May 2008 Vol. 1 No. 1

OncologyTheOncologyPharmacist

The

PharmacistThe Official Newspaper of Record for the

Hem/Onc Pharmacist™

© 2008 Green Hill HealthCare Communications LLC

Trends in PharmacyEducationAn interview with Rebecca S. Finley, PharmD, MS,Founding Dean, Jefferson School of Pharmacy, Philadelphia

EDITOR’S LETTERA forum addressing the clinicaland professional concerns ofoncology pharmacists in prac-tice and in training

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NEWTECHNOLOGYAn automated system increas-es the safety of chemotherapypreparation

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MEDICALMINUTES FDA deadlines may compro-mise drug safety

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FDA WATCHSafety First program to monitordrugs after approval

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MAY 2008 • VOL. 1, NO.1 www.theoncologypharmacist.com

THE US FOOD AND DRUG Administration’s (FDA)Oncologic Drugs Advisory Committee (ODAC) on March13, 2008, recommended that the use of erythropoiesis-stimulating agents (ESAs) be substantially limited in thetreatment of anemia in patients with cancer. The com-mittee made the recommendation after hearing addi-tional evidence from a recently published meta-analysisshowing that ESAs increase the risk of blood clots anddeath in patients taking these agents for chemotherapy-induced anemia.

The committee recommended that use of ESAs berestricted to only those cancer patients with advanceddisease and that all patients receiving these drugs berequired to complete a written consent form beforeusing one of these agents. The committee also recom-mended that these drugs not be used in patients withbreast cancer or head and neck cancer. This was thethird ODAC meeting held just to examine safety issues

Further Limits on Use of ESAsin Cancer Patients Expected

Continued on 1

IN RESPONSE TO THE GROWINGneed for pharmacists in the UnitedStates and as part of a new modelof interprofessional education,Thomas Jefferson University (TJU)in Philadelphia has established aSchool of Pharmacy, which willenroll its first class in fall 2008. TheSchool of Pharmacy is part of theJefferson College of HealthProfessions, which also includes aSchool of Health Professions and aSchool of Nursing. In this interview,Rebecca S. Finley, PharmD, MS,founding dean of the School ofPharmacy, discusses the school’sobjectives and curriculum and cur-rent trends in pharmacy education,including the expanding role of

pharmacists in oncology care andother specialized fields.

WHY IS THERE A NEED FOR A NEW SCHOOLOF PHARMACY?

The decision by TJU to open aschool of pharmacy was based onseveral indicators. First, the findingsof the Pharmacy Manpower Project,Inc, published in 2002, showed thatthere would be a shortfall of asmany as 157,000 pharmacists by2020.1 This report indicated that the“aging of Americans, specifically thebaby boomers,” would dramaticallyincrease medication utilization inthe United States. Implementationof the Medicare Part D prescriptiondrug benefit also will increase med-ication utilization and thus thedemand for pharmacists. Secondly, amajor priority of TJU identified inour most recent strategic planninginitiative is to enhance the scopeand effectiveness of interprofession-al education (in response to theInstitute of Medicine Report).2 TJUrecognized that pharmacy wasneeded to complete our compre-

hensive model of interprofessionalhealthcare education. In addition,pharmacy education is in greatdemand in the United States, andinformation provided by theAmerican Association of Colleges ofPharmacy indicated that there aremore qualified applicants thanseats in existing pharmacy schools.3

Finally, the TJU Hospital has a longand distinguished history of excel-lence in pharmacy practice andpharmacy residency training, beingthe oldest accredited residencyprogram in the United States, and itis viewed as a premier institutionto partner with for our academicprogram.

Besides TJU, six other newschools of pharmacy have beengranted precandidate status by theAccreditation Council on PharmacyEducation (ACPE). Precandidate sta-tus denotes a developmental pro-gram (with no currently enrolledstudents), which is expected tomature in accord with stated plansand within a defined time period.

Continued on Page 12

POLICY WATCHApproval of biogenerics seen as one

way to reduce healthcare spending

page 9

CLINICAL TRIALSMultinational trial to compare target-

ed therapies for breast cancer

page 19

RECENT FDAAPPROVALS

New drugs approved for CLL, breastcancer, osteosarcoma

page 19

ANNOUNCING CE CREDIT AT NO CHARGEGreen Hill HealthCare Communications, LLC, ispartnering with the University of NebraskaMedical Center (UNMC) Center for ContinuingEducation and the UNMC College of Nursing,Continuing Education to provide a complimen-tary CE activity in each issue.

page 4

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Nerve

Submucosa

Mucosa

GELCLAIR® CoatingPrescribe 6 boxes of GELCLAIR®

for a 30 day supply

GELCLAIR® provides soothing, long-lasting pain relief1 at the first sign of oral mucositis.

Contains no alcohol and no lidocaine, so patients won’t experience drying, stinging or numbing.

For additional information, visit www.gelclair.com or call 1-877-GELCLAIR.

GELCLAIR® is available at yourlocal pharmacy and at:

Ingredients: Water, Maltodextrin, Propylene Glycol, Polyvinylpyrrolidone (PVP), Sodium Hyaluronate, Potassium Sorbate, Sodium Benzoate, Hydroxyethylcellulose, PEG-40 Hydrogenated Castor Oil, Disodium Edetate,Benzalkonium Chloride, Flavoring, Saccharin Sodium, Glycyrrhetinic Acid. Contents: 15 mL per single-use packet. Commercial boxes contain 15 single-use packets. (NDC 24477-010-15) Indications: GELCLAIR® has amechanical action indicated for the management of pain and relief of pain by adhering to the mucosal surface of the mouth, soothing oral lesions of various etiologies, including oral mucositis/stomatitis (may be causedby chemotherapy or radiation therapy), irritation due to oral surgery, traumatic ulcers caused by braces or ill-fitting dentures, or disease. Also indicated for diffuse aphthous ulcers. Contraindications: The administrationof GELCLAIR® is contraindicated in any patient with a known or suspected hypersensitivity to any of its ingredients. Side effects: At the time of producing this leaflet, no adverse effects have been reported in clinicaltrials with the use of GELCLAIR®. Postmarketing reports have included infrequent complaints of burning sensation in the mouth.

Reference: 1. Innocenti M, Moscatelli G, Lopez S. Efficacy of Gelclair® in reducing pain in patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:455-457.

GELCLAIR® is a registered trademark of Helsinn Healthcare SA, Lugano, Switzerland. Manufactured for Helsinn Healthcare SA, Lugano, Switzerland. Marketed and distributed by EKR Therapeutics, Inc., Cedar Knolls, NJ 07927.

©2008 EKR Therapeutics, Inc. All rights reserved. GEL070

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Now serving patients nationwideToll Free: 877-977-9118

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May 2008 THE ONCOLOGY PHARMACIST 1

Medical Minutes

MANY MEDICATIONS ARE APPROVED by the US Food and DrugAdministration (FDA) on the brink of congressionally mandateddeadlines, and those drugs are more likely to face later regulatoryintervention than those approved with greater deliberation, accord-ing to a new study by Harvard researchers. Drugs fast-tracked by theFDA are more likely to eventually be withdrawn from global marketsfor safety reasons, undergo manufacturing revisions, or face labelingchanges, according to the study published in the March 27, 2008issue of the New England Journal of Medicine (N Engl J Med. 2008;358:1354-1361.)

“We found that while these deadlines speed up the approvalprocess, many drugs are approved right up against the deadline,which might lead to unintended consequences with regard to drugsafety,” said Daniel Carpenter, PhD, who is a professor of governmentat Harvard’s Faculty of Arts and Sciences. “This suggests that drugsafety might improve under an FDA approval protocol that is moreflexible and less driven by deadline pressures and more by stablegrowth in FDA resources.”

The deadlines imposed on the FDA’s drug-approval process werefirst enacted as part of the Prescription Drug User Fee Act (PDUFA) of1992, which mandated that the FDA must act on 90% of all drug can-didates within 12 months of submission or face funding cuts. Thetimeline was tightened to 10 months as part of the 1997 FDAModernization Act, a timeline extended by Congress in 2002 as partof the bioterrorism legislation and renewed again in 2007.

Some observers have suggested that these deadlines lead to therushed approval of medications, a theory Dr Carpenter tested byexamining data on the timing of FDA approvals dating back to 1950.He found that the enactment of PDUFA in 1992 appeared to intro-duce a temporal discontinuity into FDA review cycles, with dispro-portionate approvals coming in the 2 months immediately beforedeadlines. Compared with drugs approved at a more measured pacein the months after the deadline, those approved right before thereview clock expired were far more likely to require later regulatoryintervention.

“Drugs rushed to approval just before the deadline are two to threetimes more likely to eventually be pulled off shelves due to safetyconcerns, two to seven times more likely to receive added labelwarnings known as ‘black box revisions,’ twice as likely to experi-ence changes in manufacture, and two to seven times more likely tobe voluntarily discontinued by manufacturers due to weak clinicaldemand,” said Dr Carpenter.

Tamoxifen May Help Treat Mania in Bipolar DisorderPatients

A small, 3-week trial of tamoxifen may decrease symptoms ofmania in patients with bipolar disorder, according to a new studyby researchers in Turkey. Tamoxifen interferes with the effects ofthe hormone estrogen, which accounts for its effects against breastcancer. However, tamoxifen also inhibits the actions of a family ofenzymes known as protein kinase C. Abnormal levels of activity bythese enzymes have been associated with bipolar disorder andrelated dysfunctions, such as distractibility, impaired judgments,and disorganized thoughts.

Researchers at the Dokuz Eylul University Medical School inIzmir, Turkey, conducted a clinical trial with 66 patients age 18 to 60years, all of whom were diagnosed with bipolar disorder and werecurrently in a manic state or a mixed state that included mania.

Participants were randomly assigned to take tamoxifen (40 mg to80 mg per day) or placebo for up to 3 weeks. Participants in bothgroups also were given up to 5 mg per day of lorazepam as neededto control their symptoms.

A total of 50 patients (29 assigned to tamoxifen and 21 assignedto placebo) completed the 21-day trial. The researchers found thatthe tamoxifen group had significantly lower scores on tests used tomeasure the severity of mania at the end of the 3-week period,while those in the placebo group had scores that slightly increased.In addition, 48% of patients in the tamoxifen group responded tothe drug (defined as a reduction of at least half in mania scores)compared with 5% of those taking placebo, and 28% (tamoxifengroup) versus 0% achieved cutoff scores for mania remission.

The researchers also found that patients taking tamoxifen usedless lorazepam during the study: an average of 25.2 mg comparedwith 41.8 mg (placebo group). Moreover, all the patients used lesslorazepam as the trial progressed and the rate of decrease was 2.5times greater with tamoxifen-treated patients. Both tamoxifen andplacebo were well tolerated. The findings from this study have beenpublished in the Archives of General Psychiatry (Arch Gen Psychiatry.2008;65:255-263).

New Study Suggests Some Cancer Trials May HaveIncorrectly Reported Success

A new study reviewing 75 group-randomized cancer trials over a 5-year stretch showed that fewer than half of those studies usedappropriate statistical methods to analyze the results. The reviewsuggests that some trials may have reported that interventions toprevent disease or reduce cancer risks were effective when, in fact,they might not have been.

More than a third of the trials contained statistical analyses thatthe reviewers considered inappropriate to assess the effects of anintervention being studied. The review authors also found that 88%of those studies reported statistically significant interventioneffects that, because of analysis flaws, could be misleading to sci-entists and policymakers.

