May 2008 Vol. 1 No. 1

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EDITOR’S LETTER A forum addressing the clinical and professional concerns of oncology pharmacists in practice and in training

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NEW TECHNOLOGY

MEDICAL MINUTES

An automated system increases the safety of chemotherapy preparation

FDA deadlines may compromise drug safety

Safety First program to monitor drugs after approval

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MAY 2008 • VOL. 1, NO.1

The

FDA WATCH

www.theoncologypharmacist.com

Oncology

The Official Newspaper of Record for the Hem/Onc Pharmacist

Pharmacist

™

Trends in Pharmacy Education

ANNOUNCING CE CREDIT AT NO CHARGE

An interview with Rebecca S. Finley, PharmD, MS, Founding Dean, Jefferson School of Pharmacy, Philadelphia IN RESPONSE TO THE GROWING need for pharmacists in the United States and as part of a new model of interprofessional education, Thomas Jefferson University (TJU) in Philadelphia has established a School of Pharmacy, which will enroll its first class in fall 2008. The School of Pharmacy is part of the Jefferson College of Health Professions, which also includes a School of Health Professions and a School of Nursing. In this interview, Rebecca S. Finley, PharmD, MS, founding dean of the School of Pharmacy, discusses the school’s objectives and curriculum and current trends in pharmacy education, including the expanding role of

pharmacists in oncology care and other specialized fields.

WHY IS THERE A NEED FOR A NEW SCHOOL OF PHARMACY? The decision by TJU to open a school of pharmacy was based on several indicators. First, the findings of the Pharmacy Manpower Project, Inc, published in 2002, showed that there would be a shortfall of as many as 157,000 pharmacists by 2020.1 This report indicated that the “aging of Americans, specifically the baby boomers,” would dramatically increase medication utilization in the United States. Implementation of the Medicare Part D prescription drug benefit also will increase medication utilization and thus the demand for pharmacists. Secondly, a major priority of TJU identified in our most recent strategic planning initiative is to enhance the scope and effectiveness of interprofessional education (in response to the Institute of Medicine Report).2 TJU recognized that pharmacy was needed to complete our compre-

Green Hill HealthCare Communications, LLC, is partnering with the University of Nebraska Medical Center (UNMC) Center for Continuing Education and the UNMC College of Nursing, Continuing Education to provide a complimentary CE activity in each issue.

hensive model of interprofessional healthcare education. In addition, pharmacy education is in great demand in the United States, and information provided by the American Association of Colleges of Pharmacy indicated that there are more qualified applicants than seats in existing pharmacy schools.3 Finally, the TJU Hospital has a long and distinguished history of excellence in pharmacy practice and pharmacy residency training, being the oldest accredited residency program in the United States, and it is viewed as a premier institution to partner with for our academic program.

Besides TJU, six other new schools of pharmacy have been granted precandidate status by the Accreditation Council on Pharmacy Education (ACPE). Precandidate status denotes a developmental program (with no currently enrolled students), which is expected to mature in accord with stated plans and within a defined time period.

THE US FOOD AND DRUG Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) on March 13, 2008, recommended that the use of erythropoiesisstimulating agents (ESAs) be substantially limited in the treatment of anemia in patients with cancer. The committee made the recommendation after hearing additional evidence from a recently published meta-analysis showing that ESAs increase the risk of blood clots and death in patients taking these agents for chemotherapyinduced anemia.

The committee recommended that use of ESAs be restricted to only those cancer patients with advanced disease and that all patients receiving these drugs be required to complete a written consent form before using one of these agents. The committee also recommended that these drugs not be used in patients with breast cancer or head and neck cancer. This was the third ODAC meeting held just to examine safety issues

Continued on Page 12

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POLICY WATCH

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Further Limits on Use of ESAs in Cancer Patients Expected

CLINICAL TRIALS

Approval of biogenerics seen as one way to reduce healthcare spending

Multinational trial to compare targeted therapies for breast cancer

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RECENT FDA APPROVALS New drugs approved for CLL, breast cancer, osteosarcoma

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© 2008 Green Hill HealthCare Communications LLC

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Gelclair ® can bring a smile to the face of patients with oral mucositis

Soothing the way to relief

NDC 24477-010 -15 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.

GELCLAIR® Coating Mucosa

Prescribe 6 boxes of GELCLAIR® for a 30 day supply GELCLAIR® is available at your local pharmacy and at:

Submucosa

Nerve

Now serving patients nationwide Toll Free: 877-977-9118

For additional information, visit www.gelclair.com or call 1-877-GELCLAIR. 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 a mechanical 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 caused by 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 administration of 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 clinical trials 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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MEDICAL MINUTES

Medical Minutes Medical Minutes

MANY MEDICATIONS ARE APPROVED by the US Food and Drug Administration (FDA) on the brink of congressionally mandated deadlines, and those drugs are more likely to face later regulatory intervention than those approved with greater deliberation, according to a new study by Harvard researchers. Drugs fast-tracked by the FDA are more likely to eventually be withdrawn from global markets for safety reasons, undergo manufacturing revisions, or face labeling changes, according to the study published in the March 27, 2008 issue of the New England Journal of Medicine (N Engl J Med. 2008;358: 1354-1361.)

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

The deadlines imposed on the FDA’s drug-approval process were first enacted as part of the Prescription Drug User Fee Act (PDUFA) of 1992, which mandated that the FDA must act on 90% of all drug candidates within 12 months of submission or face funding cuts. The timeline was tightened to 10 months as part of the 1997 FDA Modernization Act, a timeline extended by Congress in 2002 as part of the bioterrorism legislation and renewed again in 2007.

Some observers have suggested that these deadlines lead to the rushed approval of medications, a theory Dr Carpenter tested by examining data on the timing of FDA approvals dating back to 1950.

He found that the enactment of PDUFA in 1992 appeared to introduce a temporal discontinuity into FDA review cycles, with disproportionate approvals coming in the 2 months immediately before deadlines. Compared with drugs approved at a more measured pace in the months after the deadline, those approved right before the review clock expired were far more likely to require later regulatory intervention.

“Drugs rushed to approval just before the deadline are two to three times more likely to eventually be pulled off shelves due to safety concerns, two to seven times more likely to receive added label warnings known as ‘black box revisions,’ twice as likely to experience changes in manufacture, and two to seven times more likely to be voluntarily discontinued by manufacturers due to weak clinical demand,” said Dr Carpenter.

Tamoxifen May Help Treat Mania in Bipolar Disorder Patients A small, 3-week trial of tamoxifen may decrease symptoms of mania in patients with bipolar disorder, according to a new study by researchers in Turkey. Tamoxifen interferes with the effects of the hormone estrogen, which accounts for its effects against breast cancer. However, tamoxifen also inhibits the actions of a family of enzymes known as protein kinase C. Abnormal levels of activity by these enzymes have been associated with bipolar disorder and related dysfunctions, such as distractibility, impaired judgments, and disorganized thoughts.

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

May 2008

Participants were randomly assigned to take tamoxifen (40 mg to 80 mg per day) or placebo for up to 3 weeks. Participants in both groups also were given up to 5 mg per day of lorazepam as needed to control their symptoms.

A total of 50 patients (29 assigned to tamoxifen and 21 assigned to placebo) completed the 21-day trial. The researchers found that the tamoxifen group had significantly lower scores on tests used to measure 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 to the drug (defined as a reduction of at least half in mania scores) compared with 5% of those taking placebo, and 28% (tamoxifen group) versus 0% achieved cutoff scores for mania remission.

The researchers also found that patients taking tamoxifen used less lorazepam during the study: an average of 25.2 mg compared with 41.8 mg (placebo group). Moreover, all the patients used less lorazepam as the trial progressed and the rate of decrease was 2.5 times greater with tamoxifen-treated patients. Both tamoxifen and placebo were well tolerated. The findings from this study have been published in the Archives of General Psychiatry (Arch Gen Psychiatry.

2008;65:255-263).

BY JOHN SCHIESZER

John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute.

He can be reached at medminutes@aol.com.

MEDICAL MINUTES MEDICAL MINUTES MEDICAL MINUTES MEDICAL

Study Finds FDA Deadlines May Compromise Drug Safety

by Rushing Approval

New Study Suggests Some Cancer Trials May Have Incorrectly Reported Success A new study reviewing 75 group-randomized cancer trials over a 5-year stretch showed that fewer than half of those studies used appropriate statistical methods to analyze the results. The review suggests that some trials may have reported that interventions to prevent 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 that the reviewers considered inappropriate to assess the effects of an intervention being studied. The review authors also found that 88% of those studies reported statistically significant intervention effects that, because of analysis flaws, could be misleading to scientists and policymakers.

“We cannot say any specific studies are wrong. We can say that the analysis used in many of the papers suggests that some of them probably were overstating the significance of their findings,” said lead author of the review study David Murray, who is professor and chair of epidemiology in the College of Public Health at Ohio State University, Columbus. “If researchers use the wrong methods, and claim an approach was effective, other people will start using that approach. If it really wasn’t effective, then they’re wasting time, money, and resources and going down a path that they shouldn’t be going down.”

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

In group-randomized trials, researchers randomly assign identifiable groups to specific conditions and observe outcomes for members of those groups to assess the effects of an intervention under study. In analyzing the outcomes of such trials, researchers should take into account any similarities among group members or any common influences affecting the members of the same group, explained Dr Murray. But too often, this review found that the common ground among group members was not factored into the final statistical analysis.

