps lessenthe occurrence of myalgias and arthralgias.6

A study presented during the 2007 AmericanCollege of Pharmacy meeting showed that com-bination therapy with ESA and IV iron can saveabout $100 per week for an individual patient.This estimate factored in the decreased ESAdosage required to reach the target hemoglobinlevel in patients who also received IV iron.7

Although the results of recent studies areencouraging, long-term trials are still needed tobetter assess the potential effects on survival ofIV iron supplementation. Comparing the differ-ent IV iron formulations as well to determinethe most cost-effective preparation will furtherimprove the management of CRA.

References1. Hedenus M, Birgegard G. The role of iron supplementation dur-

ing epoietin treatment for cancer-related anemia. Med Oncol.2008 May 13. [Epub ahead of print.]

2. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intra-venous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoet-in alfa. J Clin Oncol. 2008;26:1619-1625.

3. Auerbach M, Ballard H. Intravenous iron in oncology. J NatlCompr Canc Netw. 2008;6:585-592.

4. Cavill I, Auerbach M, Bailie G, et al. Iron and the anaemia ofchronic disease: a review and strategic recommendations. CurrMed Res Opin. 2006;22:731-737.

5. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicen-ter, controlled trial comparing the efficacy and safety of darbe-poetin alpha administered every 3 weeks with or without intra-venous iron in patients with chemotherapy-induced anemia. JClin Oncol. 2008;26:1611-1618.

6. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenousiron for anaemia. Lancet. 2007;369:1502-1504.

7. Auerbach M. Should intravenous iron be the standard of care inoncology? J Clin Oncol. 2008;26:1579-1581.

Treatment of Cancer Anemia with Erythropoiesis-stimulating Agents andIntravenous Iron Supplementation: A Nurse’s Perspective

C O M M E N TA RY

BY MANUEL G. AFABLE II, RN, BSNTaussig Cancer Institute, Cleveland Clinic Foundation, Ohio



Table. Published Studies of Iron Supplementation and ESAs in Cancer Anemia

Patients enrolled Baseline iron Type and dose Response Source (N)/diagnosis status Randomization of IV iron parameter Results/statisticsHedenus, et al12 67/Lymphoproliferative Stainable iron in Epoetin beta 30,000 U Iron sucrose Mean Hb (g/dL) at PP: 11.8 vs 13.0/

malignancies the bone marrow weekly vs epoetin beta 1000 mg IV the end of treatment P = .0001+ IV iron

Auerbach, et al13 157/ Nonmyeloid Ferritin ≤450 pmol/L Epoetin alfa 40,000 U Iron dextran 1100 mg Mean Hb increase (g/dL) ITT: 0.9 vs 1.5 vs malignancies (19% or ≤675 pmol/L with every week vs epoetin to 2400 mg (every week 2.5 vs 2.4/P = .02 lymphoid tumors) TSAT ≤19% vs epoetin alfa + IV iron group) 1000 to 3000 mg IV iron groups vs

every week vs epoetin alfa (TDI group) no-iron and oral-+ IV iron TDI iron groups

Henry, et al14 187/Nonmyeloid Serum ferritin >100 ng/mL Epoetin alfa 40,000 U Iron gluconate 1000 mg Increase in Hb from 1.5 vs 1.6 vs 2.4/malignancies or TSAT >15% every week vs epoetin alfa baseline to last value P = .0092 vs oral

+ oral iron vs epoetin alfa (g/dL) iron; P = .0044 vs+ IV iron every week no iron

Bastit, et al16 396/Nonmyeloid Serum ferritin >10 ng/mL Darbepoetin 500 µg every Iron gluconate or iron Hb >12 g/dL or >2 g/dL 73% vs 86%/ malignancies or TSAT >15% 3 weeks ± oral iron vs sucrose 1200 mg increase; RBC transfusions P = .011; 20% vs

darbepoetin + IV iron 9%/P = .005every 3 weeks

Pedrazzoli, et al17 149/Solid tumors Serum ferritin >100 ng/mL Darbepoetin (150 µg every Iron gluconate 750 mg Achievement of Hb ≥12 PP, 70% vs (colorectal, lung, and TSAT >20% week) vs darbepoetin + IV g/dL or ≥2 g/dL increase 92.5%/P = .0033breast, gynecologic) iron every week