“We cannot say any specific studies are wrong. We can say thatthe analysis used in many of the papers suggests that some ofthem probably were overstating the significance of their findings,”said lead author of the review study David Murray, who is professorand chair of epidemiology in the College of Public Health at OhioState University, Columbus. “If researchers use the wrong meth-ods, and claim an approach was effective, other people will startusing that approach. If it really wasn’t effective, then they’re wast-ing time, money, and resources and going down a path that theyshouldn’t be going down.”

Dr Murray and his colleagues call for investigators to collaboratewith statisticians familiar with group-randomized study methodsand for funding agencies and journal editors to ensure that suchstudies show evidence of proper design planning and data analysis.

In group-randomized trials, researchers randomly assign identi-fiable groups to specific conditions and observe outcomes formembers of those groups to assess the effects of an interventionunder study. In analyzing the outcomes of such trials, researchersshould take into account any similarities among group members orany common influences affecting the members of the same group,explained Dr Murray. But too often, this review found that the com-mon ground among group members was not factored into the finalstatistical analysis.

“In science, generally we allow for being wrong 5% of the time. Ifyou use the wrong analysis methods with this kind of study, youmight be wrong half the time. We’re not going to advance scienceif we’re wrong half the time,” said Dr Murray, who is also a memberof the Cancer Control Program in Ohio State’s ComprehensiveCancer Center.

Medical Minutes

BY JOHN SCHIESZER

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

Study Finds FDA DeadlinesMay Compromise Drug Safetyby Rushing Approval

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Feature Articles5 Genitourinary Cancers

New agent shows promise for advanced prostate cancer

8 New TechnologyEnsuring safe chemotherapy preparation

13 GastrointestinalCancersSignificance of flat or depressed colorectal lesions debated

16 FDA WatchSafety First program to monitor drug safety after approval

17 Gynecologic CancersMaximizing adherence to aromatase

inhibitors

Departments

1 Medical Minutes

6 Trends in Prostate Cancer

9 Policy Watch

11 Trends in Hematologic Cancer

15 Trends in Colorectal Cancer

Trends in Lung Cancer

18 Trends in Breast Cancer

19 Clinical Trials Update

Recent FDA Approvals

20 Meetings

PUBLISHING STAFFPublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Senior Production ManagerStephanie Laudien

Client Service ManagersJohn W. [email protected]

Russell [email protected]

Director of Human ResourcesBlanche [email protected]

[email protected]

241 Forsgate Drive, Suite 205CJamesburg, NJ 08831

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

David Baribeault, RPh, BCOPBoston Medical CenterBoston, MA

Sylvia Bartel, RPh, MPHDana Farber Cancer InstituteBoston, MA

Marlo Blazer, RPh, PharmDOhio State Comprehensive Cancer CenterJames Cancer Hospital and Solove Research InstituteColumbus, OH

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

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

Christopher Fausel, PharmDIndiana University 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 Regional Cancer CenterGreensboro, NC

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

Cindy Ippoliti, PharmD New York Presbyterian Hospital/ Weill Cornell MedicalSchoolNew York, NY

Jim Koeller, MSUniversity of Texas at AustinSan Antonio,TX

Helen L. Leather, BPharmUniversity of FloridaGainesville, FL

Christopher J. Lowe, PharmDCleveland Clinic Taussig Cancer CenterCleveland, OH

Robert B. MacArthur, PharmDColumbia University Medical CenterNew York, NY

Emily Mackler, PharmD, BCOPUniversity of Michigan Ann Arbor, MI

Patrick Medina, PharmD, BCOPUniversity of Oklahoma College of PharmacyTulsa, OK

Laura Boehnke Michaud, PharmD, BCOP,FASHPThe 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

Keith M. Olsen, PharmD, FCCP, FCCMUniversity of Nebraska College of PharmacyOmaha, NE

Debra L. Phillips, PharmDEast Carolina UniversityGreenville, NC

John M.Valgus, PharmD, BCOPUniversity of North CarolinaChapel Hill, NC

EDITORIAL BOARD

Vol. 1, No. 1 May 2008

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

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Our vision extends beyond science

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

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

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

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

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

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

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

© 2008 Genentech, Inc. All rights reserved. 8111602

www.BioOncology.com



Editor’s Letter

IN THE LITTLE MORE THAN A DECADE since the first certificationexamination in oncology pharmacy was given, the field has seenmany changes. Increasingly, pharmacists are called on to play a vari-ety of roles not only in the hospital setting but in community prac-tices as well. A major change has been the trend toward increasinguse of oral chemotherapies, which puts greater responsibility on thepatient to take the medication properly. Changes in reimbursementunder the Medicare Modernization Act of 2003 too have had a majorimpact on practice of oncology pharmacy.

As part of the cancer care team, oncology pharmacists haveresponsibilities for ordering and dispensing drugs, advising patientsand caregivers on proper drug handling and administration, andmaking recommendations about side effect management and avoid-ance of drug interactions. It is critical, therefore, for oncology phar-macists to be informed about new therapies and to keep up withresults of clinical trials reported at medical meetings and in themedical literature. But they also have financial and administrativeresponsibilities and must be familiar with the latest federal and stateregulatory policies and insurance coding and reimbursement issues,such as coverage for off-label drug use by Medicare and private

insurers. In addition to ensuring adequate reimbursement for thehospital or clinic, oncology pharmacists also must advise patientsabout Medicare and Medicaid policies, private insurance coverage,and patient assistance programs.

The Oncology Pharmacist, the only newspaper written specificallyfor members of this expanding specialty, will address not only theclinical issues relevant to the practice of oncology but also practicemanagement, professional education and training, and financial andregulatory issues. To help busy pharmacists meet their continuingeducation needs, The Oncology Pharmacist has entered into a partner-ship with the Center for Continuing Education at the University ofNebraska Medical Center, and, starting with the next issue, will pro-vide an article offering ACPE credit in each issue.

Perhaps most important, The Oncology Pharmacist will be an interac-tive forum for oncology pharmacists in practice and in training to dis-cuss the issues—clinical and professional—of greatest concern tothem. We invite your comments, suggestions, and contributions abouttopics, people, and programs you would like to read about and discusswith your colleagues. Please write to us at [email protected] tell us what you would like to see in upcoming issues.

Introducing The Oncology Pharmacist

SUSAN GOODIN,PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

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EREDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive, Suite 205C, Jamesburg, 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 indi-vidual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journalshould be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. The ideasand opinions expressed in The Oncology Pharmacist™, do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or otherproduct mention in The Oncology Pharmacist™, should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturerwith questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to personsor property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information cur-rently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treat-ing physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every efforthas been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the EditorialDirector. ISSN #Applied for in April 2008.

The Oncology Pharmacist™, is published 5 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. Telephone:732.992.1899. Fax: 732.656.7938. Copyright ©2008 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist™ logo is a trademark of GreenHill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechan-ical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

TO HELP MEET THE CONTINUING EDUCATION needs of busy practi-tioners, Green Hill HealthCare Communications, LLC, publisher of TheOncology Nurse and The Oncology Pharmacist, is partnering with theUniversity of Nebraska Medical Center (UNMC), Center for ContinuingEducation and the UNMC College of Nursing Continuing NursingEducation to provide a complimentary continuing education activityin each issue, starting in the June 2008 issue. Accredited articles willprovide a concise review of a recent article in the peer-reviewed liter-ature or a report on a presentation at a major medical meeting,accompanied by a case report illustrating the key clinical points andcommentaries by an oncology nurse and an oncology pharmacist onhow the findings may apply to oncology practice.

The UNMC College of Nursing Continuing Nursing Education isaccredited as a provider of continuing nursing education by theAmerican Nurses Credentialing Center’s (ANCC) Commission onAccreditation. Additionally, the nursing activities will be providedunder Iowa Provider #78. Provider also approved by the CaliforniaBoard of Registered Nursing, Provider #13699.

The UNMC, Center for Continuing Education is accredited by the

Accreditation Council for Pharmacy Education (ACPE) as a provider ofcontinuing pharmacy education.

The editorial boards of The Oncology Nurse and The Oncology Pharmacistwill review the medical literature and presentations at major medicalmeetings to identify topics of interest to both oncology nurses andoncology pharmacists.Articles will be reviewed by the UNMC, Center forContinuing Education and the UNMC College of Nursing ContinuingNursing Education for medical accuracy and balance and to ensure thatthey meet criteria for continuing education materials set by the ANCC,the Iowa Board of Nursing, the California Board of Registered Nursing,and the ACPE. Readers will be able to complete the post-test and receivecredit online.

Upcoming issues will feature an article on identifying patients at riskfor anaphylaxis associated with EGFR inhibitor therapy and one on dos-ing considerations when administering cancer drugs to obese patients.We invite your suggestions about topics of greatest concern to you andyour colleagues as well as feedback on how well we are meeting youreducational needs. Please write to us at [email protected] andlet us know what you would like to see in future issues.

Green Hill HealthCare Communications toPartner with University of Nebraska MedicalCenter for Complimentary ContinuingEducation for Healthcare Professionals



Genitourinary Cancers

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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

leuprolide. Degarelix was welltolerated with no serious sideeffects that were deemed treat-ment-related.

“We need treatments that bet-ter mimic surgical castration butwithout the devastating seque-lae, and degarelix has a nearly

immediate effect on testos-terone levels on a par with thatof surgery,” John Anderson, MD,consultant urologic surgeon,

Royal Hallamshire Hospital inSheffield, UK, said at a news conference.

—Jill Stein

MILAN—New findings demonstratethat the investigational gonadotropin-releasing hormone (GnRH) blockerdegarelix is not only as effective asstandard androgen deprivation thera-py (ADT) involving the GnRH agonistleuprolide in patients with prostatecancer but also accelerates testos-terone suppression.

Data are from a phase 3 trial pre-sented at the 23rd Annual Meeting ofthe European Association of Urology.

Laurento Boccon-Gibod, MD,professor of urology at CHUHopital Bichat-Claude Bernard inParis, presented results in 610 menwho received one of two doses ofsubcutaneous degarelix (80 or 160mg monthly) or leuprolide depot,7.5 mg monthly, over 12 months.

The trial enrolled men with his-tologically confirmed adenocarci-noma of the prostate (of any stage)for which androgen ablation wasindicated. Men who requiredneoadjuvant hormonal therapywere ineligible.

“GnRH agonists are the mainstayof ADT for prostate cancer; howev-er, important limitations include adelayed effect on testosterone andprostate-specific antigen (PSA)along with a testosterone surge andpossible symptoms of flare,” DrBoccon-Gibod pointed out.

In the trial, suppression oftestosterone to 0.5 ng/mL at allmonthly measurements from day28 to day 364 was considered atreatment response. The study wasdesigned to demonstrate statisti-cal noninferiority of degarelix ver-sus leuprolide 7.5 mg for treat-ment response.

Results showed that both dosesof degarelix were at least as effec-tive as leuprolide in terms ofresponse to treatment. Suppressionof testosterone levels to 0.5 ng/mLoccurred significantly faster inpatients receiving degarelix than inthose receiving leuprolide. By day 3,97% and 96% of degarelix-treatedpatients (160 mg and 80 mg, respec-tively) and 0% of those receivingleuprolide demonstrated a treat-ment response.