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

T HE O NCOLOGY P HARMACIST

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CONTENTS

Vol. 1, No. 1 Feature Articles 5 Genitourinary Cancers New agent shows promise for advanced prostate cancer

CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS CONTENTS

8 New Technology Ensuring safe chemotherapy preparation

13 Gastrointestinal Cancers

May 2008 Departments 1

Medical Minutes

6

Trends in Prostate Cancer

9

Safety First program to monitor drug safety after approval

17 Gynecologic Cancers

Editorial Director Karen Rosenberg karen@greenhillhc.com Senior Production Manager Stephanie Laudien

Policy Watch

11

Trends in Hematologic Cancer

15

Trends in Colorectal Cancer

Client Service Managers John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com

Trends in Lung Cancer

Director of Human Resources Blanche Marchitto blanche@greenhillhc.com

18

Trends in Breast Cancer

Circulation circulation@greenhillhc.com

19

Clinical Trials Update

GH Green Hill HealthCare Communications

Significance of flat or depressed colorectal lesions debated

16 FDA Watch

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com

, LLC ™

™

Recent FDA Approvals

20

Your Innovative Partners in Medical Media

241 Forsgate Drive, Suite 205C Jamesburg, NJ 08831

Meetings

Maximizing adherence to aromatase inhibitors

EDITORIAL BOARD EDITOR-IN-CHIEF Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ David Baribeault, RPh, BCOP Boston Medical Center Boston, MA Sylvia Bartel, RPh, MPH Dana Farber Cancer Institute Boston, MA Marlo Blazer, RPh, PharmD Ohio State Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Columbus, OH Bryna Delman Ewachiw, BS, PharmD Johns Hopkins Bayview Medical Center Baltimore, MD Beth Faiman, RN, MSN, CNP,AOCN Cleveland Clinic Taussig Cancer Center Cleveland, OH Christopher Fausel, PharmD Indiana University Cancer Center Indianapolis, IN Rebecca S. Finley, PharmD, MS Jefferson School of Pharmacy Philadelphia, PA

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T HE O NCOLOGY P HARMACIST

David C. Gammon, BSPharm University of Massachusetts Memorial Hospital Worcester, MA

Robert B. MacArthur, PharmD Columbia University Medical Center New York, NY

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Emily Mackler, PharmD, BCOP University of Michigan Ann Arbor, MI

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

Patrick Medina, PharmD, BCOP University of Oklahoma College of Pharmacy Tulsa, OK

Lew Iacovelli, BS, PharmD, BCOP, CPP Moses H. Cone Regional Cancer Center Greensboro, NC

Laura Boehnke Michaud, PharmD, BCOP, FASHP The University of Texas MD Anderson Cancer Center Houston,TX

Andrea A. Iannucci, PharmD, BCOP University of California Davis Medical Center Sacramento, CA

Deborah Moradi, PharmD The Angeles Clinic and Research Institute Los Angeles, CA

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

LeAnn Best Norris, PharmD, BCPS South Carolina College of Pharmacy Columbia, SC

Jim Koeller, MS University of Texas at Austin San Antonio,TX

Keith M. Olsen, PharmD, FCCP, FCCM University of Nebraska College of Pharmacy Omaha, NE

Helen L. Leather, BPharm University of Florida Gainesville, FL

Debra L. Phillips, PharmD East Carolina University Greenville, NC

Christopher J. Lowe, PharmD Cleveland Clinic Taussig Cancer Center Cleveland, OH

John M.Valgus, PharmD, BCOP University of North Carolina Chapel Hill, NC

May 2008

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Our

vision extends beyond science

…making today’s therapies more accessible and tomorrow’s breakthroughs more achievable Supporting 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 tomorrow Genentech BioOncology invests deeply in research and development and is an industry leader in investing a percentage of annual revenues 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 medical needs who are uninsured or rendered uninsured by payer denial and who meet specific medical criteria to receive proper medical treatment. The Genentech Access to Care Foundation may be available to help those who are not able to obtain Genentech therapeutics for financial reasons.

www.BioOncology.com

© 2008 Genentech, Inc.

All rights reserved.

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Editor’s Letter EDITOR’S LETTER

Introducing The Oncology Pharmacist

EDITOR’S LETTER EDITOR’S LETTER EDITOR’S LETTER EDITOR’S EDITOR’S LETTER

SUSAN GOODIN, PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

IN THE LITTLE MORE THAN A DECADE since the first certification examination in oncology pharmacy was given, the field has seen many changes. Increasingly, pharmacists are called on to play a variety of roles not only in the hospital setting but in community practices as well. A major change has been the trend toward increasing use of oral chemotherapies, which puts greater responsibility on the patient to take the medication properly. Changes in reimbursement under the Medicare Modernization Act of 2003 too have had a major impact on practice of oncology pharmacy.

As part of the cancer care team, oncology pharmacists have responsibilities for ordering and dispensing drugs, advising patients and caregivers on proper drug handling and administration, and making recommendations about side effect management and avoidance of drug interactions. It is critical, therefore, for oncology pharmacists to be informed about new therapies and to keep up with results of clinical trials reported at medical meetings and in the medical literature. But they also have financial and administrative responsibilities and must be familiar with the latest federal and state regulatory 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 the hospital or clinic, oncology pharmacists also must advise patients about Medicare and Medicaid policies, private insurance coverage, and patient assistance programs.

The Oncology Pharmacist, the only newspaper written specifically for members of this expanding specialty, will address not only the clinical issues relevant to the practice of oncology but also practice management, professional education and training, and financial and regulatory issues. To help busy pharmacists meet their continuing education needs, The Oncology Pharmacist has entered into a partnership with the Center for Continuing Education at the University of Nebraska Medical Center, and, starting with the next issue, will provide an article offering ACPE credit in each issue.

Perhaps most important, The Oncology Pharmacist will be an interactive forum for oncology pharmacists in practice and in training to discuss the issues—clinical and professional—of greatest concern to them. We invite your comments, suggestions, and contributions about topics, people, and programs you would like to read about and discuss with your colleagues. Please write to us at editorial@greenhillhc.com and tell us what you would like to see in upcoming issues.

Green Hill HealthCare Communications to Partner with University of Nebraska Medical Center for Complimentary Continuing Education for Healthcare Professionals TO HELP MEET THE CONTINUING EDUCATION needs of busy practitioners, Green Hill HealthCare Communications, LLC, publisher of The Oncology Nurse and The Oncology Pharmacist, is partnering with the University of Nebraska Medical Center (UNMC), Center for Continuing Education and the UNMC College of Nursing Continuing Nursing Education to provide a complimentary continuing education activity in each issue, starting in the June 2008 issue. Accredited articles will provide a concise review of a recent article in the peer-reviewed literature or a report on a presentation at a major medical meeting, accompanied by a case report illustrating the key clinical points and commentaries by an oncology nurse and an oncology pharmacist on how the findings may apply to oncology practice.

The UNMC College of Nursing Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. Additionally, the nursing activities will be provided under Iowa Provider #78. Provider also approved by the California Board of Registered Nursing, Provider #13699.

The UNMC, Center for Continuing Education is accredited by the

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

The editorial boards of The Oncology Nurse and The Oncology Pharmacist will review the medical literature and presentations at major medical meetings to identify topics of interest to both oncology nurses and oncology pharmacists. Articles will be reviewed by the UNMC, Center for Continuing Education and the UNMC College of Nursing Continuing Nursing Education for medical accuracy and balance and to ensure that they 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 receive credit online.

Upcoming issues will feature an article on identifying patients at risk for anaphylaxis associated with EGFR inhibitor therapy and one on dosing considerations when administering cancer drugs to obese patients.

We invite your suggestions about topics of greatest concern to you and your colleagues as well as feedback on how well we are meeting your educational needs. Please write to us at editorial@greenhillhc.com and let us know what you would like to see in future issues.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual 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 journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Jamesburg, NJ 08831. The ideas and 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 other product 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 manufacturer with 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 persons or 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 currently 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 treating 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 effort has 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 Editorial Director. 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 Green Hill 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 mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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New GnRH Blocker is Effective in Advanced Prostate Cancer leuprolide. Degarelix was well tolerated with no serious side effects that were deemed treatment-related.

immediate effect on testosterone levels on a par with that of surgery,” John Anderson, MD, consultant urologic surgeon,

Royal Hallamshire Hospital in Sheffield, UK, said at a news conference.

—Jill Stein

POWER AND PERFORMANCE VIDAZA hits MDS with the strength of 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 included dizziness (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 and toxicity, but at a minimum, prior to each dosing cycle.

• Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. In addition, azacitidine and its metabolites are substantially excreted by the kidneys 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 may be useful to monitor renal function.

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

VIDAZA is FDA-approved for the treatment of all myelodysplastic syndrome (MDS) subtypes2‡: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, or CMMoL. 9221 Study Design: A randomized, open-label, phase III study comparing the efficacy and safety of 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 a dose of 75 mg/m2 daily for 7 days every 4 weeks. Dosage adjustments were allowed based on response 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% decrease in bone marrow blasts and improvement of bone marrow dyspoiesis (for RAEB, RAEB-T, and CMMoL only) plus, for all subtypes, at least a 50% restoration in the deficit from normal of baseline white cells, hemoglobin, and platelets (if abnormal at baseline) and no blasts in the peripheral circulation maintained for at least 4 weeks. For CMMoL, if white cells were elevated at baseline, PR also required at least a 75% reduction in the excess count over the upper limit of normal, maintained for at least 4 weeks.

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

*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.

VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation.

All rights reserved. 2007288 May 2007 Printed in the USA.

References: 1. Data on file. Pharmion Corporation.

2. VIDAZA full prescribing information.

000862_phvirt_jco_power_fa4.indd1 1

May 2008

“We need treatments that better mimic surgical castration but without the devastating sequelae, and degarelix has a nearly

GENITOURINARY CANCERS GENITOURINARY CANCERS

MILAN—New findings demonstrate that the investigational gonadotropinreleasing hormone (GnRH) blocker degarelix is not only as effective as standard androgen deprivation therapy (ADT) involving the GnRH agonist leuprolide in patients with prostate cancer but also accelerates testosterone suppression.

Data are from a phase 3 trial presented at the 23rd Annual Meeting of the European Association of Urology.

Laurento Boccon-Gibod, MD, professor of urology at CHU Hopital Bichat-Claude Bernard in Paris, presented results in 610 men who received one of two doses of subcutaneous degarelix (80 or 160 mg monthly) or leuprolide depot, 7.5 mg monthly, over 12 months.

The trial enrolled men with histologically confirmed adenocarcinoma of the prostate (of any stage) for which androgen ablation was indicated. Men who required neoadjuvant hormonal therapy were ineligible.

“GnRH agonists are the mainstay of ADT for prostate cancer; however, important limitations include a delayed effect on testosterone and prostate-specific antigen (PSA) along with a testosterone surge and possible symptoms of flare,” Dr Boccon-Gibod pointed out.

In the trial, suppression of testosterone to 0.5 ng/mL at all monthly measurements from day 28 to day 364 was considered a treatment response. The study was designed to demonstrate statistical noninferiority of degarelix versus leuprolide 7.5 mg for treatment response.

Results showed that both doses of degarelix were at least as effective as leuprolide in terms of response to treatment. Suppression of testosterone levels to 0.5 ng/mL occurred significantly faster in patients receiving degarelix than in those receiving leuprolide. By day 3, 97% and 96% of degarelix-treated patients (160 mg and 80 mg, respectively) and 0% of those receiving leuprolide demonstrated a treatment response.

