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TOP Jul/Aug 08 THE ONCOLOGY PHARMACIST™,The Official Newspaper of Record

for the Hematology/OncologyPharmacist, will provide objective,targeted coverage of the wide spec-

trum of oncology events, trends,products, individuals, organiza-tions, and legislation that affect

both hematology/oncology health-care delivery and product utiliza-

tion and visibility. The scope of cov-erage will include a unique presen-tation of news and events that are

shaping cancer patient care writtenspecifically by and for

Hematology/Oncology Pharmacists.The Oncology Pharmacist is theONLY newspaper in the marketdirected specifically to the busy

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OncologyTheOncologyPharmacist

The

PharmacistThe Official Newspaper of Record for the

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The



Organizations for the PotentialOncology Practitioner: WhichOnes to Join and How Many?Patrick Medina, PharmD, BCOP

Oklahoma University College of Pharmacy, Tulsa

MEDICAL MINUTESHPV-related cancers of tongue

and tonsils respond better to

therapy

page 1

JUNE 2008 • VOL. 1, NO.2 www.theoncologypharmacist.com

D uring the first year of phar-macy school, students oftenjoin numerous organizations

for several reasons, including socialand professional networking, resumebuilding, and increasing knowledgein perceived areas of interest. As a

student’s interests become morefocused and career paths are clari-fied, the number and type of organ-izations that he or she belongs towill also narrow. Organizations playa vital role in the professionalgrowth of students and residents

and are also integral in maintaininglifelong learning and professionaldevelopment as a pharmacist.

Many organizations are availablefor professional and educationalgrowth for students and residents

RECENT FDAAPPROVALS

New regimens for HER2-positive

breast cancer

page 10

INTERVIEWChristopher Lowe, PharmD,

Taussig Cancer Center

page 12

© 2008 Green Hill HealthCare Communications, LLC

PRESORTED STANDARD

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PERMIT #651

CANCER CENTERPROFILEMultidisciplinary team at Cleveland

Clinic Taussig Cancer Center

provides patient-centered care

page 12

NEW TECHNOLOGYRFA ablation procedure effective

alternative for treating Barrett’s

esophagus

page 8

PHARMACY EDUCATION AND TRAINING

Continued on page 7

Cetuximab-inducedHypersensitivity:Case Reports and Discussion of Management

page 16

President Bush signs the Genetic Nondiscrimination

Information Act of 2008 into law.

page 5

POLICY WATCH

W ith the diagnosis of cancer comes the reali-ty of an unforgiving disease process thatrenders the body’s natural defenses impo-

tent. While this causes great anguish in and of itself, itis often what comes next that proves to be more trou-blesome. The cancer treatment itself presents formida-ble challenges to patients—the chemotherapy-inducedneutropenia, persistent nausea and vomiting, alopecia,

Prevention and Management of

Oral Mucositis

SAN FRANCISCO—Prescribing practices appear tobe changing when it comes to erythropoiesis-stimulat-ing agents (ESAs), according to new data presented atthe Academy of Managed Care Pharmacy’s 20thAnnual Meeting and Showcase. Researchers foundthat between 2005 and 2006, there was a decrease in

AMCP:New Study Looks at Use of ESAs

in Real World Practice

Continued on page 13

SUPPORTIVE CARE

Continued on page 6

Complimentary CE Credit

PHARMACY PRACTICE

Whi

te H

ouse

pho

to b

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

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Dear Colleague:

The Oncology Pharmacist features articles written by and for oncology pharmacists and specifically addresses the issuespharmacists and their colleagues face every day in clinical practice. A unique feature of The Oncology Pharmacist is thateach issue will an include a continuing education activity accredited by the University of Nebraska Medical Center,Center for Continuing Education. Pharmacists will be able to complete the post-test and obtain credit online at nocharge. Other unique features include articles specifically written for pharmacy students and residents as well as arti-cles on practice management and financial and regulatory issues affecting the practice of pharmacy.

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TOPcovertip_July_Aug 08 7/28/08 10:42 AM Page 1

PEER-SPECTIVESINTERACTIVE PEER-TO-PEER DISCUSSIONS IN HEMATOLOGY/ONCOLOGY

™

GET IN ON THE

DISCUSSION• Up-to-date, clinically relevant medical infor-

mation presented in a simple, streamlinedformat

• Commentaries from experts in the fields ofhematology and oncology provide perspec-tives on patient care

• Interactive polling feature allows you torespond to the data presented and viewresponses from your peers

• Opportunities to earn professional continuingeducation credits

The mission of peer-spectives is to provide physicians, nurses, and pharmacists with the latestmedical advances in hematology and oncologythrough online, interactive, educational activities

� To participate in peer-spectives, go towww.coexm.com

� Registration is quick and free

� CME/CE credits are offered at the end ofmost activities

� Registered users will be notified by emailas new activities become available

www.coexm.com

David Baribeault, RPh, BCOPBoston Medical CenterBoston, MA

Sylvia Bartel, RPh, MPHDana Farber Cancer InstituteBoston, MA

Deborah Blamble, PharmD,BCOPUniversity of Texas MD AndersonCancer CenterHouston, TX

Marlo Blazer, RPh, PharmDJames Cancer Hospital & SoloveResearch InstituteColumbus, OH

Bryna Delman Ewachiw, BS,PharmDJohns Hopkins Bayview MedicalCenterBaltimore, MD

Anjana Elefante, PharmD, BSc,BScPhm, RPhRoswell Park Cancer InstituteBuffalo, NY

Beth Faiman, RN, MSN, CNP,AOCN Cleveland Clinic Taussig CancerInstituteCleveland, OH

Christopher Fausel, PharmD,BCPS, BCOPIndiana University Simon CancerCenterIndianapolis, IN

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

David C. Gammon, BSPharmUniversity of MassachusettsMemorial HospitalWorcester, MA

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

Sandra Horowitz, PharmD,RPhUniversity of Texas MD AndersonCancer CenterHouston, TX

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

Andrea A. Iannucci, PharmD,BCOPUniversity of California DavisMedical CenterSacramento, CA

Cindy Ippoliti, PharmDNew York PresbyterianHospital/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

Emily Mackler, PharmD, BCOPUniversity of Michigan HealthSystem & College of PharmacyAnn Arbor, MI

Patrick Medina, PharmD,BCOPOklahoma University College ofPharmacyTulsa, OK

Laura Boehnke Michaud,PharmD, BCOP, FASHPUniversity of Texas MD AndersonCancer CenterHouston, TX

Deborah Moradi, PharmDThe Angeles Clinic and ResearchInstituteLos Angeles, CA

LeAnn Best Norris, PharmD,BCPSSouth Carolina College ofPharmacyColumbia, SC

Debra Phillips, PharmDEast Carolina UniversityGreenville, NC

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

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

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


The



EDITORIAL BOARD

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

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TOPcovertip_July_Aug 08 7/28/08 10:42 AM Page 2


The



HOPA Sets Goals forFuture Growth ofOncology Pharmacy An interview with Jim Koeller, MS

ASCOBisphosphonate prolongs cancer-free survival in endocrine-sensi-tive breast cancer

page 10

JULY/AUGUST 2008 • VOL. 1, NO.3 www.theoncologypharmacist.com

Jim Koeller, MS, is the immediatepast president of the Hematology/Oncology Pharmacy Association

(HOPA) and a member of the edito-rial board of The OncologyPharmacist. In this interview, MrKoeller discusses the highlights ofthis year’s HOPA Conference and

shares his views on the future ofoncology pharmacy.

How did you become involved with oncologypharmacy?

I fell into oncology pharmacyalmost by happenstance. I received

my master’s degree from theUniversity of Wisconsin. After com-pleting my residency, I learned thatthe cancer center in Madison waslooking for someone to coordinatetheir phase 1 oncology drug develop-ment program. I had spent some

CONFERENCENEWS

Preventing emesis after stem celltransplant

page 8

PROSTATE CANCERStudy shows reduction of prostate

cancer risk with finasteride

page 19

© 2008 Green Hill Healthcare Communications, LLC

PRESORTED STANDARD

U.S. POSTAGE

PAIDLEBANON JUNCTION, KY

PERMIT #651

AMCPOff-label use and other issues in man-agement of oncology drugs were dis-cussed at the AMCP annual meeting

page 14

CANCER CENTERPROFILEH. Lee Moffitt Cancer Center &Research Institute emphasizespersonalized care

page 12

PHARMACY PRACTICE

Continued on page 7

Program #CIK 9828: Calculating the Dosage ofAnticancer Drugs in Obese Patients:A Clinical Challenge

page 16

More than 4000 studies were presented at the 44thAnnual Meeting of the American Society of ClinicalOncology

page 10

ASCO ANNUAL MEETING

AMCP: Strategies for NavigatingOncology Management

Discussed at Symposium

MANAGED CARE PHARMACY

Continued on page 9

Complimentary CE Credit

CONFERENCE NEWS

CHICAGO—Everolimus, an oral agent that targetsthe mammalian target of rapamycin (mTOR) protein,may emerge as a new standard of care for patientswith metastatic renal cell carcinoma (RCC) whosedisease has progressed despite treatment with a tyro-

ASCO: Oral ImmunosuppressantEnhances PFS in Resistant

Metastatic RCC

W ith 23 new oncology agents targeted forpotential launch in the coming year,oncology drugs dominate the pipeline, far

outnumbering drugs those in other therapeutic cate-gories. Strategies for managing these agents in the man-


TOP July_Aug 7/28/08 10:12 AM Page Cov1

Today I learned...handling hazardous medications safely doesn’thave to slow me down.

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A drug developed to fight cancer is now showing promise as atreatment for pulmonary hypertension, according to researchers atthe University of Chicago Medical Center. In the first human trialof sorafenib as a treatment for pulmonary hypertension, eight of thefirst nine patients increased their ability to exercise. Six of ninepatients had significant improvements in right ventricular ejectionfraction. Four patients had a significant decrease in pulmonaryartery pressure.

“We have drugs that may slow progression of the disease, butnothing that can stop or reverse the process,” said study authorMardi Gomberg-Maitland, MD, assistant professor of medicine atthe University of Chicago. “To see theseimprovements in such a short time is quitepromising. Although evaluation of thisdrug is at a very early stage, and this studyfocused on safety and tolerability, we aregenuinely excited about the results.”

Sorafenib was originally evaluated at theUniversity of Chicago as a treatment forkidney cancer. Dr Gomberg-Maitland andher colleagues recognized that its effectsalso might slow the growth and thicken-ing of the pulmonary artery walls.

The trial enrolled patients with pul-monary hypertension who had stable dis-ease. Patients continued to take their stan-dard medications, primarily prostacyclin incombination with sildenafil. They also tooksorafenib for 16 weeks, but at doses lowerthan those given to cancer patients.

Most of the patients in the trialincreased their exercise capacity, as meas-ured by time on a treadmill or a 6-minutewalk test. They had an 8% improvement,on average, in right ventricular ejectionfraction, as measured by three-dimension-al echocardiography. Four patients hadsignificant improvements in the ability ofthe heart to pump blood to the lungs, asmeasured by cardiac catheterization. “All

patients had some improvement,” noted Dr Gomberg-Maitland.“Some had dramatic improvement.”

The side effects of the drug have been relatively mild. The mostcommon adverse effects in cancer patients were rashes, tendernessand itching on the hands and feet, and some mild diarrhea andfatigue. For patients with pulmonary hypertension, diarrhea and hairloss were often the biggest concerns. Patients taking prostacyclinsoften have facial rashes and flushing, but the sorafenib appeared tohave reduced this effect. Dr Gomberg-Maitland said because of thedrug’s apparent potential and limited side effects, a multicenter, phase2, placebo-controlled, cross-over study is being organized.

New research findings may hold promise for cancer patients whohave developed allergies to chemotherapy drugs. Investigators inBoston have just completed a study demonstrating the success andsafety of rapid desensitization. The treatment allows nearly allpatients to tolerate temporarily the chemotherapy drugs to whichthey previously experienced allergic reactions.

The standardized procedure takes 4 to 8 hours and involves admin-istering the targeted dose of medicine intravenously or intraperi-toneally in incremental steps. The initial desensitizations occur in themedical intensive care unit, but most of the subsequent infusions arehandled in an outpatient setting.

Of the 98 patients tested during a total of 413 desensitization treat-ments, 94% had no reaction or only mild reactions to the medica-tion. No life-threatening reactions or deaths occurred during thestudy. “The [study] findings provide the first safety data on high-risksensitizations done to cancer patients who could not otherwisereceive their first-line therapy. The desensitizations may prolong theirlives,” said study investigator Mariana Castells, MD, PhD, director ofthe desensitization program at Brigham and Women’s Hospital andassociate professor of medicine at Harvard Medical School, Boston.

The patients studied were primarily women receiving treatmentfor breast, ovarian, or other gynecologic cancers. During the study,

patients were successfully desensitized to seven common chemother-apy drugs: carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomaldoxorubicin, and rituximab.

Previous studies have indicated that up to 27% of patientsreceiving more than seven cycles of some common chemotherapydrugs develop allergic sensitivity to the medications. With somedrugs, many patients experience a reaction on their first exposure.The reactions can be severe and potentially fatal. This presentshealthcare professionals and patients with a paradoxical chal-lenge: continue potentially life-saving treatment while risking adeadly allergic reaction or avoid the life-threatening reaction byswitching to a less-effective drug?

This new research offers a third option, according to Dr Castells.At Brigham and Women’s Hospital, clinicians have already adoptedthe standardized rapid desensitization, and the investigators hopethat other institutions will follow suit. “A universal protocol for rapiddesensitization can be tailored to the patient’s needs and be used safe-ly. The protocol should become universal once we are granted apatent,” explained Dr Castells. “The take-home message for oncolo-gy pharmacists is that they need to educate others about thisapproach. The protocol can be administered only by trained person-nel, and an allergist should supervise the procedure.”

July/August 2008 GREEN HILL HEALTHCARE COMMUNICATIONS 1

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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].

A gene therapy approach is showing con-siderable promise in a phase 3 clinical trial forhead and neck cancer. This treatment usesAdvexin (Ad5CMV-p53), a modified aden-ovirus that expresses the tumor-suppressinggene p53.

“Cells become cancerous because p53 nolonger functions. Restoring p53 works unlikeany current cancer treatment because it treatsthe cancer genome,” said Jack Roth, MD, aprofessor in the Department of Thoracic andCardiovascular Surgery at M.D. AndersonCancer Center, Houston, Texas. Dr Rothinvented the drug and is co-founder ofIntrogen Therapeutics, Inc, which manufac-tures Advexin.

He said the p53 gene is inactivated inmany types of cancer. Its normal role is to haltthe division of a defective cell and then forcethe cell to kill itself. The trial, which includ-ed 123 patients, showed that p53 expressionin the patient’s tumor before treatment is areliable biomarker for how to treat head and

neck cancer. Patients with a favorable p53profile who received Advexin had a mediansurvival of 7.2 months, compared with 2.7months for those whose tumor expressed highlevels of mutant p53 before treatment. Inaddition, the researchers found that patientswith this unfavorable profile did better withmethotrexate, resulting in median survival of5.9 months.