The GnRH blocker did not cause atestosterone surge or microsurge andwas associated with a more rapidreduction in PSA levels than leupro-lide. After 14 days of treatment,median PSA levels had declined by65% and 64% in patients receivingdegarelix (160 and 80 mg, respective-ly) and 18% in patients receiving

New GnRH Blocker is Effective in AdvancedProstate Cancer



Trends in Prostate Cancer

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

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extension if present. After a meanfollow-up of 43 months, fourpatients developed metastases.Significant predictors of the devel-opment of metastases on univari-ate analysis were baseline serumprostate-specific antigen level,presence of extracapsular exten-sion at MR imaging, and degree ofextracapsular extension. The soleindependent predictive variable onmultivariate analysis was meandiameter of extracapsular exten-sion (relative hazard ratio, 2.06; P = .007). Of five patients with extra-capsular extension of more than 5mm at pretreatment MR imaging,three developed metastases at 24 to63 months after therapy. (McKennaDA, et al. Radiology. 2008; 247:141-146.)

Prostate Cancer Patients PickTreatments That May WorsenQuality of Life

Patients with prostate cancer andpreexisting dysfunction often selectrelatively contraindicated or mis-matched treatments associated withworsening of symptoms and pooreroutcomes, according to researchersat Massachusetts General Hospital.

Prostate cancer treatment choiceswere examined in 438 patients withprostate cancer, of whom 389 (89%)reported preexisting dysfunction.Preexisting obstructive uropathy andbowel dysfunction were consideredrelative contraindications tobrachytherapy (BT) and external-beam radiation therapy (EBRT),respectively, because they increasepatients’ vulnerability to treatment-related toxicity. Baseline sexual dys-function was considered to negatethe intended benefit of nerve-spar-ing radical prostatectomy (NSRP),which is to preserve sexual function.Overall, more than one third of thepatients received mismatched treat-ments. Treatment mismatches didnot significantly increase with clini-cal complexity. The strategy ofwatchful waiting was used infre-quently, even in patients with con-traindications to all treatmentoptions. Treatment choices wereassociated with patient age andcomorbidities but not preexistingdysfunction. Mismatched BT andEBRT led to worsened urinary andbowel symptoms, respectively, andNSRP did not improve outcomes inpatients with baseline sexual dys-function. (Chen RC, et al. Cancer.2008;112:61-68).

MR Imaging Helps Predict ProstateCancer Recurrence

Pretreatment endorectal magneticresonance (MR) imaging findings areimportant predictors of posttreatmentmetastatic recurrence in patientsundergoing external-beam radiation

therapy for prostate cancer. The findingis based on a retrospective study of 80men (mean age, 59 years) with biopsy-proved prostate cancer who underwentendorectal MR imaging of the prostateprior to external-beam radiation thera-py. All MR imaging studies were inde-

pendently reviewed by two experiencedreaders who recorded tumor T stage andthe radial diameter of extracapsular

Overall, more than one third of the patientsreceived mismatched treatments.

Trends in Prostate Cancer



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LAS VEGAS—At the award presentation at the 42nd Midyear ClinicalMeeting of the American Society of Health-System Pharmacists inLas Vegas, University of Kansas pharmacy administrators describedan innovative method for increasing the safety of chemotherapypreparation.

Many academic medical center pharmacies—including the inpa-tient pharmacy at the University of Kansas Hospital—use the syringepullback method for checking chemotherapy preparations. In theisolated chemotherapy preparation room, a pharmacy technicianfills the syringe with medication and injects it into an intravenous(IV) solution bag. The pharmacist then checks the plunger of anempty syringe to determine the volume of medication added to anadmixture. With this method a pharmacist typically does not checkthe volume of the syringe prior to injection into the IV solution bag.“There has to be a lot of trust between the pharmacist and techni-cian that the syringe was pulled back accurately,” said Brian O’Neal,MS, PharmD, assistant pharmacy director at the University of KansasHospital, in Kansas City. “There just shouldn’t be assumptions inchemotherapy preparation,” he added.

To reduce the risks associated with the syringe pullback method,Dr O’Neal and his colleagues instituted use of Telepharmacy forSterile Room Med preparation hardware and software to take digitalphotographs during the chemotherapy preparation process. Thesephotographs, taken at critical risk points in chemotherapy prepara-tion, along with the patient’s medication order can be reviewedremotely by pharmacists. Additional goals of the project were toimprove the readability of chemotherapy-vial labels and to reducethe risk of selecting the wrong chemotherapeutic medicationthrough the use of barcode technology. “The objective of the pro-gram,” Dr O’Neal explained, “was to find a way to improve safety byincreasing the presence of the pharmacist at critical risk points dur-ing the preparation process, while making the most efficient use ofthe limited availability of clinical pharmacists.”

With the assistance of an automation vendor (ScriptPro; Mission),a telepharmacy inspection camera designed to take digital picturesat various stages of the chemotherapy preparation process in a bio-

logical safety cabinet was placed in the clean room. First, a techni-cian scans the barcode on the vial. A computer match to the patient’srecord ensures that the correct formulation has been selected. Thetechnician then takes photos of the work label, the vials and fluidsto be used, and, lastly, the syringe (before injection into the bag). Apharmacist views these photos from a “check station” in the anteroom when verifying the finished product. Confirmation of thereview steps and related images are archived as part of the electron-ic record and are available for future reference.

After 1 month, this process demonstrated safety improvements infour main areas:

• Verifying chemotherapy products with barcode technologyhelped to ensure that the correct drug was selected.

• Inspecting photographs of the syringe before it was injected into thebag of fluid increased the likelihood of detecting technicians’ errors.

• Digitally enlarging the small font on chemotherapy vials helpedpharmacists to accurately check the finished product.

• Disposing contaminated syringes and vials in thechemotherapy preparation area reduced the riskof contaminating other areas of the clean room.

This use of telepharmacy and barcode technologyresulted in a pharmacist’s intervention in 1.1% (fourof 363) of prepared doses during the data collectionperiod (July 1 through July 31, 2007). An interventionwas defined as a pharmacist’s request to increasevolume, decrease volume, or to remake the product.

“The improvements in safety and accountability ledus to discontinue use of the syringe pullback methodfor checking chemotherapy,” Dr O’Neal said. “Withoutinterrupting workflow, a pharmacist can now observethe riskiest steps of chemotherapy preparation, thusincreasing the odds of detecting errors. Our com-pounding error rate is no longer unknown andunidentifiable. By documenting and reviewing more ofthe steps in the chemotherapy preparation processwith telepharmacy and barcode technology, we havesignificantly increased our chances of catching errorsbefore they leave the pharmacy.”

More information about the ScriptPro Tele-pharmacy for Sterile Room Med Preparation andother technology for pharmacies, can be found atwww.scriptpro.com.

Automated System Increases Safety of Chemotherapy Preparation

Screen shot combines inspection images of syringe, fluid bag, medication vial, andprescription label.

Pharmacy technician is capturing images using an inspection camerainside the biological safety cabinet.



Policy Watch

MEMBERS OF CONGRESS, THE BUSH ADMINISTRATION, and privatepayers are calling for legislation that would allow approval of genericbiologics, or biogenerics, as one way to reduce spending on specialtypharmaceuticals for cancer and other conditions. According to areport in The Wall Street Journal (March 20, 2008), employers, healthinsurers, and pharmacy benefit managers are exploring novel ways tocontain spending, including approval of biogenerics, because special-ty drugs are a major factor in escalating healthcare costs. Other meas-ures being considered are tighter enforcement of step-therapy poli-cies, restrictions on off-label drug use, and a “pay-for-performance”strategy in which the price of a drug depends on its efficacy.

Specialty drugs account for about 60% of new medications submittedfor US Food and Drug Administration (FDA) approval, and The New YorkTimes (April 19, 2008) reports that spending on these drugs increased16.5% in 2006, totaling about $62 billion, or about 23% of overall drugsales in the United States that year.

Bills that could lead to an approval pathway for biogenerics havebeen introduced in both the House and Senate but there is controver-sy about the details. According to the American Society of ClinicalOncology (www.asco.org), “One of the main points of contention inthese legislative proposals is the degree to which biogenerics can besubstituted for the brand name product (so-called interchangeability).”A bill introduced in the Senate last year (S. 1695) includes basic datarequirements needed to categorize a biogeneric as a “biosimilar” prod-uct, whereas the House bill (H.R. 1038) contains fewer data require-ments and allows the FDA greater leeway in determining whether abiogeneric is “comparable” to the brand product. Provisions of bothbills would allow substitution of the biosimilar or comparable productwithout approval of the healthcare professional who prescribed it ifthe manufacturer has provided evidence that the biosimilar productcan be expected to produce the same clinical result as the brand prod-uct in any given patient.

Report Cites Progress and Challenges in ImprovingState Pain Policies

Both cancer patients and survivors commonly experience pain that,if unrelieved, can adversely affect their functioning, productivity, andeven their will to live. “Increasingly, unrelieved pain is becoming rec-ognized as a significant public health problem in the United States,”according to a recent report by Aaron M. Gilman, PhD, and other mem-bers of the Pain & Policy Studies Group (PPSG) (CA Cancer J Clin.2007;57:341-353). Among the factors contributing to inadequate painmanagement are healthcare practitioners’ concerns about regulatoryscrutiny and restrictive drug control and healthcare policies governingmedical use of prescription drugs.

The PPSG established a research program to evaluate US federal andstate policies on medical use of pain medication using a methodologybased on the principle of Balance. The group’s latest report, whichdescribes the results of three national policy evaluations, shows “there

has been substantial progresssince the policy-evaluation processbegan in 2000,” the authors state, “butthere is much more opportunity forimprovement.” They say it is crucial forhealthcare practitioners to be familiarwith their state’s pain policies and offersuggestions for the role they can play inimproving these policies. “Positive policychange is a crucial first step….but withno implementation has little practi-cal value,” they write. “Policiesmust be put into prac-tice through advocacyand education.”

MassachusettsProposal to LimitDrug Reps Gifts StirsControversy

A bill being drafted byMassachusetts legislatorswould prohibit physiciansfrom accepting even token gifts, such as apen or a slice of pizza, from drug manufac-turers. Doctors who accepted such a giftcould have to pay up to $5,000 in finesand serve up to 2 years in prison. Theproposed legislation has generatedheated discussion by supportersand opponents of the bill, as shown byresponses posted on The Wall Street Journal’s Health Blog (http://blogs.wsj.com/health/2008/04/17/bring-on-the-drug-reps/?mod=WSJBlog?mod=WS...). Some argue that the company sales represen-tatives do provide some useful information, especially about newdrugs. Others, though skeptical about the information drug repre-sentatives provide say they want to decide for themselves whetheror not to see them, without government interference. In an April 17,2008 editorial in The Boston Herald (www.bostonherald.com/news/opinion/op_ed/view.bg?articleid=1087609), Drs Dennis Ausiello andThomas Stossel write, “We believe the best approach to optimize costeffectiveness of product prescribing is to promote more, not less,interaction among all stakeholders involved in health-care delivery,including company marketing reps.”

Survey Shows Physicians Increasingly FavorNational Health Insurance

Results of a nationwide survey indicate that the majority of USphysicians now support the concept of national health insurance(Ann Intern Med. 2008;148:566-567). Of 2,193 physicians whoresponded to the survey, 59% expressed support for legislation toestablish a national health insurance program, whereas 32%opposed it, and 9% had no opinion. The number in favor of nation-al health insurance represents a 10% increase compared with asimilar poll conducted in 2002, in which only 49% of respondentsendorsed such a plan. Fifty-five percent of respondents favored anincremental approach to achieving universal coverage, whereas25% opposed incremental reform. Another 14% favored incremen-tal reform but were opposed to national health insurance. TheAmerican Medical Association is against government-run nation-al health insurance and instead proposes expanding coveragethrough tax credits.

