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Oncology

Pharmacist

The Official Newspaper of Record for the Hem/Onc Pharmacist

Dear Colleague: The Oncology Pharmacist features articles written by and for oncology pharmacists and specifically addresses the issues pharmacists and their colleagues face every day in clinical practice. A unique feature of The Oncology Pharmacist is that each issue will an include a continuing education activity accredited by the University of Nebraska Medical Center, Center for Continuing Education. Pharmacists will be able to complete the post-test and obtain credit online at no charge. Other unique features include articles specifically written for pharmacy students and residents as well as articles on practice management and financial and regulatory issues affecting the practice of pharmacy. For your free subscription, please complete and return the FREE Subscription Request card below. Postage is prepaid, so simply fill out the card and drop it in the mail. We look forward to receiving feedback on what you would like to see in future issues of The Oncology Pharmacist. —Susan Goodin, PharmD, FCCP, BCOP Editor-in-Chief

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MEDICAL MINUTES HPV-related cancers of tongue and tonsils respond better to therapy

NEW TECHNOLOGY RFA ablation procedure effective alternative for treating Barrett’s esophagus

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JUNE 2008 • VOL. 1, NO.2

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CANCER CENTER PROFILE Multidisciplinary team at Cleveland Clinic Taussig Cancer Center provides patient-centered care

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POLICY WATCH

PHARMACY EDUCATION AND TRAINING

Organizations for the Potential Oncology Practitioner: Which Ones to Join and How Many? Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy, Tulsa

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uring the first year of pharmacy school, students often join numerous organizations for several reasons, including social and professional networking, resume building, and increasing knowledge in perceived areas of interest. As a

student’s interests become more focused and career paths are clarified, the number and type of organizations that he or she belongs to will also narrow. Organizations play a vital role in the professional growth of students and residents

and are also integral in maintaining lifelong learning and professional development as a pharmacist. Many organizations are available for professional and educational growth for students and residents

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President Bush signs the Genetic Nondiscrimination Information Act of 2008 into law.

New Study Looks at Use of ESAs in Real World Practice

ith the diagnosis of cancer comes the reality of an unforgiving disease process that renders the body’s natural defenses impotent. While this causes great anguish in and of itself, it is often what comes next that proves to be more troublesome. The cancer treatment itself presents formidable challenges to patients—the chemotherapy-induced neutropenia, persistent nausea and vomiting, alopecia,

SAN FRANCISCO—Prescribing practices appear to be changing when it comes to erythropoiesis-stimulating agents (ESAs), according to new data presented at the Academy of Managed Care Pharmacy’s 20th Annual Meeting and Showcase. Researchers found that between 2005 and 2006, there was a decrease in

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Cetuximab-induced Hypersensitivity: Case Reports and Discussion of Management

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INTERVIEW Christopher Lowe, PharmD, Taussig Cancer Center

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PEER-SPECTIVES

INTERACTIVE PEER-TO-PEER DISCUSSIONS IN HEMATOLOGY/ONCOLOGY

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Susan Goodin

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PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ

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DISCUSSION • Up-to-date, clinically relevant medical information presented in a simple, streamlined format • Commentaries from experts in the fields of hematology and oncology provide perspectives on patient care • Interactive polling feature allows you to respond to the data presented and view responses from your peers • Opportunities to earn professional continuing education credits The mission of peer-spectives is to provide physicians, nurses, and pharmacists with the latest medical advances in hematology and oncology through online, interactive, educational activities

David Baribeault, RPh, BCOP Boston Medical Center Boston, MA Sylvia Bartel, RPh, MPH Dana Farber Cancer Institute Boston, MA

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

Emily Mackler, PharmD, BCOP University of Michigan Health System & College of Pharmacy Ann Arbor, MI

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

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

Deborah Blamble, PharmD, BCOP University of Texas MD Anderson Sandra Horowitz, PharmD, Cancer Center RPh Houston, TX University of Texas MD Anderson Cancer Center Marlo Blazer, RPh, PharmD Houston, TX James Cancer Hospital & Solove Research Institute Lew Iacovelli, BS, PharmD, Columbus, OH BCOP, CPP Moses H. Cone Health System Bryna Delman Ewachiw, BS, Greensboro, NC PharmD Johns Hopkins Bayview Medical Andrea A. Iannucci, PharmD, Center BCOP Baltimore, MD University of California Davis Medical Center Anjana Elefante, PharmD, BSc, Sacramento, CA BScPhm, RPh Roswell Park Cancer Institute Cindy Ippoliti, PharmD Buffalo, NY New York Presbyterian Hospital/Weill Cornell Beth Faiman, RN, MSN, CNP, Medical School AOCN New York, NY Cleveland Clinic Taussig Cancer Institute Jim Koeller, MS Cleveland, OH University of Texas at Austin San Antonio, TX Christopher Fausel, PharmD, Helen L. Leather, BPharm BCPS, BCOP Indiana University Simon Cancer University of Florida Gainesville, FL Center Indianapolis, IN Christopher J. Lowe, PharmD Rebecca S. Finley, PharmD, Novant Health MS Winston Salem, NC Jefferson School of Pharmacy Philadelphia, PA

Laura Boehnke Michaud, PharmD, BCOP, FASHP University of Texas MD Anderson Cancer Center Houston, TX Deborah Moradi, PharmD The Angeles Clinic and Research Institute Los Angeles, CA LeAnn Best Norris, PharmD, BCPS South Carolina College of Pharmacy Columbia, SC Debra Phillips, PharmD East Carolina University Greenville, NC Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

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ASCO Bisphosphonate prolongs cancerfree survival in endocrine-sensitive breast cancer

CANCER CENTER PROFILE H. Lee Moffitt Cancer Center & Research Institute emphasizes personalized care

AMCP Off-label use and other issues in management of oncology drugs were discussed at the AMCP annual meeting

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JULY/AUGUST 2008 • VOL. 1, NO.3

The

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Oncology

The Official Newspaper of Record for the Hem/Onc Pharmacist

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ASCO ANNUAL MEETING

PHARMACY PRACTICE

HOPA Sets Goals for Future Growth of Oncology Pharmacy An interview with Jim Koeller, MS More than 4000 studies were presented at the 44th im Koeller, MS, is the immediate shares his views on the future of my master’s degree from the Annual Meeting of the American Society of Clinical past president of the Hematology/ oncology pharmacy. University of Wisconsin. After comOncology

J

Oncology Pharmacy Association (HOPA) and a member of the editorial board of The Oncology Pharmacist. In this interview, Mr Koeller discusses the highlights of this year’s HOPA Conference and