The GnRH blocker did not cause a testosterone surge or microsurge and was associated with a more rapid reduction in PSA levels than leuprolide. After 14 days of treatment, median PSA levels had declined by 65% and 64% in patients receiving degarelix (160 and 80 mg, respectively) and 18% in patients receiving

†

6/19/07 1:54:43 PM

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GENITOURINARY CANCERS

Genitourinary Cancers

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Trends in Prostate Cancer TRENDS IN PROSTATE CANCER

Trends in Prostate Cancer MR Imaging Helps Predict Prostate Cancer Recurrence

therapy for prostate cancer. The finding is based on a retrospective study of 80 men (mean age, 59 years) with biopsyproved prostate cancer who underwent endorectal MR imaging of the prostate prior to external-beam radiation therapy. All MR imaging studies were inde-

Pretreatment endorectal magnetic resonance (MR) imaging findings are important predictors of posttreatment metastatic recurrence in patients undergoing external-beam radiation

Brief Summary of Prescribing Information VIDAZA (azacitidine for injection) only For subcutaneous and intravenous use only INDICATIONS AND USAGE VIDAZA is indicated for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

CONTRAINDICATIONS VIDAZA 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).

WARNINGS Pregnancy - Teratogenic Effects: Pregnancy Category D VIDAZA 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/m (approximately 8% of the recommended human daily dose on a mg/m basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3–12 mg/m (approximately 4%–16% the recommended human daily dose on a mg/m basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4–8 (postimplantation) at a dose of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m basis), although treatment in the preimplantation period (on gestation days 1–3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3–12 mg/m (approximately 8% the recommended human daily dose on a mg/m basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m on gestation days 9 and 10; average live animals per litter was reduced to 9% 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 avoid becoming pregnant while receiving treatment with VIDAZA. Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of premating effects of azacitidine exposure on male fertility and embryonic viability.)

PRECAUTIONS General Treatment with VIDAZA is associated with neutropenia and thrombocytopenia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response as described in DOSAGE AND ADMINISTRATION. Safety and effectiveness of VIDAZA in patients with MDS and hepatic or renal impairment have not been studied as these patients were excluded from the clinical trials.

Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L. Azacitidine is contraindicated in patients with advanced malignant 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 Patients Patients should inform their physician about any underlying liver or renal disease.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VIDAZA. Men should be advised to not father a child while receiving treatment with VIDAZA. Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy.

Drug Interactions No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted.

(See CLINICAL PHARMACOLOGY.) ®

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Carcinogenesis, Mutagenesis, Impairment of Fertility The 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/m , approximately 8% the recommended human daily dose on a mg/m basis) administered IP 3 times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m , approximately 8% the recommended human daily dose on a mg/m basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m (approximately 20%–80% the recommended human daily dose on a mg/m basis) revealed an increased incidence of testicular tumors compared 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/m (approximately 9% the recommended human daily dose on a mg/m basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats three times per week for 11 or 16 weeks at doses of 15–30 mg/m (approximately 20%–40%, the recommended human daily dose on a mg/m basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. (See WARNINGS.) Pregnancy Teratogenic Effects: Pregnancy Category D. (See WARNINGS.) Nursing Mothers It 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 Use Safety and effectiveness in pediatric patients have not been established.

Geriatric Use Of 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 may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION section).

ADVERSE REACTIONS Overview Adverse 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 IV Route): 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 Information The data described below reflect exposure to VIDAZA in 268 patients, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately 1 year). VIDAZA was studied primarily in supportive-care-controlled and uncontrolled 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, and 94% white, and had MDS or AML. The population in the IV study (n = 48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m .

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 was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months.

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Overall, more than one third of the patients received mismatched treatments. pendently reviewed by two experienced readers who recorded tumor T stage and the radial diameter of extracapsular

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

All VIDAZAc Observationd (N=220) (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) 36 (16.4) 9 (9.8) Epistaxis 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) 32 (14.5) 8 (8.7) Skin lesion 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) 28 (12.7) 12 (13.0) Hypokalemia Upper respiratory tract 28 (12.7) 4 (4.3) infection 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) 22 (10.0) 2 (2.2) Rhinorrhea 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 17 (7.7) 1 (1.1) decreased Lethargy 17 (7.7) 2 (2.2) Oral mucosal 17 (7.7) 3 (3.3) petechiae 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) 15 (6.8) 1 (1.1) Hemorrhoids 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 13 (5.9) 1 (1.1) hemorrhage

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

All VIDAZAc Observationd (N=220) (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 11 (5.0) 0 granuloma Injection site 11 (5.0) 0 pigmentation changes 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) 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 patient are 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: cholecystitis Immune 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 80301 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Edition Date: 9 January 2007 Brief Summary of Prescribing Information VIDAZA is a registered trademark of Pharmion Corporation. © 2007 Pharmion Corporation. All rights reserved.

VIDB010907A January 2007 Printed in USA.

extension if present. After a mean follow-up of 43 months, four patients developed metastases.

Significant predictors of the development of metastases on univariate analysis were baseline serum prostate-specific antigen level, presence of extracapsular extension at MR imaging, and degree of extracapsular extension. The sole independent predictive variable on multivariate analysis was mean diameter of extracapsular extension (relative hazard ratio, 2.06; P = .007). Of five patients with extracapsular extension of more than 5 mm at pretreatment MR imaging, three developed metastases at 24 to 63 months after therapy. (McKenna DA, et al. Radiology. 2008; 247:141-146.)

Prostate Cancer Patients Pick Treatments That May Worsen Quality of Life Patients with prostate cancer and preexisting dysfunction often select relatively contraindicated or mismatched treatments associated with worsening of symptoms and poorer outcomes, according to researchers at Massachusetts General Hospital.

Prostate cancer treatment choices were examined in 438 patients with prostate cancer, of whom 389 (89%) reported preexisting dysfunction.

Preexisting obstructive uropathy and bowel dysfunction were considered relative contraindications to brachytherapy (BT) and externalbeam radiation therapy (EBRT), respectively, because they increase patients’ vulnerability to treatmentrelated toxicity. Baseline sexual dysfunction was considered to negate the intended benefit of nerve-sparing radical prostatectomy (NSRP), which is to preserve sexual function.

Overall, more than one third of the patients received mismatched treatments. Treatment mismatches did not significantly increase with clinical complexity. The strategy of watchful waiting was used infrequently, even in patients with contraindications to all treatment options. Treatment choices were associated with patient age and comorbidities but not preexisting dysfunction. Mismatched BT and EBRT led to worsened urinary and bowel symptoms, respectively, and NSRP did not improve outcomes in patients with baseline sexual dysfunction. (Chen RC, et al. Cancer.

2008;112:61-68).

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New Technology NEW TECHNOLOGY

Automated System Increases Safety of Chemotherapy Preparation

NEW TECHNOLOGY NEW TECHNOLOGY NEW TECHNOLOGY NEW TECHNOLOGY

LAS VEGAS—At the award presentation at the 42nd Midyear Clinical Meeting of the American Society of Health-System Pharmacists in Las Vegas, University of Kansas pharmacy administrators described an innovative method for increasing the safety of chemotherapy preparation.

Many academic medical center pharmacies—including the inpatient pharmacy at the University of Kansas Hospital—use the syringe pullback method for checking chemotherapy preparations. In the isolated chemotherapy preparation room, a pharmacy technician fills the syringe with medication and injects it into an intravenous (IV) solution bag. The pharmacist then checks the plunger of an empty syringe to determine the volume of medication added to an admixture. With this method a pharmacist typically does not check the volume of the syringe prior to injection into the IV solution bag.

“There has to be a lot of trust between the pharmacist and technician that the syringe was pulled back accurately,” said Brian O’Neal, MS, PharmD, assistant pharmacy director at the University of Kansas Hospital, in Kansas City. “There just shouldn’t be assumptions in chemotherapy preparation,” he added.

To reduce the risks associated with the syringe pullback method, Dr O’Neal and his colleagues instituted use of Telepharmacy for Sterile Room Med preparation hardware and software to take digital photographs during the chemotherapy preparation process. These photographs, taken at critical risk points in chemotherapy preparation, along with the patient’s medication order can be reviewed remotely by pharmacists. Additional goals of the project were to improve the readability of chemotherapy-vial labels and to reduce the risk of selecting the wrong chemotherapeutic medication through the use of barcode technology. “The objective of the program,” Dr O’Neal explained, “was to find a way to improve safety by increasing the presence of the pharmacist at critical risk points during the preparation process, while making the most efficient use of the limited availability of clinical pharmacists.”

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

Screen shot combines inspection images of syringe, fluid bag, prescription label.

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

logical safety cabinet was placed in the clean room. First, a technician scans the barcode on the vial. A computer match to the patient’s record ensures that the correct formulation has been selected. The technician then takes photos of the work label, the vials and fluids to be used, and, lastly, the syringe (before injection into the bag). A pharmacist views these photos from a “check station” in the ante room when verifying the finished product. Confirmation of the review steps and related images are archived as part of the electronic record and are available for future reference.

After 1 month, this process demonstrated safety improvements in four main areas: • Verifying chemotherapy products with barcode technology helped to ensure that the correct drug was selected.

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

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

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

This use of telepharmacy and barcode technology resulted in a pharmacist’s intervention in 1.1% (four of 363) of prepared doses during the data collection period (July 1 through July 31, 2007). An intervention was defined as a pharmacist’s request to increase volume, decrease volume, or to remake the product.

“The improvements in safety and accountability led us to discontinue use of the syringe pullback method for checking chemotherapy,” Dr O’Neal said. “Without interrupting workflow, a pharmacist can now observe the riskiest steps of chemotherapy preparation, thus increasing the odds of detecting errors. Our compounding error rate is no longer unknown and unidentifiable. By documenting and reviewing more of the steps in the chemotherapy preparation process with telepharmacy and barcode technology, we have significantly increased our chances of catching errors before they leave the pharmacy.”

More information about the ScriptPro Telepharmacy for Sterile Room Med Preparation and other technology for pharmacies, can be found at medication vial, and www.scriptpro.com.

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Policy Watch

Employers, health insurers, and pharmacy benefit managers are exploring novel ways to contain spending, including approval of biogenerics Report Cites Progress and Challenges in Improving State Pain Policies Both cancer patients and survivors commonly experience pain that, if unrelieved, can adversely affect their functioning, productivity, and even their will to live. “Increasingly, unrelieved pain is becoming recognized as a significant public health problem in the United States,” according to a recent report by Aaron M. Gilman, PhD, and other members of the Pain & Policy Studies Group (PPSG) (CA Cancer J Clin.

2007;57:341-353). Among the factors contributing to inadequate pain management are healthcare practitioners’ concerns about regulatory scrutiny and restrictive drug control and healthcare policies governing medical use of prescription drugs.