Policy Watch

Legislators, Payers SupportApproval of Biogenerics

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Employers, health insurers, and pharmacybenefit managers are exploring novelways to contain spending, includingapproval of biogenerics


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with ESAs, and it now appears even further restrictionswill soon be placed on the use of ESAs in patients withcancer.

There are currently three FDA-approved ESAs on themarket in the United States: epoetin alfa (Procrit), epo-etin alfa (Epogen), and darepoetin alfa (Aranesp). TheFDA revised label warnings on ESAs in 1997, 2004, 2005,and 2007 to reflect new safety information.

“There are now eight trials in which patients withcancer who received ESAs have shorter survival and/orpoorer tumor control than patients receiving similaranticancer treatments but no ESAs. The committeeadvised the FDA that product labeling be revised,” FDAspokeswoman Crystal Rice said in an interview. “Inaddition, ODAC recommended that patients should nottake ESAs until their hemoglobin level falls below 10 g/dL.The FDA is considering the advice of the ODACin planning the next steps.”

Taken together, all eight studies showed more rapidtumor growth or shortened survival when patientswith breast, non–small-cell lung, head and neck, lym-phoid, or cervical cancers received ESAs comparedwith patients who did not receive ESAs. In all theserecent studies, ESAs were administered in an attemptto achieve a hemoglobin level of 12 g/dL or greater,although many patients did not reach that level.

ESAs are a bioengineered version of a natural proteinmade in the kidneys that stimulates the bone marrowto produce more red blood cells. FDA-approved uses ofESAs are for the treatment of anemia in patient withchronic kidney failure and for cancer patients whoseanemia is caused by chemotherapy. ESAs are alsoapproved for patients infected with HIV whose anemia

is caused by the HIV drug zidovudine. ESAs are alsoapproved to reduce the number of transfusions duringand after major surgery.

On November 30, 2007, Amgen, the manufacturer ofthe three ESAs, provided the FDA with informationfrom the 733-patient PREPARE study of women whoreceived chemotherapy before undergoing surgery forbreast cancer. After 3 years, 14% of the patients whoreceived darepoetin alfa to treat their anemia had diedcompared with 9.8% of those who did not receive thedrug. Tumor growth was also faster in patients receiv-ing the ESA.

Charles L. Bennett, MD, PHD, and his colleagues con-ducted a phase 3 trial to examine the rate of venousthromboembolism (VTE) and death associated withESA administration for the treatment of anemia in can-cer patients (JAMA. 2008;299:914-924). The findingsindicated that the risk of death was significantly high-er for cancer patients who were treated with an ESAcompared with the placebo group. The researchersidentified 51 clinical trials involving 13,611 patientsand compared survival rates. VTE was evaluated in 38trials that included 8,172 patients. The researchersfound that there was a significantly increased risk(57%) of VTE among patients receiving ESAs comparedwith those who received placebo.

“The basic science and clinical data raise a real con-cern.We are far from confirmed about what is happen-ing here, but it appears the patients will now have todecide if they want to take the risks,” said Dr Bennett,in an interview. “The data show a 10% increase in mor-tality in patients on ESAs, so there are quantity of lifeand quality of life issues involved.”

Dr Bennett, who is professor of geriatrics and eco-nomics at the Northwestern University Feinberg Schoolof Medicine, Chicago, Ill, said it is important for clini-

cians to be fully aware of what basic science and clini-cal data show in regard to the use of ESAs. He said thedata do not support the idea that these agents improvequality or quantity of life.

But not everyone agrees. Some clinicians and phar-macists are concerned that further restrictions on theuse of ESAs may greatly impact the care of many can-cer patients and put prescribing physicians in a diffi-cult position.

“If you are going to restrict a drug, what becomes theclinicians’ alternative for treatment? The alternativefor clinicians is a blood transfusion, and blood transfu-sions are not without their problems related to risk,toxicity, cost, inconvenience, and just accessibility,”said Byron Peters, RPh, director of the WashingtonUniversity Cancer Center Pharmacy, St. Louis, Mo. “Ourblood supply in this country is not good.We have a warin Iraq, and we have many shortages in parts of thecountry every day. There are consequences for everyaction,” he continued. “These patients are still going toneed to be treated, and we may have to go back toblood transfusions. The ESAs are more long-lastingwhereas transfusions are short-lived.”

Mr Peters also questions the validity of the latestreview studies because they include data from whenprescribing practices were much different than theyare today. “There are a lot of data that are not pertinentto today’s practice, but they are still being considered inthe FDA’s ultimate decision on these drugs,” he said “Inthe meta-analysis studies, they were using it at muchhigher stopping points, and that is not standard ofpractice today. They were treated at significantly high-er hemoglobin levels and, clearly, the higher you go, thehigher the risk for problems.”

—John Schieszer

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SHemotologic TrendsTrends in Hematologic Cancer Fused PET/CT Imaging Useful in DeterminingResponse to Radiotherapy in B-cell NHLA NEW STUDY SUGGESTS THAT USE of combinedfusion fluorine 18 fluorodeoxyglucose (FDG) positronemission tomographic (PET)/computed tomographic(CT) imaging is superior to CT imaging alone in theevaluation of yttrium 90 (90Y)–ibritumomab tiuxetanradioimmunotherapy treatment of B-cell non-Hodgkin’s lymphoma (NHL). A group of 10 patients(mean age, 52 years) with relapsed or refractory NHLunderwent FDG PET/CT imaging both 14 to 27 daysbefore treatment with 90Y–ibritumomab tiuxetan and4 to 6 months after treatment. Interpretation of CTimages alone resulted in classification of eightpatients as responders to treatment, of whom twowere classified as having a complete response. At re-evaluation with fused PET/CT imaging, two patientshad residual lesions at CT that did not show evi-dence of FDG avidity. Both of these patients wereclassified as partial responders according to CT cri-teria alone and reclassified as complete respondersat PET/CT. Both of these patients were free of evidentdisease after ≥18 months of follow-up. Theresearchers concluded that the use of CT imagingalone may underestimate 90Y–ibritumomab tiuxetanresponses by classifying inactive residual CT massesas residual disease. Combined PET/CT scanning

could help avoid unnecessary follow-up treatments.(Ulaner GA, et al. Radiology. 2008;246:895-902.)

SGX393 Inhibits CML Mutant Clone andHelps Preempt Emergence of Resistance

SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl, a deregulated tyrosine kinase thatcauses chronic myeloid leukemia (CML). Bcr-AblT315I

is resistant to Abl kinase inhibitors in current useand is emerging as the most frequent cause of sal-vage therapy failure in patients with CML. In pre-clinical studies, SGX393 blocked the growth ofleukemia cell lines and primary hematopoieticcells expressing Bcr-AblT315I, with minimal toxicityagainst Bcr-Abl–negative cell lines or normal bonemarrow. Screening for Bcr-Abl mutants emergingin the presence of SGX393 revealed a concentra-tion-dependent reduction in the number and rangeof mutations. Combining SGX393 with nilotinib ordasatinib preempted the emergence of resistantBcr-Abl subclones, including Bcr-AblT315I. Thesefindings suggest that treatment with the combina-tion of SGX393 and currently available Abl kinaseinhibitors may be a useful strategy for inhibitingthe emergence of Bcr-Abl mutants in patients withPhiladelphia chromosome-positive CML. (O’Hare T,et al. Proc Natl Acad Sci. 2008;105:5507-5512.)

Chemotherapy Plus RadioimmunotherapyEffective in Untreated Follicular NHL

The combination of fludarabine and mitoxantroneplus yttrium-90 (90Y)-labelled ibritumomab tiuxetan iseffective and tolerable in previously untreated patientswith follicular non-Hodgkin’s lymphoma (NHL). In anonrandomized, open-label, phase 2 study, 61 patientswith stage III or IV untreated indolent follicular NHLreceived oral fludarabine and intravenous mitox-antrone every 28 days for six cycles. Patients who hadat least a partial response (PR) without significanthematologic toxicity at 4 to 6 weeks after completionof the sixth cycle of chemotherapy received one courseof 90Y-labelled ibritumomab tiuxetan. Of the 61patients who received six cycles of fludarabine andmitoxantrone, 43 had a complete response (CR) and 17had a PR. A total of 57 patients (43 with CR and 14 withPR) were deemed eligible for subsequent 90Y-labelledibritumomab tiuxetan. Of the 14 patients who had PRafter the initial treatment, 12 achieved CR after 90Y-labelled ibritumomab tiuxetan. By the end of theentire treatment regimen, 55 of 57 patients achievedCR. Three-year progression-free survival was 76% and3-year overall survival was 100%. Of the 57 patientswho completed therapy, 36 had grade 3 or 4 hemato-logic side effects, and 21 received blood transfusions.(Zinzani PL, et al. Lancet Oncol. 2008;9:352-358.)

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This designation authorizes the new school to enroll their first class.In addition, 10 other new schools have advanced candidate status,which means that they have enrolled students but have not yet grad-uated their first class. New schools are not eligible for full accredita-tion status until they have graduated their first class.

HOW MIGHT THE JEFFERSON PROGRAM DIFFER FROM THOSE OF EXISTING PHARMA-CY SCHOOLS? ARE THERE ANY INNOVATIVE FEATURES IN YOUR CURRICULUM?

As mentioned above, a key objective of the TJU School ofPharmacy is to ensure that our students are prepared to practiceeffectively in interprofessional groups as well as to solve prob-lems independently. We are building opportunities throughoutthe curriculum for students to work with the Jefferson nursing,medical, and health professions (physical therapy, occupationaltherapy, etc) students in a variety of academic and communityoutreach initiatives. A major goal of our program is to prepare ourgraduates for leadership roles, so we will focus on optimizingtheir leadership skills, effectiveness in teams, and their ability tointegrate emerging healthcare issues into contemporary pharma-cy practice. Throughout the professional curriculum, studentswill have the opportunity to enhance their communication, criti-cal thinking, and collaborative skills along with understandingand, most important, applying the biomedical, pharmaceutical,social/behavioral, administrative, and clinical sciences.

HOW HAS PHARMACY TRAINING CHANGED IN THE PAST 10 YEARS?The most important change in pharmacy education over the past

10 years was that beginning in 2000, the only degree recognized tolead to professional practice as a pharmacist is the Doctor ofPharmacy (PharmD) degree, which typically requires 6 academicyears (2 years prepharmacy courses followed by 4 years of profes-sional pharmacy coursework). Before 2000, both a 5-year Bachelor ofScience and the PharmD degree were available. With this changecame an increased focus on patient care-related (ie, clinical) training,which prepares pharmacists to take an active role in making med-ication-related decisions. All pharmacists are now trained to makeevidence-based decisions regarding medication therapy for individ-ual patients as well as population-based decisions (such as thedevelopment of clinical practice guidelines). The newest ACPEaccreditation standards, which were implemented on July 1, 2007,provide for more experiential education throughout the entire cur-riculum, so that students will interact with practicing pharmacists,other healthcare professionals, and patients throughout the fourprofessional years of the PharmD program. These new standardsnow hold schools far more accountable than before to demonstratethat they are achieving their stated objectives.