ESAs indicates erythropoiesis-stimulating agents; TSAT, transferring saturation; IV, intravenous; TDI, total dose infusion; ITT, intention-to-treat population; PP, per-protocol population; Hb, hemoglobin; RBC, red blood cell.

there was evidence of FID (TSAT, 13%; serum fer-ritin, 106 ng/dL). The patient was kept on DA inconjunction with IV iron gluconate 125 mg weekly.Administration of DA plus IV iron resulted in pro-gressive improvement of Hb up to normal values(12.3 g/dL) at week 5 of combined treatment. Notoxic effects related to IV iron or DA infusion weredocumented. The patient is progression free withnormal Hb at 10 months from completion of sixcycles of chemotherapy.

This patient with breast cancer developed FID inthe course of ESA therapy, which is highly likelythe reason for lack of hematopoietic response toDA. In fact, correction (and subsequent preven-tion) of iron deficiency by the addition of IV iron toESA therapy normalized Hb values, allowing thepatient to better tolerate chemotherapy whileavoiding the risk of red blood cell transfusions.

References1. Ludwig H, Fritz E. Anaemia in cancer patients. Sem Oncol. 1998;25(3 suppl

7):2-6.2. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med.

2005;352:1011-1023.3. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in

patients with cancer: 2007 American Society of Clinical Oncology/AmericanSociety of Hematology clinical practice guideline update. J Clin Oncol.2008;26:132-149.

4. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietinand cancer patients: updated meta-analysis of 57 studies including 9353patients. J Natl Cancer Inst. 2006;98:708-714.

5. Cella D, Dobrez D, Glaspy J. Control of cancer-related anemia with erythro-poietic agents: a review of evidence for improved quality of life and clinicaloutcomes. Ann Oncol. 2003;14:511-519.

6. Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemotherapy

patients treated with epoetin alfa is independent of disease response or tumortype: results from a prospective community oncology study. Procrit StudyGroup. J Clin Oncol. 1998;16:3412-3425.

7. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled,randomized phase III trial of darbepoetin alfa in lung cancer patients receivingchemotherapy. J Natl Cancer Inst. 2002;94:1211-1220.

8. Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study ofiron supplementation in patients treated with erythropoietin. Kidney Int.1996;50:1694-1699.

9. Beguin Y. Erythropoietic agents and iron. In Bokemeyer C and Ludwig H, eds:Anaemia in Cancer: European School of Oncology Scientific Updates, 6. 2nd ed.Philadelphia, PA: Elsevier; 2005: 199-220.

10. Auerbach M. Clinical update: intravenous iron for anaemia. Lancet.2007;369:1502-1504.

11. Chertow GM, Mason PD, Vaage-Nilsen O, et al. Update on adverse drugevents associated with parenteral iron. Nephrol Dial Transplant.2006;21:378-382.

12. Hedenus M, Birgegard G, Nasman P, et al. Addition of intravenous iron to epo-etin beta increases hemoglobin response and decreases epoetin dose require-ment in anemic patients with lymphoproliferative malignancies: a randomizedmulticenter study. Leukemia. 2007;21:627-632.

13. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes theresponse to recombinant human erythropoietin in cancer patients withchemotherapy-related anemia: a multicenter, open label, randomized trial. JClin Oncol. 2004;22:1301-1307.

14. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconateimproves response to epoetin alfa versus oral iron or no iron in anemicpatients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242.

15. Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use oferythropoietic agents in anaemic patients with cancer: 2006 update. Eur JCancer. 2007;43:258-270.

16. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, con-trolled trial comparing the efficacy and safety of darbepoetin alfa administeredevery 3 weeks with or without intravenous iron in patients with chemothera-py-induced anemia. J Clin Oncol. 2008;26:1611-1618.

17. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous ironsupplementation in patients with chemotherapy-related anemia without irondeficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619-1625.

18. Besarab A, Amin N, Ahsan M, et al. Optimization of epoetin therapy withintravenous iron therapy in hemodialysis patients. J Am Soc Nephrol.2000;1:530-538.

To receive complimentary CE credit:

1. Log onto www.theoncologypharmacist.com.2. Click on UNMC logo on homepage.

3. Register to participate.

4. Enter program number #CIK 9944.


ErratumIn the June 2008 issue of The OncologyPharmacist, an incorrect UPN number wasstated for the activity (THE INCORRECT UPNIS 447-000-08-067-H04-P).

The correct UPN is 447-000-08-467-H04-P andcarries 1 credit. For those individuals thathave completed this activity, new statementsof credit will be sent with the correct UPNnumber. Sorry for the inconvenience.

In the July/August 2008 issue of The OncologyPharmacist, an incorrect UPN number wasstated for the activity (THE INCORRECT UPNIS 447-000-08-150-H04-P). The correct UPN is447-000-08-450-H04-P.


mal blood counts. Overall, 18 (24%)of 74 patients responded to ATG, 20(48%) of 42 patients responded toATG plus CsA, and one (8%) of 13patients responded to CsA. In a mul-tivariate analysis, younger age was themost significant factor predicting afavorable response to therapy. Otherfavorable factors affecting treatmentresponse were HLA-DR15 positivityand combination ATG plus CsAtreatment (P = .001 and P = .048,respectively). (Sloand EM, et al. J Clin Oncol. 2008;26:2505-2511.)

>>> Intensive Chemotherapywith Stem Cell RescueEffective in Peripheral T-cellLymphoma

Intensive chemotherapy plus autolo-gous stem cell transplantation (ASCT) iseffective with manageable toxicity inpatients with peripheral T-cell lymphoma(PTCL). A group of 41 patients (medianage, 47 years) with PTCL received threecourses of high-dose cyclophosphamide2000 mg/m2/day, adriamycin 90mg/m2/day, vincristine, and prednisonealternating with three courses of etopo-

side, cisplatin, cytarabine, and pred-nisone. Of the 41 patients, 28 (68%)responded to chemotherapy. ASCT wascarried out in 17 patients. The completeresponse (CR) rate following ASCT was51%. During a median follow-up of 3.2years, five of 21 patients with CR relapsedand two died due to secondary neoplasms.At 4 years, the rates of progression-freeand overall survival were 30% and 39%,respectively. The main variable predict-ing survival was the InternationalPrognostic Index. (Mercadal S, et al. AnnOncol. 2008;19:958-963.)