“The important finding is that patientswho benefit from treatment can be identifiedwith the p53 biomarker. The biomarker willenable physicians to personalize treatment,”said Dr Roth.

Patients treated with Advexin experi-enced fewer harmful side effects, such aspneumonia, than those who receivedmethotrexate. The incidence of inflamma-tion of the mouth lining and a decrease inwhite blood cells, for example, both droppedto zero for those receiving Advexin. “Thatcertainly results in a better quality of life,”noted Dr Roth.

Gene Therapy Showing Promise for End-stage Head and Neck Cancer

Antidote for Chemotherapy Allergy May Allow Cancer Patients to Receive Medicine Safely

Cancer Drug May Help Patients with Heart-Lung Disease

TOP July_Aug 7/28/08 10:13 AM Page 1

Feature Articles

8 Conference News Reports from the HOPA/ISOPP Joint AnnualConference

10 Conference News Reports from the 44th Annual Meeting of the American Society of Clinical Oncology

12 Cancer Center ProfileH. Lee Moffitt Cancer Center & Research Institute Oncology

16 Continuing Education Calculating the dosage of anticancer drugs inobese patients

19 Prostate CancerFinasteride May Help Reduce Prostate Cancer Risk

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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. 3 July/August 2008


™

EDITORIAL BOARD

EDITOR-IN-CHIEF

Susan Goodin PharmD, FCCP, BCOPCancer Institute of NewJersey

New Brunswick, NJ

Departments

1 Medical Minutes

5 News Notes

7 Cartoon

13 Leadership andCommunication Skillsfor Pharmacists

19 Trends in ProstateCancer

20 Trends in Lung Cancer

20 Trends in HematologicCancer

21 Meetings

2 GREEN HILL HEALTHCARE COMMUNICATIONS July/August 2008


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…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



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W hat an exciting time to be an oncology pharmacist!Nearly 1000 people from 40 countries attended theHOPA/ISOPP 2008 Joint Annual Conference in

Anaheim. Sessions started in early morning and continuedthroughout the day covering both clinical and nonclinicalissues pertinent to oncology pharmacy practice in various set-tings. Platform and poster sessions provided an opportunity foroncology pharmacy residents and clinicians to present theirresearch findings and interact with colleagues. It was evidentthat many oncology pharmacists today are recent graduateswith long careers ahead of them and will need ongoing educa-tion throughout their careers not only to achieve or maintaincertification but also to keep up with the fast pace of oncologydrug development. As Jim Koeller notes in the interview in thisissue, oncology pharmacy practice is an increasingly sophisti-cated and specialized field, and there is a great need for contin-uing education.

The CE article in this issue addresses a challenging andimportant issue for oncology pharmacists and other healthcareprofessionals. With the prevalence of obesity in our society, it iscritical to determine how best to calculate drug dosages in over-weight and obese patients to achieve optimal results. Research

is also needed on what modifications in therapy may be neededfor other groups—women, children, the elderly, those withcomorbidities, and others with special needs.

Personalizing therapy to meet the particular needs of individ-ual patients is a major emphasis at the H. Lee Moffitt CancerCenter in Tampa, Florida. Their Total Cancer Care initiative,discussed in this issue, aims to create personalized cancer carefor patients with different types of cancer through genetics. Theinitiative also seeks to address the needs of family members andto follow patients throughout the continuum of care.

As reports from ASCO and other recent meetings support, pro-viding high-quality care does not end with making a diagnosis andprescribing a treatment. Pharmacists, nurses, and other members ofthe healthcare team often need to make modifications in treat-ment regimens and work with patients and caregivers to lessen themany possible adverse effects of therapy and provide support andencouragement. Advances in side effect prevention and manage-ment described in this issue offer new options for helping patientsthroughout the course of treatment.

We welcome your thoughts on this issue and suggestions onwhat topics you would like to see covered in future issues. Pleasesend your comments to [email protected].

A Letter from the Editor

SUSAN GOODIN,PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

EDITORIAL CORRESPONDENCE should be addressed toEDITORIAL DIRECTOR, The Oncology Pharmacist™, 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: [email protected]. YEARLY SUBSCRIPTION RATES:United States and possessions: individuals, $105.00; institutions,$135.00; single issues $17.00. Orders will be billed at individual rateuntil proof of status is confirmed. Prices are subject to change with-out notice. Correspondence regarding permission to reprint all orpart of any article published in this journal should be addressed toREPRINT PERMISSIONS DEPARTMENT, Green HillHealthcare Communications, LLC, 241 Forsgate Drive, Suite 205C,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 manufactur-er’s claims. Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the products mentioned.Neither the Editorial Board nor the Publisher assumes any responsibil-ity 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,however, lies with the prescribing physician. Please convey any errors tothe Editorial Director. ISSN #Applied for in April 2008.

The Oncology Pharmacist™, is published 5 times a year by Green HillHealthcare Communications, LLC, 241 Forsgate Drive, Suite205C, 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: Treatment of Anemia in Cancer Patients with ESAs and IV Iron

Reports from HOPA, ASCO

Ensuring Safe Chemotherapy Administration

Setting Up a Chemotherapy Prep Area in a Community Practice

Using Nanoparticles to Deliver Chemotherapy

Oncology Patient Participation in Clinical Trials

New Approaches to the Treatment of Pediatric Neuroblastoma

For a free subscription go to www.theoncologypharmacist.com



NEW

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POWER ANDPERFORMANCEVIDAZA hits MDS with the strengthof transfusion independence.1,2

• 44% of red blood cell (RBC) transfusion-dependent patients achieved RBC transfusion independence.1*

• Median time to RBC transfusion independence was about 2.5 months.1

• In responding patients,† transfusion independence was durable, lasting a median of 330 days.2

Important Safety Information• VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or

mannitol and in patients with advanced malignant hepatic tumors.• In clinical studies, the most commonly occurring adverse reactions by SC

route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%),vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%),fatigue (35.9%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions includeddizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%),injection site reaction (13.6%), aggravated fatigue (12.7%), and malaise (10.9%).The most common adverse reactions by IV route also included petechiae (45.8%),weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%).

• Because treatment with VIDAZA is associated with neutropenia and thrombocytopenia,complete blood counts should be performed as needed to monitor response andtoxicity, but at a minimum, prior to each dosing cycle.

• Because azacitidine is potentially hepatotoxic in patients with severe preexistinghepatic impairment, caution is needed in patients with liver disease. In addition,azacitidine and its metabolites are substantially excreted by the kidneys and therisk of toxic reactions to this drug may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreased renal function,it may be useful to monitor renal function.

• VIDAZA may cause fetal harm. While receiving treatment with VIDAZA, women ofchildbearing potential should avoid becoming pregnant, and men should avoidfathering a child. In addition, women treated with VIDAZA should not nurse.

Please see the brief summary of prescribing information on the adjacent page.

VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome(MDS) subtypes2‡: RA or RARS (if accompanied by neutropenia orthrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL.9221 Study Design: A randomized, open-label, phase III study comparing the efficacy and safetyof VIDAZA plus supportive care vs supportive care alone. 191 patients (132 male, 59 female,age 31–92) with all 5 subtypes of MDS classified according to the French, American, British (FAB)classification system were studied. VIDAZA was administered to patients subcutaneously at adose of 75 mg/m2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based onresponse or adverse events. The primary study endpoint was response rate.Response Criteria: Complete response was defined as <5% blasts in the bone marrow,absence of blasts in the peripheral circulation, and normal CBC (if abnormal at baseline)maintained for at least 4 weeks. Partial response was defined as at least a 50% decreasein bone marrow blasts and improvement of bone marrow dyspoiesis (for RAEB, RAEB-T, andCMMoL only) plus, for all subtypes, at least a 50% restoration in the deficit from normal ofbaseline white cells, hemoglobin, and platelets (if abnormal at baseline) and no blasts in theperipheral circulation maintained for at least 4 weeks. For CMMoL, if white cells were elevatedat baseline, PR also required at least a 75% reduction in the excess count over the upper limitof normal, maintained for at least 4 weeks.*Of the 66 VIDAZA-treated patients who were RBC transfusion dependent at baseline, 29 (44%) achieved RBC

transfusion independence.1†CR + PR = 16%.‡According to the FAB Classification System.

References: 1. Data on file. Pharmion Corporation.2. VIDAZA full prescribing information.

VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation.All rights reserved. 2007288 May 2007 Printed in the USA.

000862_phvirt_jco_power_fa4.indd1 1 6/19/07 1:54:43 PM

� Antioxidants May ReduceEffectiveness of CancerTreatments

Patients with cancer who arereceiving chemotherapy or radia-tion therapy should avoid use ofsupplements containing high lev-els of antioxidants, according to anew report. Many cancer patientstake antioxidant supplements be-cause they believe they willincrease the effectiveness of theirtreatment. Researchers from theNaval Medical Center in SanDiego, California, however, foundthat these supplements may, infact, reduce the effectiveness ofchemotherapy or radiation, oreven increase toxicities. Theresearchers reviewed data frompublished randomized clinical tri-als that examined the use ofantioxidants by patients undergo-ing cytotoxic therapy. Althoughthe findings were inconclusive, theresearchers suggest that antioxi-dants may protect cancer cells justas they do normal cells, therebydecreasing the effectiveness ofchemotherapy and radiation(Lawenda BD, et al. J Natl CancerInst. 2008;100:773-783).

� Possible Link BetweenPediatric Cancer and TNFBlockers Investigated

The US Food and DrugAdministration (FDA) is investi-gating a possible link betweenpediatric cancer and the use oftumor necrosis factor (TNF)blockers in light of recently diag-nosed cases of lymphoma andother cancers in children andyoung adults. During the past 10years, the FDA has learned ofabout 30 cases of cancer in chil-dren taking TNF blockers,including infliximab, etanercept,and adalimumab, which are pre-scribed for such autoimmune dis-orders as juvenile idiopathicarthritis, rheumatoid arthritis,psoriatic arthritis, and Crohn’sdisease. The link between TNFblockers and cancer is not new,as all four drugs already carrywarnings about the possiblerisks, but the FDA is nowrequiring all of the manufactur-ers of TNF blockers indicatedfor pediatric use to provide

information about all cases of cancerreported in children taking the drugs(MedPage Today. June 4, 2008).

� QOL Scores Predict Survival forPatients with Head and Neck Cancer

Low quality-of-life (QOL) scores mayindicate poor survival for patients withhead and neck cancer, according to a

recent study. A total of 495 patients withhead and neck cancer completed a ques-tionnaire, which assessed physical andemotional QOL. The University ofMichigan investigators found a high asso-ciation between general physical healthand QOL issues and survival. Patients withdifficulty with pain, eating, and speechwere significantly less likely to survive

than were other patients. The researchersconclude that QOL instruments may bevaluable screening tools to identifypatients who are at high risk for poor sur-vival and should be followed more closely(Karvonen-Gutierrez CA, et al. J ClinOncol. 2008;26:2754-2760).

News Notes

Antioxidants mayprotect cancercells just as theydo normal cells.

Continued on page 6



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Brief Summary of Prescribing Information VIDAZA® (azacitidine for injection) onlyFor subcutaneous and intravenous use onlyINDICATIONS AND USAGEVIDAZA is indicated for treatment of patients withthe following myelodysplastic syndrome subtypes: refractoryanemia or refractory anemia with ringed sideroblasts(if accompanied by neutropenia or thrombocytopeniaor requiring transfusions), refractory anemia withexcess blasts, refractory anemia with excess blasts intransformation, and chronic myelomonocytic leukemia.CONTRAINDICATIONSVIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. VIDAZA is also contraindicated in patients with advanced malignant hepatic tumors. (See PRECAUTIONS).WARNINGSPregnancy - Teratogenic Effects: Pregnancy Category DVIDAZA may cause fetal harm when administered to a pregnant woman. Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2

basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 atdoses of ~3–12 mg/m2 (approximately 4%–16% therecommended human daily dose on a mg/m2 basis).In rats, azacitidine was clearly embryotoxic when given IPon gestation days 4–8 (postimplantation) at a dose of6 mg/m2 (approximately 8% of the recommended humandaily dose on a mg/m2 basis), although treatment in thepreimplantation period (on gestation days 1–3) had noadverse effect on the embryos. Azacitidine caused multiplefetal abnormalities in rats after a single IP dose of 3–12 mg/m2 (approximately 8% the recommended humandaily dose on a mg/m2 basis) given on gestation day 9,10, 11 or 12. In this study azacitidine caused fetal deathwhen administered at 3-12 mg/m2 on gestation days 9and 10; average live animals per litter was reduced to9% of control at the highest dose on gestation day 9.Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, clubfoot,syndactyly, oligodactyly), and others (micrognathia,gastroschisis, edema, and rib abnormalities).There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.Women of childbearing potential should be advised to avoidbecoming pregnant while receiving treatment with VIDAZA.Use in MalesMen should be advised to not father a child while receiving treatment with VIDAZA. (See PRECAUTIONS:Carcinogenesis, Mutagenesis, Impairment of Fertilityfor discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.)PRECAUTIONSGeneralTreatment with VIDAZA is associated with neutropeniaand thrombocytopenia. Complete blood counts should beperformed as needed to monitor response and toxicity, but ata minimum, prior to each dosing cycle. After administrationof the recommended dosage for the first cycle, dosage forsubsequent cycles should be reduced or delayed based onnadir counts and hematologic response as described inDOSAGE AND ADMINISTRATION.Safety and effectiveness of VIDAZA in patients with MDSand hepatic or renal impairment have not been studiedas these patients were excluded from the clinical trials.Because azacitidine is potentially hepatotoxic in patientswith severe preexisting hepatic impairment, cautionis needed in patients with liver disease. Patients withextensive tumor burden due to metastatic disease havebeen rarely reported to experience progressive hepaticcoma and death during azacitidine treatment, especiallyin such patients with baseline albumin <30 g/L.Azacitidine is contraindicated in patients with advancedmalignant hepatic tumors (See CONTRAINDICATIONS).Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held as described in DOSAGE AND ADMINISTRATION.Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys (see DOSAGE AND ADMINISTRATION section).Information for PatientsPatients should inform their physician about any underlying liver or renal disease. Women of childbearing potential should be advised to avoidbecoming pregnant while receiving treatment with VIDAZA.Men should be advised to not father a child while receiving treatment with VIDAZA.Laboratory TestsComplete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, priorto each cycle. Liver chemistries and serum creatinineshould be obtained prior to initiation of therapy.Drug InteractionsNo formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted. (See CLINICAL PHARMACOLOGY.)