IS THERE MORE INTEREST IN SPECIALIZING IN SPECIFIC FIELDS LIKE ONCOLOGY THAN INTHE PAST?

Although postgraduate accredited residency programs (emphasiz-ing advanced practice and leadership development) for pharmacistshave been available since the 1940s and structured fellowship pro-grams (more focused on research) since the 1970s, the advent of thePharmD-only degree resulted in an increased emphasis by schools ofpharmacy as well as employers (especially hospitals and healthcaresystems) on post-PharmD training. The number of these postgradu-ate training programs has grown significantly, and many practicesettings require such training for employment. Most practicing phar-macists are “generalists,” but the number of specialty areas for phar-macists has continued to broaden over the past several decades.Some areas of specialty pharmacy practice correspond to well-known specialties in medicine and nursing, such as oncology, pedi-atrics, cardiology, nutrition, nephrology, infectious diseases, and psy-chiatry; other pharmacy specialties focus on knowledge and skillsthat are unique to pharmacy practice, such as compounding, nuclearpharmacy, or pharmacy administration. An example of an emergingspecialty interest in pharmacy is informatics.

Oncology has been an area of interest formany pharmacists for several decades.Theterm oncology pharmacist first appeared inthe early 1970s, and in the early 1980s, theAmerican Society of Health-SystemPharmacists (ASHP) implemented the firstpostgraduate residency training standardsfor oncology pharmacists. Soon after that,the first oncology fellowship programsemerged as well. Almost all health sys-tems that provide oncology care readilyrecognized the need for pharmacists withspecialized expertise and recruited these highly trained individuals.

Organizations such as the American Society of ClinicalOncology (ASCO) and the Oncology Nursing Society (ONS) alsorecognized the importance to patient safety in having well-trained oncology pharmacists. In the early 1990s, ASHP, with thesupport of ASCO, ONS, and a number of other organizations, peti-tioned the Board of Pharmaceutical Specialties for designation ofOncology Pharmacy as a specialty within pharmacy practice. Thisdesignation was approved, and the first certifying examinationwas administered in 1996. There are currently 757 board-certifiedoncology pharmacists. The Hematology Oncology PharmacistsAssociation currently has more than 900 members. Clearly, as thefield of oncology has expanded, the number of pharmacists inter-ested in and practicing in oncology has increased.

WHAT OPPORTUNITIES ARE THERE FOR ADVANCED TRAINING FOR A PHARMACY STUDENTINTERESTED IN ONCOLOGY?

Currently,ASHP accredits 39 specialty residency programs in oncol-ogy.These are referred to as PGY2 programs because all oncology res-idents must first complete a PGY1 1-year residency training programbefore beginning their oncology specialty training.There are six to 10well-established fellowship programs for pharmacists in oncology.

I believe that if pharmacy students are interested in oncology theyshould consult with their faculty advisor, the director of experientialeducation at their institution, and any of their faculty members whohave an interest or expertise in this field. Those individuals canassist the student in identifying experiential rotations and electivecoursework that may complement the oncology material in therequired curriculum and also help them to identify potential careermentors. A student thinking about a career as an oncology pharma-cist who is involved in direct patient care or research should plan onat least 2 years of postgraduate training (eg, PGY1 residency followedby a PGY2 oncology specialty residency). Students may also want tocontact preceptors of accredited oncology residency programsdirectly to find out specifics about the program and what type ofbackground they expect from applicants (eg, would applicants needto have completed at least one oncology rotation during theirPharmD training or their PGY1 residency?).

WHAT ARE THE EMPLOYMENT POSSIBILITIES FOR A PHARMACY STUDENT INTERESTED INONCOLOGY? HOW DOES ONE GET STARTED IN THE FIELD?

Oncology pharmacists are employed by cancer centers, hospi-tals with inpatient and/or outpatient oncology services, schoolsof pharmacy, pharmaceutical companies (regulatory affairs, druginformation, medical science liaisons, research positions), largeambulatory oncology group practices, health plans with oncologyservices, medical education companies with oncology offerings,and other medical publishers. In addition, some oncology phar-macists are employed by medical schools (usually in researchpositions) and other research organizations.

—Karen Rosenberg

References1. Knapp, DA. Professionally determined need for pharmacy services in 2020. Am J

Pharm Educ. 2002;66:421-429.2. Institute of Medicine. Health professions education. A bridge to quality. National

Academy of Sciences. 2003.3. American Association of Colleges of Pharmacy. http://www.aacp.org/Docs/

MainNavigation/InstitutionalData/8855_2008.pdf

REBECCA S. FINLEY,PharmD, MS

TRENDS IN PHARMACYContinued from cover

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Study Stirs Debate About Importance of Flat orDepressed Colorectal LesionsPREVENTION OF COLORECTAL CANCER (CRC) has tra-ditionally focused on detecting and removing poly-poid, or protruding, lesions. A new study that showeda higher percentage of high-grade dysplasia and sub-mucosal invasive cancer in flat or depressed colorec-tal lesions than in polypoid lesions (JAMA. 2008;299:1027-1035) has generated much discussion.

The investigators found that four (0.96%) of the 227flat or depressed neoplasms detected contained inva-sive cancer, and another 11 (3.3%) harbored high-gradedysplasia. Eight (0.61%) of 1,308 polypoid neoplasmsfound in the patients harbored invasive cancer, andfive (0.38%) contained high-grade dysplasia.

In the published analysis, the investigators groupedtogether high-grade dysplasia—which they label car-cinoma in situ—and submucosal invasive carcinoma.They concluded that nonpolypoid morphology isassociated with an adjusted odds ratio of 9.78 for“containing carcinoma.”

These findings and their implications for clinicalpractice are subject to different interpretations,however.

Lead investigator Roy Soetikno, MD, MSc, and hiscoauthors stand by their nomenclature and findings,concluding that if clinicians miss flat or depressedlesions, this can have serious consequences forpatients. “In the West, there is a tendency to avoid theterminology carcinoma [and use high-grade dysplasiainstead of carcinoma in situ], but this has no relevanceto the pathologic criteria or to the implications of thediagnosis,” said Dr Soetikno, chief of gastroenterology,Veterans Affairs Palo Alto Health Care System.“Carcinoma in situ or high-grade dysplasia is danger-ous; it is just one step before invasive cancer. But at

the same time it can be removed completely to pre-vent cancer.”

However Jerome Waye, MD, one of the investigatorsin the multicenter American National Polyp Study,counsels caution when evaluating the results. “If youlook at the lesions that contained invasive carcinomain the JAMA study, there were only two in the flat ade-noma group, and two in the depressed adenoma group—that’s only one tenth of one percent of the cases,”said Dr Waye, who is a gastroenterologist in privatepractice and a clinical professor of medicine, MountSinai School of Medicine, New York. “And the field hasreally abandoned the term carcinoma in situ in favor ofhigh-grade dysplasia, because the word carcinoma is mis-leading. In the colon, high-grade dysplasia is not omi-nous, because it’s not cancer.”

Dr Waye added that a post hoc analysis of theNational Polyp Study specimens by him and his col-leagues supports the view that nonpolypoid lesionsare not dangerous. They confirmed in a review of thepathology slides that while 27% of all of the adeno-mas they removed were flat, lesions with this type ofmorphology were not associated with a higher riskfor high-grade dysplasia at initial colonoscopy com-pared with the sessile lesions (Clin GastroenterolHepatol. 2004;2:905-911). Furthermore, they also werenot associated with a higher rate of advanced adeno-ma at follow-up surveillance.

Robert Petras, MD, national director, gastroin-testinal pathology, AmeriPath/Quest Diagnostics,Cleveland, agrees with Dr Waye’s points—includinghis underlying contention that clinicians are notmissing nonpolypoid lesions. “There isn’t a whole lotof evidence that we in America are missing these flat

lesions,” said Dr Petras. “If we were missing them,you’d expect a tremendous number of interval can-cers—a much higher rate than we have. …We mayalso have nomenclature differences. This may alsoexplain why the Japanese have such a marveloussurvival rate following resection for stomach cancer—many of what they report as cancer cases don’tactually have cancer by Western criteria.”

The Flat Lesion Study led by Dr Soetikno involved1,819 patients undergoing elective colonoscopy atthe Veterans Affairs Palo Alto Health Care Systembetween July 2003 and June 2004. Of the 1,819patients, 0.94% had a total of 2,770 lesions; 1,535,were neoplastic and 1,235 were nonneoplastic.Among the neoplastic lesions, 1,308 were polypoid.Of these, 209 were flat—including the two invasive-cancer and seven high-grade dysplasia lesions—andanother 18 were depressed—including two invasivecancers and four high-grade dysplasia lesions.Among the 1,235 nonneoplastic lesions, 1,155 werepolyploid and 80 were flat.

The investigators removed every polyp theydetected, including using endoscopic mucosalresection to remove four of the seven flat lesionswith high-grade dysplasia, and surgery to removethe other three.

“At the end of the day, one interval cancer is onetoo many,” said Dr Soetikno. “The patient, referringphysician, and insurer expect a high-quality colorec-tal cancer screening colonoscopy—one that encom-passes the detection, diagnosis, and removal of allneoplasms, both polypoid and nonpolypoid.”

—Rosemary Frei

Routine H Pylori Screening Recommended byHigh-powered Consensus GroupROUTINE HELICOBACTER PYLORI SCREENING ofAmerican populations at high risk for gastric cancermay be on its way. Attendees of the Asia-PacificGastric Cancer Consensus conference are calling for H pylori screening and treatment in all adults at highrisk of gastric cancer, including asymptomatic indi-viduals (Am J Gastroenterol. 2008;103:510-514; J Gastro-enterol Hepatol. 2008;23:351-365).

“There is no doubt that this set of recommenda-tions will generate controversy.… However, after care-fully weighing all of the available evidence, it is ouropinion that waiting another 20 years to obtain all thehard data will lead to a substantial number of unnec-essary deaths from preventable cancer,” the consen-sus panel authors conclude.

According to the panel, populations in the UnitedStates at high risk for gastric cancer may be candi-dates for routine screening programs. These includeKorean men in Los Angeles, who have an age-stan-dardized gastric-cancer incidence rate of more than40/100,000, and Alaskan native men, who have a rateof 36/100,000. Moreover, the rate of gastric cancer inAsian men in California and in Iowa is higher thanamong other American men, at 22.2 and 49.7cases/100,000, respectively. This is according to infor-

mation from the Surveillance Epidemiology and EndResults database from 2000-2004.

The consensus conference was supported by theJournal of Gastroenterology and Hepatology and by theAsian Pacific Association of Gastroenterology. Two ofthe three lead authors have consulted for, been onadvisory boards or speakers’ bureaus for, or receivedresearch support from, a variety of drug companies,including the manufacturers of the drugs they recom-mend for H pylori eradication.

The team reviewed the literature, and also per-formed a meta-analysis, which indicated that thepooled relative risk of developing gastric cancer after H pylori eradication is 0.56 (95% confidence interval 0.4-0.8). They concluded that eradication would lead toreduction of not only gastric cancer rates, but also ofpeptic ulcer disease, peptic ulcer bleeding and deaths,and dyspepsia and functional dyspepsia, and that itwould decrease the number of upper endoscopies andamount of long-term acid suppression required.

The team noted the optimal choice of antibiotictherapy for positive cases depends on local andnational treatment guidelines, but that 1 week oftriple therapy, such as with clarithromycin, amoxi-cillin, and a proton pump inhibitor should suffice.The

most commonly used proton pump inhibitors includeesomeprazole and omeprazole. The team said theybelieve such treatment will not increase the preva-lence of antibiotic resistance, nor other potential neg-ative sequalae.