How did you become involved with oncology pharmacy? I fell into oncology pharmacy almost by happenstance. I received

pleting my residency, I learned that the cancer center in Madison was looking for someone to coordinate their phase 1 oncology drug development program. I had spent some

Complimentary CE Credit

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MANAGED CARE PHARMACY

CONFERENCE NEWS

AMCP:

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Strategies for Navigating Oncology Management Discussed at Symposium

Oral Immunosuppressant Enhances PFS in Resistant Metastatic RCC

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page 10

ith 23 new oncology agents targeted for potential launch in the coming year, oncology drugs dominate the pipeline, far outnumbering drugs those in other therapeutic categories. Strategies for managing these agents in the man-

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

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

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PROSTATE CANCER Study shows reduction of prostate cancer risk with finasteride

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MEDICAL MINUTES

Medical Minutes BY JOHN SCHIESZER

Antidote for Chemotherapy Allergy May Allow Cancer Patients to Receive Medicine Safely John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at medminutes@aol.com.

New research findings may hold promise for cancer patients who have developed allergies to chemotherapy drugs. Investigators in Boston have just completed a study demonstrating the success and safety of rapid desensitization. The treatment allows nearly all patients to tolerate temporarily the chemotherapy drugs to which they previously experienced allergic reactions. The standardized procedure takes 4 to 8 hours and involves administering the targeted dose of medicine intravenously or intraperitoneally in incremental steps. The initial desensitizations occur in the medical intensive care unit, but most of the subsequent infusions are handled in an outpatient setting. Of the 98 patients tested during a total of 413 desensitization treatments, 94% had no reaction or only mild reactions to the medication. No life-threatening reactions or deaths occurred during the study. “The [study] findings provide the first safety data on high-risk sensitizations done to cancer patients who could not otherwise receive their first-line therapy. The desensitizations may prolong their lives,” said study investigator Mariana Castells, MD, PhD, director of the desensitization program at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, Boston. The patients studied were primarily women receiving treatment for breast, ovarian, or other gynecologic cancers. During the study,

patients were successfully desensitized to seven common chemotherapy drugs: carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, and rituximab. Previous studies have indicated that up to 27% of patients receiving more than seven cycles of some common chemotherapy drugs develop allergic sensitivity to the medications. With some drugs, many patients experience a reaction on their first exposure. The reactions can be severe and potentially fatal. This presents healthcare professionals and patients with a paradoxical challenge: continue potentially life-saving treatment while risking a deadly allergic reaction or avoid the life-threatening reaction by switching to a less-effective drug? This new research offers a third option, according to Dr Castells. At Brigham and Women’s Hospital, clinicians have already adopted the standardized rapid desensitization, and the investigators hope that other institutions will follow suit. “A universal protocol for rapid desensitization can be tailored to the patient’s needs and be used safely. The protocol should become universal once we are granted a patent,” explained Dr Castells. “The take-home message for oncology pharmacists is that they need to educate others about this approach. The protocol can be administered only by trained personnel, and an allergist should supervise the procedure.”

A drug developed to fight cancer is now showing promise as a patients had some improvement,” noted Dr Gomberg-Maitland. treatment for pulmonary hypertension, according to researchers at “Some had dramatic improvement.” the University of Chicago Medical Center. In the first human trial The side effects of the drug have been relatively mild. The most of sorafenib as a treatment for pulmonary hypertension, eight of the common adverse effects in cancer patients were rashes, tenderness first nine patients increased their ability to exercise. Six of nine and itching on the hands and feet, and some mild diarrhea and patients had significant improvements in right ventricular ejection fatigue. For patients with pulmonary hypertension, diarrhea and hair fraction. Four patients had a significant decrease in pulmonary loss were often the biggest concerns. Patients taking prostacyclins artery pressure. often have facial rashes and flushing, but the sorafenib appeared to “We have drugs that may slow progression of the disease, but have reduced this effect. Dr Gomberg-Maitland said because of the nothing that can stop or reverse the process,” said study author drug’s apparent potential and limited side effects, a multicenter, phase Mardi Gomberg-Maitland, MD, assistant professor of medicine at 2, placebo-controlled, cross-over study is being organized. the University of Chicago. “To see these improvements in such a short time is quite Gene Therapy Showing Promise for End-stage promising. Although evaluation of this drug is at a very early stage, and this study Head and Neck Cancer focused on safety and tolerability, we are A gene therapy approach is showing con- neck cancer. Patients with a favorable p53 genuinely excited about the results.” siderable promise in a phase 3 clinical trial for profile who received Advexin had a median Sorafenib was originally evaluated at the head and neck cancer. This treatment uses survival of 7.2 months, compared with 2.7 University of Chicago as a treatment for Advexin (Ad5CMV-p53), a modified aden- months for those whose tumor expressed high kidney cancer. Dr Gomberg-Maitland and ovirus that expresses the tumor-suppressing levels of mutant p53 before treatment. In her colleagues recognized that its effects gene p53. also might slow the growth and thickenaddition, the researchers found that patients “Cells become cancerous because p53 no with this unfavorable profile did better with ing of the pulmonary artery walls. longer functions. Restoring p53 works unlike methotrexate, resulting in median survival of The trial enrolled patients with pulany current cancer treatment because it treats 5.9 months. monary hypertension who had stable disthe cancer genome,” said Jack Roth, MD, a ease. Patients continued to take their stan“The important finding is that patients professor in the Department of Thoracic and who benefit from treatment can be identified dard medications, primarily prostacyclin in Cardiovascular Surgery at M.D. Anderson with the p53 biomarker. The biomarker will combination with sildenafil. They also took Cancer Center, Houston, Texas. Dr Roth enable physicians to personalize treatment,” sorafenib for 16 weeks, but at doses lower invented the drug and is co-founder of said Dr Roth. than those given to cancer patients. Introgen Therapeutics, Inc, which manufacMost of the patients in the trial Patients treated with Advexin experitures Advexin. increased their exercise capacity, as measenced fewer harmful side effects, such as He said the p53 gene is inactivated in pneumonia, than those who received ured by time on a treadmill or a 6-minute many types of cancer. Its normal role is to halt methotrexate. The incidence of inflammawalk test. They had an 8% improvement, the division of a defective cell and then force tion of the mouth lining and a decrease in on average, in right ventricular ejection the cell to kill itself. The trial, which includ- white blood cells, for example, both dropped fraction, as measured by three-dimensioned 123 patients, showed that p53 expression to zero for those receiving Advexin. “That al echocardiography. Four patients had in the patient’s tumor before treatment is a certainly results in a better quality of life,” significant improvements in the ability of reliable biomarker for how to treat head and noted Dr Roth. the heart to pump blood to the lungs, as measured by cardiac catheterization. “All July/August 2008