Carcinogenesis, Mutagenesis, Impairment of FertilityThe potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP 3 times per week for 52 weeks. An increased incidence oftumors in the lymphoreticular system, lung, mammarygland, and skin was seen in mice treated with azacitidineIP at 2.0 mg/kg (6.0 mg/m2, approximately 8% therecommended human daily dose on a mg/m2 basis) once aweek for 50 weeks. A tumorigenicity study in rats dosedtwice weekly at 15 or 60 mg/m2 (approximately 20%–80%the recommended human daily dose on a mg/m2 basis)revealed an increased incidence of testicular tumorscompared with controls.The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m2

(approximately 9% the recommended human daily doseon a mg/m2 basis) daily for 3 days prior to mating withuntreated female mice resulted in decreased fertilityand loss of offspring during subsequent embryonic andpostnatal development. Treatment of male rats three timesper week for 11 or 16 weeks at doses of 15–30 mg/m2

(approximately 20%–40%, the recommended human dailydose on a mg/m2 basis) resulted in decreased weight ofthe testes and epididymides, and decreased sperm countsaccompanied by decreased pregnancy rates and increasedloss of embryos in mated females. In a related study,male rats treated for 16 weeks at 24 mg/m2 resulted inan increase in abnormal embryos in mated females whenexamined on day 2 of gestation. (See WARNINGS.)PregnancyTeratogenic Effects: Pregnancy Category D.(See WARNINGS.)Nursing MothersIt is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions, women treated with azacitidine should not nurse.Pediatric UseSafety and effectiveness in pediatric patients have not been established.Geriatric UseOf the total number of patients in the 3 clinical studies described in CLINICAL STUDIES, above, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse events observed in patients 65 years and older compared to younger patients. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it maybe useful to monitor renal function (see DOSAGE ANDADMINISTRATION section).ADVERSE REACTIONSOverviewAdverse Reactions Described in Other Labeling Sections: neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma.Most Commonly Occurring Adverse Reactions (SC or IVRoute): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also include petechiae, rigors, weakness and hypokalemia.Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route):Discontinuation: leukopenia (5.0%),thrombocytopenia (3.6%), neutropenia (2.7%).Dose Held: leukopenia (4.5%), neutropenia (4.5%), febrile neutropenia (2.7%).Dose Reduced: leukopenia (4.5%), neutropenia (4.1%), thrombocytopenia (3.2%).Discussion of Adverse Reactions InformationThe data described below reflect exposure to VIDAZAin 268 patients, including 116 exposed for 6 cycles(approximately 6 months) or more and 60 exposed forgreater than 12 cycles (approximately 1 year). VIDAZAwas studied primarily in supportive-care-controlled anduncontrolled trials (n = 150 and n = 118, respectively).The population in the subcutaneous studies (n = 220)was 23 to 92 years old (mean 66.4 years), 68% male, and94% white, and had MDS or AML. The population in the IVstudy (n = 48) was 35 to 81 years old (mean 63.1 years),65% male, and 100% white. Most patients receivedaverage daily doses between 50 and 100 mg/m2.The following table presents the most common adverse events, whether or not considered drug related by investigators, occurring in at least 5% of patients treated with VIDAZA in the supportive-care-controlled trial and the uncontrolled subcutaneous trial combined.It is important to note that duration of exposure waslonger for the VIDAZA-treated group than for theobservation group: patients received VIDAZA for a meanof 11.4 months while mean time in the observation armwas 6.1 months.

Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a

Table 4: Most Frequently Observed Adverse Events (>5% in All VIDAZA)a Continued

a Mean VIDAZA exposure = 11.4 months. Mean time in observation arm = 6.1 months.

b Multiple reports of the same preferred terms for a patientare only counted once within each treatment group.

c Includes events from all patients exposed to VIDAZA, including patients after crossing over from observation.

d Includes events from observation period only; excludes any events after crossover to VIDAZA.

For SC VIDAZA administration, nausea, vomiting, diarrhea, and constipation all tended to increase in incidence with increasing doses of VIDAZA. Nausea, vomiting, injection site erythema, constipation, rigors, petechiae, injection site pain, dizziness, injection site bruising, anxiety, hypokalemia, insomnia, epistaxis, and rales tended to be more pronounced during the first 1-2 cycles of SC VIDAZA treatment compared with later cycles of treatment. There did not appear to be any adverse events that increased in frequency over the course of treatment. There did not appear to be any relevant differences in adverse events by gender.Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious treatment-related adverse events occurring at a rate of <5% (not described in Table 4) were reported: Blood and lymphatic system disorders:agranulocytosis, bone marrow depression, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions:catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.Hepatobiliary disorders: cholecystitisImmune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, blastomycosis, injection site infection, Klebsiella sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.Metabolism and nutrition disorders: dehydration.Musculoskeletal and connective tissue disorders:bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified:leukemia cutis. Nervous system disorders: convulsions, intracranial hemorrhage.Psychiatric disorders: confusion. Renal and urinary disorders: hematuria, loin pain, renal failure.Respiratory, thoracic and mediastinal disorders:hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.Surgical and medical procedures: cholecystectomy.Vascular disorders: orthostatic hypotension. Manufactured for: Pharmion Corporation Boulder, CO 80301Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146

Edition Date: 9 January 2007 Brief Summary ofPrescribing InformationVIDAZA is a registered trademark of Pharmion Corporation.© 2007 Pharmion Corporation. All rights reserved.VIDB010907A January 2007 Printed in USA.

Preferred Termb All VIDAZAc

(N=220)Observationd

(N=92)

At least 1 TEAE 219 (99.5) 89 (96.7)

Nausea 155 (70.5) 16 (17.4)

Anemia 153 (69.5) 59 (64.1)

Thrombocytopenia 144 (65.5) 42 (45.7)

Vomiting 119 (54.1) 5 (5.4)

Pyrexia 114 (51.8) 28 (30.4)

Leukopenia 106 (48.2) 27 (29.3)

Diarrhea 80 (36.4) 13 (14.1)

Fatigue 79 (35.9) 23 (25.0)

Injection site erythema 77 (35.0) 0

Constipation 74 (33.6) 6 (6.5)

Neutropenia 71 (32.3) 10 (10.9)

Ecchymosis 67 (30.5) 14 (15.2)

Cough 65 (29.5) 14 (15.2)

Dyspnea 64 (29.1) 11 (12.0)

Weakness 64 (29.1) 19 (20.7)

Rigors 56 (25.5) 10 (10.9)

Petechiae 52 (23.6) 8 (8.7)

Injection site pain 50 (22.7) 0

Arthralgia 49 (22.3) 3 (3.3)

Headache 48 (21.8) 10 (10.9)

Anorexia 45 (20.5) 6 (6.5)

Pain in limb 44 (20.0) 5 (5.4)

Pharyngitis 44 (20.0) 7 (7.6)

Back pain 41 (18.6) 7 (7.6)

Contusion 41 (18.6) 9 (9.8)

Dizziness 41 (18.6) 5 (5.4)

Edema peripheral 41 (18.6) 10 (10.9)

Erythema 37 (16.8) 4 (4.3)

Chest pain 36 (16.4) 5 (5.4)

Epistaxis 36 (16.4) 9 (9.8)

Febrile neutropenia 36 (16.4) 4 (4.3)

Myalgia 35 (15.9) 2 (2.2)

Weight decreased 35 (15.9) 10 (10.9)

Abdominal pain 34 (15.5) 12 (13.0)

Pallor 34 (15.5) 7 (7.6)

Nasopharyngitis 32 (14.5) 3 (3.3)

Pitting edema 32 (14.5) 9 (9.8)

Skin lesion 32 (14.5) 8 (8.7)

Dyspnea exertional 31 (14.1) 15 (16.3)

Injection site bruising 31 (14.1) 0

Rash 31 (14.1) 9 (9.8)

Injection site reaction 30 (13.6) 0

Anxiety 29 (13.2) 3 (3.3)

Appetite decreased 28 (12.7) 8 (8.7)

Fatigue aggravated 28 (12.7) 4 (4.3)

Hypokalemia 28 (12.7) 12 (13.0)

Upper respiratory tract infection

28 (12.7) 4 (4.3)

Pruritus 27(12.3) 11 (12.0)

Abdominal tenderness 26 (11.8) 1 (1.1)

Depression 26 (11.8) 7 (7.6)

Productive cough 25 (11.4) 4 (4.3)

Insomnia 24 (10.9) 4 (4.3

Malaise 24 (10.9) 1 (1.1)

Pain 24 (10.9) 3 (3.3)

Pneumonia 24 (10.9) 5 (5.4)

Abdominal pain upper 23 (10.5) 3 (3.3)

Crackles lung 23 (10.5) 8 (8.7)

Sweating increased 23 (10.5) 2 (2.2)

Cardiac murmur 22 (10.0) 8 (8.7)

Rhinorrhea 22 (10.0) 2 (2.2)

Gingival bleeding 21 (9.5) 4 (4.3)

Lymphadenopathy 21 (9.5) 3 (3.3)

Herpes simplex 20 (9.1) 5 (5.4)

Hematoma 19 (8.6) 0

Night sweats 19 (8.6) 3 (3.3)

Rales 19 (8.6) 8 (8.7)

Tachycardia 19 (8.6) 6 (6.5)

Wheezing 19 (8.6) 2 (2.2)

Cellulitis 18 (8.2) 4 (4.3)

Dysuria 18 (8.2) 2 (2.2)

Breath sounds decreased

17 (7.7) 1 (1.1)

Lethargy 17 (7.7) 2 (2.2)

Oral mucosal petechiae

17 (7.7) 3 (3.3)

Stomatitis 17 (7.7) 0

Urinary tract infection 17 (7.7) 5 (5.4)

Peripheral swelling 16 (7.3) 5 (5.4)

Dyspepsia 15 (6.8) 4 (4.3)

Hemorrhoids 15 (6.8) 1 (1.1)

Hypotension 15 (6.8) 2 (2.2)

Injection site pruritus 15 (6.8) 0

Transfusion reaction 15 (6.8) 0

Pleural effusion 14 (6.4) 6 (6.5)

Abdominal distension 13 (5.9) 4 (4.3)

Muscle cramps 13 (5.9) 3 (3.3)

Post procedural hemorrhage

13 (5.9) 1 (1.1)

Preferred Termb All VIDAZAc

(N=220)Observationd

(N=92)

At least 1 TEAE 219 (99.5) 89 (96.7)

Postnasal drip 13 (5.9) 3 (3.3)

Rhonchi 13 (5.9) 2 (2.2)

Syncope 13 (5.9) 5 (5.4)

Urticaria 13 (5.9) 1 (1.1)

Anemia aggravated 12 (5.5) 5 (5.4)

Loose stools 12 (5.5) 0

Nasal congestion 12 (5.5) 1 (1.1)

Atelectasis 11 (5.0) 2 (2.2)

Chest wall pain 11 (5.0) 0

Dry skin 11 (5.0) 1 (1.1)

Dysphagia 11 (5.0) 2 (2.2)

Dyspnea exacerbated 11 (5.0) 3 (3.3)

Hypoesthesia 11 (5.0) 1 (1.1)

Injection site granuloma

11 (5.0) 0

Injection sitepigmentation changes

11 (5.0) 0

Injection site swelling 11 (5.0) 0

Mouth hemorrhage 11 (5.0) 1 (1.1)

Post procedural pain 11 (5.0) 2 (2.2)

Sinusitis 11 (5.0) 3 (3.3)

Skin nodule 11 (5.0) 1 (1.1)

Tongue ulceration 11 (5.0) 2 (2.2)

000862_phvirt_jco_power_fa4.indd2 2 6/19/07 1:55:05 PM

practices that are using the models haveseen overall declines in patient waittimes of 33%; increased efficiency ofchemotherapy staff and infusion roomresources by 16%; improvements rang-ing from 12% to 16% in the timelinessand completeness of orders; andimproved efficiency for physicians ofabout 10% to 15%.

� Oncology ReimbursementSolutions Aims to Improve BillingEfficiency

US Oncology, Inc has announced theintroduction of Oncology Reimburse-ment Solutions (ORS), an oncology-focused billing and reimbursement serv-ice. ORS offers community oncologypractices a comprehensive revenue cyclemanagement program to ensure accuratereimbursement for their services. Because

proper denial management is essential foran efficient revenue cycle process, ORSwill resolve the reasons that claims areinitially denied, helping to ensure theyare approved when they are first submit-ted. ORS also provides a curriculum ofoncology billing and coding educationthat includes web-based articles, audioconferences, and webcasts, and helps inaccessing patient assistance programs.Last year, the ORS Patient AssistanceSupport team obtained more than $14million in funding for disadvantagedpatients with cancer.

� Practice Management ModelsShow Benefits for OncologyPractices

A practice management model, creat-ed by US Oncology for oncology prac-tices, has been shown to be beneficial inenhancing patient access to advancedcancer care while improving efficiency forthe practice. The model, using anapproach often found in manufacturingsettings, is focused on defining and meas-uring a problem; determining the prob-lem’s cause; and initiating change andmaintaining improvements. Oncology

NEWS NOTESContinued from page 5

Erratum

I n the article “KRAS MutationsPredictive of Response toPanitumumab Monotherapy in

mCRC” in the May issue, the num-ber of patients with KRAS muta-tions was inadvertently misstated.The corrected article appears in itsentirety below:

KRAS Mutations Predictiveof Response toPanitumumabMonotherapy in mCRC

KRAS status should be consid-ered when determining whetherpatients with metastatic colorectalcancer (mCRC) are candidates forpanitumumab monotherapy becauseKRAS mutations are predictive oflack of clinical response to the epi-dermal growth factor inhibitor. Thisfinding comes from a phase 3 studycomparing panitumumab mono-therapy with best supportive care(BSC) in patients with chemothera-py-refractory mCRC. The investiga-tors used polymerase chain reactionon DNA from tumor secretions todetect KRAS mutations, and theycompared the effect of panitumum-ab monotherapy on progression-freesurvival (PFS) in patients withmutant versus wild-type (WT; ie,nonmutated) KRAS. Of 463patients originally enrolled, 427(92%) were included in the KRASanalyses. KRAS mutations wereidentified in 184 (43%) of these 427patients. The effect of panitumumabon PFS was significantly greater (P <.0001) in patients with WT KRASthan in those with mutant KRAS.In the WT KRAS group, medianPFS was 12.3 weeks for panitumum-ab-treated patients compared with7.3 weeks for those who receivedBSC. Seventeen percent of patientswith WT KRAS but none of thosewith mutant KRAS responded topanitumumab. Overall survival waslonger in the WT KRAS group thanin the mutant KRAS group.Consistent with longer exposure tothe drug, more grade III treatmenttoxicities were observed in the WTKRAS group. No significant differ-ences in toxicity were foundbetween the WT KRAS group andthe overall population. (AmadoRG, et al. J Clin Oncol. 2008;26:1626-1634.)



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time working in oncology as a clinicalpharmacist, but I didn’t have any spe-cial training per se outside of the stan-dard residency rotation in oncologybecause it didn’t exist at the time.The senior oncologist interviewed meand gave me the job. So I just kind offell into oncology pharmacy, and Ithink some people still do that today.

How did the oncology phar-macy specialty become established?

The whole pharmacy specialtyprocess was established by theAmerican Society of Health-SystemPharmacists (ASHP) Board ofPharmaceutical Specialties (BPS)with submissions from various organi-zations. Nuclear pharmacy was one ofthe first, followed by nutrition andthen pharmacotherapy. Back in the1980s, ASHP had what they calledspecial interest groups, or SIGs. Theoncology specialty practice came outof the oncology SIG group of ASHP.