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

May 2008

De rnie

MEMBERS OF CONGRESS, THE BUSH ADMINISTRATION, and private payers are calling for legislation that would allow approval of generic biologics, or biogenerics, as one way to reduce spending on specialty pharmaceuticals for cancer and other conditions. According to a report in The Wall Street Journal (March 20, 2008), employers, health insurers, and pharmacy benefit managers are exploring novel ways to contain spending, including approval of biogenerics, because specialty drugs are a major factor in escalating healthcare costs. Other measures being considered are tighter enforcement of step-therapy policies, 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 submitted for US Food and Drug Administration (FDA) approval, and The New York Times (April 19, 2008) reports that spending on these drugs increased 16.5% in 2006, totaling about $62 billion, or about 23% of overall drug sales in the United States that year.

Bills that could lead to an approval pathway for biogenerics have been introduced in both the House and Senate but there is controversy about the details. According to the American Society of Clinical Oncology (www.asco.org), “One of the main points of contention in these legislative proposals is the degree to which biogenerics can be substituted for the brand name product (so-called interchangeability).”

A bill introduced in the Senate last year (S. 1695) includes basic data requirements needed to categorize a biogeneric as a “biosimilar” product, whereas the House bill (H.R. 1038) contains fewer data requirements and allows the FDA greater leeway in determining whether a biogeneric is “comparable” to the brand product. Provisions of both bills would allow substitution of the biosimilar or comparable product without approval of the healthcare professional who prescribed it if the manufacturer has provided evidence that the biosimilar product can be expected to produce the same clinical result as the brand product in any given patient.

has been substantial progress since the policy-evaluation process began in 2000,” the authors state, “but there is much more opportunity for improvement.” They say it is crucial for healthcare practitioners to be familiar with their state’s pain policies and offer suggestions for the role they can play in improving these policies. “Positive policy change is a crucial first step….but with no implementation has little practical value,” they write. “Policies must be put into practice through advocacy and education.”

©iS toc kph oto .co m/A ndr ew

Legislators, Payers Support Approval of Biogenerics

Massachusetts Proposal to Limit Drug Reps Gifts Stirs Controversy A bill being drafted by Massachusetts legislators would prohibit physicians from accepting even token gifts, such as a pen or a slice of pizza, from drug manufacturers. Doctors who accepted such a gift could have to pay up to $5,000 in fines and serve up to 2 years in prison. The proposed legislation has generated heated discussion by supporters and opponents of the bill, as shown by responses 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 representatives do provide some useful information, especially about new drugs. Others, though skeptical about the information drug representatives provide say they want to decide for themselves whether or 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 and Thomas Stossel write, “We believe the best approach to optimize cost effectiveness 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 Favor National Health Insurance Results of a nationwide survey indicate that the majority of US physicians now support the concept of national health insurance (Ann Intern Med. 2008;148:566-567). Of 2,193 physicians who responded to the survey, 59% expressed support for legislation to establish a national health insurance program, whereas 32% opposed it, and 9% had no opinion. The number in favor of national health insurance represents a 10% increase compared with a similar poll conducted in 2002, in which only 49% of respondents endorsed such a plan. Fifty-five percent of respondents favored an incremental approach to achieving universal coverage, whereas 25% opposed incremental reform. Another 14% favored incremental reform but were opposed to national health insurance. The American Medical Association is against government-run national health insurance and instead proposes expanding coverage through tax credits.

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POLICY WATCH POLICY WATCH POLICY WATCH POLICY WATCH POLICY WATCH

POLICY WATCH

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with ESAs, and it now appears even further restrictions will soon be placed on the use of ESAs in patients with cancer.

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

“There are now eight trials in which patients with cancer who received ESAs have shorter survival and/or poorer tumor control than patients receiving similar anticancer treatments but no ESAs. The committee advised the FDA that product labeling be revised,” FDA spokeswoman Crystal Rice said in an interview. “In addition, ODAC recommended that patients should not take ESAs until their hemoglobin level falls below 10 g/dL. The FDA is considering the advice of the ODAC in planning the next steps.”

Taken together, all eight studies showed more rapid tumor growth or shortened survival when patients with breast, non–small-cell lung, head and neck, lymphoid, or cervical cancers received ESAs compared with patients who did not receive ESAs. In all these recent studies, ESAs were administered in an attempt to 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 protein made in the kidneys that stimulates the bone marrow to produce more red blood cells. FDA-approved uses of ESAs are for the treatment of anemia in patient with chronic kidney failure and for cancer patients whose anemia is caused by chemotherapy. ESAs are also approved for patients infected with HIV whose anemia

is caused by the HIV drug zidovudine. ESAs are also approved to reduce the number of transfusions during and after major surgery.

On November 30, 2007, Amgen, the manufacturer of the three ESAs, provided the FDA with information from the 733-patient PREPARE study of women who received chemotherapy before undergoing surgery for breast cancer. After 3 years, 14% of the patients who received darepoetin alfa to treat their anemia had died compared with 9.8% of those who did not receive the drug. Tumor growth was also faster in patients receiving the ESA. Charles L. Bennett, MD, PHD, and his colleagues conducted a phase 3 trial to examine the rate of venous thromboembolism (VTE) and death associated with ESA administration for the treatment of anemia in cancer patients (JAMA. 2008;299:914-924). The findings indicated that the risk of death was significantly higher for cancer patients who were treated with an ESA compared with the placebo group. The researchers identified 51 clinical trials involving 13,611 patients and compared survival rates. VTE was evaluated in 38 trials that included 8,172 patients. The researchers found that there was a significantly increased risk (57%) of VTE among patients receiving ESAs compared with those who received placebo.

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

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

cians to be fully aware of what basic science and clinical data show in regard to the use of ESAs. He said the data do not support the idea that these agents improve quality or quantity of life.

But not everyone agrees. Some clinicians and pharmacists are concerned that further restrictions on the use of ESAs may greatly impact the care of many cancer patients and put prescribing physicians in a difficult position.

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

Mr Peters also questions the validity of the latest review studies because they include data from when prescribing practices were much different than they are today. “There are a lot of data that are not pertinent to today’s practice, but they are still being considered in the FDA’s ultimate decision on these drugs,” he said “In the meta-analysis studies, they were using it at much higher stopping points, and that is not standard of practice today. They were treated at significantly higher hemoglobin levels and, clearly, the higher you go, the higher the risk for problems.”

HEMATOLOGIC TRENDS IVE CARE SUPPORTIVE CARE

Continued from cover

—John Schieszer

Hemotologic Trends Trends in Hematologic Cancer Fused PET/CT Imaging Useful in Determining Response to Radiotherapy in B-cell NHL A NEW STUDY SUGGESTS THAT USE of combined fusion fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging is superior to CT imaging alone in the evaluation of yttrium 90 (90Y)–ibritumomab tiuxetan radioimmunotherapy treatment of B-cell nonHodgkin’s lymphoma (NHL). A group of 10 patients (mean age, 52 years) with relapsed or refractory NHL underwent FDG PET/CT imaging both 14 to 27 days before treatment with 90Y–ibritumomab tiuxetan and 4 to 6 months after treatment. Interpretation of CT images alone resulted in classification of eight patients as responders to treatment, of whom two were classified as having a complete response. At reevaluation with fused PET/CT imaging, two patients had residual lesions at CT that did not show evidence of FDG avidity. Both of these patients were classified as partial responders according to CT criteria alone and reclassified as complete responders at PET/CT. Both of these patients were free of evident disease after ≥18 months of follow-up. The researchers concluded that the use of CT imaging alone may underestimate 90Y–ibritumomab tiuxetan responses by classifying inactive residual CT masses as residual disease. Combined PET/CT scanning

May 2008

could help avoid unnecessary follow-up treatments.

(Ulaner GA, et al. Radiology. 2008;246:895-902.)

SGX393 Inhibits CML Mutant Clone and Helps Preempt Emergence of Resistance SGX393 is a potent inhibitor of native and T315Imutant Bcr-Abl, a deregulated tyrosine kinase that causes chronic myeloid leukemia (CML). Bcr-AblT315I is resistant to Abl kinase inhibitors in current use and is emerging as the most frequent cause of salvage therapy failure in patients with CML. In preclinical studies, SGX393 blocked the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-AblT315I, with minimal toxicity against Bcr-Abl–negative cell lines or normal bone marrow. Screening for Bcr-Abl mutants emerging in the presence of SGX393 revealed a concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted the emergence of resistant Bcr-Abl subclones, including Bcr-Abl T315I. These findings suggest that treatment with the combination of SGX393 and currently available Abl kinase inhibitors may be a useful strategy for inhibiting the emergence of Bcr-Abl mutants in patients with Philadelphia chromosome-positive CML. (O’Hare T, et al. Proc Natl Acad Sci. 2008;105:5507-5512.)

Chemotherapy Plus Radioimmunotherapy Effective in Untreated Follicular NHL The combination of fludarabine and mitoxantrone plus yttrium-90 (90Y)-labelled ibritumomab tiuxetan is effective and tolerable in previously untreated patients with follicular non-Hodgkin’s lymphoma (NHL). In a nonrandomized, open-label, phase 2 study, 61 patients with stage III or IV untreated indolent follicular NHL received oral fludarabine and intravenous mitoxantrone every 28 days for six cycles. Patients who had at least a partial response (PR) without significant hematologic toxicity at 4 to 6 weeks after completion of the sixth cycle of chemotherapy received one course of 90Y-labelled ibritumomab tiuxetan. Of the 61 patients who received six cycles of fludarabine and mitoxantrone, 43 had a complete response (CR) and 17 had a PR. A total of 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent 90Y-labelled ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 achieved CR after 90Ylabelled ibritumomab tiuxetan. By the end of the entire treatment regimen, 55 of 57 patients achieved CR. Three-year progression-free survival was 76% and 3-year overall survival was 100%. Of the 57 patients who completed therapy, 36 had grade 3 or 4 hematologic side effects, and 21 received blood transfusions.

(Zinzani PL, et al. Lancet Oncol. 2008;9:352-358.)

T HE O NCOLOGY P HARMACIST

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HEMATOLOGIC TRENDS

FURTHER LIMITS ON USE OF ESAs

SUPPORTIVE CARE

Supportive Care

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Pharmacy Education and Training PHARMACY EDUCATION AND TRAINING PHARMACY EDUCATION AND TRAINING PHARMACY EDUCATIO

TRENDS IN PHARMACY Continued from cover 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 graduated their first class. New schools are not eligible for full accreditation status until they have graduated their first class.