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1

MEDICAL MINUTES

Cancer Drug May Help Patients with Heart-Lung Disease


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Vol. 1, No. 3

July/August 2008

Feature Articles CONTENTS

8

PUBLISHING STAFF

Departments

Conference News Reports from the HOPA/ISOPP Joint Annual Conference

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

1

Medical Minutes

5

News Notes

Editorial Director Karen Rosenberg karen@greenhillhc.com

7

Cartoon

Managing Editor Lara J. Reiman

13

12 Cancer Center Profile H. Lee Moffitt Cancer Center & Research Institute Oncology

Publisher Philip Pawelko phil@greenhillhc.com

Leadership and Communication Skills for Pharmacists Cancer

20 Trends in Lung Cancer

Calculating the dosage of anticancer drugs in obese patients

20 Trends in Hematologic Cancer

Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com

19 Trends in Prostate

16 Continuing Education

Senior Production Manager Stephanie Laudien

Director of Human Resources Blanche Marchitto blanche@greenhillhc.com Circulation circulation@greenhillhc.com

GH Green Hill Healthcare Communications

, LLC ™

19 Prostate Cancer Finasteride May Help Reduce Prostate Cancer Risk

21 Meetings

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

Beth Faiman, RN, MSN, APRN, BC, AOCN

Christopher J. Lowe, PharmD

Cleveland Clinic Taussig Cancer Center Cleveland, OH

Novant Health Winston Salem, NC

Christopher Fausel, PharmD

Helen McFarland, PharmD, BCOP

Indiana University Simon Cancer Center Indianapolis, IN

Union Memorial Hospital Baltimore, MD

EDITOR-IN-CHIEF

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Susan Goodin

Jefferson School of Pharmacy Philadelphia, PA

PharmD, FCCP, BCOP

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

David C. Gammon, BSPharm

Cancer Institute of New Jersey New Brunswick, NJ

University of Massachusetts Memorial Hospital Worcester, MA

EDITORIAL BOARD

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

David Baribeault, RPh, BCOP Boston Medical Center Boston, MA

Sylvia Bartel, RPh, MPH Dana Farber Cancer Institute Boston, MA

Deborah Blamble, PharmD, BCOP University of Texas MD Anderson Cancer Center Houston, TX

Marlo Blazer, RPh, PharmD

CONTENTS

James Cancer Hospital & Solove Research Institute Columbus, OH

Bryna Delman Ewachiw, BS, PharmD Johns Hopkins Bayview Medical Center Baltimore, MD

Anjana Elefante, PharmD, BSc, BScPhm, RPh Roswell Park Cancer Institute Buffalo, NY 2

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

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

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

Cindy Ippoliti, PharmD

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

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

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

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

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

New York Presbyterian Hospital/Weill Cornell Medical School New York, NY

Timothy G. Tyler, PharmD, FCSHP

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

University of Texas at Austin San Antonio, TX

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Helen L. Leather, BPharm

Gary C. Yee, PharmD, FCCP, BCOP

University of Florida Gainesville, FL

University of Nebraska College of Pharmacy Omaha, NE

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Desert Regional Medical Center Palm Springs, CA

July/August 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

A Letter from the Editor hat an exciting time to be an oncology pharmacist! Nearly 1000 people from 40 countries attended the HOPA/ISOPP 2008 Joint Annual Conference in Anaheim. Sessions started in early morning and continued throughout the day covering both clinical and nonclinical issues pertinent to oncology pharmacy practice in various settings. Platform and poster sessions provided an opportunity for oncology pharmacy residents and clinicians to present their research findings and interact with colleagues. It was evident that many oncology pharmacists today are recent graduates with long careers ahead of them and will need ongoing education throughout their careers not only to achieve or maintain certification but also to keep up with the fast pace of oncology drug development. As Jim Koeller notes in the interview in this issue, oncology pharmacy practice is an increasingly sophisticated and specialized field, and there is a great need for continuing education. The CE article in this issue addresses a challenging and important issue for oncology pharmacists and other healthcare professionals. With the prevalence of obesity in our society, it is critical to determine how best to calculate drug dosages in overweight and obese patients to achieve optimal results. Research

W

SUSAN GOODIN, PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

Coming Soon CE article: Treatment of Anemia in Cancer Patients with ESAs and IV Iron

Reports from HOPA, ASCO Ensuring Safe Chemotherapy Administration Setting Up a Chemotherapy Prep Area in a Community Practice Using Nanoparticles to Deliver Chemotherapy

EDITOR’S LETTER

Oncology Patient Participation in Clinical Trials New Approaches to the Treatment of Pediatric Neuroblastoma

For a free subscription go to www.theoncologypharmacist.com 4

G REEN H ILL H EALTHCARE C OMMUNICATIONS

is also needed on what modifications in therapy may be needed for other groups—women, children, the elderly, those with comorbidities, and others with special needs. Personalizing therapy to meet the particular needs of individual patients is a major emphasis at the H. Lee Moffitt Cancer Center in Tampa, Florida. Their Total Cancer Care initiative, discussed in this issue, aims to create personalized cancer care for patients with different types of cancer through genetics. The initiative also seeks to address the needs of family members and to follow patients throughout the continuum of care. As reports from ASCO and other recent meetings support, providing high-quality care does not end with making a diagnosis and prescribing a treatment. Pharmacists, nurses, and other members of the healthcare team often need to make modifications in treatment regimens and work with patients and caregivers to lessen the many possible adverse effects of therapy and provide support and encouragement. Advances in side effect prevention and management described in this issue offer new options for helping patients throughout the course of treatment. We welcome your thoughts on this issue and suggestions on what topics you would like to see covered in future issues. Please send your comments to Karen@greenhillhc.com.

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist™, 241 Forsgate Drive, Suite 205C, Monroe Twp, 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, Monroe Twp, 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, Monroe Twp, NJ 08831. Telephone: 732.656.7935. 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.