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

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan®

(rituximab) is indicated for the treatment of patients with: Relapsed or refractory,low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previouslyuntreated follicular, CD20-positive, B-cell NHL in combination with CVPchemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy;Previously untreated diffuse large B-cell, CD20-positive NHL in combination withCHOP or other anthracycline-based chemotherapy regimens. WARNINGS ANDPRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal,infusion reactions. Severe reactions typically occurred during the first infusion withtime 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, or anaphylactoid events. Premedicatepatients with an antihistamine and acetaminophen prior to dosing. Institutemedical management (e.g., glucocorticoids, epinephrine, bronchodilators, oroxygen) for infusion reactions as needed. Depending on the severity of theinfusion reaction and the required interventions, consider resumption of theinfusion at a minimum 50% reduction in rate after symptoms have resolved.Closely monitor the following patients: those with preexisting cardiac orpulmonary conditions, those who experienced prior cardiopulmonary adversereactions, and those with high numbers of circulating malignant cells(>25,000/mm3). [See Boxed Warning, Warnings and Precautions, AdverseReactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volumefollowed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, orhyperphosphatemia, can occur within 12–24 hours after the first infusion. FatalTLS cases have occurred after administration of Rituxan. A high number ofcirculating malignant cells (�25,000/mm3) or high tumor burden confers a greaterrisk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.Correct electrolyte abnormalities, monitor renal function and fluid balance, andadminister supportive care, including dialysis as indicated. [See Boxed Warning.]Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fataloutcome, can occur in patients treated with Rituxan. These reactions includeparaneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of thesereactions has varied from 1–13 weeks following Rituxan exposure. DiscontinueRituxan in patients who experience a severe mucocutaneous reaction. The safetyof readministration of Rituxan to patients with severe mucocutaneous reactionshas not been determined. [See Boxed Warning, Adverse Reactions.] ProgressiveMultifocal Leukoencephalopathy (PML) JC virus infection resulting in PMLand death can occur in Rituxan-treated patients with hematologic malignancies orwith autoimmune diseases for which Rituxan has not been approved. The majorityof patients with hematologic malignancies diagnosed with PML received Rituxanin combination with chemotherapy or as part of a hematopoietic stem celltransplant. The patients with autoimmune diseases had prior or concurrentimmunosuppressive therapy and were diagnosed with PML within 12 months oftheir last infusion of Rituxan. Consider the diagnosis of PML in any patientpresenting with new-onset neurologic manifestations. Evaluation of PML includes,but is not limited to, consultation with a neurologist, brain MRI, and lumbarpuncture. Discontinue Rituxan and consider discontinuation or reduction of anyconcomitant chemotherapy or immunosuppressive therapy in patients whodevelop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV)Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepaticfailure, and death can occur in patients with hematologic malignancies treatedwith Rituxan. The median time to the diagnosis of hepatitis was approximately 4months after the initiation of Rituxan and approximately one month after the lastdose. Screen patients at high risk of HBV infection before initiation of Rituxan.Closely monitor carriers of hepatitis B for clinical and laboratory signs of activeHBV infection for several months following Rituxan therapy. Discontinue Rituxanand any concomitant chemotherapy in patients who develop viral hepatitis, andinstitute appropriate treatment including antiviral therapy. Insufficient data existregarding the safety of resuming Rituxan in patients who develop hepatitissubsequent to HBV reactivation. [See Adverse Reactions.] Other Viral InfectionsThe following additional serious viral infections, either new, reactivated, orexacerbated, have been identified in clinical studies or postmarketing reports. Themajority of patients received Rituxan in combination with chemotherapy or as partof a hematopoietic stem cell transplant. These viral infections includedcytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, WestNile virus, and hepatitis C. In some cases, the viral infections occurred as late asone year following discontinuation of Rituxan and have resulted in death. [SeeAdverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after allinfusions of Rituxan for patients who develop clinically significant arrhythmias orwho have a history of arrhythmia or angina. [See Adverse Reactions.] RenalSevere, including fatal, renal toxicity can occur after Rituxan administration inpatients with hematologic malignancies. Renal toxicity has occurred in patientswith high numbers of circulating malignant cells (>25,000/mm3) or high tumorburden who experience tumor lysis syndrome and in patients with NHLadministered concomitant cisplatin therapy during clinical trials. The combinationof cisplatin and Rituxan is not an approved treatment regimen. Use extremecaution if this non-approved combination is used in clinical trials and monitorclosely for signs of renal failure. Consider discontinuation of Rituxan for patientswith a rising serum creatinine or oliguria. Bowel Obstruction and PerforationAbdominal pain, bowel obstruction and perforation, in some cases leading todeath, can occur in patients receiving Rituxan in combination with chemotherapy.In postmarketing reports, the mean time to documented gastrointestinal