HOW MIGHT THE JEFFERSON PROGRAM DIFFER FROM THOSE OF EXISTING PHARMACY SCHOOLS? ARE THERE ANY INNOVATIVE FEATURES IN YOUR CURRICULUM? As mentioned above, a key objective of the TJU School of Pharmacy is to ensure that our students are prepared to practice effectively in interprofessional groups as well as to solve problems independently. We are building opportunities throughout the curriculum for students to work with the Jefferson nursing, medical, and health professions (physical therapy, occupational therapy, etc) students in a variety of academic and community outreach initiatives. A major goal of our program is to prepare our graduates for leadership roles, so we will focus on optimizing their leadership skills, effectiveness in teams, and their ability to integrate emerging healthcare issues into contemporary pharmacy practice. Throughout the professional curriculum, students will have the opportunity to enhance their communication, critical thinking, and collaborative skills along with understanding and, 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 to lead to professional practice as a pharmacist is the Doctor of Pharmacy (PharmD) degree, which typically requires 6 academic years (2 years prepharmacy courses followed by 4 years of professional pharmacy coursework). Before 2000, both a 5-year Bachelor of Science and the PharmD degree were available. With this change came an increased focus on patient care-related (ie, clinical) training, which prepares pharmacists to take an active role in making medication-related decisions. All pharmacists are now trained to make evidence-based decisions regarding medication therapy for individual patients as well as population-based decisions (such as the development of clinical practice guidelines). The newest ACPE accreditation standards, which were implemented on July 1, 2007, provide for more experiential education throughout the entire curriculum, so that students will interact with practicing pharmacists, other healthcare professionals, and patients throughout the four professional years of the PharmD program. These new standards now hold schools far more accountable than before to demonstrate that they are achieving their stated objectives.

IS THERE MORE INTEREST IN SPECIALIZING IN SPECIFIC FIELDS LIKE ONCOLOGY THAN IN THE PAST? Although postgraduate accredited residency programs (emphasizing advanced practice and leadership development) for pharmacists have been available since the 1940s and structured fellowship programs (more focused on research) since the 1970s, the advent of the PharmD-only degree resulted in an increased emphasis by schools of pharmacy as well as employers (especially hospitals and healthcare systems) on post-PharmD training. The number of these postgraduate training programs has grown significantly, and many practice settings require such training for employment. Most practicing pharmacists are “generalists,” but the number of specialty areas for pharmacists has continued to broaden over the past several decades.

Some areas of specialty pharmacy practice correspond to wellknown specialties in medicine and nursing, such as oncology, pediatrics, cardiology, nutrition, nephrology, infectious diseases, and psychiatry; other pharmacy specialties focus on knowledge and skills that are unique to pharmacy practice, such as compounding, nuclear pharmacy, or pharmacy administration. An example of an emerging specialty interest in pharmacy is informatics.

12

T HE O NCOLOGY P HARMACIST

Oncology has been an area of interest for many pharmacists for several decades.The term oncology pharmacist first appeared in the early 1970s, and in the early 1980s, the American Society of Health-System Pharmacists (ASHP) implemented the first postgraduate residency training standards for oncology pharmacists. Soon after that, the first oncology fellowship programs emerged as well. Almost all health systems that provide oncology care readily REBECCA S. FINLEY, PharmD, MS recognized the need for pharmacists with specialized expertise and recruited these highly trained individuals.

Organizations such as the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) also recognized the importance to patient safety in having welltrained oncology pharmacists. In the early 1990s, ASHP, with the support of ASCO, ONS, and a number of other organizations, petitioned the Board of Pharmaceutical Specialties for designation of Oncology Pharmacy as a specialty within pharmacy practice. This designation was approved, and the first certifying examination was administered in 1996. There are currently 757 board-certified oncology pharmacists. The Hematology Oncology Pharmacists Association currently has more than 900 members. Clearly, as the field of oncology has expanded, the number of pharmacists interested in and practicing in oncology has increased.

WHAT OPPORTUNITIES ARE THERE FOR ADVANCED TRAINING FOR A PHARMACY STUDENT INTERESTED IN ONCOLOGY? Currently, ASHP accredits 39 specialty residency programs in oncology. These are referred to as PGY2 programs because all oncology residents must first complete a PGY1 1-year residency training program before beginning their oncology specialty training. There are six to 10 well-established fellowship programs for pharmacists in oncology.

I believe that if pharmacy students are interested in oncology they should consult with their faculty advisor, the director of experiential education at their institution, and any of their faculty members who have an interest or expertise in this field. Those individuals can assist the student in identifying experiential rotations and elective coursework that may complement the oncology material in the required curriculum and also help them to identify potential career mentors. A student thinking about a career as an oncology pharmacist who is involved in direct patient care or research should plan on at least 2 years of postgraduate training (eg, PGY1 residency followed by a PGY2 oncology specialty residency). Students may also want to contact preceptors of accredited oncology residency programs directly to find out specifics about the program and what type of background they expect from applicants (eg, would applicants need to have completed at least one oncology rotation during their PharmD training or their PGY1 residency?).

WHAT ARE THE EMPLOYMENT POSSIBILITIES FOR A PHARMACY STUDENT INTERESTED IN ONCOLOGY? HOW DOES ONE GET STARTED IN THE FIELD? Oncology pharmacists are employed by cancer centers, hospitals with inpatient and/or outpatient oncology services, schools of pharmacy, pharmaceutical companies (regulatory affairs, drug information, medical science liaisons, research positions), large ambulatory oncology group practices, health plans with oncology services, medical education companies with oncology offerings, and other medical publishers. In addition, some oncology pharmacists are employed by medical schools (usually in research positions) and other research organizations.

—Karen Rosenberg

References

1. 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

May 2008

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Gastrointestinal Cancers the same time it can be removed completely to prevent cancer.”

However Jerome Waye, MD, one of the investigators in the multicenter American National Polyp Study, counsels caution when evaluating the results. “If you look at the lesions that contained invasive carcinoma in the JAMA study, there were only two in the flat adenoma 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 private practice and a clinical professor of medicine, Mount Sinai School of Medicine, New York. “And the field has really abandoned the term carcinoma in situ in favor of high-grade dysplasia, because the word carcinoma is misleading. In the colon, high-grade dysplasia is not ominous, because it’s not cancer.”

Dr Waye added that a post hoc analysis of the National Polyp Study specimens by him and his colleagues supports the view that nonpolypoid lesions are not dangerous. They confirmed in a review of the pathology slides that while 27% of all of the adenomas they removed were flat, lesions with this type of morphology were not associated with a higher risk for high-grade dysplasia at initial colonoscopy compared with the sessile lesions (Clin Gastroenterol Hepatol. 2004;2:905-911). Furthermore, they also were not associated with a higher rate of advanced adenoma at follow-up surveillance.

Robert Petras, MD, national director, gastrointestinal pathology, AmeriPath/Quest Diagnostics, Cleveland, agrees with Dr Waye’s points—including his underlying contention that clinicians are not missing nonpolypoid lesions. “There isn’t a whole lot of 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 cancers—a much higher rate than we have. …We may also have nomenclature differences. This may also explain why the Japanese have such a marvelous survival rate following resection for stomach cancer —many of what they report as cancer cases don’t actually have cancer by Western criteria.”

The Flat Lesion Study led by Dr Soetikno involved 1,819 patients undergoing elective colonoscopy at the Veterans Affairs Palo Alto Health Care System between July 2003 and June 2004. Of the 1,819 patients, 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 invasivecancer and seven high-grade dysplasia lesions—and another 18 were depressed—including two invasive cancers and four high-grade dysplasia lesions.

Among the 1,235 nonneoplastic lesions, 1,155 were polyploid and 80 were flat.

The investigators removed every polyp they detected, including using endoscopic mucosal resection to remove four of the seven flat lesions with high-grade dysplasia, and surgery to remove the other three.

“At the end of the day, one interval cancer is one too many,” said Dr Soetikno. “The patient, referring physician, and insurer expect a high-quality colorectal cancer screening colonoscopy—one that encompasses the detection, diagnosis, and removal of all neoplasms, both polypoid and nonpolypoid.”

—Rosemary Frei

Routine H Pylori Screening Recommended by High-powered Consensus Group ROUTINE HELICOBACTER PYLORI SCREENING of American populations at high risk for gastric cancer may be on its way. Attendees of the Asia-Pacific Gastric Cancer Consensus conference are calling for H pylori screening and treatment in all adults at high risk of gastric cancer, including asymptomatic individuals (Am J Gastroenterol. 2008;103:510-514; J Gastroenterol Hepatol. 2008;23:351-365).

“There is no doubt that this set of recommendations will generate controversy.… However, after carefully weighing all of the available evidence, it is our opinion that waiting another 20 years to obtain all the hard data will lead to a substantial number of unnecessary deaths from preventable cancer,” the consensus panel authors conclude.

According to the panel, populations in the United States at high risk for gastric cancer may be candidates for routine screening programs. These include Korean men in Los Angeles, who have an age-standardized gastric-cancer incidence rate of more than 40/100,000, and Alaskan native men, who have a rate of 36/100,000. Moreover, the rate of gastric cancer in Asian men in California and in Iowa is higher than among other American men, at 22.2 and 49.7 cases/100,000, respectively. This is according to infor-

May 2008

mation from the Surveillance Epidemiology and End Results database from 2000-2004.

The consensus conference was supported by the Journal of Gastroenterology and Hepatology and by the Asian Pacific Association of Gastroenterology. Two of the three lead authors have consulted for, been on advisory boards or speakers’ bureaus for, or received research support from, a variety of drug companies, including the manufacturers of the drugs they recommend for H pylori eradication.

The team reviewed the literature, and also performed a meta-analysis, which indicated that the pooled relative risk of developing gastric cancer after H pylori eradication is 0.56 (95% confidence interval 0.40.8). They concluded that eradication would lead to reduction of not only gastric cancer rates, but also of peptic ulcer disease, peptic ulcer bleeding and deaths, and dyspepsia and functional dyspepsia, and that it would decrease the number of upper endoscopies and amount of long-term acid suppression required.

The team noted the optimal choice of antibiotic therapy for positive cases depends on local and national treatment guidelines, but that 1 week of triple therapy, such as with clarithromycin, amoxicillin, and a proton pump inhibitor should suffice. The

most commonly used proton pump inhibitors include esomeprazole and omeprazole. The team said they believe such treatment will not increase the prevalence of antibiotic resistance, nor other potential negative sequalae.