July/August 2008


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I Antioxidants May Reduce Effectiveness of Cancer Treatments

Patients with cancer who are receiving chemotherapy or radiation therapy should avoid use of supplements containing high levels of antioxidants, according to a new report. Many cancer patients take antioxidant supplements because they believe they will increase the effectiveness of their treatment. Researchers from the Naval Medical Center in San Diego, California, however, found that these supplements may, in fact, reduce the effectiveness of chemotherapy or radiation, or even increase toxicities. The researchers reviewed data from published randomized clinical trials that examined the use of antioxidants by patients undergoing cytotoxic therapy. Although the findings were inconclusive, the researchers suggest that antioxidants may protect cancer cells just as they do normal cells, thereby decreasing the effectiveness of chemotherapy and radiation (Lawenda BD, et al. J Natl Cancer Inst. 2008;100:773-783).

Antioxidants may protect cancer cells just as they do normal cells.

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

I QOL Scores Predict Survival for Patients with Head and Neck Cancer

Low quality-of-life (QOL) scores may indicate poor survival for patients with head and neck cancer, according to a

recent study. A total of 495 patients with head and neck cancer completed a questionnaire, which assessed physical and emotional QOL. The University of Michigan investigators found a high association between general physical health and QOL issues and survival. Patients with difficulty with pain, eating, and speech were significantly less likely to survive

than were other patients. The researchers conclude that QOL instruments may be valuable screening tools to identify patients who are at high risk for poor survival and should be followed more closely (Karvonen-Gutierrez CA, et al. J Clin Oncol. 2008;26:2754-2760). Continued on page 6

NEWS NOTES

News Notes

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

I Possible Link Between Pediatric Cancer and TNF Blockers Investigated

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.

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.

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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.

NEWS NOTES

The US Food and Drug Administration (FDA) is investigating a possible link between pediatric cancer and the use of tumor necrosis factor (TNF) blockers in light of recently diagnosed cases of lymphoma and other cancers in children and young adults. During the past 10 years, the FDA has learned of about 30 cases of cancer in children taking TNF blockers, including infliximab, etanercept, and adalimumab, which are prescribed for such autoimmune disorders as juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease. The link between TNF blockers and cancer is not new, as all four drugs already carry warnings about the possible risks, but the FDA is now requiring all of the manufacturers of TNF blockers indicated for pediatric use to provide

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NEWS NOTES I Oncology Reimbursement

NEWS NOTES

Solutions Aims to Improve Billing Efficiency

US Oncology, Inc has announced the introduction of Oncology Reimbursement Solutions (ORS), an oncologyfocused billing and reimbursement service. ORS offers community oncology practices a comprehensive revenue cycle management program to ensure accurate reimbursement for their services. Because

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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I Practice Management Models

proper denial management is essential for an efficient revenue cycle process, ORS will resolve the reasons that claims are initially denied, helping to ensure they are approved when they are first submitted. ORS also provides a curriculum of oncology billing and coding education that includes web-based articles, audio conferences, and webcasts, and helps in accessing patient assistance programs. Last year, the ORS Patient Assistance Support team obtained more than $14 million in funding for disadvantaged patients with cancer.

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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. 2

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A practice management model, created by US Oncology for oncology practices, has been shown to be beneficial in enhancing patient access to advanced cancer care while improving efficiency for the practice. The model, using an approach often found in manufacturing settings, is focused on defining and measuring a problem; determining the problem’s cause; and initiating change and maintaining improvements. Oncology

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

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

Preferred Term

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At least 1 TEAE Nausea Anemia Thrombocytopenia Vomiting Pyrexia Leukopenia Diarrhea Fatigue Injection site erythema Constipation Neutropenia Ecchymosis Cough Dyspnea Weakness Rigors Petechiae Injection site pain Arthralgia Headache Anorexia Pain in limb Pharyngitis Back pain Contusion Dizziness Edema peripheral Erythema Chest pain Epistaxis Febrile neutropenia Myalgia Weight decreased Abdominal pain Pallor Nasopharyngitis Pitting edema Skin lesion Dyspnea exertional Injection site bruising Rash Injection site reaction Anxiety Appetite decreased Fatigue aggravated Hypokalemia Upper respiratory tract infection Pruritus Abdominal tenderness Depression Productive cough Insomnia Malaise Pain Pneumonia Abdominal pain upper Crackles lung Sweating increased Cardiac murmur Rhinorrhea Gingival bleeding Lymphadenopathy Herpes simplex Hematoma Night sweats Rales Tachycardia Wheezing Cellulitis Dysuria Breath sounds decreased Lethargy Oral mucosal petechiae Stomatitis Urinary tract infection Peripheral swelling Dyspepsia Hemorrhoids Hypotension Injection site pruritus Transfusion reaction Pleural effusion Abdominal distension Muscle cramps Post procedural hemorrhage

All VIDAZA (N=220) 219 (99.5) 155 (70.5) 153 (69.5) 144 (65.5) 119 (54.1) 114 (51.8) 106 (48.2) 80 (36.4) 79 (35.9) 77 (35.0) 74 (33.6) 71 (32.3) 67 (30.5) 65 (29.5) 64 (29.1) 64 (29.1) 56 (25.5) 52 (23.6) 50 (22.7) 49 (22.3) 48 (21.8) 45 (20.5) 44 (20.0) 44 (20.0) 41 (18.6) 41 (18.6) 41 (18.6) 41 (18.6) 37 (16.8) 36 (16.4) 36 (16.4) 36 (16.4) 35 (15.9) 35 (15.9) 34 (15.5) 34 (15.5) 32 (14.5) 32 (14.5) 32 (14.5) 31 (14.1) 31 (14.1) 31 (14.1) 30 (13.6) 29 (13.2) 28 (12.7) 28 (12.7) 28 (12.7) 28 (12.7)

c

d

Observation (N=92) 89 (96.7) 16 (17.4) 59 (64.1) 42 (45.7) 5 (5.4) 28 (30.4) 27 (29.3) 13 (14.1) 23 (25.0) 0 6 (6.5) 10 (10.9) 14 (15.2) 14 (15.2) 11 (12.0) 19 (20.7) 10 (10.9) 8 (8.7) 0 3 (3.3) 10 (10.9) 6 (6.5) 5 (5.4) 7 (7.6) 7 (7.6) 9 (9.8) 5 (5.4) 10 (10.9) 4 (4.3) 5 (5.4) 9 (9.8) 4 (4.3) 2 (2.2) 10 (10.9) 12 (13.0) 7 (7.6) 3 (3.3) 9 (9.8) 8 (8.7) 15 (16.3) 0 9 (9.8) 0 3 (3.3) 8 (8.7) 4 (4.3) 12 (13.0) 4 (4.3)