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME(TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVEMULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious,including fatal infusion reactions. Deaths within 24 hours of Rituxaninfusion have occurred. Approximately 80% of fatal infusion reactionsoccurred in association with the first infusion. Carefully monitorpatients during infusions. Discontinue Rituxan infusion and providemedical treatment for Grade 3 or 4 infusion reactions [see Warningsand Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS):Acute renal failure requiring dialysis with instances of fatal outcomecan occur in the setting of TLS following treatment of non-Hodgkin’slymphoma (NHL) patients with Rituxan [see Warnings and Precautions,Adverse Reactions]. Severe Mucocutaneous Reactions: Severe,including fatal, mucocutaneous reactions can occur in patientsreceiving Rituxan [see Warnings and Precautions, Adverse Reactions].Progressive Multifocal Leukoencephalopathy (PML): JC virus infectionresulting in PML and death can occur in patients receiving Rituxan [seeWarnings and Precautions, Adverse Reactions].

perforation was 6 (range 1–77) days in patients with NHL. Perform a thoroughdiagnostic evaluation and institute appropriate treatment for complaints ofabdominal pain, especially early in the course of Rituxan therapy. [See AdverseReactions.] Immunization The safety of immunization with live viral vaccinesfollowing Rituxan therapy has not been studied and vaccination with live virusvaccines is not recommended. For NHL patients, the benefits of primary orbooster vaccinations should be weighted against the risks of delay in initiation ofRituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete bloodcounts (CBC) and platelet counts at regular intervals during Rituxan therapy andmore frequently in patients who develop cytopenias [see Adverse Reactions]. Theduration of cytopenias caused by Rituxan can extend months beyond thetreatment period. ADVERSE REACTIONS The most common adverse reactions ofRituxan (incidence �25%) observed in patients with NHL are infusion reactions,fever, chills, infection, asthenia, and lymphopenia. The most important seriousadverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML,other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstructionand perforation. Clinical Trials Experience Non-Hodgkin’s LymphomaBecause clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly comparedto rates in the clinical trials of another drug and may not reflect the rates observedin practice. The data described below reflect exposure to Rituxan in 1606patients, with exposures ranging from a single infusion up to 6–8 months. Rituxanwas studied in both single-agent and active-controlled trials (n = 356 and n =1250). These data were obtained in adults with low-grade, follicular, or DLBCLNHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,given as a single agent weekly for up to 8 doses, in combination withchemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.Infusion Reactions In the majority of patients with NHL, infusion reactionsconsisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, orhypertension occurred during the first Rituxan infusion. Infusion reactions typicallyoccurred within 30 to 120 minutes of beginning the first infusion and resolvedwith slowing or interruption of the Rituxan infusion and with supportive care(diphenhydramine, acetaminophen, and intravenous saline). The incidence ofinfusion reactions was highest during the first infusion (77%) and decreased witheach 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. Theoverall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%,and fungal 1%). [See Warnings and Precautions.] In randomized, controlledstudies where Rituxan was administered following chemotherapy for thetreatment of follicular or low-grade NHL, the rate of infection was higher amongpatients who received Rituxan. In diffuse large B-cell lymphoma patients, viralinfections occurred more frequently in those who received Rituxan. Cytopeniasand hypogammaglobulinemia In patients with NHL receiving rituximabmonotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% ofpatients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),anemia (3%), and thrombocytopenia (2%). The median duration of lymphopeniawas 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116days). A single occurrence of transient aplastic anemia (pure red cell aplasia) andtwo occurrences of hemolytic anemia following Rituxan therapy occurred duringthe single-arm studies. In studies of monotherapy, Rituxan-induced B-celldepletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgGserum levels occurred in 14% of these patients. Single-Agent Rituxan Adversereactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies ofRituxan administered as a single agent. Most patients received Rituxan 375mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Events 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 andup to 6 months after Rituxan infusion. Rituxan in Combination WithChemotherapy Adverse reactions information below is based on 1250 patientswho received Rituxan in combination with chemotherapy or followingchemotherapy. Rituxan in Combination With Chemotherapy for Low-GradeNHL In Study 4, patients in the R-CVP arm experienced a higher incidence ofinfusional toxicity and neutropenia compared to patients in the CVP arm. Thefollowing adverse reactions occurred more frequently (�5%) in patients receivingR-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 reactionswere reported more frequently (�5%) in patients receiving Rituxan following CVPcompared to patients who received no further therapy: 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 thatoccurred more frequently (�2%) in the Rituxan arm compared with those whoreceived no further therapy (4% vs. 1%). Rituxan in Combination WithChemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions,regardless of severity, were reported more frequently (�5%) in patients age �60years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lungdisorder (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