Martin Blaser, MD, who is Frederick H. King professor of internal medicine, chair, Department of Medicine, and professor of microbiology, Langone Medical Center, New York University, wrote in 1999 that H pylori eradication may cause a marked increase in cases of gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma (J Infect Dis. 1999;179:1523-1530).

“They misquoted me in the consensus recommendation paper—they said I believed eradicating H pylori has more risks than benefits. But I didn’t say that; I said we don’t know. And we still don’t know,” Dr Blaser told The Oncology Pharmacist. “For example, we don’t yet know how to accurately identify all the high-risk people. And also, we have been involved in studies that show children who don’t have H pylori are at higher risk of having asthma.… Everybody’s painting the world in a black and white way—and H pylori is gray.”

—RF

T HE O NCOLOGY P HARMACIST

13

GASTROINTESTINAL CANCERS GASTROINTESTINAL CANCERS

PREVENTION OF COLORECTAL CANCER (CRC) has traditionally focused on detecting and removing polypoid, or protruding, lesions. A new study that showed a higher percentage of high-grade dysplasia and submucosal invasive cancer in flat or depressed colorectal lesions than in polypoid lesions (JAMA. 2008; 299:1027-1035) has generated much discussion.

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

In the published analysis, the investigators grouped together high-grade dysplasia—which they label carcinoma in situ—and submucosal invasive carcinoma.

They concluded that nonpolypoid morphology is associated with an adjusted odds ratio of 9.78 for “containing carcinoma.”

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

Lead investigator Roy Soetikno, MD, MSc, and his coauthors stand by their nomenclature and findings, concluding that if clinicians miss flat or depressed lesions, this can have serious consequences for patients. “In the West, there is a tendency to avoid the terminology carcinoma [and use high-grade dysplasia instead of carcinoma in situ], but this has no relevance to the pathologic criteria or to the implications of the diagnosis,” said Dr Soetikno, chief of gastroenterology, Veterans Affairs Palo Alto Health Care System.

“Carcinoma in situ or high-grade dysplasia is dangerous; it is just one step before invasive cancer. But at

GASTROINTESTINAL CANCERS

Study Stirs Debate About Importance of Flat or Depressed Colorectal Lesions

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The

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TRENDS IN COLORECTAL CANCER

Trends in Colorectal Cancer Trends in Colorectal Cancer

Colonoscopy Follow-up Guidelines Found to Have Limited Predictive Value RESULTS OF A NATIONAL CANCER INSTITUTE study suggest that the number and size of polyps removed at colonoscopy are of limited value in predicting recurrence of advanced adenoma. The findings raise questions about the adenoma-based risk-stratification system used in current postpolypectomy colonoscopy surveillance guidelines. The subjects of the study were 1,905 participants in the Polyp Prevention Study who had adenoma removed at baseline and underwent repeat 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% for those classified as at high risk under the current guidelines and 4% for those considered to be at low risk. The authors note that misclassification of patients as high or low risk may mean that potentially preventable colorectal cancers are missed or that limited endoscopic resources are unduly burdened. The findings, they say, point to the need to improve the predictive ability of the guidelines. (Laiyemo A, et al. Ann Intern Med. 2008;148:419-426.)

CT Colonography May Be Better than Colonoscopy for CRC Screening COMPUTED TOMOGRAPHIC COLONOGRAPHY (CTC) may be both more clinically effective and cost-

effective than colonoscopy with or without ultrasonography for screening for colorectal cancer (CRC), Italian researchers report. The advantages, however, are seen when findings such as extracolonic cancer and abdominal aortic aneurysms as well as colorectal neoplasia are considered. The researchers used a computerized Markov model to simulate the occurrence of colorectal neoplasia, extracolonic cancers, and abdominal aortic aneurysms in a hypothetical cohort of 100,000 50year-old subjects. They compared CTC with optical colonoscopy (OC) with or without one-time abdominal ultrasonograph (OC-US). In the simulated population, CTC was found to be the dominant screening strategy, adding 1,458 life-years compared with OC and 462 life-years compared with OC-US. CTC was also less costly than the other techniques, the savings being $266 and $449 per person compared with OC and OC-US, respectively. The gains for CTC were largely attributable to a reduced number of deaths due to abdominal aortic aneurysm. The CRC prevention rate was slightly better with optical colonoscopy with or without ultrasonography than with CTC; this was offset, however, by gains related to abdominal aortic aneurysm. All three methods were more costeffective than no screening. (Hassan C, et al. Arch Intern Med. 2008;168:696-705.)

TRENDS IN LUNG CANCER TRENDS IN COLOR

KRAS STATUS SHOULD be considered when determining whether patients with metastatic colorectal cancer (mCRC) are candidates for panitumumab monotherapy because KRAS mutations are predictive of lack of clinical response to the epidermal growth factor inhibitor. This finding comes from a phase 3 study comparing panitumumab monotherapy with best supportive care (BSC) in patients with chemotherapy-refractory mCRC. The investigators used polymerase chain reaction on DNA from tumor secretions to detect KRAS mutations, and they compared the effect of panitumumab monotherapy on progression-free survival (PFS) in patients with mutant versus wild-type (WT; ie, nonmutated) KRAS. Of 463 patients in whom KRAS status was ascertained, 427 (92%) had KRAS mutations. The effect of panitumumab on PFS was significantly greater (P < .0001) in patients with WT KRAS than in those with mutant KRAS. In the WT KRAS group, median PFS was 12.3 weeks for panitumumab-treated patients compared with 7.3 weeks for those who received BSC. Seventeen percent of patients with WT KRAS but none of those with mutant KRAS responded to panitumumab. Overall survival was longer in the WT KRAS group than in the mutant KRAS group.

Consistent with longer exposure to the drug, more grade III treatment toxicities were observed in the WT KRAS group. No significant differences in toxicity were found between the WT KRAS group and the overall population. (Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.)

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

Trends in Lung Cancer Trends in Lung Cancer Combination Chemotherapy Better than Erlotinib in First-line Management of NSCLC COMBINATION CHEMOTHERAPY with carboplatin and paclitaxel is superior to erlotinib in previously untreated patients with advanced nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC), according to the findings of a phase 2 study. A group of 103 patients with advanced NSCLC were randomized to receive erlotinib 150 mg orally daily until progression or to standard therapy with carboplatin and paclitaxel for up to four cycles.

Partial responses were 2% in the erlotinib group and 12% in the standard therapy. Median progressionfree survival was 1.9 months in the erlotinib group and 3.5 months in the standard therapy group (hazard ratio [HR] = 1.45; P = .06). Median survival times were 6.5 and 9.7 months in the erlotinib and standard therapy groups, respectively (HR = 1.73; P = .018).

Rash and diarrhea were more common with

May 2008

ProApolipoprotein A1 was significantly increased (P <.05) in patients with central nervous system disease. erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with standard therapy. Quality of life was similar in both groups.

(Lilenbaum R, et al. J Clin Oncology. 2008;26:863-869.)

ProApolipoprotein Provides Early Detection of Brain Metastases in Patients with Lung Cancer SERUM PROAPOLIPOPROTEIN A1 MAY be an effective tool when used in conjunction with serum S100â&#x20AC;&#x161; for imaging-independent diagnosis of metastatic brain tumors in patients with lung cancer. Serum markers of blood-brain barrier dysfunction were measured in 103 patients with lung cancer. More than 50% of the

patients presented with magnetic resonance imaging changes consistent with chronic cerebrovascular disease and reflected by elevated serum S100 levels.

Proteomic techniques allowed discrimination between patients with brain metastases and those affected by cerebrovascular ischemic changes without infiltrating tumor. ProApolipoprotein A1, transferrin, haptoglobin, and transthyretin were upregulated in patients affected by chronic cerebrovascular disease and brain metastases compared with those affected only by vascular diseases. ProApolipoprotein A1 was significantly increased (P <.05) in patients with central nervous system disease. (Marchi N, et al.

Cancer. 2008;112:1313-1324.)

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TRENDS IN LUNG

KRAS Mutations Predictive of Response to Panitumumab Monotherapy in mCRC

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FDA Watch FDA WATCH

FDA Launches Safety First Program To Monitor Drugs After Approval THE US FOOD AND DRUG Administration (FDA) is making a significant shift in its approach to monitoring drugs after they are approved. It has just launched its Safety First initiative. Under this initiative, the FDA will devote as much attention to postmarket safety issues as it has to drug development.

On February 26, 2008, Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) at the FDA, issued a staff memo stating that the Safety First objectives include the creation of a collaborative, multidisciplinary, team-based approach to the review of drug safety. The overall goal is to ensure that significant postmarket safety issues are of the highest priority.

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

She said it is hoped that pharmacists will welcome this new program because it will help instill confidence on the part of the American public. Some pharmacists as well as physicians have been vocal about what they perceive as the FDA’s slowness to respond to potential serious side effects that may emerge only after a medicine reaches the market. The Safety First initiative aims to eliminate this concern.

FDA WATCH FDA WATCH FDA WATCH FDA WATCH FDA WATCH FDA WATCH

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

“We get a half a million adverse events a year reported to us. We can’t put a deadline on all those. That is unreasonable and unnecessary. So, we have to decide when we are going to start tracking something. We need to define a postmarketing issue and decide what are the issues and what the specific issues are that we are going to track and how we are going to do it,” said Ms Henderson in an interview with The Oncology Pharmacist.

As part of this initiative, an advanced computational center is being set up to support quantitative scientists and the FDA’s medical reviewers in the management and analysis of large datasets.

The FDA hopes to have early parts of this program in place by the end of the year.

Many pharmacists have noted that not a month goes by that they do not hear about another unexpected toxicity with a specific drug and wonder whether it will lead to a new black box warning. Over the past 10 years, a stream of drugs, including drugs for diabetes, ulcer disease, cholesterol-lowering, obesity, and arthritis, have been recalled or undergone labeling changes because of increased risks of heart and lung problems and even deaths associated with their use. This had led to a growing speculation that some drugs are getting to the market place too quickly.

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

Mr Peters expects that this new initiative will help ensure the safety of a wide variety of medications. He pointed out that many of the drugs that have been recalled or had new black box warnings placed on them were used for everything from heart disease to obesity. As a result, he said a very large number of Americans have been directly affected. He said part of the problem is that drugs are tested in a very tightly controlled patient population and the prescribing is done in a very precise manner.

“We see more toxicities in large populations. The study groups exclude people with certain conditions, and so there is a lot of built-in bias in a sense. They are building in a bias by eliminating certain risk groups. But those conditions may be commonplace in the general population,” said Mr Peters. “These drugs go through a lot of investigation and there is excellent science, but when they hit widespread populations and individuals take medicines in ways in which they are not prescribed, then things begin to drift out of the model they were tested in.”