I was the chairman of ASHP’s oncol-ogy SIG group at the time the petitionto establish oncology as a specialty wasdrafted. One of our tasks was to establishour standard of practice. We spent a lotof time with many oncology pharmacistsfrom around the country trying to puttogether our petition. The first petitionthat we submitted to the BPS wasturned down because it was not viewedas being sufficient to justify the special-ty. The oncology specialty practicealmost died at that time. But there werefour of us who would not accept thatand we never gave up. It became a 6-year process for us to finally get oncolo-gy pharmacy recognized as a specialty.

How did these efforts lead tothe establishment of HOPA?

There was really only one annualoncology specialty meeting at thattime, that being M.D. Anderson’s can-cer conference. We saw a need foradditional programming and continu-ing education for oncology pharmacy.For a while, many of us in the UnitedStates participated (and still do) inthe International Society of OncologyPharmacy Practice (ISOPP). TheISOPP group meets every 2 years andtravels around the world. We feltISOPP did not provide a consistentsource of continuing education tooncology pharmacists in this country.

So a small group of pharmacists and amedical advertising company puttogether an oncology specialty pro-gram—the first one was called “MakingA Difference in Oncology”—and thatconference went on for 3 days as a con-tinuing education program in oncologypharmacy. Later, it was decided that ifHOPA was ever going to get off theground as a national organization,using the “Making A Difference” con-ference would be a good venue and

eventually lead to the programmingstructure of HOPA.

What impact do you thinkHOPA has made on the oncol-ogy pharmacy specialty?

HOPA is still a young group. Weare in the first of a 3-year strategicplan for our organization. Certainlythe organization met a long-timeneed to have a formal group thatwould bring together oncology phar-macists from around the country.With the large increase in the num-ber of cancer drugs, biologics, genetherapy, and targeted molecular ther-apies, oncology pharmacy hasbecome a very sophisticated practice.HOPA was established at a very goodtime to provide infrastructure, bringpeople together, provide educationand training, and keep people up todate on these new developments.

Oncology changes faster thanmany other specialty practices, sothere is a great need for continuingeducation. Even within oncology,there are several subspecialty areasnow within our organization, andpeople are forming smaller SIGs (ie,research, pediatrics, BMT). We arenow being recognized by other pro-fessional organizations as a source ofspecific information related to oncol-ogy pharmacy, which is remarkableconsidering we are a relatively neworganization. We are also part of athree-group consortium with ASHPand the American College ofClinical Pharmacy to provide recerti-fication for oncology pharmacy as aspecialty.

What was your role regard-ing this year’s HOPA/ISOPPconference?

ISOPP intended to come to theUnited States in 2008 and had peti-tioned HOPA to hold a one-time jointmeeting. This was decided before Ibecame president. A lot of the yearwas spent putting this joint meetingtogether. We had an oversight groupof four people, two from HOPA andtwo from ISOPP, which oversaw thewhole process.

Putting the meeting togetherrequired a huge effort. The program-ming at this year’s meeting was threetimes the amount of our last meeting,and the attendance was doubled.More than 1000 people attended thisyear’s meeting. My job was to makesure everything worked, but I takealmost no credit for that. The meetingrequired the hard work of many differ-ent HOPA and ISOPP members.

What were some of the high-lights of this year’sHOPA/ISOPP meeting?

Our goal at this year’s meeting wasto provide topics that would serve theneeds of both the HOPA membershipand international attendees. Some ofthe things we do clinically in the

United States are not done in othercountries. The challenge was to pro-vide programs and information perti-nent to people from all over the world.I think we accomplished this goal withour keynote address on safe medica-tion practices, which is a major WorldHealth Organization issue and cer-tainly an issue within this country.

Could you explain some of thedifferences between oncologypharmacy practice in theUnited States and other coun-tries?

The oncology pharmacy activitiesin many other countries revolve pri-marily around drug preparation,preparation safety, and managinghazardous materials, which areindeed key functions. In the UnitedStates, we have the additional ele-ments of clinical practice and directpatient care. In some countries,oncology pharmacists are not quiteup to that level yet.

How was this dichotomyaddressed at the annualmeeting?

We provided a good number ofsessions and workshops, some withcommon themes and others morespecialized. We had a fantasticturnout in the poster sessions, withalmost 200 posters. A new feature atthis year’s meeting was the research

platform presentations. We wantedto provide a format for youngtrainees and residents to becomeinvolved in. That has been one ofthe goals of our organization andseemed to work very well this year.

Is there anything you mighthave done differently at thisyear’s meeting, or would like tosee happen at future meetings?

Overall, I think the meeting wentfantastically well. Personally, I wouldlike to see an increased emphasis onthe community practice setting atfuture meetings and to expand ourtechnician activities. I think weshould work to provide more specificprogramming related to communitypractice for oncology pharmacists. Wedon’t want to limit our reach to oncol-ogy pharmacists in medical centers,universities, and cancer centers. Wewant to reach out to all oncologypharmacy practitioners.

What are some of the greatestchallenges currently facingoncology pharmacy?

One of the greatest challenges rightnow is manpower—recruiting trainees,developing trainee programs and spe-cialty residencies. We need to increasethe number of people trained in oncolo-gy pharmacy. Currently there are morejobs than we have people.

HOPA SETS GOALS Continued from cover

“There’s one side effect. It may kill you.”

CARTOON

With the large increase in the number of can-cer drugs, biologics, gene therapy, and targetedmolecular therapies, oncology pharmacy hasbecome a very sophisticated practice.

Continued on page 8


Oncology drug management isanother major challenge. Communitypractices are under increasing pressureto upgrade their standards of oncologydrug preparation. Standardized treat-ment protocols for community prac-tices are popping up all over. Some ofthese protocols call for the generationof data to document outcomes anddemonstrate value of service. I thinkwe will see a push for more standard-ized care in the near future. This willprovide huge opportunities for oncolo-gy pharmacists in the coming years.

What needs to change on the academic level for thesechallenges to be betteraddressed?

I think universities need to devel-op better standards for academictraining in oncology pharmacy. Oneof the elements of our strategic planis to provide leadership and guidanceto the universities as far as suggestedcurriculum.

What are some of the otherobjectives of the strategicplan?

We currently have a 3-year strategicplan for HOPA. In addition to theeducational objectives, the plan callsfor efforts to develop our organization-al infrastructure and increase ourmembership. We also plan to increaseour legislative and regulatory activi-ties. Another goal is to increase therecognition and awareness of oncologypharmacists by the public and otherhealthcare providers. All of theseplans were developed with the primarygoal of improving patient care.

—David S. MacDougall


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ANAHEIM—Palonosetron (PALO) is safeand effective for the prevention of emesisin patients receiving high-dose melphalanchemotherapy before stem cell transplant(SCT), according to researchers atOregon Health and Science UniversityHospital, Portland.

PALO is a second-generation 5-hydrox-ytryptamine (5-HT)3 receptor antagonistrecently approved for the prevention ofacute or delayed chemotherapy-inducednausea and vomiting (CINV) in patientsreceiving either moderately or highly emeto-genic cancer chemotherapy. PALO has alonger half-life and a higher binding affinitythan first-generation 5-HT3 receptor antago-nists and is typically administered as a single0.25-mg intravenous (IV) dose 30 minutesbefore the start of chemotherapy.

SCT conditioning regimens have beenassociated with significant rates of emesis

and high use of antiemetic rescue treat-ment. The efficacy of first-generationantiemetics in this clinical setting hasbeen disappointing.

In a randomized, phase 2, double-blind study, 73 patients with multiplemyeloma receiving 2-day conditioningwith high-dose melphalan (100 mg/m2

twice daily) before SCT were treatedwith one, two, or three daily doses ofPALO (0.25 mg IV) or placebo beforeSCT. All patients received dexametha-sone on days 1 and 2 after SCT.

The primary study end point was com-plete prevention of emesis throughout the7-day study. Secondary end points includ-ed rescue antiemetic use, adverse events,and other parameters.

In the groups receiving 1-day, 2-day, and3-day PALO, the rates of complete emesisprevention were 42%, 42%, and 44%,

respectively. Rescue antiemetics wererequired by 8%, 33%, and 24% of thosereceiving 1-day, 2-day, and 3-day PALO,respectively, reported Joseph Bubalo,PharmD, and colleagues.

Complete response rates (no emesis andno rescue antiemetic use) for the overall 7-day study were 8%, 21%, and 20% (P = .14)for the groups receiving 1-day, 2-day, and 3-day PALO, respectively. Overall and onindividual study days, two or three doses ofPALO were more effective than one dosefor emesis prevention without rescue use.

PALO was well tolerated, and the mostcommon adverse events were diarrhea(16%), constipation (12%), headache(11%), and insomnia (8%).

The researchers noted that the recentlyapproved label change allowing PALO tobe dosed more than once per week mayhelp optimize CINV prevention inpatients receiving a variety of multiday,high-dose chemotherapy regimens.

—DSM

ANAHEIM—Myelosuppression has a nega-tive impact on clinical response rates andhealth-related quality of life (HRQOL) inpatients with chronic myeloid leukemia(CML), according to a recent data analysis.

Myelosuppression is associated withincreased morbidity and mortality in patientswith cancer, and the presence of treatment-emergent myelosuppression is a major chal-lenge in the management of patients withCML. The impact of myelosuppression ontreatment responses and HRQOL in patientswith CML is not well known.

To help clarify these relationships, datafrom a phase 3 study of imatinib versus inter-feron-alfa combined with cytarabine in 1016patients with newly diagnosed, previouslyuntreated Philadelphia chromosome-positiveCML were analyzed by researchers atPharmerit North America, Bethesda, Md.Myelosuppression was categorized as anyevent of neutropenia, thrombocytopenia, oranemia at the 3-month follow-up.

The composite efficacy end point (thera-peutic response) was defined as the patientachieving either a complete hematologicresponse or a complete cytogenic response bythe 3-month visit. The impact of myelosup-pression on HRQOL was determined usingthe Functional Assessment of CancerTherapy (FACT), FACT—Biologic Re-sponse Modifier (FACT-BRM), and othervalidated questionnaires at 3 months.

A therapeutic response was achieved by71% of the patients without myelosuppres-sion and 54% of those with myelosuppres-sion, reported Jennifer Stephens, PharmD,and colleagues. The difference in responserates between the patients with and withoutmyelosuppression was statistically significant(P <.0001).

In the myelosuppression group, clinicallymeaningful declines were observed in thephysical well-being and functional well-beingdomains of the FACT survey and in theTreatment Outcome Index (TOI). In thegroup without myelosuppression, clinicallymeaningful declines were observed in thephysical well-being domain of the FACT sur-vey, but no significant change was observedin the TOI.

Compared with the patients withoutmyelosuppression, those with myelosup-pression had greater declines for physicaland functional well-being and the physicaland cognitive/emotional domains of theFACT-BRM survey. The declines in globalscore and TOI were significantly greater forpatients with myelosuppression.

There was a trend towards improvedemotional well-being between baseline and3 months in both patient groups, suggestingan improved ability of patients to feel bet-ter able to cope with their illness, less wor-ried, and less sad when receiving treatmentfor their illness.

These findings underscore the negativeimpact of myelosuppression on treatmentresponse rates and HRQOL in patientswith CML and may be useful in the selec-tion of appropriate therapies in patientswith CML. Particularly those who havefailed or are intolerant of imatinib, theresearchers concluded. —DSM

HOPA: Palonosetron Safe, Effective in Patients

Receiving Melphalan for SCT

HOPA: Myelosuppression Decreases Response

Rates, HRQOL in Patients with CML

HOPA SETS GOALS Continued from page 7

For MoreNews from

HOPA

see theSeptember

Issue

The presence of treat-ment-emergent myelo-suppression is a majorchallenge.

Continued on page 9


sine kinase inhibitor, according to data presented atthe 44th annual meeting of the American Societyof Oncology. Progression-free survival (PFS) wassignificantly enhanced in everolimus recipientscompared with placebo in a randomized, double-blind, multicenter phase 3 trial.

The mTOR protein regulates cell division andblood vessel growth in cancer cells, and is a majorroute to resistance in targeted cancer therapies.Everolimus is currently approved as an immuno-suppressant for prevention of rejection of organsafter transplant.

“This is the first phase 3 trial that establish-es clinical benefits and provides safety informa-tion for this new agent,” said the study’s leadinvestigator Robert J. Motzer, MD, attendingphysician, Memorial Sloane-Kettering CancerCenter, New York.

Historically, metastatic RCC has been difficult totreat. An effective treatment option when diseaseprogresses despite the use of targeted agents such assorafenib and sunitinib is an unmet clinical need,Dr Motzer noted. “It is an unmet clinical need thathas now been filled,” he said. “Everolimus should bethe standard of care in this setting.”

The study included 410 patients with metastat-ic RCC with a clear cell component who were ran-

domized in a 2:1 ratio to 10 mg of everolimus oral-ly or placebo (Table). Treatment was given in 28-day cycles, allowing for assessment of response andsafety. All patients had stopped responding toeither sorafenib or sunitinib or both within theprevious 6 months. “This was a heavily pretreatedgroup,” Dr Motzer pointed out. Patients hadreceived up to three therapies previously.

The study was terminated early by the inde-pendent data monitoring committee after thesecond interim analysis (when 60% of the tar-geted number of events had accrued) becauseof the large efficacy difference in favor of

everolimus, Dr Motzer said. After 6 months, the median PFS was 4.0 months

in patients assigned to everolimus versus 1.9months in those assigned to placebo (hazard ratio0.30; P <.0001) (Table). Everolimus was signifi-cantly superior to placebo in all three prognosticgroups (favorable, intermediate, poor).

Twenty-six percent of patients assigned toeverolimus had no disease progression, comparedwith only 2% assigned to placebo. Because patients

in the placebo group were permitted to cross over toeverolimus if they showed signs of progression whilereceiving placebo, an analysis of median overall sur-vival was not conducted.

The most common adverse events in theeverolimus group were stomatitis (incidence of40% with everolimus vs 8% with placebo), anemia(28% vs 15%), and weakness (28% vs 20%). Theincidence of severe (grade 3 or 4) toxicity was 3%or less for each side effect. Quality-of-life measureswere not significantly different between patientsrandomized to everolimus or placebo.

The study has been published in the July 23online issue of The Lancet (doi:10.1016/S0140-6736(08)61039-9).

—Wayne Kuznar

After 6 months, the

median PFS was 4.0

months in patients

assigned to everolimus

versus 1.9 months in

those assigned to placebo.

www.theoncologypharmacist.com

• View current and past issues

• Register to receive your free subscription

• Access CE activities

• Obtain author guidelines

Table. Outcome in Different Prognostic Groups

Median MedianPrognostic Hazard PFS (mo): PFS (mo): group N ratio* P value everolimus placebo

Overall 410 0.30 <.0001 4.0 1.9

Favorable 118 0.35 <.0001 5.5 2.2

Intermediate 231 0.25 <.0001 3.9 1.8

Poor 61 0.39 .009 3.6 1.9*Everolimus versus placebo.PFS indicates progression-free survival.

Robert J. Motzer, MD, speaking at ASCO.

Reach us online at


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CHICAGO—The addition of biannualinfusions of zoledronic acid to hormonetherapy improves disease-free survivaland recurrence-free survival in pre-menopausal women with hormone-sen-sitive early-stage breast cancer, reportedMichael Gnant, MD, at the 44th annualmeeting of the American Society ofClinical Oncology.