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

Any Adverse Events 99 57Body as a Whole 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 System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

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

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

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

Metabolic and Nutritional Disorders 38 3

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

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

and 4 adverse reactions and serious adverse reactions. In Study 7, a review ofcardiac toxicity determined that supraventricular arrhythmias or tachycardiaaccounted 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 morefrequently among patients in the R-CHOP arm compared with those in the CHOParm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade3 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). Immunogenicity As with all therapeutic proteins, there is a potentialfor immunogenicity. The observed incidence of antibody (including neutralizingantibody) positivity in an assay is highly dependent on several factors includingassay sensitivity and specificity, assay methodology, sample handling, timing ofsample collection, concomitant medications, and underlying disease. For thesereasons, comparison of the incidence of antibodies to Rituxan with the incidenceof 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%) patientswith low-grade or follicular NHL receiving single-agent Rituxan. Three of the fourpatients had an objective clinical response. The clinical relevance of HACAformation in rituximab treated patients is unclear. Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use ofRituxan in hematologic malignancies. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drug exposure.Decisions to include these reactions in labeling are typically based on one or moreof the following factors: (1) seriousness of the reaction, (2) frequency of reporting,or (3) strength of causal connection to Rituxan. Hematologic: prolongedpancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscositysyndrome 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 multifocalleukoencephalopathy (PML), increase in fatal infections in HIV-associatedlymphoma, and a reported increased incidence of Grade 3 and 4 infections inpatients with previously treated lymphoma without known HIV infection.Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed withRituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There areno adequate and well-controlled studies of rituximab in pregnant women. Non-Hodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions thatrequire treatment. Rituximab should be used during pregnancy only if the potentialbenefit to the mother justifies the potential risk to the fetus. Rituximab is agenetically engineered IgG molecule, and IgG crosses the human placenta.Reproduction studies in cynomolgus monkeys at maternal exposures similar tohuman therapeutic exposures showed no evidence of teratogenic effects.However, B-cell lymphoid tissue was reduced in the offspring of treated dams. TheB-cell counts returned to normal levels, and immunologic function was restoredwithin 6 months of birth. Other than target B lymphocytes, rituximab is not knownto bind to any normal human tissues in an ex vivo assay. However, it is not knownif binding occurs to unique embryonic or fetal tissue receptors in vivo. NursingMothers It is not known whether Rituxan is secreted into human milk. However,Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG isexcreted in human milk. Published data suggest that antibodies in breast milk donot enter the neonatal and infant circulations in substantial amounts. Theunknown risks to the infant from gastrointestinal or limited systemic exposure toRituxan should be weighed against the known benefits of breastfeeding.Pediatric Use The safety and effectiveness of Rituxan in pediatric patients havenot been established. Geriatric Use Diffuse Large B-Cell NHL Among patientswith DLBCL evaluated in three randomized, active-controlled trials, 927 patientsreceived Rituxan in combination with chemotherapy. Of these, 396 (43%) wereage 65 or greater and 123 (13%) were age 75 or greater. No overall differencesin effectiveness were observed between these patients and younger patients.Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred morefrequently among elderly patients. Serious pulmonary adverse reactions were alsomore common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan inlow-grade or follicular, CD20-positive, B-cell NHL did not include sufficientnumbers of patients aged 65 and over to determine whether they responddifferently from younger subjects. OVERDOSAGE There has been no experiencewith overdosage in human clinical trials. Single doses of up to 500 mg/m2 havebeen given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility No long term animalstudies have been performed to establish the carcinogenic or mutagenic potentialof Rituxan or to determine potential effects on fertility in males or females.PATIENT COUNSELING INFORMATION Patients should be provided the RituxanMedication Guide and provided an opportunity to read prior to each treatmentsession. Because caution should be exercised in administering Rituxan to patientswith active infections, it is important that the patient’s overall health be assessedat each visit and any questions resulting from the patient’s reading of theMedication Guide be discussed. Rituxan is detectable in serum for up to sixmonths following completion of therapy. Individuals of childbearing potentialshould use effective contraception during treatment and for 12 months afterRituxan therapy.