©iStockphoto.com/Michael Krinke

—John Schieszer

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GYNECOLOGIC CANCERS

Gynecologic Cancers Maximizing Adherence to Aromatase Inhibitors for Early-stage Breast Cancer THE FLOOD OF NEW DATA flowing to clinicians via their computer screens and in medical libraries is making it clear that oral therapies are effective for first- or second-line treatment of early-stage breast cancer.

What is not clear, however, is how many patients are adherent, hence whether they are receiving the full short- and long-term benefits from these treatments. A recent study has shown that adherence to aromatase inhibitors falls as low as 62% by the time patients have taken these drugs for 3 years. The standard of care is to take adjuvant hormone therapy for a total of 5 years.

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

Adherence to oral antineoplastic agents in typical care settings is dramatically worse than that seen in clinical trials, and this may translate into lower efficacy of therapy when compared with outcomes observed in clinical trials.

The aromatase inhibitors anastrozole, exemastane, and letrozole were all approved in late 2005 by the US Food and Drug Administration as oral therapies for adjuvant treatment of earlystage breast cancer in postmenopausal women. Anastrazole and exemastane were approved for hormone-receptor-positive disease, while letrozole was approved for both receptor-positive and receptorstatus-unknown cases. Moreover, anastrozole and letrozole were approved as first-line therapy, while exemastane was approved for use after initial tamoxifen treatment.

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

©iStockphoto.com/Paul-André Belleisle

GYNECOLOGIC CANCERS GYNECOLOGIC GYNECOLOGIC CANCERS

Data Support Aromatase Use in Early Breast Cancer

ity of disease-free survival compared with tamoxifen. Anastrozole was also associated with a lower average time to recurrence, a lower incidence of new contralateral breast cancer and a longer time to distant recurrence, although it did not have an appreciable effect on rates of death after recurrence or overall survival.

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

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

Adherence Levels Far From Perfect In 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 adherence rates are not even close to 100% among women taking aromatase inhibitors (J Clin Oncol. 2008;26:556-562). The research, led by Ann Partridge, MD, MPH, found the rates were 82% to 88% in the first year after women started taking the medications, and dropped as low as 62% during the third year.

Dr Partridge, medical oncologist, Dana-Farber Cancer Institute, and an assistant professor of medicine, Harvard Medical School, Boston, and her co-investigators pooled claims data between January 2002 and March 2004 from the MarketScan employer-based claims database and from two large American health plans. They captured the records of 7,132 women with early breast cancer and at least 12 months of follow-up records of women who were taking anastrazole, including 999 with at least 24 months of follow-up data.

Anastrozole initiation was defined as no evidence of endocrine therapy for at least 4 consecutive months before the first anastrozole-prescription claim.

The team found the annual mean medication possession ratio—the ratio of number of days elapsed to number of days during which the patients were covered by a prescription they had filled for anastrozole or another hormonal agent they had switched to—was approximately 86% among the women who had taken anastrozole for 12 consecutive months. By the second year,

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Gynecologic Cancers GYNECOLOGIC CANCERS

MAXIMIZING ADHERENCE Continued from page17 the rates had fallen a notch, however, to 75% among women in the MarketScan database, 82% among those enrolled in one of the large national plans, and 68% among those in the other national plan. By the third year, the rates fell even lower to 72%, 79%, and 62%, respectively. The investigators found that women who stopped taking anastrozole during the first year appeared to do so gradually.

“Our findings of suboptimal adherence among a substantial proportion of women in the so-called real world provide further evidence that adherence to oral antineoplastic agents in typical care settings is dramatically worse than that seen in clinical trials, and this may translate into lower efficacy of therapy when compared with outcomes observed in clinical trials,” the investigators concluded.

What Can Be Done?

GYNECOLOGIC CA TRENDS IN BREAST CANCER

One question is whether increased adherence is associated with improved outcome. Another is how the adherence rates can be increased. Perhaps surprisingly, the first question has not been answered yet, but a lot of effort has been made to answer the second one.

Many clinicians are trained that the best approach to improving adherence is to remind their patients at each visit that they should take every single pill prescribed because this is the only way to maximize benefits from the medications. But does that work?

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

ly published paper by Dr Partridge, Dr Wickerham, and three other researchers outlined recommendations for increasing adherence to adjuvant therapy for breast cancer (Community Oncol. 2007;4:725-730).

The authors are all part of the Compliance Strategic Initiative, a multidisciplinary collaborative effort created to optimize adherence. The team’s recommendations include tailoring communication to the individual patient, keeping messages simple, and enhancing the patient’s equal value in the “adherence equation” by means such as encouraging use of pill boxes or medication diaries.

Dr Wickerham adds that nurses are critical to this equation. “Often patients are reluctant to admit to the doctor that they’re having trouble taking their medication, but they’ll be more open with the nurses or other medical professionals in the office,” said Dr Wickerham. “I hear it all the time because I talk about this around the country. And we’ve been dealing with this in our clinical trials for a long time; we teach our nurses how best to improve adherence.”

Wendy Smith, MSN, nurse practitioner, West Clinic, Corinth, Miss, and board member, Community Oncology Alliance, Washington, DC, affirms that developing a solid, trusting relationship is more valuable than any other patient-clinician factor, particularly for early-stage breast cancer, when the cost-benefit ratio may 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 with them, such as directing them to a patient prescription assistance program or helping them get coverage

through their insurance program.…Or if they have side effects such as hot flashes and muscle aches when they start therapy, if we can be good listeners we can often help them cope; as a result many women can adjust to those side effects and continue to take the medication.”

Dr Partridge also concurs that making patients partners in their treatment is critical. “We have to try harder to understand why people are not adherent, educate them about the goals of therapy, and help them to make the best decisions for themselves,” she observed. “For some people, not taking a drug might be the right thing for them. If it makes the patient miserable, she might say, ‘No thank you, I’d rather take my chances with not using the medication.’ But our job is at least to help patients understand the value of the medications—because if they don’t understand that, how can they make the right decision about taking the medication?”

A putative approach is to profile patients and target only those who are most likely to be nonadherent.

Some work is being done in that area, says Dr Wickerham, but it has not made much headway. He notes that for the foreseeable future, the bulk of success in increasing patient adherence will rest on individual clinics’ priorities and their staff’s people skills.

“Some are far superior to others. It comes down to a nurse or nurses who are willing and able to take the time to impact adherence,” he said. “And that, in turn, comes from the people who run the clinics, who make this a priority.”

—Rosemary Frei

Trends in Breast Cancer Trends in Breast Cancer

TRENDS IN BREAST

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Mammography and MRI Combined Provide Greater Benefit for Women with BRCA1 Mutation

Genomic Information Along with Clinical Risk Stratification May Refine Breast Cancer Prognoses

sensitive to docetaxel, etoposide, and topotecan.

(Acharya CR, et al. JAMA. 2008;299:1574-1587.)

ANNUAL SCREENING USING A COMBINATION of mammography and magnetic resonance imaging (MRI) was shown to have greater benefit for women who carry the BRCA1 mutation. The study was conducted using a Markov computer model consisting of 500,000 women 25 years of age who were asymptomatic BRCA1 carriers to determine the effect of MRI screening on clinical outcomes of breast cancer. Three screening strategies were compared: clinical surveillance, annual MRI, and annual combined MRI/mammography.The annual combined strategy of MRI/mammography detected the most cancers, with a program sensitivity of 70% versus 39% with mammography alone. Cancers were also identified earlier and were smaller: the median invasive tumor size seen with mammography alone was 1.9 cm, and 36% to 52% of tumors were 2 cm or smaller; with MRI, 1.3 cm, and 66% of all tumors were 2 cm or smaller; with combination screening, 1.1 cm, and 73% of tumors were 2 cm or smaller. An increase in average life expectancy of 1.38 years and a reduction in breast cancer mortality of 22% were also observed with combination screening.

This strategy, however, was associated with a high rate of false-positive results: between 80% and 84% of women eventually had at least one false-positive result, and more than 25% underwent unnecessary biopsies.

(Lee JM, et al. Radiology. 2008;246:763-771.)

INTEGRATING GENE EXPRESSION SIGNATURES with clinical risk stratification may more accurately determine the prognosis of breast cancer patients, according to an analysis of 964 breast tumor samples. Using a clinicopathologic prognostic model, subjects were divided into three relapse risk categories: low, intermediate, and high. In each category, gene expression signatures showed subclusters having prognostic significance.

Among low-risk patients five clusters were found, each with distinctive prognostic significance (P <.02). Median relapse-free survival time for patients in cluster 4 (poor prognosis) was 16 and 19 months less than those in clusters 1 and 5 (good to intermediate prognosis), respectively. Patients at intermediate risk had six clusters of prognostic significance. Median relapse-free survival time for cluster 3 (poor prognosis) was 54 months less than cluster 2 (good prognosis). Findings were similar for high-risk patients; genomic differences indicated patients in cluster 4 (poor prognosis) had inferior relapse-free survival compared with those in other clusters (cluster 1, P = .03; cluster 5, P = .01). Median relapse-free survival time for cluster 4 was 15 and 8 months less than clusters 1 and 5 (good prognosis), respectively. Additionally, based on gene expression signatures, the researchers predicted which patients may be sensitive to various chemotherapies; for example, patients with a poor prognosis were likely to be resistant to adriamycin and paclitaxel and

COX-2 Expression May Predict Breast Cancer Risk in Women with Atypical Hyperplasia

T HE O NCOLOGY P HARMACIST

EXPRESSION OF THE CYCLOOXYGENASE-2 (COX-2) enzyme may help predict breast cancer risk, according to a recent study that included 331 women with atypical hyperplasia. The women underwent a benign breast biopsy and were then followed up for a median of 15 years. Among 100 women having atypical ductal hyperplasia, 77% had no or weak COX-2 staining (categories 0 or 1+), 13% had moderate (category 2+) staining, and 10% had strong (category 3+) staining; 122 women had atypical lobular hyperplasia, and 47 (39%) had categories 0 or 1+ staining, 53 (43%) had category 2+ staining, and 22 (18%) had category 3+ staining (P <.001).

Strong staining also correlated with increasing age (>45 years, P = .01). Of the 235 women for whom COX-2 staining was available, 41 (17%) developed breast cancer, indicating a borderline statistically significant relationship (P = .07). Specifically, risk after 15 and 20 years of follow-up among women with categories 0 or 1+ COX-2 staining was 13% and 14%; category 2+ staining, 19% and 24%; and category 3+ staining, 25% and 31%, respectively. Median time to breast cancer development among the 18 women who had category 0 or 1+ staining was 11.4 years and among the 23 women who had category 2+ and 3+ staining, 11.8 years. (Visscher DW, et al. J Natl Cancer Inst. 2008;100:421-427.)