27(12.3) 26 (11.8) 26 (11.8) 25 (11.4) 24 (10.9) 24 (10.9) 24 (10.9) 24 (10.9) 23 (10.5) 23 (10.5) 23 (10.5) 22 (10.0) 22 (10.0) 21 (9.5) 21 (9.5) 20 (9.1) 19 (8.6) 19 (8.6) 19 (8.6) 19 (8.6) 19 (8.6) 18 (8.2) 18 (8.2) 17 (7.7)

11 (12.0) 1 (1.1) 7 (7.6) 4 (4.3) 4 (4.3 1 (1.1) 3 (3.3) 5 (5.4) 3 (3.3) 8 (8.7) 2 (2.2) 8 (8.7) 2 (2.2) 4 (4.3) 3 (3.3) 5 (5.4) 0 3 (3.3) 8 (8.7) 6 (6.5) 2 (2.2) 4 (4.3) 2 (2.2) 1 (1.1)

17 (7.7) 17 (7.7)

2 (2.2) 3 (3.3)

17 (7.7) 17 (7.7) 16 (7.3) 15 (6.8) 15 (6.8) 15 (6.8) 15 (6.8) 15 (6.8) 14 (6.4) 13 (5.9) 13 (5.9) 13 (5.9)

0 5 (5.4) 5 (5.4) 4 (4.3) 1 (1.1) 2 (2.2) 0 0 6 (6.5) 4 (4.3) 3 (3.3) 1 (1.1)

Preferred Term

b

At least 1 TEAE Postnasal drip Rhonchi Syncope Urticaria Anemia aggravated Loose stools Nasal congestion Atelectasis Chest wall pain Dry skin Dysphagia Dyspnea exacerbated Hypoesthesia Injection site granuloma Injection site pigmentation changes Injection site swelling Mouth hemorrhage Post procedural pain Sinusitis Skin nodule Tongue ulceration

All VIDAZA (N=220) 219 (99.5) 13 (5.9) 13 (5.9) 13 (5.9) 13 (5.9) 12 (5.5) 12 (5.5) 12 (5.5) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0)

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Observation (N=92) 89 (96.7) 3 (3.3) 2 (2.2) 5 (5.4) 1 (1.1) 5 (5.4) 0 1 (1.1) 2 (2.2) 0 1 (1.1) 2 (2.2) 3 (3.3) 1 (1.1) 0

11 (5.0)

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11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0) 11 (5.0)

0 1 (1.1) 2 (2.2) 3 (3.3) 1 (1.1) 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.

practices that are using the models have seen overall declines in patient wait times of 33%; increased efficiency of chemotherapy staff and infusion room resources by 16%; improvements ranging from 12% to 16% in the timeliness and completeness of orders; and improved efficiency for physicians of about 10% to 15%.

Erratum

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n the article “KRAS Mutations Predictive of Response to Panitumumab Monotherapy in mCRC” in the May issue, the number of patients with KRAS mutations was inadvertently misstated. The corrected article appears in its entirety below:

KRAS Mutations Predictive of Response to Panitumumab Monotherapy in mCRC 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 originally enrolled, 427 (92%) were included in the KRAS analyses. KRAS mutations were identified in 184 (43%) of these 427 patients. 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.)

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HOPA SETS GOALS Continued from cover

time working in oncology as a clinical pharmacist, but I didn’t have any special training per se outside of the standard residency rotation in oncology because it didn’t exist at the time. The senior oncologist interviewed me and gave me the job. So I just kind of fell into oncology pharmacy, and I think some people still do that today.

How did the oncology pharmacy specialty become established? The whole pharmacy specialty process was established by the American Society of Health-System Pharmacists (ASHP) Board of Pharmaceutical Specialties (BPS) with submissions from various organizations. Nuclear pharmacy was one of the first, followed by nutrition and then pharmacotherapy. Back in the 1980s, ASHP had what they called special interest groups, or SIGs. The oncology specialty practice came out of the oncology SIG group of ASHP. I was the chairman of ASHP’s oncology SIG group at the time the petition to establish oncology as a specialty was drafted. One of our tasks was to establish our standard of practice. We spent a lot of time with many oncology pharmacists from around the country trying to put together our petition. The first petition that we submitted to the BPS was turned down because it was not viewed as being sufficient to justify the specialty. The oncology specialty practice almost died at that time. But there were four of us who would not accept that and we never gave up. It became a 6year process for us to finally get oncology pharmacy recognized as a specialty. How did these efforts lead to the establishment of HOPA? There was really only one annual oncology specialty meeting at that time, that being M.D. Anderson’s cancer conference. We saw a need for additional programming and continuing education for oncology pharmacy. For a while, many of us in the United States participated (and still do) in the International Society of Oncology Pharmacy Practice (ISOPP). The ISOPP group meets every 2 years and travels around the world. We felt ISOPP did not provide a consistent source of continuing education to oncology pharmacists in this country. So a small group of pharmacists and a medical advertising company put together an oncology specialty program—the first one was called “Making A Difference in Oncology”—and that conference went on for 3 days as a continuing education program in oncology pharmacy. Later, it was decided that if HOPA was ever going to get off the ground as a national organization, using the “Making A Difference” conference would be a good venue and July/August 2008

eventually lead to the programming structure of HOPA.

What impact do you think HOPA has made on the oncology pharmacy specialty? HOPA is still a young group. We are in the first of a 3-year strategic plan for our organization. Certainly the organization met a long-time need to have a formal group that would bring together oncology pharmacists from around the country. With the large increase in the number of cancer drugs, biologics, gene therapy, and targeted molecular therapies, oncology pharmacy has become a very sophisticated practice. HOPA was established at a very good time to provide infrastructure, bring people together, provide education and training, and keep people up to date on these new developments. Oncology changes faster than many other specialty practices, so there is a great need for continuing education. Even within oncology, there are several subspecialty areas now within our organization, and people are forming smaller SIGs (ie, research, pediatrics, BMT). We are now being recognized by other professional organizations as a source of specific information related to oncology pharmacy, which is remarkable considering we are a relatively new organization. We are also part of a three-group consortium with ASHP and the American College of Clinical Pharmacy to provide recertification for oncology pharmacy as a specialty. What was your role regarding this year’s HOPA/ISOPP conference? ISOPP intended to come to the United States in 2008 and had petitioned HOPA to hold a one-time joint meeting. This was decided before I became president. A lot of the year was spent putting this joint meeting together. We had an oversight group of four people, two from HOPA and two from ISOPP, which oversaw the whole process. Putting the meeting together required a huge effort. The programming at this year’s meeting was three times the amount of our last meeting, and the attendance was doubled. More than 1000 people attended this year’s meeting. My job was to make sure everything worked, but I take almost no credit for that. The meeting required the hard work of many different HOPA and ISOPP members. What were some of the highlights of this year’s HOPA/ISOPP meeting? Our goal at this year’s meeting was to provide topics that would serve the needs of both the HOPA membership and international attendees. Some of the things we do clinically in the