Martin Blaser, MD, who is Frederick H. King profes-sor of internal medicine, chair, Department ofMedicine, and professor of microbiology, LangoneMedical Center, New York University, wrote in 1999that H pylori eradication may cause a marked increasein cases of gastroesophageal reflux disease, Barrett’sesophagus, and esophageal adenocarcinoma (J InfectDis. 1999;179:1523-1530).

“They misquoted me in the consensus recommen-dation paper—they said I believed eradicating H pylorihas more risks than benefits. But I didn’t say that; I saidwe don’t know. And we still don’t know,” Dr Blaser toldThe Oncology Pharmacist. “For example, we don’t yetknow how to accurately identify all the high-risk peo-ple. And also, we have been involved in studies thatshow children who don’t have H pylori are at higher riskof having asthma.… Everybody’s painting the world ina black and white way—and H pylori is gray.”

—RF

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Trends in Colorectal CancerTrends in Colorectal Cancer

KRAS Mutations Predictive of Response toPanitumumab Monotherapy in mCRCKRAS STATUS SHOULD be considered when determining whether patients with metastatic col-orectal cancer (mCRC) are candidates for panitu-mumab monotherapy because KRAS mutations arepredictive of lack of clinical response to the epi-dermal growth factor inhibitor. This finding comesfrom a phase 3 study comparing panitumumabmonotherapy with best supportive care (BSC) inpatients with chemotherapy-refractory mCRC. Theinvestigators used polymerase chain reaction onDNA from tumor secretions to detect KRAS muta-tions, and they compared the effect of panitu-mumab monotherapy on progression-free survival(PFS) in patients with mutant versus wild-type(WT; ie, nonmutated) KRAS. Of 463 patients inwhom KRAS status was ascertained, 427 (92%) hadKRAS mutations. The effect of panitumumab onPFS was significantly greater (P < .0001) in patientswith WT KRAS than in those with mutant KRAS. Inthe WT KRAS group, median PFS was 12.3 weeksfor panitumumab-treated patients compared with7.3 weeks for those who received BSC. Seventeenpercent of patients with WT KRAS but none ofthose with mutant KRAS responded to panitu-mumab. Overall survival was longer in the WTKRAS group than in the mutant KRAS group.Consistent with longer exposure to the drug, moregrade III treatment toxicities were observed in theWT KRAS group. No significant differences in toxi-city were found between the WT KRAS group andthe overall population. (Amado RG, et al. J ClinOncol. 2008;26:1626-1634.)

Colonoscopy Follow-up Guidelines Found toHave Limited Predictive ValueRESULTS OF A NATIONAL CANCER INSTITUTE studysuggest that the number and size of polyps removed atcolonoscopy are of limited value in predicting recur-rence of advanced adenoma. The findings raise ques-tions about the adenoma-based risk-stratification system used in current postpolypectomy colonoscopysurveillance guidelines. The subjects of the study were1,905 participants in the Polyp Prevention Study whohad adenoma removed at baseline and underwentrepeat colonoscopy at 1 year and 4 years. At 4 years,6.6% of patients had recurrence of advanced adenoma.The rate of advanced adenoma recurrence was 9% forthose classified as at high risk under the current guide-lines and 4% for those considered to be at low risk.Theauthors note that misclassification of patients as highor low risk may mean that potentially preventable col-orectal cancers are missed or that limited endoscopicresources are unduly burdened. The findings, they say,point to the need to improve the predictive ability ofthe guidelines. (Laiyemo A, et al. Ann Intern Med.2008;148:419-426.)

CT Colonography May Be Better thanColonoscopy for CRC ScreeningCOMPUTED TOMOGRAPHIC COLONOGRAPHY (CTC)may be both more clinically effective and cost-

effective than colonoscopy with or without ultra-sonography for screening for colorectal cancer(CRC), Italian researchers report. The advantages,however, are seen when findings such as extra-colonic cancer and abdominal aortic aneurysms aswell as colorectal neoplasia are considered. Theresearchers used a computerized Markov model tosimulate the occurrence of colorectal neoplasia,extracolonic cancers, and abdominal aorticaneurysms in a hypothetical cohort of 100,000 50-year-old subjects. They compared CTC with opticalcolonoscopy (OC) with or without one-timeabdominal ultrasonograph (OC-US). In the simu-lated population, CTC was found to be the domi-nant screening strategy, adding 1,458 life-yearscompared with OC and 462 life-years comparedwith OC-US. CTC was also less costly than theother techniques, the savings being $266 and $449per person compared with OC and OC-US, respec-tively. The gains for CTC were largely attributableto a reduced number of deaths due to abdominalaortic aneurysm. The CRC prevention rate wasslightly better with optical colonoscopy with orwithout ultrasonography than with CTC; this wasoffset, however, by gains related to abdominal aor-tic aneurysm. All three methods were more cost-effective than no screening. (Hassan C, et al. ArchIntern Med. 2008;168:696-705.)

The effect of panitumumab on PFS was significantly greater (P < .0001) in patients with WT KRAS than in those withmutant KRAS.

Trends in Lung Cancer Combination Chemotherapy Better thanErlotinib in First-line Management ofNSCLCCOMBINATION CHEMOTHERAPY with carboplatinand paclitaxel is superior to erlotinib in previouslyuntreated patients with advanced non–small-celllung cancer (NSCLC), according to the findings of aphase 2 study. A group of 103 patients with advancedNSCLC were randomized to receive erlotinib 150 mgorally daily until progression or to standard therapywith carboplatin and paclitaxel for up to four cycles.Partial responses were 2% in the erlotinib group and12% in the standard therapy. Median progression-free survival was 1.9 months in the erlotinib groupand 3.5 months in the standard therapy group (haz-ard ratio [HR] = 1.45; P = .06). Median survival timeswere 6.5 and 9.7 months in the erlotinib and stan-dard therapy groups, respectively (HR = 1.73; P = .018).Rash and diarrhea were more common with

erlotinib; emesis, alopecia, peripheral neuropathy,and fatigue were more common with standard ther-apy. Quality of life was similar in both groups.(Lilenbaum R, et al. J Clin Oncology. 2008;26:863-869.)

ProApolipoprotein Provides Early Detectionof Brain Metastases in Patients with LungCancer SERUM PROAPOLIPOPROTEIN A1 MAY be an effectivetool when used in conjunction with serum S100‚ forimaging-independent diagnosis of metastatic braintumors in patients with lung cancer. Serum markersof blood-brain barrier dysfunction were measured in103 patients with lung cancer. More than 50% of the

patients presented with magnetic resonance imag-ing changes consistent with chronic cerebrovasculardisease and reflected by elevated serum S100 levels.Proteomic techniques allowed discrimination be-tween patients with brain metastases and thoseaffected by cerebrovascular ischemic changes with-out infiltrating tumor. ProApolipoprotein A1, trans-ferrin, haptoglobin, and transthyretin were upregulat-ed in patients affected by chronic cerebrovascular dis-ease and brain metastases compared with thoseaffected only by vascular diseases. ProApolipoproteinA1 was significantly increased (P <.05) in patients withcentral nervous system disease. (Marchi N, et al.Cancer. 2008;112:1313-1324.)

Trends in Lung Cancer

ProApolipoprotein A1 was significantly increased (P <.05) inpatients with central nervous system disease.

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THE US FOOD AND DRUGAdministration (FDA) ismaking a significant shiftin its approach to monitor-ing drugs after they areapproved. It has just launched its Safety First initiative. Under thisinitiative, the FDA will devote as much attention to postmarket safe-ty issues as it has to drug development.

On February 26, 2008, Janet Woodcock, MD, director of the Center forDrug Evaluation and Research (CDER) at the FDA, issued a staff memostating that the Safety First objectives include the creation of a collab-orative, multidisciplinary, team-based approach to the review of drugsafety. The overall goal is to ensure that significant postmarket safetyissues are of the highest priority.

“We are trying to strengthen our postmarketing surveillance. Wehave learned a lot of lessons from the past,” said Deborah Henderson,RN, MSN, who is the director of the Office of Executive Programs atCDER at the FDA. “It makes a difference when you put managementaround these issues to add accountability. The biggest part of this is toput in timelines and to bring accountability to the process.”

She said it is hoped that pharmacists will welcome this newprogram because it will help instill confidence on the part of theAmerican public. Some pharmacists as well as physicians havebeen vocal about what they perceive as the FDA’s slowness torespond to potential serious side effects that may emerge onlyafter a medicine reaches the market. The Safety First initiativeaims to eliminate this concern.

“We get a half a million adverse events a year reported to us. Wecan’t put a deadline on all those. That is unreasonable and unneces-sary. So, we have to decide when we are going to start tracking some-thing. We need to define a postmarketing issue and decide what arethe issues and what the specific issues are that we are going to trackand how we are going to do it,” said Ms Henderson in an interview withThe Oncology Pharmacist.

As part of this initiative, an advanced computational center isbeing set up to support quantitative scientists and the FDA’s med-ical reviewers in the management and analysis of large datasets.The FDA hopes to have early parts of this program in place by theend of the year.

Many pharmacists have noted that not a month goes by that they donot hear about another unexpected toxicity with a specific drug andwonder whether it will lead to a new black box warning. Over the past10 years, a stream of drugs, including drugs for diabetes, ulcer disease,cholesterol-lowering, obesity, and arthritis, have been recalled orundergone labeling changes because of increased risks of heart andlung problems and even deaths associated with their use. This had ledto a growing speculation that some drugs are getting to the marketplace too quickly.

“One death is one death too many, and when someone dies from adrug that was supposed to heal, that is a real cause forconcern to all of us,” said pharmacist Byron Peters,RPh, director of the Washington University CancerCenter Pharmacy, St. Louis, Mo. “The new program istimely. In hindsight, you can say it is overdue, but thestories have begun to accumulate. I think it is the rightresponse at the right time. Maybe this should havebeen set up sooner, but that is easy to say now.”

Mr Peters expects that this new initiative will helpensure the safety of a wide variety of medications. Hepointed out that many of the drugs that have beenrecalled or had new black box warnings placed onthem were used for everything from heart disease toobesity. As a result, he said a very large number ofAmericans have been directly affected. He said part ofthe problem is that drugs are tested in a very tightlycontrolled patient population and the prescribing isdone in a very precise manner.

“We see more toxicities in large populations. Thestudy groups exclude people with certain conditions,and so there is a lot of built-in bias in a sense. Theyare building in a bias by eliminating certain riskgroups. But those conditions may be commonplace inthe general population,” said Mr Peters. “These drugsgo through a lot of investigation and there is excellentscience, but when they hit widespread populationsand individuals take medicines in ways in which theyare not prescribed, then things begin to drift out of themodel they were tested in.”

—John Schieszer

FDA Launches Safety FirstProgram To Monitor Drugs After Approval

The overall goal is to ensure that significant postmarket safetyissues are of the highest priority.

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THE FLOOD OF NEW DATAflowing to clinicians viatheir computer screens andin medical libraries is mak-ing it clear that oral thera-pies are effective for first- orsecond-line treatment ofearly-stage breast cancer.

What is not clear, however, is how many patients are adherent, hencewhether they are receiving the full short- and long-term benefits fromthese treatments. A recent study has shown that adherence to aro-matase inhibitors falls as low as 62% by the time patients have takenthese drugs for 3 years. The standard of care is to take adjuvant hor-mone therapy for a total of 5 years.