Data obtained from a large random-ized clinical trial add to preclinical find-ings that zoledronic acid may have ananticancer effect. Zoledronic acid is cur-rently indicated for the treatment ofpatients with multiple myeloma anddocumented bone metastases from solidtumors, in conjunction with standardantineoplastic therapy.

The Australian Breast and ColorectalCancer Study Group Trial 12 wasdesigned to compare the efficacy oftamoxifen and anastrazole with or with-out zoledronic acid in women withendocrine-responsive stage I or II breastcancer with <10 positive nodes. All1803 women enrolled underwent sur-gery to remove the primary tumor and

ovarian suppression with goserelinacetate (3.6 mg subcutaneously every28 days for the duration of the trial)before being randomized to one of fourtreatment arms:

• Tamoxifen (20 mg/day)• Tamoxifen (20 mg/day) plus zole-

dronic acid (4 mg intravenous [IV]every 6 months)

• Anastrazole (1 mg/day)• Anastrazole (1 mg/day) plus zole-

dronic acid (4 mg IV every 6months)

Treatment duration was 3 years;median follow-up was 5 years. Overalldisease-free survival was 94%, andoverall survival was 98.2%. There wasno difference in the primary endpoint—disease-free survival—betweenpatients randomized to tamoxifen oranastrazole (P = .59). Women random-ized to zoledronic acid had a 36%reduction (P = .11) in the risk of arelapse event compared with womennot randomized to zoledronic acid.

“When you further subdivide theresults and look at event subcate-gories…zoledronic acid basicallyreduced events in all of the subcate-gories, not only bone metastasis, whichone might have anticipated, but alsolocoregional recurrences, distant non-bone metastases, and also contralateralbreast cancer,” said Dr Gnant, profes-sor of surgery, Medical University ofVienna. “This is in fact an indication

that zoledronic acid exerts itsbenefit through a variety ofmechanisms…kind of creatinga tumor-hostile environmentin our patients that helps tokill micrometastases, or dor-mants (as well call them),everywhere in the body.”

Recurrence-free survival wasimproved by 35% (P = .015) byadding zoledronic acid toendocrine therapy comparedwith endocrine therapy alone.There was a nonsignificanttrend (P = .10) toward im-proved overall survival in thezoledronic acid group.

Zoledronic acid was gener-ally well tolerated. Notably,there were no confirmed casesof osteonecrosis of the jaw,“which is very reassuring,” DrGnant said. Osteonecrosis ofthe jaw has been reported incancer patients who are treat-ed with IV bisphosphonates,although many patients whohave developed osteonecrosisof the jaw while receiving bisphos-phonate therapy were also receivingchemotherapy and corticosteroids.There was also no evidence of renaltoxicity with zoledronic acid.

The overall excellent disease-freesurvival and overall survival in thestudy with endocrine therapy and

zoledronic acid mean that womenwith endocrine-responsive earlybreast cancer can be spared the sideeffects of cytotoxic therapy afterlocoregional treatment, Dr Gnantconcluded.

—WK

ASCO: Bisphosphonate

Prolongs Cancer-freeSurvival in Endocrine-sensitive Breast Cancer

Michael Gnant, MD, speaking at ASCO.

CHICAGO—Vitamin D deficiency isassociated with worse outcomes inwomen with early breast cancer. Inaddition, high-dose vitamin D supple-mentation can provide relief of symp-toms, such as joint pain and fatigue,related to vitamin D deficiency fromaromatase inhibitor therapy in post-menopausal women with breast cancer.

These findings come from two sepa-rate studies presented at the 44th

annual meeting of the AmericanSociety of Clinical Oncology.

A study of 512 consecutively enrolledpatients between 1989 and 1996 withnewly diagnosed breast cancer, conduct-ed at three hospitals in Toronto, showedthat 38% of the patients had vitamin Ddeficiency, and another 39% had levelsconsidered to be insufficient, saidPatricia J. Goodwin, MD, one of theinvestigators.

Low vitamin D levels were asso-ciated with tumor grade and adju-vant chemotherapy. Comparedwith patients with sufficient vita-min D levels, those with insuffi-cient levels had a 94% decrease (P = .02) in distant disease-freesurvival and a 73% worse (P =.02) overall survival at 10 years.

Nonetheless, high-dose vitaminD supplementation is prematurein patients with breast cancer, saidDr Goodwin, chair in breastresearch, Mount Sinai Hospital,Toronto. She added that morecurrent research should be con-ducted to ascertain whether vita-min D deficiency exists at thelevel it did during enrollment ofpatients into this study.

Vitamin D supplementation is,

however, justified in women with inva-sive breast cancer who are vitamin D-deficient when starting an aromataseinhibitor, said Qamar J. Khan, MD,who presented a study in which high-dose but not standard-dose vitamin Drelieved joint pain and fatigue invitamin D-deficient women takingletrozole.

“All women starting an aromataseinhibitor should be screened for vita-min D deficiency, and attemptsshould be made to optimize vitaminD levels,” said Dr Khan, associateprofessor of oncology, Cancer Centerof Kansas, Wichita.

About one fourth of women withinvasive breast cancer who receiveadjuvant aromatase inhibitors experi-ence joint pain or stiffness. About onefourth also report fatigue while beingtreated with an aromatase inhibitor.

In a 16-week prospective study, 60women with invasive breast cancer whowere candidates for aromatase inhibitortherapy had serum vitamin D levelsmeasured at baseline, 10 weeks, and 16weeks. All women were started on 2.5mg/day of letrozole and 1200 mg/day ofcalcium plus 600 IU/day of vitamin D.Women who had serum vitamin D levels≤40 ng/mL at week 4 had their vitaminD dosage increased to 50,000 IU/day forthe next 12 weeks.

Fatigue, pain severity, joint paindisability, and menopausal symptomswere assessed via questionnaire atbaseline, week 4, and week 16.

Sixty-four percent of the womenhad vitamin D deficiency (<32ng/mL) at baseline; 49 of the 50women who received high-dose vita-min D had serum vitamin D levels>32 ng/mL by week 10. With stan-dard-dose (600 IU/day) vitamin D,serum vitamin D levels dropped inseven of nine women.

With standard-dose vitamin D,joint pain improved in only 8% ofwomen and worsened in 34%. Duringweeks 4 through 16, when the vitaminD-deficient women at week 4 wereswitched to high-dose vitamin D,joint pain improved in 21% and wors-ened in 32%.

Similarly, fatigue scores were morelikely to improve during high-dosevitamin D therapy and were more like-ly to worsen during standard-dose vita-min D therapy.

“Given that these women arebeing subjected to an aromataseinhibitor, which causes bone loss,just for the bone health alone theyshould have optimal levels of vitaminD,” said Dr Khan.

Health Assessment Questionnaire IIscores, designed to study the effects ofan intervention on activities of dailyliving, were stable from baseline toweek 4 (during standard-dose vitaminD therapy) but declined (improved)from weeks 4 to 16 (during high-dosevitamin D therapy).

—WK

ASCO:Low Vitamin D Associated with Worse Outcomes

in Patients with Breast Cancer


OncologyNurse

TheOncologyNurse

The

The Official Newspaperof Record for

the Hem/Onc Nurse™


The



A Newsletter Series for Cancer Care Professionals

Center of Excellence Media, along with Editor-in-Chief

Sagar Lonial, MD, of Emory University, will proudly offer the

multidisciplinary cancer team at your center a series of

newsletters focusing on the challenges in treating patients

with multiple myeloma.

SAGAR LONIAL, MDAssociate Professor of

Hematology and Oncology

Emory University

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Each newsletter will feature:

• Contributions from thought-leading physicians,pharmacists, and nurses

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Target Audience

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Learning Objectives

At 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

Accreditation

PhysiciansThis activity has been planned and implemented in accordance with the Essential Areas and

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Supported by an educational grant from Millennium Pharmaceuticals, Inc.

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™E Center of Excellence Media, LLCCenter of Excellence Media, LLC

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H. Lee Moffitt Cancer Center & Research Institute

W hen H. Lee Moffitt, then a Florida StateRepresentative conceived of the centerthat now bears his name back in 1978,

he had no idea that 30 years later his name would besynonymous with innovative and comprehensivecancer care.

Moffitt, a cancer survivor, was alarmed by Florida’shigh rate of cancer. The state needed a center thatwould help eradicate cancer as a public health threatthrough patient care, education, and research. Floridaranks second in the nation for its rates of cancer inci-dence and mortality. Initially, Moffitt’s vision was metwith resistance—where would the funding comefrom? But with the help of the Floridian government,he was able to raise $70 million dollars initially. In1981, the Florida legislature passed a bill to secure theplanning for the H. Lee Moffitt Cancer Center &Research Institute on the Tampa campus of theUniversity of South Florida. Notably, funding for theinitial $70 million needed for construction of the cen-ter came mainly from the state’s cigarette tax.

In 1983, the center celebrated its groundbreaking,and by 1986, the center started admitting patients.The success was inspiring, and the center continuedto grow, in physical size and in reputation.

In 1998, the center expanded its research andclinical areas thanks to a $100 million grant from theFlorida legislature. This was followed by earning thestatus of a National Cancer Institute Cancer Center.Earning this highly regarded distinction has translat-ed into doubled research funding and a 130%increase in patient referrals. Moffitt has also earnedthe honor of being named in US News & WorldReport as one of America’s Best Hospitals. In addi-tion to its main campus in Tampa, the center has 15affiliates in Florida, one in Georgia, and two inPuerto Rico. The Moffitt Cancer Center providesthe most marrow and blood transplants in theSoutheastern United States.

Personalized cancer careIn its vision to “be the leader in scientific dis-

covery and translation into compassionate care,cures, and prevention of cancer,” the center isconstantly growing, expanding, and evolving tokeep current and remain innovative. The cen-ter’s latest initiative is to expand its personalizedoncology research. The center started collabo-rating with Merck & Co in 2006 to developmore personalized treatment for different typesof cancers that affect individuals. This TotalCancer Care initiative was started to test everytumor and 30,000 genes of patients with cancer.The goal is to create personalized individualcancer care through genetics and to help savemore lives by 2010. Working in conjunctionwith the University of Florida and ShandsHealthcare, the partnership will encompass the spec-trums of patient care, research, and education. Thegoals of this collaboration include quality improve-ment in cancer care, helping to address the needs ofsurviving family members, and, lastly, tissue/data col-lection to create more custom-tailored therapies foreach patient. Executive Director, Willian S. Dalton,MD, PhD, stated at a media conference, “Total CancerCare is intended to streamline pathways to cancer careand to follow the patient through screening, diagnosis,and treatment of cancer, incorporating translationalresearch at each step along this continuum of care.”

Caring for the caregiver One of the initiatives of note at Moffitt is a program

called Caring for the Caregiver, which provides stressmanagement training, nutritional counseling, andadvice on problem-solving techniques and communi-cation strategies to family members of patients wholive at home. Another unique service on offer isCancer Answers, a toll-free telephone service staffedby registered nurses, who answer queries on such mat-ters as cancer detection, prevention, risk, diagnosis,treatment, and research.

Robert Bradbury, RPh, the clinical coordinator ofthe pharmacy has been a pharmacist since 1975, andhas been on staff at Moffitt for 20 years. There are 65pharmacists on staff at the center, and they work invarious areas, such as the central pharmacy, retailpharmacy, and on clinical trials. There are also round-ing pharmacists integrated into different areas and dif-ferent roles. All are board-certified in oncology.According to Bradbury, Florida has the most board-certified pharmacists in the nation. He says, “We takepride in being integrated with the patient care modelat Moffitt so the patients have an advocate for theirdrug therapy.” Bradbury enjoys his interaction withpatients, saying, “No one is more pleasant to workwith than cancer patients. They’re very thankful forour interaction. It’s a great opportunity to be of com-fort and to improve outcomes for our patients. Oneperson can really make a difference.”

Nurse Serena Moody has been on staff at Moffitt fora little over a year, and gives rave reviews of her pro-fessional experience there, with both other staff mem-bers and patients. She speaks warmly about herpatients and their families, saying how grateful she isto be able to provide care and comfort for them, andhow positive their interactions are. Many cancer

patients and their families are glad to be at Moffitt,she says, and this creates a positive environment. Sheadmits, however, that her job can be emotionallystrenuous and is grateful for the support that Moffittprovides for its staff. Not only are ongoing profession-al workshops provided, but there is an extensive men-toring program for new nurses. In recognition of itsefforts to encourage staff nurses to seek oncology cer-tification, the Moffitt Cancer Center received the2008 Employer Recognition Award from theOncology Nursing Certification Corporation.

—Amy Johansson

Photo courtesy of The Moffitt Cancer Center

Photo courtesy of The Moffitt Cancer Center

Moffitt Facts:Number of beds: 162

Number of inpatients: 726

Number of outpatients: 264,523

Number of staff: 3800 employees

(800+ research faculty, 300+ physicians)

Executive Director:William S. Dalton, MD, PhD

Publication: Cancer Control Journal

(peer-reviewed journal with a readership of 13,000)

Funding: For 2008, Moffitt received

approximately $66 million in grants.

Research programs:Molecular oncology, immunology, drug

discovery, experimental/therapeutic,

genetic immunotherapy, behavior oncolo-

gy, cancer screening, prevention, and

detection, digital imaging, tobacco

research and intervention, molecular

screening

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Iinterview many professionals in allwalks of life every week, and onequestion that always comes up is:

How do you find out what your patientreally needs when they don’t communi-cate well. The answer I often hear is “bylistening.”

Professionals in pharmacy, nursing,or any other business often forget thatlistening is a two-part exercise, neitherof them passive. The first part of theexercise is planning and asking a vari-ety questions that will get your patientthinking about his needs. After all, pa-tients and clients are often busy peoplewho, contrary to our perceptions, don’tspend a lot of time thinking about howour services might help them. Theyneed some help getting started. So wehave to ask the questions that will pro-voke thought and uncover the realproblems.

The second part is listening. Askingyour patient all the correct questions iswasted if you don’t hear what he or sheis saying, either in words, or more sub-tly, in tones or partial hints. Being agood listener requires more than justkeeping quiet while the other person istalking. Sometimes we’re even think-ing about our next question while theyare answering our last question! Do youhear everything that is being said? Doyou understand it completely?

Here are some tips on how tobecome a more effective listener:

Focus in on the basic message

Try to pinpoint the main ideas theperson is expressing. Ask yourself whatthe speaker is trying to say. If you’re notsure, ask. “Mr. Jones, I believe what Iheard is . . . Am I on track?”

Understand what is being saidKeep asking yourself if you understand

what is being said. If you don’t, ask forclarification—and keep asking until youare sure you fully understand. “Mr. Jones,I’m not sure I understand how this relatesto that. Can you help me out?” What youdon’t understand, you can’t recall.Additionally, if you don’t understandwhat is being said, your mind is morelikely to wander, and your listening effec-tiveness diminishes.