With the large increase in the number of cancer drugs, biologics, gene therapy, and targeted molecular therapies, oncology pharmacy has become a very sophisticated practice. United States are not done in other countries. The challenge was to provide programs and information pertinent to people from all over the world. I think we accomplished this goal with our keynote address on safe medication practices, which is a major World Health Organization issue and certainly an issue within this country. Could you explain some of the differences between oncology pharmacy practice in the United States and other countries? The oncology pharmacy activities in many other countries revolve primarily around drug preparation, preparation safety, and managing hazardous materials, which are indeed key functions. In the United States, we have the additional elements of clinical practice and direct patient care. In some countries, oncology pharmacists are not quite up to that level yet. How was this dichotomy addressed at the annual meeting? We provided a good number of sessions and workshops, some with common themes and others more specialized. We had a fantastic turnout in the poster sessions, with almost 200 posters. A new feature at this year’s meeting was the research

PHARMACY PRACTICE

7/28/08

platform presentations. We wanted to provide a format for young trainees and residents to become involved in. That has been one of the goals of our organization and seemed to work very well this year. Is there anything you might have done differently at this year’s meeting, or would like to see happen at future meetings? Overall, I think the meeting went fantastically well. Personally, I would like to see an increased emphasis on the community practice setting at future meetings and to expand our technician activities. I think we should work to provide more specific programming related to community practice for oncology pharmacists. We don’t want to limit our reach to oncology pharmacists in medical centers, universities, and cancer centers. We want to reach out to all oncology pharmacy practitioners. What are some of the greatest challenges currently facing oncology pharmacy? One of the greatest challenges right now is manpower—recruiting trainees, developing trainee programs and specialty residencies. We need to increase the number of people trained in oncology pharmacy. Currently there are more jobs than we have people. Continued on page 8

CARTOON

PHARMACY PRACTICE

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“There’s one side effect. It may kill you.” G REEN H ILL H EALTHCARE C OMMUNICATIONS

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HOPA SETS GOALS

HOPA:

Continued from page 7

CONFERENCE NEWS

Oncology drug management is another major challenge. Community practices are under increasing pressure to upgrade their standards of oncology drug preparation. Standardized treatment protocols for community practices are popping up all over. Some of these protocols call for the generation of data to document outcomes and demonstrate value of service. I think we will see a push for more standardized care in the near future. This will provide huge opportunities for oncology pharmacists in the coming years. What needs to change on the academic level for these challenges to be better addressed? I think universities need to develop better standards for academic training in oncology pharmacy. One of the elements of our strategic plan is to provide leadership and guidance to the universities as far as suggested curriculum.

For More News from

HOPA see the September Issue

What are some of the other objectives of the strategic plan? We currently have a 3-year strategic plan for HOPA. In addition to the educational objectives, the plan calls for efforts to develop our organizational infrastructure and increase our membership. We also plan to increase our legislative and regulatory activities. Another goal is to increase the recognition and awareness of oncology pharmacists by the public and other healthcare providers. All of these plans were developed with the primary goal of improving patient care. —David S. MacDougall

Myelosuppression Decreases Response Rates, HRQOL in Patients with CML ANAHEIM—Myelosuppression has a negative impact on clinical response rates and health-related quality of life (HRQOL) in patients with chronic myeloid leukemia (CML), according to a recent data analysis. Myelosuppression is associated with increased morbidity and mortality in patients with cancer, and the presence of treatmentemergent myelosuppression is a major challenge in the management of patients with CML. The impact of myelosuppression on treatment responses and HRQOL in patients with CML is not well known.

The presence of treatment-emergent myelosuppression is a major challenge. To help clarify these relationships, data from a phase 3 study of imatinib versus interferon-alfa combined with cytarabine in 1016 patients with newly diagnosed, previously untreated Philadelphia chromosome-positive CML were analyzed by researchers at Pharmerit North America, Bethesda, Md. Myelosuppression was categorized as any event of neutropenia, thrombocytopenia, or anemia at the 3-month follow-up. The composite efficacy end point (therapeutic response) was defined as the patient achieving either a complete hematologic response or a complete cytogenic response by the 3-month visit. The impact of myelosuppression on HRQOL was determined using the Functional Assessment of Cancer Therapy (FACT), FACT—Biologic Response Modifier (FACT-BRM), and other validated questionnaires at 3 months.

HOPA: Palonosetron Safe, Effective in Patients Receiving Melphalan for SCT

CONFERENCE NEWS

ANAHEIM—Palonosetron (PALO) is safe and effective for the prevention of emesis in patients receiving high-dose melphalan chemotherapy before stem cell transplant (SCT), according to researchers at Oregon Health and Science University Hospital, Portland. PALO is a second-generation 5-hydroxytryptamine (5-HT)3 receptor antagonist recently approved for the prevention of acute or delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving either moderately or highly emetogenic cancer chemotherapy. PALO has a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists and is typically administered as a single 0.25-mg intravenous (IV) dose 30 minutes before the start of chemotherapy. SCT conditioning regimens have been associated with significant rates of emesis 8

G REEN H ILL H EALTHCARE C OMMUNICATIONS

and high use of antiemetic rescue treatment. The efficacy of first-generation antiemetics in this clinical setting has been disappointing. In a randomized, phase 2, doubleblind study, 73 patients with multiple myeloma receiving 2-day conditioning with high-dose melphalan (100 mg/m2 twice daily) before SCT were treated with one, two, or three daily doses of PALO (0.25 mg IV) or placebo before SCT. All patients received dexamethasone on days 1 and 2 after SCT. The primary study end point was complete prevention of emesis throughout the 7-day study. Secondary end points included rescue antiemetic use, adverse events, and other parameters. In the groups receiving 1-day, 2-day, and 3-day PALO, the rates of complete emesis prevention were 42%, 42%, and 44%,