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CLINICAL TRIALS UPDATE

Clinical Trials Update Clinical Trials Update Two widely used targeted therapies for human epidermal growth factor 2 (HER2)-positive breast cancer will be compared in the large multinational Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial. Women in North America are now being enrolled in the phase 3 trial, which will recruit 8,000 women with HER2-positive breast cancer in 50 countries. The study is the first global initiative jointly developed by academic breast cancer research networks in different parts of the world in which all care and data collection are standardized regardless of where patients are treated. The two networks are the Breast Cancer Intergroup of North America and the Breast International Group.

Both agents being used in the trial—trastuzumab (Herceptin) and lapatinib (Tykerb) are already approved by the US Food and Drug Administration (FDA) for HER2-positive breast cancer. Women with stage I or II breast cancer who have already had surgery to remove their tumors will be randomized to receive either trastuzumab or lapatinib alone, trastuzumab followed by lapatinib, or the two agents in combination. All participants must have completed four or more cycles of anthracycline-based chemotherapy, and those for whom taxane chemotherapy is indicated will receive paclitaxel (Taxol) along with their assigned target therapy. Edith Perez, MD, of the Mayo Clinic in 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 Prevent Cisplatin-associated Hearing Loss in Children Announced Adherex Technologies of Research Triangle Park, NC, has announced activation of a phase 3 trial of sodium thiosulfate (STS) to prevent hearing loss in children treated with cisplatin. The trial is being conducted in collaboration with the Children’s Oncology Group (COG).

More than 60% of children treated with cisplatin experience some degree of hearing loss and some become deaf.

The multicenter trial will enroll children 1 to 18 years of age who are scheduled 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 baseline and at follow-up using standardized audiometric tests. The trial is expected to enroll up to 120 children over approximately 3 years in up to 230 COG centers in the United States, Canada, Australia, and Europe.

David Freyer, MD, professor of medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, is principal investigator.

Monoclonal Antibody for Ewing Sarcoma to be Studied Enrollment in a trial of a new treatment for Ewing sarcoma has begun in the United States. Centers across the United States and in France, Italy, Germany, and the United Kingdom will also participate in the trial, which will investigate the use of an investigational monoclonal antibody, R1507, in patients with Ewing sarcoma. The agent, made by Hoffman-LaRoche, inhibits insulin-like growth factor 1 receptor (IGF-1R). Ewing sarcoma, which affects mostly children, adolescents, and young adults, has been linked with mutated genes that promote production of IGF-1R.

CLINICAL TRIALS UPDATE

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

Enrollment in Phase 2 Trial of PDX for PTCL Completed Enrollment in a phase 2 trial of pralatrexate (PDX) for relapsed or refractory peripheral T-cell lymphoma (PTCL), for which there is currently no approved treatment. The trial known as the Pralatrexate in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) is an international, multicenter, open-label, single-arm study. Patients with relapsed or refractory PTCL who progressed after at least one prior treatment receive 30 mg/m2 of PDX once a week for 6 weeks followed by 1 week of rest per treatment cycle. Participants also receive vitamin B12 and a folic acid supplement. An independent data monitoring committee has completed three interim analyses of safety data and has recommended continuation of the trial at each analysis.

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

• Bevacizumab for Advanced HER2-negative Breast Cancer. The FDA has granted accelerated approval for bevacizumab (Avastin; Genentech) in combination with paclitaxel for first-line treatment of women who have not received chemotherapy for metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Use of the antiangiogenesis agent for advanced cancer was granted under the FDA’s accelerated approval program. A full review of data from two phase 3 trials will be required for the accelerated approval to be converted into a full approval.

• Levoleucovorin for Osteosarcoma. Spectrum Pharmaceuticals has received FDA approval for Levoleucovorin for Injection (formerly known as ISO-Vorin) for treatment of osteosarcoma. The novel folate analog is indicated after high-dose methotrexate therapy in patients with osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdose of folic acid antagonists.

May 2008

• CellSearch for Monitoring Prostate Cancer. The FDA has granted an expanded clearance for the CellSearch System (Veridex, LLC) as an aid in monitoring patients with metastatic prostate cancer. The system is currently cleared monitoring patients with metastatic breast or colorectal cancer. It is the first diagnostic test that automates detection and enumeration of circulating tumor cells in a blood sample, which aids in predicting progression-free and overall survival in patients with metastatic breast, colorectal, and prostate cancer.

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

FDA APPROVALS

• Bendamustine for Chronic Lymphocytic Leukemia. The US Food and Drug Administration (FDA) has approved bendamustine hydrochloride (Treanda; Cephalon) for injection for first- and second-line treatment of chronic lymphocytic leukemia (CLL). The novel chemotherapy agent is the first product approved for CLL since 2001. CLL is an orphan indication, but Cephalon has filed bendamustine for use in non-Hodgkin’s lymphoma.

FDA APPROVALS

Recent FDA Approvals

FDA Appoints First Chief Scientist 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’s first Chief Scientist. In this position, Dr Torti will support the launch of the FDA Fellowship Program, which potentially could attract as many as 2,000 professionals of varying disciplines for a 2-year training program. His office will also work to ensure the quality and regulatory focus of the FDA’s intramural research programs and place special emphasis on the importance of clinical research trials. Dr Torti is currently Charles L. Spurr Professor of Medicine, Chair, Department of Cancer Biology, and Director, Comprehensive Cancer Center at Wake Forest University School of Medicine in Winston-Salem, NC.

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Meetings

September 25-28

October 21-25

October 30-November 1

4th Annual Oncology Congress San Francisco, CA www.oncologycongress.com

50th Annual Meeting American Society for Therapeutic Radiology and Oncology Baltimore, MD www.astro.org

61st Annual Symposium on Cancer Research Houston, TX www.mdanderson.org

10th International Conference on Malignant Lymphoma Lugano, Switzerland www.lymphcon.ch/

5th Annual Meeting International Society of Gastrointestinal Oncology Arlington, VA www.isgio.org

October 19-21

Chemotherapy Foundation Symposium XXVI New York, NY www.chemotherapyfoundation.org

June 12-15

October 16-18

October 23-26

June 4-7

13th Congress of the European Hematology Association Copenhagen, Denmark www.ehaweb.org

June 18-21 Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners 2008 Conference Anaheim, CA www.hoparx.org Ninth International Lung Cancer Congress Koloa, HI www.cancerconferences.com/thoracic/9th_lcc/ index.php

June 22-25 World Conference on Interventional Oncology Los Angeles, CA www.wcio2008.com

June 25-28 10th World Congress on Gastrointestinal Cancer Barcelona, Spain www.worldgicancer.com

June 26-28 21st International Supportive Care in Cancer Symposium Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Houston, TX www.mascc.org

July 19-23 American Association of Colleges of Pharmacy 2008 Annual Meeting Chicago, Il www.aacp.org 7th International Conference on Head and Neck Cancer The American Head and Neck Society San Francisco, CA www.ahns.info

July 24-26 3rd Interamerican Breast Cancer Conference Cancun, Mexico www.imedex.com/calendars/oncology.asp

August 3-8 Methods in Clinical Cancer Research Joint ASCO/AACR Workshop Vail, CO www.aacr.org

August 14-16 American Society of Health-System Pharmacists 2008 Residency Preceptors Conference Washington, DC www.ashp.org

August 27-31 International Union Against Cancer (UICC) World Cancer Congress Geneva, Switzerland www.uicc-congress08.org

September 5-7 2008 Breast Cancer Symposium Washington, DC www.astro.org

September 17-20 25th National Oncology Economics Conference San Francisco, CA www.accc-cancer.org

September 19-20 9th Annual Perspectives in Colorectal Cancer Miami, FL www.imedex.com

September 21-25 American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting Boston, MA www.astro.org

May 2008

September 25-27

9th Meeting of the International Society of Geriatric Oncology Montreal, Canada www.cancerworld.org/siog

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

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

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

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; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved.

Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.

Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.]

Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases for which Rituxan has not been approved. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy and were diagnosed with PML within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan.

Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy.

In postmarketing reports, the mean time to documented gastrointestinal

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perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence *25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse 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 obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. 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 with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.

Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.]

Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.

Table 1 Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs.

1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving RCHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure.

Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection.

Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. NonHodgkin’s lymphoma and severe rheumatoid arthritis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Rituximab is a genetically engineered IgG molecule, and IgG crosses the human placenta.

Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects.

However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Other than target B lymphocytes, rituximab is not known to bind to any normal human tissues in an ex vivo assay. However, it is not known if binding occurs to unique embryonic or fetal tissue receptors in vivo. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from gastrointestinal or limited systemic exposure to Rituxan should be weighed against the known benefits of breastfeeding.

Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients.

Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) frequently among elderly patients. Serious pulmonary adverse reactions were also Any Adverse Events 99 57 Respiratory System 38 4 more common among the elderly, including pneumonia and pneumonitis. LowBody as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Chills 33 3 Bronchospasm 8 1 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 numbers of patients aged 65 and over to determine whether they respond Headache 19 1 Metabolic and Nutritional Abdominal Pain 14 1 Disorders 38 3 differently from younger subjects. OVERDOSAGE There has been no experience Pain 12 1 Angioedema 11 1 with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Flushing 5 0 LDH Increase 7 0 Heme and Lymphatic System 67 48 Digestive System 37 2 Carcinogenesis, Mutagenesis, Impairment of Fertility No long term animal Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 studies have been performed to establish the carcinogenic or mutagenic potential Neutropenia 14 6 Vomiting 10 1 of Rituxan or to determine potential effects on fertility in males or females.

Thrombocytopenia 12 2 Nervous System 32 1 Anemia 8 3 Dizziness 10 1 PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Skin and Appendages 44 2 Anxiety 5 1 Night Sweats 15 1 Musculoskeletal System 26 3 Medication Guide and provided an opportunity to read prior to each treatment Rash 15 1 Myalgia 10 1 session. Because caution should be exercised in administering Rituxan to patients Pruritus 14 1 Arthralgia 10 1 Urticaria 8 1 Cardiovascular System 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy.

Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs.

3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no 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. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years 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%).

Detailed safety data collection in these studies was primarily limited to Grade 3

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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 RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

in 7-year OS in GELA* trial 1,2

• 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 multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years 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 LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among 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 previously untreated 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-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. 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 with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society 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 patients with 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.

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