Don’t get distractedDon’t let trivial things like the

speaker’s appearance or random noisesdivert your attention from what he orshe is saying. Listen to the speaker’swhole sentence. Listen not only forcontent, but context. Anytime youcatch yourself being distracted bysomething that draws your attentionaway from the speaker’s words, make aconscious effort to focus back on thewords. Do that by creating word imagesthat match the speaker’s words.

Listen with your “gut”The speaker’s tone and body lan-

guage will impart meaning. Body lan-guage accounts for 55% of communica-tion and tonality 38%. The words areonly 7% of the process. These subtleclues are quickly picked up by theunconscious mind and leave us with aparticular feeling about the speaker.When you are left with a “feeling”about someone after a conversation—that they are sincere, they are hidingsomething, they can’t be trusted, etc—it is a sign that your unconscious mindhas put two and two together and comeup with an evaluation.

Become personally absorbed in whatis being said. You can’t listen effectivelyif you are only “going through themotions.” Every subject has some inter-esting angle, some impact on you, orsomething you can learn. To uncoverthose elements, you must first abandonyour prejudiced or preconceived ideas. Ifyou enter into a conversation with thenotion that the other person has noth-ing of interest or importance to say, youwill miss what is important. An attitudeof curiosity about a patient’s or cowork-er’s concerns and needs is flattering andcan become both a bonding experienceand a communications tool.

Get InvolvedTo keep your active attention on what

is being said, offer comments. If the situ-ation permits, offer your own perspective

on what is being said. Ask a question orrelate a relevant story that reinforceswhat the person is saying, or represents adifferent point of view. Ask yourself ifwhat the person is saying relates to othersituations or experiences. Third-partystories are an excellent way to confirmthat you’ve got it right.

In summary, listen proactivelyThere is more to listening than just

passively hearing the words someone isspeaking. Remember, neither question-ing or listening is a passive activity.

©2008 Sandler Training, Inc. The Sandler Sales Institute is an international sales and manage-ment training/consulting firm since 1967. For more information goto www.sandler.com

Leadership and Communication Skills for Pharmacists

Are You REALLY Listening? By Jim Barnoski

Jim Barnoski is a trainer with Sandler TrainingCenter.


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The




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To begin receiving issues of The Oncology Pharmacist, simply fill out your subscription card

IN FULL or register online at www.theoncologypharmacist.com

Your subscription at NO CHARGE is just a signature away!

Written by and for oncology pharmacist offering you the following:

• Concise reviews of hot topics in the peer-reviewed literatureby clinical specialists with key point ‘takeaways’

• Coverage of key research studies and on-the-scene reportsfrom oncology medical meetings

• Continuing education articles at no charge and post-tests,offering you a convenient way to obtain CE hours

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aged care setting were discussed from a consul-tant’s viewpoint and a health plan’s viewpoint atthe 20th Annual Meeting and Showcase of theAcademy of Managed Care Pharmacy held in SanFrancisco in April.

Off-label use of oncology drugsDebbie Stern, RPh, vice president of Pharmacy

Rxperts, Inc, a managed care consulting firm,observed that there is a trend to require prior author-ization and to manage off-label use. Data from theEMD Serono Injectable Digest, a Web-based marketresearch survey conducted in the first quarter of 2008,show that many respondents are now requiring peer-reviewed published studies to support off-label use:51% require at least one peer-reviewed publishedstudy to support off-label use and 63% require two orthree. Approximately 67% do not support off-labeluse, and 72% require compendia listing for off-labeldrug use.

Challenges in managing oncology drugsOne of the greatest challenges associated with

oncology drugs has been trying to move oncologistsfrom the “buy-and-bill” mentality in addition to lackof survival benefit data, lack of published guidelineson drug use, and lack of outcomes data. Ms Sternnoted that, despite approval by the US Food and DrugAdministration, oncology drugs are perceived as lack-ing clarity on outcomes and survival benefit. Anotherchallenge arose with regard to how cancer care hasevolved in some cases from acute to chronic, resultingin long-term patient exposure to medications. Thishas required adjusting the care mentality from cure tomaintenance, similar to managing patients withhypertension, asthma, and diabetes, she said.

Managing specialty drugsThere are third-party vendors now who specialize in

assisting with medical benefit management of special-ty drugs, medical costs in particular. Vendor servicesinclude converting J-codes to National Drug Codes,managing oral oncology and/or infused oncologyagents, adjudicating some or all medical benefit spe-cialty drugs, and performing clinical and utilizationmanagement of specialty drugs. Although the vastmajority of respondents to the survey did not plan touse any of these vendors, Ms Stern predicted that atti-tudes are likely to change in time, and use of the ven-dors will increase.

Future management strategies in themarketplace

There is a growing recognition that with the num-ber of products that have come into the marketplace,oral oncology products will now be considered spe-cialty drugs and require the use of specialty pharmacy.Instituting a first fill for oral oncology agents is fairlynew. This was instituted to see whether patientscould tolerate the agent prescribed for them.

The Great-West Healthcare experienceKerri Miller, PharmD, vice president pharmacy

services, Great-West Healthcare, provided the healthplan perspective on oncology management. Dr Millernoted that Great-West’s pharmacy side is growing asa result of the use of oral oncology drugs. They collab-orate with network management, pricing, qualitymanagement, and case management to maintain abalanced approach. Collaboration is more critical inoncology than with other specialties, Dr Miller said.

The challenges Great-West has faced include find-ing and using drugs with the lowest cost from a vari-

ety of vendors rather than through typical retail con-tracts; having varying regional reimbursement sched-ules; keeping up with the volume of new drugs andindications; managing unit costs, quantities, and indi-cations; and preventing inconsistency or duplicationin their pharmacy and disease management programs.

By contracting with multiple vendors, Great-West has been able to minimize impact from limit-ed-distribution drugs and ensure appropriate cover-age and the best drug prices. This arrangement hasalso helped them leverage between vendors. Theywere further able to define their specialty drugs list,among which are the oncology drugs. They com-monly see fourth-tier coinsurance, with 20% pre-scription maximums and a cap on a per-prescriptionbasis. Fewer than 10% of their groups are using thisbenefit. In 2005, they implemented a retail lock-outof specialty drugs. Members could then get their firstspecialty drug at a retail pharmacy, and subsequentprescriptions would have to be filled by one ofGreat-West’s preferred vendors.

Having multiple vendors helps to retain a sense ofhealthy competition in the field while providingaccess to nearly all limited-distribution drugs, accord-ing to Dr Miller. The specialty list has provided con-sistency, and, over time, lessened member com-plaints. More than 85% of their specialty drug utiliza-tion goes to one of their preferred vendors for phar-macy claims, resulting in $2 to $3 million per year inadditional savings beyond what they would havesaved had the prescriptions been processed at theretail rate.

Utilization managementGreat-West has expanded their policies beyond

oncology support drugs and is now focusing on oncol-ogy itself, Dr Miller explained. This requires partner-ing with disease management vendors to assist withpolicy development and review. They are currentlyusing multiple resources, such as the NationalComprehensive Cancer Network, to develop poli-cies. Dr Miller noted that input from oncologists wascritical for making decisions about off-label use.Great-West also found it expeditious to use the“grandfathering” approach when implementing priorauthorization on existing therapies.

Great-West has had a relatively low rate of denials(less than 5%), partly resulting from an increase inawareness from their provider network. They haveincreased communication with their case manage-ment team, improved coordination with their diseasemanagement vendors, and were able to provide feed-back to their provider network department.

Oncology disease managementDisease management was outsourced to Matria

Healthcare, formerly Quality Oncology. Great-Westuses an internal referral process through its customerservices division. All members currently undergoingactive treatment are case managed. An oncologynurse is assigned to each patient, and a team of casemanagers and oncology nurses is available 24 hoursa day, 7 days a week.

Nurses take an active role in helping patients andtheir family members understand their disease andtreatment. Dr Miller said this approach has helpedpatients avoid unwarranted emergency departmentvisits and unplanned admissions. All the informa-tion gathered is shared with the treating oncologist.

Although cancer prevalence among plan membershas increased from 8.4 per 1000 members per year inyear 1 to 9.3 per 1000 members per year in year 3,Great-West has seen a 16% reduction in acute hospi-tal days per 1000 members and a 10% reduction inreadmissions. Their complication-related admissionsare 20% below the national average, and 49% of theireligible patients participate in hospice programs. Onthe whole, Dr Miller observed, there is a high level ofpatient and provider satisfaction.

On the medical benefit side, she noted thatGreat-West’s reimbursement approach has loweredthe impact on individual providers. Their J-codes,for example, are linked to specific drugs for easyidentification and medical management. Great-West is considering initiating a higher percent reim-bursement rate for generic drugs to preventproviders from using higher cost drugs to reap ahigher reimbursement rate.

On the medical benefits side, Dr Miller noted thereis a 35% to 45% discount off the billed amount foroncology drugs, an increased awareness within theprovider network department with regard to contract-ing strategies, an increased opportunity to redirect tospecialists when possible, minimal provider complaintsand no network dis-enrollments, and, finally, improvednegotiation opportunities not only with providers butalso with home health vendors.

Great-West hopes to expand its prior authoriza-tion and collaborate more extensively with internalpartners, disease management, and case manage-ment. Finally, Dr Miller said there is a need to alignprovider incentives for quality and cost-efficiencyand to meet the continual challenge to find betterways to collect and analyze data and provide optimaloncology care.

—Sandy Paton

MANAGED CARE PHARMACYContinued from cover

Photo courtesy of AMCP


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Continuing EducationProgram #CIK 9828 • RELEASE DATE: August 1, 2008 • EXPIRATION DATE: July 31, 2009

D osing recommendations for cancer drugs are ordinarilydrawn from studies in patients thought to best representthose who are most likely to receive the drug in clinical

practice. Unfortunately, the obese patient is usually not consid-ered the typical candidate for the drug. Thus, at least for now, dos-ing recommendations for obese patients are less grounded in sci-ence than for nonobese patients.

In the absence of standardized dosing guidelines for cancerdrugs in obese patients, dosing recommendations are often extrap-olated to this population arbitrarily when the dose must be stand-ardized to a particular patient variable such as body surface area(BSA) to minimize the risk of toxicity. The problem is compound-ed by the lack of information on the effect of obesity on the phar-macokinetics and pharmacodynamics of anticancer drugs.

In the clinical setting, drug doses for obese patients are calculat-ed using a variety of empiric dosing regimens, ranging from usingthe patient’s BSA up to an arbitrary cut-off or relying on an alter-nate estimate of the patient’s weight, such as predicted normalweight, among others. Because these dosing regimens are untest-ed, patients are at significant risk of being underdosed, whichintroduces the potential for suboptimal treatment outcomes.

With a growing number of obese adults with cancer, it becomesincreasingly important to identify reliable means of calculatingdosages of anticancer drugs in this population.

To address this question, we need to better understand the phys-iologic effects of obesity on drug disposition. My coworkers and Ire-evaluated data from published studies of eight anticancer drugs

that enrolled a total of 1,206 adult cancer patients and comparedfindings in obese and lean patients. Patients were classified asobese if their body mass index (BMI) was ≥30 kg/m2, whereas leanpatients had a BMI <25 kg/m2. Using actual area under the curve(AUC) in lean patients as the target standard, we aimed to definethe weight descriptor that provides the same AUC in an obesepatient as in a lean patient. The weight descriptors we looked atincluded predicted normal weight, lean body mass, adjusted idealbody weight (IBW), and the mean of IBW and actual body weight(ABW). The anticancer agents included carboplatin, cisplatin,docetaxel, doxorubicin, irinotecan, paclitaxel, topotecan, andtroxacitabine.

Findings• The disposition of some, but not all, drugs is significantly altered

in obese patients.• The absolute clearance of cisplatin, paclitaxel, and troxacitabine

was significantly increased in obese patients. However, this wasnot seen with carboplatin, docetaxel, irinotecan, or topotecan.

• With doxorubicin, systemic clearance was significantly reducedby approximately 30% in obese women but not in obese men.

Recommendations• For most of the drugs we evaluated, weight scalars used to calcu-

late BSA should take into account ABW, irrespective of size. Infact, ABW is the most accurate and precise descriptor for calcu-lating anticancer drug doses for obese patients. For example, a

Calculating the Dosage of Anticancer Drugs inObese Patients: A Clinical Challenge

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 9828.

• 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, especiallythose caring for cancer patients.

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:• Describe current methods of calculating dosage of anticancer drugs for obese patients• Summarize the findings of studies of eight anticancer drugs in lean and obese patients• Evaluate the potential utility of alternative weight descriptors in dose calculation for

obese patients

EDITORIAL BOARDSharyn D. Baker, PharmD, PhDDepartment of PharmaceuticalSciencesSt Jude Children’s Research HospitalMemphis, TN 38105-2794

David Gregornik, PharmD, BCNSPSt Jude Children’s Research HospitalMemphis, TN 38105-2794

Kimberly S. Hamilton, RN, BSNChronic Leukemia and MyelomaProgramCleveland ClinicCleveland, OH 44195

Robert J. Ignoffo, PharmD, FASHPTouro UniversityVallejo, CA

PLANNING COMMITTEE Lois ColburnExecutive DirectorCenter for Continuing EducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

Brenda Ram, CMPCoordinator Center for ContinuingEducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

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

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

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

REVIEWERGary C. Yee, PharmD, FCCP, BCOPProfessorDepartment of Pharmacy PracticeUniversity of Nebraska MedicalCenter986405 Nebraska Medical CenterOmaha, NE 68198-6045

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 significantor substantial relationship with providers of commercialproducts and/or devices discussed in this activity and/orwith any commercial supporter of this activity:

• Lois Colburn• Brenda Ram, CMP• Karen Rosenberg• Lara J. Reiman• Cass Hammond, RN, MSN, CRNP• Sharyn D. Baker, Pharm, PhD• David Gregornik, PharmD, BCNSP • Kimberly S. Hamilton, RN, BSN• Robert J. Ignoffo, PharmD, FASHP

ACCREDITATION The University of Nebraska Medical Center,Center for Continuing Education is accreditedby the Accreditation Council for PharmacyEducation as a provider of continuing pharma-cy education. The ACPE provider number is

447-000-08-150-H04-P. To receive the 1 contact hour ofcontinuing education credit, pharmacists should completethe activity requirements and evaluation at the conclusion ofthe activity. Approval is valid from the initial release date ofAugust 1, 2008. The expiration date is July 31, 2009. Astatement of credit will be available for printing online uponcompletion of the post-test with a score of 70% or better andthe evaluation instrument.

BY SHARYN D. BAKER, PHARMD, PHD, AND DAVID GREGORNIK, PHARMD, BCNSPPharmaceutical Sciences, St. Jude’s Children’s Research Hospital, Memphis, Tennessee

Complimentary



Continuing Education

BSA that uses ABW seems to be the best strategyfor calculating the dose for cisplatin, paclitaxel,and troxacitabine.

• The use of lean body mass or IBW is probably thebest dosing scalar for doxorubicin in obese womenand docetaxel in both men and women.

• For carboplatin, the average of ABW and IBW isthe best predictor of carboplatin clearance withinthe Bénézet/Chatelut formula that uses serum cre-atinine to calculate dose.

• When choosing an alternate size descriptor fordose calculation in the obese, it is important toconsider the particular agent and the patient’s sex.