A therapeutic response was achieved by 71% of the patients without myelosuppression and 54% of those with myelosuppression, reported Jennifer Stephens, PharmD, and colleagues. The difference in response rates between the patients with and without myelosuppression was statistically significant (P <.0001). In the myelosuppression group, clinically meaningful declines were observed in the physical well-being and functional well-being domains of the FACT survey and in the Treatment Outcome Index (TOI). In the group without myelosuppression, clinically meaningful declines were observed in the physical well-being domain of the FACT survey, but no significant change was observed in the TOI. Compared with the patients without myelosuppression, those with myelosuppression had greater declines for physical and functional well-being and the physical and cognitive/emotional domains of the FACT-BRM survey. The declines in global score and TOI were significantly greater for patients with myelosuppression. There was a trend towards improved emotional well-being between baseline and 3 months in both patient groups, suggesting an improved ability of patients to feel better able to cope with their illness, less worried, and less sad when receiving treatment for their illness. These findings underscore the negative impact of myelosuppression on treatment response rates and HRQOL in patients with CML and may be useful in the selection of appropriate therapies in patients with CML. Particularly those who have failed or are intolerant of imatinib, the researchers concluded. —DSM respectively. Rescue antiemetics were required by 8%, 33%, and 24% of those receiving 1-day, 2-day, and 3-day PALO, respectively, reported Joseph Bubalo, PharmD, and colleagues. Complete response rates (no emesis and no rescue antiemetic use) for the overall 7day study were 8%, 21%, and 20% (P = .14) for the groups receiving 1-day, 2-day, and 3day PALO, respectively. Overall and on individual study days, two or three doses of PALO were more effective than one dose for emesis prevention without rescue use. PALO was well tolerated, and the most common adverse events were diarrhea (16%), constipation (12%), headache (11%), and insomnia (8%). The researchers noted that the recently approved label change allowing PALO to be dosed more than once per week may help optimize CINV prevention in patients receiving a variety of multiday, high-dose chemotherapy regimens. —DSM Continued on page 9

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CONFERENCE NEWS Continued from cover

sine kinase inhibitor, according to data presented at the 44th annual meeting of the American Society of Oncology. Progression-free survival (PFS) was significantly enhanced in everolimus recipients compared with placebo in a randomized, doubleblind, multicenter phase 3 trial. The mTOR protein regulates cell division and blood vessel growth in cancer cells, and is a major route to resistance in targeted cancer therapies. Everolimus is currently approved as an immunosuppressant for prevention of rejection of organs after transplant. “This is the first phase 3 trial that establishes clinical benefits and provides safety information for this new agent,” said the study’s lead investigator Robert J. Motzer, MD, attending physician, Memorial Sloane-Kettering Cancer Center, New York. Historically, metastatic RCC has been difficult to treat. An effective treatment option when disease progresses despite the use of targeted agents such as sorafenib and sunitinib is an unmet clinical need, Dr Motzer noted. “It is an unmet clinical need that has now been filled,” he said. “Everolimus should be the standard of care in this setting.” The study included 410 patients with metastatic RCC with a clear cell component who were ran-

Table. Outcome in Different Prognostic Groups Prognostic group

Median PFS (mo): everolimus

Median PFS (mo): placebo

N

Hazard ratio*

P value

Overall

410

0.30

<.0001

4.0

1.9

Favorable

118

0.35

<.0001

5.5

2.2

Intermediate

231

0.25

<.0001

3.9

1.8

Poor

61

0.39

.009

3.6

1.9

CONFERENCE NEWS

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*Everolimus versus placebo. PFS indicates progression-free survival

.

domized in a 2:1 ratio to 10 mg of everolimus orally or placebo (Table). Treatment was given in 28day cycles, allowing for assessment of response and safety. All patients had stopped responding to either sorafenib or sunitinib or both within the previous 6 months. “This was a heavily pretreated group,” Dr Motzer pointed out. Patients had received up to three therapies previously. The study was terminated early by the independent data monitoring committee after the second interim analysis (when 60% of the targeted number of events had accrued) because of the large efficacy difference in favor of

everolimus, Dr Motzer said. After 6 months, the median PFS was 4.0 months in patients assigned to everolimus versus 1.9 months in those assigned to placebo (hazard ratio 0.30; P <.0001) (Table). Everolimus was significantly superior to placebo in all three prognostic groups (favorable, intermediate, poor). Twenty-six percent of patients assigned to everolimus had no disease progression, compared with only 2% assigned to placebo. Because patients

After 6 months, the median PFS was 4.0 months in patients assigned to everolimus versus 1.9 months in those assigned to placebo. in the placebo group were permitted to cross over to everolimus if they showed signs of progression while receiving placebo, an analysis of median overall survival was not conducted. The most common adverse events in the everolimus group were stomatitis (incidence of 40% with everolimus vs 8% with placebo), anemia (28% vs 15%), and weakness (28% vs 20%). The incidence of severe (grade 3 or 4) toxicity was 3% or less for each side effect. Quality-of-life measures were not significantly different between patients randomized to everolimus or placebo. The study has been published in the July 23 online issue of The Lancet (doi:10.1016/S01406736(08)61039-9). —Wayne Kuznar

CONFERENCE NEWS

Robert J. Motzer, MD, speaking at ASCO.

Reach us online at www.theoncologypharmacist.com • View current and past issues • Register to receive your free subscription • Access CE activities • Obtain author guidelines

July/August 2008

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ASCO: CONFERENCE NEWS

Bisphosphonate Prolongs Cancer-free Survival in Endocrinesensitive Breast Cancer CHICAGO—The addition of biannual infusions of zoledronic acid to hormone therapy improves disease-free survival and recurrence-free survival in premenopausal women with hormone-sensitive early-stage breast cancer, reported Michael Gnant, MD, at the 44th annual meeting of the American Society of Clinical Oncology. Data obtained from a large randomized clinical trial add to preclinical findings that zoledronic acid may have an anticancer effect. Zoledronic acid is currently indicated for the treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. The Australian Breast and Colorectal Cancer Study Group Trial 12 was designed to compare the efficacy of tamoxifen and anastrazole with or without zoledronic acid in women with endocrine-responsive stage I or II breast cancer with <10 positive nodes. All 1803 women enrolled underwent surgery to remove the primary tumor and

ovarian suppression with goserelin acetate (3.6 mg subcutaneously every 28 days for the duration of the trial) before being randomized to one of four treatment arms: • Tamoxifen (20 mg/day) • Tamoxifen (20 mg/day) plus zoledronic acid (4 mg intravenous [IV] every 6 months) • Anastrazole (1 mg/day) • Anastrazole (1 mg/day) plus zoledronic acid (4 mg IV every 6 months) Treatment duration was 3 years; median follow-up was 5 years. Overall disease-free survival was 94%, and overall survival was 98.2%. There was no difference in the primary end point—disease-free survival—between patients randomized to tamoxifen or anastrazole (P = .59). Women randomized to zoledronic acid had a 36% reduction (P = .11) in the risk of a relapse event compared with women not randomized to zoledronic acid. “When you further subdivide the results and look at event subcategories…zoledronic acid basically reduced events in all of the subcategories, not only bone metastasis, which one might have anticipated, but also locoregional recurrences, distant nonbone metastases, and also contralateral breast cancer,” said Dr Gnant, professor of surgery, Medical University of Vienna. “This is in fact an indication