“The problem of compliance is under-recognized; I talk to oncologistsaround the country, and often they’ll say, ‘It’s a problem, but not with mypatients. It’s my partner’s patients, or the other clinics’ patients,’” saidLawrence Wickerham, MD, associate chairman, National SurgicalAdjuvant Breast and Bowel Project (NSABP). “And nothing could be far-ther from the truth—lack of compliance is not linked to economic sta-tus or level of education; it’s very pervasive. The take-home message isoral medications in oncology are going to be more common, so we needto recognize this as an issue and work with our patients to improve it.”

Data Support Aromatase Use in Early Breast CancerThe aromatase inhibitors anastrozole, exemastane, and letrozole

were all approved in late 2005 by the US Food and DrugAdministration as oral therapies for adjuvant treatment of early-stage breast cancer in postmenopausal women. Anastrazole and exe-mastane were approved for hormone-receptor-positive disease,while letrozole was approved for both receptor-positive and receptor-status-unknown cases. Moreover, anastrozole and letrozole wereapproved as first-line therapy, while exemastane was approved foruse after initial tamoxifen treatment.

The effectiveness of each of the three third-generation aromataseinhibitors is backed up by a hefty evidence base. For example, a studypresented at the San Antonio Breast Cancer Symposium lastDecember and published in January 2008 in The Lancet bolstered theevidence on the efficacy of anastrozole as adjuvant treatment forearly-stage breast cancer (Lancet. 2008;9:45-53). The ATAC (Arimidex,Tamoxifen, Alone or in Combination) trial results showed that, aftera median of 100 months, anastrozole resulted in a 15% higher probabil-

ity of disease-free survival compared with tamoxifen. Anastrozole wasalso associated with a lower average time to recurrence, a lower inci-dence of new contralateral breast cancer and a longer time to distantrecurrence, although it did not have an appreciable effect on rates ofdeath after recurrence or overall survival.

Hot on the heels of this are several papers demonstrating the effica-cy of letrozole. For example, letrozole produced significantly higher ratesof disease-free survival in a study of 4,922 postmenopausal women withreceptor-positive early breast cancer randomized to letrozole or tamox-ifen (J Clin Oncol. 2008;26:1972-1979). It also provided a 63% higher prob-ability of disease-free survival even after a substantial period had passedsince discontinuation of prior tamoxifen adjuvant therapy, according tothe National Cancer Institute of Canada (NCIC) Clinical Trials Group’sMA.17 study (J Clin Oncol. 2008 Mar 10 [Epub ahead of print]).

Exemastane is also proving to be an effective treatment option. Forexample, among women switched from placebo to exemastane afterpremature closure of the NCIC MA.17 study, the medication wasassociated with a statistically significant 2% higher rate of 4-yearrelapse-free survival compared with tamoxifen, and a near-signifi-cant 2% higher rate of 4-year disease-free survival (J Clin Oncol. 2008Mar 10 [Epub ahead of print]).

Adherence Levels Far From PerfectIn the midst of these heartening results, however, another new study

is shedding some rain on the parade.A review of the records of more than 12,000 women enrolled in

three large, commercial health insurance programs showed adher-ence rates are not even close to 100% among women taking aro-matase inhibitors (J Clin Oncol. 2008;26:556-562). The research, led byAnn Partridge, MD, MPH, found the rates were 82% to 88% in the firstyear after women started taking the medications, and dropped aslow as 62% during the third year.

Dr Partridge, medical oncologist, Dana-Farber Cancer Institute, and anassistant professor of medicine, Harvard Medical School, Boston, and

her co-investigators pooled claims data between January 2002 andMarch 2004 from the MarketScan employer-based claims data-base and from two large American health plans. They capturedthe records of 7,132 women with early breast cancer and at least12 months of follow-up records of women who were taking anas-trazole, including 999 with at least 24 months of follow-up data.Anastrozole initiation was defined as no evidence of endocrinetherapy for at least 4 consecutive months before the first anastro-zole-prescription claim.

The team found the annual mean medication possessionratio—the ratio of number of days elapsed to number of days

during which the patients were coveredby a prescription they had filled foranastrozole or another hormonalagent they had switched to—wasapproximately 86% among the womenwho had taken anastrozole for 12 con-secutive months. By the second year,

Maximizing Adherence toAromatase Inhibitors for Early-stage Breast Cancer

Adherence to oral antineoplastic agents in typical care settings isdramatically worse than that seen in clinical trials, and this maytranslate into lower efficacy of therapy when compared with out-comes observed in clinical trials. G

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Mammography and MRI Combined ProvideGreater Benefit for Women with BRCA1MutationANNUAL SCREENING USING A COMBINATION of mam-mography and magnetic resonance imaging (MRI) wasshown to have greater benefit for women who carry theBRCA1 mutation. The study was conducted using aMarkov computer model consisting of 500,000 women25 years of age who were asymptomatic BRCA1 carriersto determine the effect of MRI screening on clinical out-comes of breast cancer.Three screening strategies werecompared: clinical surveillance, annual MRI, and annu-al combined MRI/mammography.The annual combinedstrategy of MRI/mammography detected the most can-cers, with a program sensitivity of 70% versus 39% withmammography alone. Cancers were also identified ear-lier and were smaller: the median invasive tumor sizeseen with mammography alone was 1.9 cm, and 36% to52% of tumors were 2 cm or smaller; with MRI, 1.3 cm,and 66% of all tumors were 2 cm or smaller; with com-bination screening, 1.1 cm, and 73% of tumors were 2cm or smaller. An increase in average life expectancy of1.38 years and a reduction in breast cancer mortality of22% were also observed with combination screening.This strategy, however, was associated with a high rateof false-positive results: between 80% and 84% ofwomen eventually had at least one false-positive result,and more than 25% underwent unnecessary biopsies.(Lee JM, et al. Radiology. 2008;246:763-771.)

Genomic Information Along with Clinical RiskStratification May Refine Breast CancerPrognoses INTEGRATING GENE EXPRESSION SIGNATURES withclinical risk stratification may more accurately deter-mine the prognosis of breast cancer patients, accordingto an analysis of 964 breast tumor samples. Using a clin-icopathologic prognostic model, subjects were dividedinto three relapse risk categories: low, intermediate, andhigh. In each category, gene expression signaturesshowed subclusters having prognostic significance.Among low-risk patients five clusters were found, eachwith distinctive prognostic significance (P <.02). Medianrelapse-free survival time for patients in cluster 4 (poorprognosis) was 16 and 19 months less than those in clus-ters 1 and 5 (good to intermediate prognosis), respective-ly. Patients at intermediate risk had six clusters of prog-nostic significance. Median relapse-free survival time forcluster 3 (poor prognosis) was 54 months less than clus-ter 2 (good prognosis).Findings were similar for high-riskpatients; genomic differences indicated patients in clus-ter 4 (poor prognosis) had inferior relapse-free survivalcompared with those in other clusters (cluster 1, P = .03;cluster 5, P = .01). Median relapse-free survival time forcluster 4 was 15 and 8 months less than clusters 1 and 5(good prognosis), respectively. Additionally, based ongene expression signatures, the researchers predictedwhich patients may be sensitive to various chemothera-pies; for example, patients with a poor prognosis werelikely to be resistant to adriamycin and paclitaxel and

sensitive to docetaxel, etoposide, and topotecan.(Acharya CR, et al. JAMA. 2008;299:1574-1587.)

COX-2 Expression May Predict Breast CancerRisk in Women with Atypical HyperplasiaEXPRESSION OF THE CYCLOOXYGENASE-2 (COX-2)enzyme may help predict breast cancer risk, accordingto a recent study that included 331 women with atypi-cal hyperplasia.The women underwent a benign breastbiopsy and were then followed up for a median of 15years. Among 100 women having atypical ductal hyper-plasia, 77% had no or weak COX-2 staining (categories 0or 1+), 13% had moderate (category 2+) staining, and10% had strong (category 3+) staining; 122 women hadatypical lobular hyperplasia, and 47 (39%) had cate-gories 0 or 1+ staining, 53 (43%) had category 2+ stain-ing, and 22 (18%) had category 3+ staining (P <.001).Strong staining also correlated with increasing age (>45years, P = .01). Of the 235 women for whom COX-2 stain-ing was available, 41 (17%) developed breast cancer,indicating a borderline statistically significant relation-ship (P = .07). Specifically, risk after 15 and 20 years offollow-up among women with categories 0 or 1+ COX-2staining was 13% and 14%; category 2+ staining, 19%and 24%; and category 3+ staining, 25% and 31%, respec-tively. Median time to breast cancer developmentamong the 18 women who had category 0 or 1+ stain-ing was 11.4 years and among the 23 women who hadcategory 2+ and 3+ staining, 11.8 years. (Visscher DW, etal. J Natl Cancer Inst. 2008;100:421-427.)

the rates had fallen a notch, however, to 75% amongwomen in the MarketScan database, 82% amongthose enrolled in one of the large national plans, and68% among those in the other national plan. By thethird year, the rates fell even lower to 72%, 79%, and62%, respectively. The investigators found thatwomen who stopped taking anastrozole during thefirst year appeared to do so gradually.

“Our findings of suboptimal adherence among asubstantial proportion of women in the so-calledreal world provide further evidence that adherenceto oral antineoplastic agents in typical care settingsis dramatically worse than that seen in clinical trials,and this may translate into lower efficacy of therapywhen compared with outcomes observed in clinicaltrials,” the investigators concluded.

What Can Be Done?One question is whether increased adherence is

associated with improved outcome. Another is howthe adherence rates can be increased. Perhaps sur-prisingly, the first question has not been answeredyet, but a lot of effort has been made to answer thesecond one.

Many clinicians are trained that the best approachto improving adherence is to remind their patientsat each visit that they should take every single pillprescribed because this is the only way to maximizebenefits from the medications. But does that work?

Many experts strongly feel a more individualizedand respectful two-way dialog is necessary. A recent-

ly published paper by Dr Partridge, Dr Wickerham,and three other researchers outlined recommenda-tions for increasing adherence to adjuvant therapyfor breast cancer (Community Oncol. 2007;4:725-730).The authors are all part of the Compliance StrategicInitiative, a multidisciplinary collaborative effort cre-ated to optimize adherence. The team’s recommen-dations include tailoring communication to the indi-vidual patient, keeping messages simple, andenhancing the patient’s equal value in the “adher-ence equation” by means such as encouraging use ofpill boxes or medication diaries.

Dr Wickerham adds that nurses are critical to thisequation. “Often patients are reluctant to admit to thedoctor that they’re having trouble taking their medica-tion, but they’ll be more open with the nurses or othermedical professionals in the office,” said DrWickerham. “I hear it all the time because I talk aboutthis around the country. And we’ve been dealing withthis in our clinical trials for a long time; we teach ournurses how best to improve adherence.”

Wendy Smith, MSN, nurse practitioner, West Clinic,Corinth, Miss, and board member, CommunityOncology Alliance, Washington, DC, affirms that devel-oping a solid, trusting relationship is more valuablethan any other patient-clinician factor, particularly forearly-stage breast cancer, when the cost-benefit ratiomay appear to patients to be skewed against them.