• The data do not support arbitrary dose capping inobese patients for any of the eight drugs studied.

• The data do not support the practice of empiricdose reduction because of obesity.

• Prospective studies are needed to refine dosingstrategies in obese patients for individualchemotherapeutic agents.

• Pharmacokinetic studies are needed to clarifywhether different subgroups of obese patients havedifferent drug dispositions.

O f all the therapeutic challenges facingthe oncologist, the dosing of anticancerdrugs in the obese cancer patient is

one of the most difficult. Only a few studieshave addressed this issue in a systematic fash-ion. This research has resulted in dosing guide-lines for specific drugs but not a generalizedstandard dosing guideline that can be appliedto all anticancer drugs. No one patient variablestands out as a key factor in the dosing ofthese agents. The use of body surface area(BSA), a standard (although unproven in a clin-ical study) for dosing of anticancer drugs in thenonobese patient, does not correlate with thepharmacokinetics or pharmacodynamics ofthese toxic agents.

A study by Baker and colleagues1 attemptsto address the issue of reliable dosing of anti-cancer drugs in the obese cancer patient. Theyused alternative weight descriptors (lean bodyweight, geometric mean between actual andlean body weight, ideal body weight, and pre-dicted normal weight) in the calculation of apatient’s BSA and then monitored drug areaunder the curve (AUC) to determine differ-ences in obese and nonobese cancer patients.Unfortunately, their results varied by individ-ual agent and even individual class (the tax-anes in particular). While absolute clearancewas increased for all drugs studied in obesepatients (cisplatin, paclitaxel, and troxcitabinewere significantly increased), there was no dif-ference in clearance when values were stan-dardized to BSA. The use of actual body weightin the BSA formula for dosing docetaxel anddoxorubicin resulted in AUCs that were 33%and 25% significantly higher than 1.0, respec-tively. This was apparently due to changes indisposition of these drugs in women, becausemen did not have significantly higher AUCratios. Using lean body weight in both menand women resulted in no difference in AUCratios.

Capping the BSA to 2.0 m2 resulted in a signif-icantly higher AUC ratio only for women receiv-ing doxorubicin, but the authors did not specif-ically discuss this. BSA capping, however, pro-duced lower AUC ratios for other agents and, ingeneral, is discouraged by the authors. This isconsistent with the study of Joerger and col-leagues,2 who showed that for each increase inBSA of 0.2m2, paclitaxel elimination wasincreased by almost 10%, suggesting that cap-ping the BSA would result in lower drug expo-sure for this agent.

With regard to carboplatin, they confirmed

that the use of the mean of actual and leanbody weight in the Bénézet-Chatelut formulaleads to the most accurate prediction of drugexposure. The authors noted that this resultwas similar to that in the study performed byBénézet and colleagues.3 This is further sup-ported by a case report by de Jonge and col-leagues,4 who reported extremely high drugexposures in a 130-kg patient receiving high-dose cyclophosphamide, thiotepa, and carbo-platin. They used adjusted body weight for car-boplatin, which lowered the AUC into the nor-mal range.

The study by Baker and colleagues is animportant addition to the scientific literatureand brings to light many of the issues thatshould be considered in the dosing of anti-cancer drugs, including sex, type of bodyweight to incorporate into dosing formulas, flatdosing, dose capping, and empiric dose reduc-tion. It appears that physiochemical propertiesof the particular drug do not significantly affectthe pharmacokinetic parameter of drug expo-sure for the drugs studied.

Recommendations• I agree with Drs Baker’s and Gregornik’s

bulleted recommendations in their review.I would add further that ideal body weightis not a good weight scalar for any of thedrug studies, and it led to a significantdecrease in drug exposure for cisplatinand paclitaxel.

• Because the world is experiencing a globalepidemic in obesity, extensive furtherresearch on dosing strategies along withthe evaluation of pharmacokinetics of anti-cancer drugs is needed in obese patients.This work should be linked to the pharma-cogenomics of anticancer drug effects.

• Studies should be performed on other com-monly used anticancer drugs, includingcyclophosphamide, thiotepa, capecitabine,other anthracyclines, and hormonal agents.

References1. Sparreboom A, Wolff AC, Mathijssen RH, et al. Evaluation of

alternate size descriptors for dose calculation of anticancerdrugs in the obese. J Clin Oncol. 2007;25:4707-4713.

2. Joerger M, Huitema AD, van den Bongard DH, et al. Quantitativeeffect of gender, age, liver function, and body size on the pop-ulation pharmacokinetics of Paclitaxel patients with solidtumors. Clin Cancer Res. 2006;12:2150-2157.

3. Bénézet S, Guimbaud R, Chatelut E, et al. How to predict carbo-platin clearance from standard morphological and biologicalcharacteristics in obese patients. Ann Oncol. 1997;8:607-609.

4. de Jonge M, Mathôt RA, Van Dam SM, et al. Extremely highexposures to in an obese patient receiving high-dosecyclophosphamide, thiotepa and carboplatin. Cancer Chemother

Calculating the Dosage of Anticancer Drugs inObese Patients: A Clinical Dilemma:A pharmacist’s perspective

C O M M E N TA RY

BY ROBERT J. IGNOFFO, PHARMD, FASHPTouro University, Vallejo, California, and the University of California, San Francisco


Program #CIK 9828 • RELEASE DATE: August 1, 2008 • EXPIRATION DATE: July 31, 2009

Table. Antineoplastic ChemotherapyProtocol

Weeks 0, 3, 6, and 26• Ifosfamide 2650 mg/m2 on days 1 to 3 of

the course

• *Carboplatin target area under the curve(AUC) = 8 mg* min/mL on day 1

Week 9• Doxorubicin 25 mg/m2 on days 1 to 3

Weeks 14, 23, and 32• Ifosfamide 2650 mg/m2 on days 1 to 3

• Doxorubicin 25 mg/m2 on days 1 and 2

Weeks 17 and 26• *Carboplatin target AUC = 8 mg* min/mL

on day 1*

• Ifosfamide 2650 mg/m2 day 1 to 3

Weeks 20, 29, and 35• *Carboplatin target AUC = 8 mg* min/mL

on day 1

• Doxorubicin 25 mg/m2 days 1 and 2

*Glomerular filtration rate (GFR) was estimated by assessment of 99Tc-DTPArenal clearance and used to target the carboplatin AUC using a modifiedCalvert formula:

Dose of carboplatin (mg/m2) = AUC × [(GFR (in mL/min/m2) × 0.93) + 15]

When choosing an alternate

size descriptor for dose calcu-

lation in the obese, it is impor-

tant to consider the particular

agent and the patient’s sex.



For more information on this topic, see SparreboomA, et al. Evaluation of alternate size descriptors fordose calculation of anticancer drugs in the obese. J Clin Oncol. 2007;25:4707-4713.

Case Report

A 21-year-old obese white woman (height, 160.7cm; weight, 106.6 kg; body mass index, 41.3 kg/m2;BSA, 2.22 m2) presented with osteosarcoma of the leftfemur.1 The patient reported that approximately 1 yearbefore diagnosis she began to experience disturbancesin her gait, when her left leg involuntarily began to“swing out” while walking. Six months before diagno-sis, she experienced intermittent left leg pain localizedto her femur. This continued for 4 months until shewas examined by her general practitioner, who pre-scribed anti-inflammatory medications. The patientreturned to her general practitioner after 18 days,complaining of worsening pain, mild night sweats, anda decrease in appetite. Her general practitionerreferred the patient to an orthopedic specialist, whoordered a radiograph of the left leg followed by mag-netic resonance imaging and a bone scan. The resultsof the diagnostic imaging studies led to referral to ourinstitution.

After the diagnosis of osteosarcoma was con-firmed, the patient was enrolled on the front-lineinvestigational protocol for osteosarcoma (Table).

As stipulated in the protocol, IBW was used tocalculate all chemotherapy doses. This patient’sIBW was estimated to be 57.5 kg. Using IBW in theGehan-George BSA equation, the patient’s dosingBSA was calculated to be 1.6 m2, a decrease of 28%.Despite this conservative approach to dosing herchemotherapy, the patient experienced appreciabletoxicity during her therapy, including two admis-sions to the intensive care unit for hypotension andsepsis, prolonged thrombocytopenia resulting indelayed therapy, and significant nausea and emesis.Carboplatin was dosed based on the patient’s indi-vidual glomerular filtration rate, which wouldaccount for obesity-related changes in renal func-tion. Based on the analysis by Sparreboom and col-leagues,2 the use of lean body mass or IBW was rec-ommended when calculating a doxorubicin dose forobese women; information on ifosfamide dosing inthe obese patients was not included in this analysis.

The patient completed her final course of thera-py approximately 40 weeks after the original diag-nosis. A computed tomography scan of the chestimmediately after completion of her chemotherapywas positive for a new small lung nodule. A follow-up image 2 months later revealed new nodules inthe right lung and a slight increase in size of theoriginal nodule. The patient underwent thoracoto-my with resection of the nodules. Gross residual dis-ease involving the diaphragm remained after sur-

gery. Pathologic examination of the nodules showedmetastatic osteosarcoma. The patient received salvage chemotherapy with several different regi-mens. Unfortunately, her disease progressedthrough this therapy, and she died 2 years after heroriginal diagnosis.

References1. Gehan EA, George SL. Estimation of human body surface area from height

and weight. Cancer Chemother Rep. 1970;54:225-235.

2. Sparreboom A, Wolff AC, Mathijssen RH, et al. Evaluation of alternate sizedescriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol.2007;25:4707-4713.

Continued from page 17

Continuing EducationProgram #CIK 9828 • RELEASE DATE: August 1, 2008 • EXPIRATION DATE: July 31, 2009

Carboplatin was dosed based

on the patient’s individual GFR,

which would account for obesi-

ty-related changes in renal

function.

To receive complimentary CE credit:

Astudy of US adults in 2002 showed that31% were obese (with a body mass index[BMI] of ≥30 kg/m2) compared with 23% in

1994.1 Studies have shown that cancers of thecolon, breast (postmenopausal), endometrium,kidney, and esophagus are associated with obe-sity. Links between obesity and cancers of thegallbladder, ovaries, and pancreas have alsobeen found, and obese adults may be atincreased risk for other types of cancer as well.2

With the increasing incidence of obesity amongUS adults, it is imperative to find ways to treatthese individuals effectively and safely whenthey do develop cancer.

Historically, appropriately conducted clinicaltrials have provided information on drug effica-cy, safety, and tolerability through several phas-es, which then translates into clinical practice,before a drug is considered for approval by theUS Food and Drug Administration. Phase 1 tri-als include a smaller group of patients, and thedrug is dosed based on preclinical research innonhuman models. Drugs given to patientsenrolled in a phase 1 study may be used for sev-eral tumor types, with the goal of determiningthe maximum tolerated dose of the drug inhumans. Phase 2 trials provide data on efficacyand tumor response in a larger group ofpatients. Information gathered from phase 2trials suggests effective dosing in a specifictumor type. Finally, phase 3 trials often includea randomized design, comparing the new ther-apy with a standard therapy, to prove superior-ity of one treatment over the other.

In my own experience in treating patientsenrolled in clinical trials, I have found thatoften patients are not excluded from clinicaltrials because of their obesity, but ratherbecause of the comorbidities associated withobesity. Exclusion criteria for many clinical tri-als include uncontrolled hypertension, cardio-vascular disease, and an Eastern CooperativeOncology Group performance status ≥2.Although several patients that I have treatedwould be considered obese with a BMI >30kg/m2, it is not clear how different response totreatment is in this special population com-pared with those with a lower BMI.

To deliver the appropriate and effectivetreatment dose to patients, especially whencalculating the dosage of most intravenoustherapies, the patient’s weight is somewhataccounted for by dosing per the body surfacearea or area under the curve calculations,given the current model. There are dose limitsand precautions to prevent against the toxicityassociated with many anticancer drugs. It isvery interesting that the findings reported byBaker and colleagues showed differences inthe disposition and absolute clearance of someof the drugs that were studied in the obesepatients. It is evident that more clinical trialsare needed to decipher how body weight, sex,and other characteristics of individual patientsaffect the dosing of their treatment regimen.

Although these questions may be answeredby a clinical trial, it would be specifically chal-lenging in any given trial, depending on thestudy end points, to do subset analyses ofpatients with a BMI >30 kg/m2 or to randomizepatients who have a greater BMI to differentdose levels. In addition, many tumor types arerare, and larger trials are difficult to conduct forthese tumor types.

Another aspect to consider would be the flatdosing of many novel oral agents for obesepatients. Several oral anticancer therapies aredosed at a specific standard amount for a dis-ease process based on doses determined in theclinical trial setting. For example, lenalidomideat the 25-mg dose is prescribed for patients withmultiple myeloma. We adjust the dose for renalimpairment, but seldom make dose adjust-ments based on the weight of the patient.

The study by Baker and colleagues will raiseawareness of the need for more clinical trialswith an emphasis on the effects of obesity andother factors that may influence the appropri-ate dose of anticancer drugs for each patient.

References1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in

obesity among U.S. adults, 1999-2000. JAMA. 2002;288:1723-1727.

2. Vainio H, Bianchini F. IARC Handbooks of Cancer Prevention. Vol. 6:Weight control and physical activity. Lyon, France: IARC Press;2002.

Calculating the Dosage of Anticancer Drugs inObese Patients: A nurse’s perspective

C O M M E N TA RY

BY KIMBERLY S. HAMILTON RN, BSNCleveland Clinic Foundation, Cleveland, Ohio

1. Log onto www.theoncologypharmacist.com.2. Click on UNMC logo on homepage.3. Register to participate.4. Enter program number CIK 9828.



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Prostate CancerAUA: Finasteride May Help Reduce the Risk of Most Prostate Cancers

ORLANDO—A reanalysis of datafrom the landmark Prostate CancerPrevention Trial (PCPT) suggeststhat finasteride may reduce the riskfor prostate cancer without boostingthe odds of aggressive tumors.

PCPT, which involved 18,822 menwho received either a placebo orfinasteride for 7 years, was stoppedearly in June 2003. The reason wasthat researchers noted that althoughfinasteride reduced the incidence ofprostate cancer in men by up to 25%,men taking this agent appeared tohave more aggressive prostate tumorsif and when they did develop the dis-ease. These findings caused concernthat finasteride may be promotinghigher-grade cancer.

Now, a new analysis of PCPT pre-sented at the 103rd Annual ScientificMeeting of the American UrologicalAssociation (AUA) has concludedthat finasteride actually reduced therisk of developing prostate cancermore than researchers had originallythought and does not increase the riskof aggressive tumors. For their newanalysis of PCPT data, the investiga-tors used advanced statistical model-ing techniques and a complete assess-ment of prostate tissue biopsies. Theyfound that finasteride did not increasedevelopment of more aggressive can-cers and that the majority of tumorsprevented were those that couldspread and cause death.

These new findings suggest thatmen should take an individualizedapproach to prostate cancer preven-tion, according to the researchers.“Because we now know that menwith even low PSAs [prostate-spe-cific antigens] can develop prostatetumors, if a man is worried about hisrisk, regardless of PSA score, he cantake an agent that is now proven tobe effective in lowering that risk,”commented study investigator IanThompson, MD, who is chairmanand professor of urology at theUniversity of Texas Health SciencesCenter, San Antonio.