Revised 1/2008 (4835504)

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

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ONCOLOGY TRENDSContinued from page 7

for ASC plus vinorelbine comparedwith ASC alone (HR, 0.80; P = .08).There were no between-group differ-ences in the predefined quality-of-life subscales (physical functioning,pain, dyspnea, and global healthstatus) at any of the assessments inthe first 6 months. (Muers MF, et al.Lancet. 2008;371:1685-1694.)

>>> Standard and High-dosePemetrexed Equivalent asSecond-line Treatment inNSCLC

High-dose pemetrexed does notimprove efficacy measures beyondstandard-dose pemetrexed whenused as second-line therapy inpatients with non-small-cell lungcancer (NSCLC). The findingemerged in a study of 588 patientswith locally advanced or metastaticNSCLC, previously treated withplatinum-based chemotherapy, whowere randomly assigned to receivestandard pemetrexed (500 mg/m2

[P500]) or high-dose pemetrexed(900 mg/m2 [P900]) every 3 weeks.P900 patients were permitted tocontinue treatment at P500. No sig-nificant differences were observedbetween the standard- and high-dose treatment arms for median sur-vival (6.7 vs 6.9 months; hazardratio [HR] = 1.0132), progression-free survival (2.6 vs 2.8 months; HR= 0.9681), or best overall tumorresponse (7.1% vs 4.3%; P = .16).The incidence of drug-related grade3/4 toxicity was typically <5% inboth treatment arms, but wasnumerically higher in the high-dosearm for most toxicity categories.Study accrual was terminated earlybecause an interim analysis indicat-ed a low probability of improvedsurvival and numerically greatertoxicity in the high-dose peme-trexed arm. (Cullen MH, et al. AnnOncol. 2008;19:939-945.)

>>>ImmunosuppressiveTherapy Improves Survival inPatients with MyelodysplasticSyndrome

Immunosuppressive therapy(IST) produces significant improve-ment in the pancytopenia of a sub-stantial proportion of patients withmyelodysplastic syndrome (MDS)and is associated with improve-ments in overall and progression-free survival. A group of 129patients with MDS received ISTusing antithymocyte globulin(ATG) or cyclosporine (CsA) incombination or alone and were fol-lowed for a median of 3 years. Ofthe 129 patients, 12 (9%) had acomplete response (CR) and 27(21%) had a partial response.Patients with a CR achieved trans-fusion independence and near-nor-

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For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

47% INCREASEin 7-year OS in GELA* trial1,2

RITUXAN+CHOP isproven to prolongsurvival in DLBCL

• At 7 years, 8 cycles of RITUXAN+CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1

• At 5 years, 8 cycles of RITUXAN+CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information

The most important serious adverse reactions of RITUXAN are fatal infusion reactions,tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocalleukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viralinfections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. Themost common adverse reactions of RITUXAN (incidence ≥25%) observed in patients withNHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5

RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adversereactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60years receiving 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%). In the GELA LNH98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias ortachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs1.0% for CHOP).5

The following Grade 3 or 4 adverse reactions occurred more frequently among patients inthe R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) andlung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequentlyamong patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia(GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.*GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previouslyuntreated elderly (age ≥60 years) DLBCL patients.3,4

†CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone.

References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOPand CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-riskpatients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al.Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients withdiffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd AmericanSociety of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B,Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patientswith diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc.5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved.3 Printed in USA on Recycled Paper 8974801 April 2008

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September/October 2008 Vol. 1 No. 4

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