“Communication skills are the basis for everything,”said Ms Smith.“For example, if they come to us and say,‘Cost is an issue,’ we can see how we can work withthem, such as directing them to a patient prescriptionassistance program or helping them get coverage

through their insurance program.…Or if they haveside effects such as hot flashes and muscle acheswhen they start therapy, if we can be good listenerswe can often help them cope; as a result manywomen can adjust to those side effects and continueto take the medication.”

Dr Partridge also concurs that making patientspartners in their treatment is critical. “We have to tryharder to understand why people are not adherent,educate them about the goals of therapy, and helpthem to make the best decisions for themselves,”she observed. “For some people, not taking a drugmight be the right thing for them. If it makes thepatient miserable, she might say, ‘No thank you, I’drather take my chances with not using the medica-tion.’ But our job is at least to help patients under-stand the value of the medications—because if theydon’t understand that, how can they make the rightdecision about taking the medication?”

A putative approach is to profile patients and targetonly those who are most likely to be nonadherent.Some work is being done in that area, says DrWickerham, but it has not made much headway. Henotes that for the foreseeable future, the bulk of suc-cess in increasing patient adherence will rest on indi-vidual clinics’ priorities and their staff’s people skills.“Some are far superior to others. It comes down to anurse or nurses who are willing and able to take thetime to impact adherence,” he said. “And that, in turn,comes from the people who run the clinics, who makethis a priority.”

—Rosemary Frei

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Targeted Therapies for HER2-positive Breast Cancer tobe Compared in ALTTO Trial

Two widely used targeted therapies for human epidermal growthfactor 2 (HER2)-positive breast cancer will be compared in the largemultinational Adjuvant Lapatinib and/or Trastuzumab TreatmentOptimisation (ALTTO) trial. Women in North America are now beingenrolled in the phase 3 trial, which will recruit 8,000 women withHER2-positive breast cancer in 50 countries.The study is the first glob-al initiative jointly developed by academic breast cancer research net-works in different parts of the world in which all care and data collec-tion are standardized regardless of where patients are treated.The twonetworks are the Breast Cancer Intergroup of North America and theBreast International Group.

Both agents being used in the trial—trastuzumab (Herceptin) andlapatinib (Tykerb) are already approved by the US Food and DrugAdministration (FDA) for HER2-positive breast cancer. Women withstage I or II breast cancer who have already had surgery to removetheir tumors will be randomized to receive either trastuzumab or lap-atinib alone, trastuzumab followed by lapatinib, or the two agents incombination. All participants must have completed four or morecycles of anthracycline-based chemotherapy, and those for whom tax-ane chemotherapy is indicated will receive paclitaxel (Taxol) alongwith their assigned target therapy. Edith Perez, MD, of the Mayo Clinicin Jacksonville, Fla, is the North American coordinator of the trial,which it is hoped will establish a model for global clinical trials.

Phase 3 Trial of Sodium Thiosulfate to PreventCisplatin-associated Hearing Loss in ChildrenAnnounced

Adherex Technologies of Research Triangle Park, NC, has announcedactivation of a phase 3 trial of sodium thiosulfate (STS) to preventhearing loss in children treated with cisplatin. The trial is being con-ducted in collaboration with the Children’s Oncology Group (COG).More than 60% of children treated with cisplatin experience somedegree of hearing loss and some become deaf.

The multicenter trial will enroll children 1 to 18 years of age who arescheduled to receive cisplatin for newly diagnosed germ cell, liver,brain, nerve tissue, or bone cancer. Participants will be randomized to

STS or placebo, and their hearing sensitivity will be evaluated at base-line and at follow-up using standardized audiometric tests.The trial isexpected to enroll up to 120 children over approximately 3 years in upto 230 COG centers in the United States, Canada, Australia, and Europe.David Freyer, MD, professor of medicine, Children’s Hospital LosAngeles, Keck School of Medicine, University of Southern California, isprincipal investigator.

Monoclonal Antibody for Ewing Sarcoma to beStudied

Enrollment in a trial of a new treatment for Ewing sarcoma hasbegun in the United States. Centers across the United States and inFrance, Italy, Germany, and the United Kingdom will also participate inthe trial, which will investigate the use of an investigational mono-clonal antibody, R1507, in patients with Ewing sarcoma. The agent,made by Hoffman-LaRoche, inhibits insulin-like growth factor 1 recep-tor (IGF-1R). Ewing sarcoma, which affects mostly children, adoles-cents, and young adults, has been linked with mutated genes that pro-mote production of IGF-1R.

Enrollment in Phase 2 Trial of PDX for PTCLCompleted

Enrollment in a phase 2 trial of pralatrexate (PDX) for relapsed orrefractory peripheral T-cell lymphoma (PTCL), for which there is cur-rently no approved treatment. The trial known as the Pralatrexate inPatients with Relapsed or Refractory Peripheral T-cell Lymphoma(PROPEL) is an international, multicenter, open-label, single-armstudy. Patients with relapsed or refractory PTCL who progressed afterat least one prior treatment receive 30 mg/m2 of PDX once a week for6 weeks followed by 1 week of rest per treatment cycle. Participantsalso receive vitamin B12 and a folic acid supplement. An independ-ent data monitoring committee has completed three interim analy-ses of safety data and has recommended continuation of the trial ateach analysis.

PROPEL is being conducted under an agreement with the FDA underits Special Protocol Assessment process. PDX received orphan drugstatus for T-cell lymphoma in July 2006 and was fast-tracked inSeptember 2006.

Clinical Trials Update

• Bendamustine for Chronic Lymphocytic Leukemia. The US Food andDrug Administration (FDA) has approved bendamustine hydrochlo-ride (Treanda; Cephalon) for injection for first- and second-line treat-ment of chronic lymphocytic leukemia (CLL). The novel chemother-apy agent is the first product approved for CLL since 2001. CLL is anorphan indication, but Cephalon has filed bendamustine for use innon-Hodgkin’s lymphoma.

• Bevacizumab for Advanced HER2-negative Breast Cancer. The FDAhas granted accelerated approval for bevacizumab (Avastin;Genentech) in combination with paclitaxel for first-line treatment ofwomen who have not received chemotherapy for metastatic humanepidermal growth factor receptor 2 (HER2)-negative breast cancer.Use of the antiangiogenesis agent for advanced cancer was grantedunder the FDA’s accelerated approval program. A full review of datafrom two phase 3 trials will be required for the accelerated approvalto be converted into a full approval.

• Levoleucovorin for Osteosarcoma. Spectrum Pharmaceuticals hasreceived FDA approval for Levoleucovorin for Injection (formerlyknown as ISO-Vorin) for treatment of osteosarcoma.The novel folateanalog is indicated after high-dose methotrexate therapy in patientswith osteosarcoma and to diminish the toxicity and counteract theeffects of impaired methotrexate elimination or inadvertent over-dose of folic acid antagonists.

• CellSearch for Monitoring Prostate Cancer. The FDA has granted anexpanded clearance for the CellSearch System (Veridex, LLC) as anaid in monitoring patients with metastatic prostate cancer. The sys-tem is currently cleared monitoring patients with metastatic breastor colorectal cancer. It is the first diagnostic test that automatesdetection and enumeration of circulating tumor cells in a blood sam-ple, which aids in predicting progression-free and overall survival inpatients with metastatic breast, colorectal, and prostate cancer.

• Amrubicin for Small-cell Lung Cancer. Amrubicin (Celgene) has beengranted orphan drug status by the FDA for the treatment of small-celllung cancer. The third-generation synthetic anthracycline analog isbeing studied for use alone or in combination with other therapies fora variety of solid tumors, including lung and breast cancer.

Recent FDA Approvals

Frank M.Torti, MD, MPH, a clinician, scientist, and researcher in molecular oncology,has been appointed Principal Deputy Commissioner of the FDA and the agency’sfirst Chief Scientist. In this position, Dr Torti will support the launch of the FDAFellowship Program, which potentially could attract as many as 2,000 professionalsof varying disciplines for a 2-year training program. His office will also work toensure the quality and regulatory focus of the FDA’s intramural research programsand place special emphasis on the importance of clinical research trials. Dr Torti iscurrently Charles L. Spurr Professor of Medicine, Chair, Department of CancerBiology, and Director, Comprehensive Cancer Center at Wake Forest UniversitySchool of Medicine in Winston-Salem, NC.

FDA Appoints First Chief Scientist

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The



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Written by and for oncology pharmacist offering you the following:

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

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TOP May_v2 5/2/08 1:58 PM Page 20

2008 Meetings

June 4-710th International Conference on Malignant LymphomaLugano, Switzerlandwww.lymphcon.ch/

June 12-1513th Congress of the European HematologyAssociationCopenhagen, Denmarkwww.ehaweb.org

June 18-21Hematology/Oncology PharmacyAssociation/International Society of OncologyPharmacy Practitioners 2008 ConferenceAnaheim, CAwww.hoparx.org

Ninth International Lung Cancer Congress Koloa, HIwww.cancerconferences.com/thoracic/9th_lcc/index.php

June 22-25World Conference on Interventional OncologyLos Angeles, CAwww.wcio2008.com

June 25-2810th World Congress on Gastrointestinal CancerBarcelona, Spainwww.worldgicancer.com

June 26-2821st International Supportive Care in CancerSymposiumMultinational Association of Supportive Care inCancer/International Society of Oral OncologyHouston, TXwww.mascc.org

July 19-23American Association of Colleges of Pharmacy2008 Annual MeetingChicago, Ilwww.aacp.org

7th International Conference on Head and NeckCancerThe American Head and Neck SocietySan Francisco, CAwww.ahns.info

July 24-263rd Interamerican Breast Cancer ConferenceCancun, Mexicowww.imedex.com/calendars/oncology.asp

August 3-8Methods in Clinical Cancer ResearchJoint ASCO/AACR WorkshopVail, COwww.aacr.org

August 14-16American Society of Health-System Pharmacists2008 Residency Preceptors ConferenceWashington, DC www.ashp.org

August 27-31International Union Against Cancer (UICC)World Cancer CongressGeneva, Switzerlandwww.uicc-congress08.org

September 5-72008 Breast Cancer SymposiumWashington, DCwww.astro.org

September 17-2025th National Oncology Economics ConferenceSan Francisco, CAwww.accc-cancer.org

September 19-209th Annual Perspectives in Colorectal CancerMiami, FLwww.imedex.com

September 21-25American Society for Therapeutic Radiology and Oncology (ASTRO)50th Annual MeetingBoston, MAwww.astro.org

September 25-284th Annual Oncology CongressSan Francisco, CAwww.oncologycongress.com

September 25-275th Annual MeetingInternational Society of GastrointestinalOncologyArlington, VAwww.isgio.org

October 16-189th Meeting of the International Society ofGeriatric OncologyMontreal, Canadawww.cancerworld.org/siog

October 21-2550th Annual MeetingAmerican Society for Therapeutic Radiology andOncologyBaltimore, MDwww.astro.org

October 19-21American Society of Health-System Pharmacists2008 Annual Leaders ConferenceChicago, ILwww.ashp.org

October 23-2610th Annual Lynn Sage Breast CancerSymposiumChicago, ILwww.lynnsagebreastcancer.org

October 30-November 161st Annual Symposium on Cancer ResearchHouston, TXwww.mdanderson.org

November 5-8Chemotherapy Foundation Symposium XXVINew York, NYwww.chemotherapyfoundation.org

November 13-182008 Multidisciplinary Lung Cancer SymposiumChicago, ILwww.oncologymeetings.org

Meetings


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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

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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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May 2008 Vol. 1 No. 1

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Transcript of May 2008 Vol. 1 No. 1