Dr Thompson said finasteride actu-ally shrinks the prostate gland. So, inthe initial study it appeared that morecancer was being found in biopsyspecimens of men who took the drug.

In the re-analysis, the researcherslooked once more at PCPT data onbiopsies taken from the 18,882 menin the study. They adjusted for treat-ment type, age, race, family history ofprostate cancer, baseline PSA levels,and the individual patient’s prostatevolume. The investigators found noevidence that the drug increased therate of aggressive tumors, but insteadactually decreased their rate by 27%.

“I believe that the drug is chemo-

suppressive,” said study coinvestiga-tor Steven Kaplan, MD, a professorof urology at Weill Cornell MedicalCollege, New York. “We know thatit reduces PSA levels, which areindicative of prostatic disease.Finasteride appears to be particular-ly adept at suppressing the moreindolent cancer. So in the future, itmight be useful to use the drug todetermine just how aggressive andneedful of treatment a particulartumor is. If the patient takes finas-teride and his PSA levels quicklydrop, he probably has a less-threat-ening tumor that may just requirewatchful waiting. But if PSA levelsrise, that tumor may need moreactive treatment.”

He said, in the meantime,researchers need to keep prostate vol-ume in mind whenever they conducttrials assessing the anticancer proper-ties of prostate-shrinking medica-tions. “Right now, the drug makerGlaxoSmithKline is testing out a sim-ilar drug, dutasteride, as a possibleagent against prostate cancer. Wehope that they will incorporateprostate volume in their analysis tohelp avoid the confusion that doggedPCPT,” explained Dr Kaplan.

The PCPT trial was funded bythe US National Cancer Instituteand Merck, which is the maker offinasteride.

—John Schieszer

Trends in Prostate Cancer

>>>Men with High-risk Prostate Cancer at LowRisk of Cancer-specific Mortality

A substantial proportion of patients with high-riskprostate cancer by currently available definitions do nothave a uniformly poor prognosis after radical prostatec-tomy (RP), according to a study of 5960 men with clin-ically localized or locally advanced prostate cancer whounderwent RP. Among the study group, eight differenthigh-risk subsets, each comprising 4% to 40% of thestudy population, were identified. Each of the identifiedhigh-risk criteria was associated with increased hazardratio (HR) for secondary cancer therapy (HR, 1.3–5.2;P <.05) and metastatic progression (HR, 2.1–6.9; P <.05). Depending on the definition of increased risk,the probability of freedom from additional therapy 10years after RP ranged from 35% to 76%. The 10-yearcumulative incidence of prostate cancer–specific mor-tality in high-risk patients ranged from 3% to 11% (HR,3.2–10.4; P <.0005) (Yossepowitch O, et al. Eur Urol.2008;53:950-959).

>>>Parenteral Estrogen Efficacy Similar toCombined Androgen Deprivation in MetastaticProstate Cancer

The anticancer efficacy of high-dose polyestradiolphosphate (PEP) is equivalent to that of combinedandrogen deprivation (CAD) in patients with prostatecancer and skeletal metastases, but the adverse effectsprofiles of these treatments are markedly different.These findings emerged in a study of 910 patients withT0-4, NX, M1, G1-3 prostate cancer and an EasternCooperative Oncology Group performance status of 0-2 who were randomized to treatment with either PEP orCAD (flutamide in combination with either triptorelinor bilateral orchidectomy). There were no differencesbetween the treatment groups in terms of biochemicalor clinical progression-free survival or overall or disease-specific survival. Cardiovascular mortality was similarin both groups, but the incidence of nonfatal cardiovas-cular events was significantly higher in the PEP armthan in the CAD arm (P <.05), predominantly due to

an increase in ischemic heart and heart decompensa-tion events in the PEP group. There were 18 graveskeletal events in the CAD group and none in the PEPgroup (P = .001) (Hedlund PO, et al. Scand J UrolNephrol. 2008;42:220-229).

>>>Treatment Choice Determines OverallSatisfaction in Prostate Cancer Survivors

Prostate cancer treatments are each associated with adistinct pattern of change in quality of life (QOL)domains, and these changes influence satisfaction withtreatment outcomes among patients and their spousesor partners. The determinants of health-related QOLafter primary treatment of prostate cancer and theeffects of such determinants on satisfaction with treat-ment outcomes were prospectively examined in 1201patients and 625 spouses or partners before and afterradical prostatectomy, brachytherapy, or external-beamradiotherapy. Among patients receiving brachytherapyor radiotherapy, adjuvant hormone therapy was associ-ated with worse outcomes across multiple QOLdomains. Patients in the brachytherapy group reportedhaving prolonged urinary irritation, bowel and sexualsymptoms, and transient problems with vitality or hormonal function. Nerve-sparing procedures helpedmitigate the adverse effects of prostatectomy on sexualfunction. Urinary incontinence was observed afterprostatectomy, but urinary irritation and obstructionimproved, particularly in patients with large prostates.No treatment-related deaths occurred, and seriousadverse events were rare. Treatment-related symptomswere worsened by obesity, larger prostate size, a highprostate-specific antigen score, and older age. Blackpatients reported lower satisfaction with the degree ofoverall treatment outcomes. QOL changes were signifi-cantly associated with the degree of outcome satisfactionamong patients and their spouses or partners (SandaMG, et al. N Engl J Med. 2008;358:1250-1261).


Did you

Know?Men who eat at least 14ounces of broccoli eachweek have a reduced risk ofprostate cancer. Broccoli,British researchers found,may affect gene expressionby changing cell-signalingpathways associated withinflammation and carcino-genesis. Source: PLoS One.July 2008.


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>>>18F-fluoro-2-deoxy-glucoseUptake Predicts Outcomes inNSCLC

Low 18F-fluoro-2-deoxy-glucose uptakeat presentation predicts a favorable prog-nosis in patients with gefitinib-treatednon-small-cell lung cancer (NSCLC).The finding is based on a retrospectiveanalysis of 84 positron emission tomogra-phy/computed tomography findings frompatients with gefitinib-treated NSCLC.Patient characteristics, response rates,and survival rates were evaluated accord-ing to the maximum standardized uptakevalue (SUV) of the primary tumor. Theresponse rates (RRs) were higher innever-smokers than in ever-smokers(41% vs 9%; P = .001), and patients withadenocarcinoma had higher RRs thanthose with other tumor histopathologies

(35% vs 9%; P = .009). The SUV wassignificantly lower in patients whowere never-smokers (P = .005),patients with adenocarcinoma (P<.001), and women (P = .017).Patients with a low SUV had higherRRs compared with those with a highSUV (53% vs 18%; P = .003). Medianprogression-free survival was signifi-cantly greater in patients with lowSUVs compared with those with highSUVs (33.1 weeks vs 8.6 weeks; P =.003). A low SUV was associated withimproved overall survival in univariate(P = .011) and multivariate (P = .043)

analysis (Na II, et al. Clin Cancer Res.2008;14:2036-2041).

>>>Gemcitabine, Cisplatin, andUFT is Effective First-line Regimenin Advanced NSCLC

The combination of gemcitabine,cisplatin, and uracil-tegafur (UFT) isan active and well-tolerated first-lineregimen in patients with advancednon–small-cell lung cancer (NSCLC),according to the findings of a phase 2study. A group of 37 chemotherapy-naive patients (median age, 60 years)with histologically or cytologically

confirmed stage IIIB or IV NSCLCand a performance status of 0 to 2received gemcitabine on days 1 and 8,cisplatin on day 1, and UFT orally ondays 1 to 14. Treatment was repeatedevery 3 weeks for up to six cycles.Complete response was achieved inone (3%) patient, partial response in17 (46%) patients, and stable diseasein 10 (27%) patients. The overallresponse rate was 48.6% on an inten-tion-to-treat basis and 54.5% inpatients in whom a response evalua-tion was possible (n = 33). The medi-an survival time was 14.7 months, the1-year survival rate was 54%, and themedian time to progression was 5.4months. Toxicities were moderate andconsisted mostly of hematologicevents. Grade 3/4 neutropenia devel-oped in 37% of patients and fourpatients experienced febrile neutrope-nia. Grade 3/4 anemia and thrombocy-topenia occurred in 19% and 5% ofpatients, respectively. Nonhematologictoxicities were mild (Shin SJ, et al.Lung Cancer. 2008;60:83-91).

>>> Gemcitabine PlusIrinotecan CombinationEffective in Patients withPreviously Treated SCLC

Gemcitabine plus irinotecan iseffective and well-tolerated inpatients with previously treatedsmall-cell lung cancer (SCLC), newdata suggest. A total of 31 patients(median age, 64 years) with SCLCwho had experienced treatment fail-ure with one prior chemotherapy reg-imen received gemcitabine andirinotecan on days 1 and 15 of a 28-day cycle. All patients were requiredto have a performance status of 0 to 2and adequate organ function atenrollment. An objective responsewas obtained in 36.7% of thepatients. The median overall survivaltime was 14.4 months, and the 1-yearsurvival rate was 51%. The primarygrade 3/4 toxicities included neu-tropenia (42%), thrombocytopenia(3%), diarrhea (9%), and liver dys-function (3%). The only grade 4 tox-icities were one case of grade 4 neu-tropenia and one case of grade 4thrombocytopenia (Ohyanagi F, etal. Cancer Chemother Pharmacol.2008;61:503-508).

Trends in Hematologic Cancer

>>>High GM-CSF AutoantibodyTiters Predict Active Disease inPatients with Myeloid Leukemia

Antibodies to granulocyte-macro-phage colony-stimulating factor (GM-CSF) are present in patients withactive myeloid leukemia and may beuseful markers of disease activity. Thefinding is based on a study of 69 patientswith acute myeloid leukemia, chronicmyeloid leukemia, or myelodysplasticsyndrome, including 19 patients whoreceived GM-CSF with peptide antigenand incomplete Freund’s adjuvant in avaccine trial for the presence or induc-tion of anti-GM-CSF antibodies. Anti-GM-CSF IgG antibodies were presentin 52% of the patients with myeloidleukemia compared with 3% of healthycontrols (P = .008) and none of 6patients with lymphoid leukemia (P =.0001). Antibody titers were unaffectedby vaccination. Anti-GM-CSF IgA andIgM antibodies were found in 33% and20% of the patients with myeloidleukemia, respectively. Anti-GM-CSFIgG titers were significantly higher inpatients with active disease than inthose in complete remission (P =.0009), but GM-CSF expression was notincreased in either group (Sergeeva A,et al. Leukemia. 2008;22:783-790).

>>>CHOP + RadioimmunotherapyEffective in Elderly Patients withDiffuse Large B-cell Lymphoma

Combination chemotherapy withcyclophosphamide, doxorubicin, vin-cristine, and prednisone (CHOP) plusradioimmunotherapy is safe and effec-tive in previously untreated elderlypatients with diffuse large B-cell lym-phoma (DLBCL). In a prospective, sin-

gle-arm, open-label, nonrandomizedphase II trial, 20 elderly patients (age>60 years) with previously untreatedDLBCL received a novel regimen con-sisting of six cycles of CHOPchemotherapy followed 6 to 10 weekslater by 90Y ibritumomab tiuxetan. Theoverall response rate to the entire treat-ment regimen was 100%, including 95%complete remission (CR) and 5% par-tial remission. Four (80%) of the fivepatients who achieved less than a CRwith CHOP improved their remissionstatus after radioimmunotherapy.

With a median follow-up of 15months, the 2-year progression-free sur-vival rate was estimated to be 75%, witha 2-year overall survival rate of 95%.The 90Y ibritumomab tiuxetan toxici-ties included grade >3 hematologic toxicity in 12 of 20 patients; the mostcommon grade >3 toxic effects wereneutropenia (12 patients) and thrombo-cytopenia (7 patients). One patientreceived transfusions of red blood cellsand/or platelets (Zinzani PL, et al. AnnOncol. 2008;19:769-773).

>>>Oral Etoposide Equal to IVDosing in Patients with NHLReceiving CHOP

Etoposide doses of 200 mg/m2

administered orally and 100 mg/m2

administered intravenously are phar-macokinetically equivalent, a findingwhich supports the use of etoposide cap-sules on days 2 and 3 of the CHOP plusetoposide protocol. The pharmacoki-netic equivalency of oral and intra-venous etoposide was examined in 10patients (median age, 56 years) withaggressive lymphomas. Treatment con-sisted of standard CHOP plus etoposide

100 mg/m2 given intravenously on day1, and 200 mg/m2 orally on days 3 and 4.Mean peak plasma level after intra-venous etoposide was significantly high-er compared with oral administration(16.3 vs 12.0 mcg/mL; P = .015). Themean bioavailability of oral etoposidewas 58% with an interpatient variabilityof 26%. Significant differences inbioavailability of oral etoposide were notobserved between the used dose levels(350, 400, and 450 mg). Mean areaunder the curve (AUC) after a 100-mg/m2 intravenous and a 200-mg/m2

oral dose of etoposide were 74.0 and84.9 mcg/h/mL, respectively (P = .481).Interpatient variability in the AUC was25% for the intravenous route and 35%after oral intake. Urinary etoposideexcretion as a percentage of the admin-istered dose was 39.4% after intravenousinfusion and 35.4% after oral intake (P= .422). Renal etoposide clearance wassimilar with intravenous and oraladministration (18.5 and 16.7 mL/min,respectively; P = .546) (Kroschinsky FP,et al. Cancer Chemother Pharmacol.2008;61:785-790).

TRENDSContinued from page 19 Trends in

Lung Cancer


The overall response

rate was 48.6% on an

intention-to-treat

basis.

The survival rate of childrenwith cancer is now nearly 80%.Almost two thirds, however,experience one or more chron-ic health problems. Source:NCI Cancer Bulletin.

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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

©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008

5 – 7 WASHINGTON, DC2008 Breast Cancer Symposiumwww.astro.org

17 – 20SAN FRANCISCO, CA25th National OncologyEconomics Conferencewww.accc-cancer.org

19 – 20 MIAMI, FL9th Annual Perspectives inColorectal Cancerwww.imedex.com

16 – 18MONTREAL, CANADA9th Meeting of the InternationalSociety of Geriatric Oncologywww.cancerworld.org/siog

17 – 18 ARLINGTON,VA

2008 ASTRO TranslationalAdvances in Radiation Oncologyand Cancer Imagingwww.astro.org

4– 8 NEW YORK, NYChemotherapy FoundationSymposium XXVIwww.chemotherapyfoundation.org

13 – 18 CHICAGO, IL2008 Multidisciplinary LungCancer Symposiumwww.oncologymeetings.org

SEPTEMBER 2008

OCTOBER 2008

6 – 9 SAN FRANCISCO, CA50th Annual Meeting andExposition American Society ofHematologywww.hematology.org

7 – 11 ORLANDO, FLAmerican Society of Health-system Pharmacists MidyearClinical Meetingwww.ashp.org

11 – 14 SAN ANTONIO,TXSan Antonio Breast CancerSymposium 2008www.sabcs.org

DECEMBER 2008

Meetings

NOVEMBER 2008

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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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