ASCO: Low Vitamin D Associated with Worse Outcomes in Patients with Breast Cancer CHICAGO—Vitamin D deficiency is associated with worse outcomes in women with early breast cancer. In addition, high-dose vitamin D supplementation can provide relief of symptoms, such as joint pain and fatigue, related to vitamin D deficiency from aromatase inhibitor therapy in postmenopausal women with breast cancer. These findings come from two separate studies presented at the 44th

CONFERENCE NEWS 10

annual meeting of the American Society of Clinical Oncology. A study of 512 consecutively enrolled patients between 1989 and 1996 with newly diagnosed breast cancer, conducted at three hospitals in Toronto, showed that 38% of the patients had vitamin D deficiency, and another 39% had levels considered to be insufficient, said Patricia J. Goodwin, MD, one of the investigators. Low vitamin D levels were associated with tumor grade and adjuvant chemotherapy. Compared with patients with sufficient vitamin D levels, those with insufficient levels had a 94% decrease (P = .02) in distant disease-free survival and a 73% worse (P = .02) overall survival at 10 years. Nonetheless, high-dose vitamin D supplementation is premature in patients with breast cancer, said Dr Goodwin, chair in breast research, Mount Sinai Hospital, Toronto. She added that more current research should be conducted to ascertain whether vitamin D deficiency exists at the level it did during enrollment of patients into this study. Vitamin D supplementation is,

G REEN H ILL H EALTHCARE C OMMUNICATIONS

that zoledronic acid exerts its benefit through a variety of mechanisms…kind of creating a tumor-hostile environment in our patients that helps to kill micrometastases, or dormants (as well call them), everywhere in the body.” Recurrence-free survival was improved by 35% (P = .015) by adding zoledronic acid to endocrine therapy compared with endocrine therapy alone. There was a nonsignificant trend (P = .10) toward improved overall survival in the zoledronic acid group. Zoledronic acid was generally well tolerated. Notably, there were no confirmed cases of osteonecrosis of the jaw, “which is very reassuring,” Dr Gnant said. Osteonecrosis of the jaw has been reported in cancer patients who are treated with IV bisphosphonates, Michael Gnant, MD, speaking at ASCO. although many patients who have developed osteonecrosis of the jaw while receiving bisphos- zoledronic acid mean that women phonate therapy were also receiving with endocrine-responsive early chemotherapy and corticosteroids. breast cancer can be spared the side There was also no evidence of renal effects of cytotoxic therapy after toxicity with zoledronic acid. locoregional treatment, Dr Gnant The overall excellent disease-free concluded. survival and overall survival in the study with endocrine therapy and —WK however, justified in women with invasive breast cancer who are vitamin Ddeficient when starting an aromatase inhibitor, said Qamar J. Khan, MD, who presented a study in which highdose but not standard-dose vitamin D relieved joint pain and fatigue in vitamin D-deficient women taking letrozole. “All women starting an aromatase inhibitor should be screened for vitamin D deficiency, and attempts should be made to optimize vitamin D levels,” said Dr Khan, associate professor of oncology, Cancer Center of Kansas, Wichita. About one fourth of women with invasive breast cancer who receive adjuvant aromatase inhibitors experience joint pain or stiffness. About one fourth also report fatigue while being treated with an aromatase inhibitor. In a 16-week prospective study, 60 women with invasive breast cancer who were candidates for aromatase inhibitor therapy had serum vitamin D levels measured at baseline, 10 weeks, and 16 weeks. All women were started on 2.5 mg/day of letrozole and 1200 mg/day of calcium plus 600 IU/day of vitamin D. Women who had serum vitamin D levels ≤40 ng/mL at week 4 had their vitamin D dosage increased to 50,000 IU/day for the next 12 weeks. Fatigue, pain severity, joint pain disability, and menopausal symptoms were assessed via questionnaire at baseline, week 4, and week 16.

Sixty-four percent of the women had vitamin D deficiency (<32 ng/mL) at baseline; 49 of the 50 women who received high-dose vitamin D had serum vitamin D levels >32 ng/mL by week 10. With standard-dose (600 IU/day) vitamin D, serum vitamin D levels dropped in seven of nine women. With standard-dose vitamin D, joint pain improved in only 8% of women and worsened in 34%. During weeks 4 through 16, when the vitamin D-deficient women at week 4 were switched to high-dose vitamin D, joint pain improved in 21% and worsened in 32%. Similarly, fatigue scores were more likely to improve during high-dose vitamin D therapy and were more likely to worsen during standard-dose vitamin D therapy. “Given that these women are being subjected to an aromatase inhibitor, which causes bone loss, just for the bone health alone they should have optimal levels of vitamin D,” said Dr Khan. Health Assessment Questionnaire II scores, designed to study the effects of an intervention on activities of daily living, were stable from baseline to week 4 (during standard-dose vitamin D therapy) but declined (improved) from weeks 4 to 16 (during high-dose vitamin D therapy). —WK July/August 2008


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The

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Oncology Nurse

The Official Newspaper of Record for the Hem/Onc Nurse

The

Oncology

The Official Newspaper of Record for the Hem/Onc Pharmacist

Pharmacist

Presents The First Annual 2008 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.

SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University

H Earn Continuing Education Credits H Each newsletter will feature:

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About Multidisciplinary Cancer Care Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community. Target Audience This educational publication is designed for physicians, nurses, and pharmacists who wish to enhance their knowledge concerning the management of patients with multiple myeloma and renal dysfunction.

Learning Objectives At the completion of this educational activity, you should be able to: • Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM) • Recognize the special challenges in pharmacologic treatment of the many patients with MM who also have renal insufficiency, especially those requiring dialysis • Discuss the results of studies showing treatments that are active and safe in MM patients with renal impairment, including those with advanced renal failure requiring dialysis

Accreditation Physicians This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of CME Consultants and Center of Excellence Media. CME Consultants is accredited by the ACCME to provide continuing medical education for physicians. CME Consultants designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Pharmacists CME Consultants is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all participants must complete an evaluation, request for credit form, and a posttest. Statements of Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09. Nurses CME Consultants is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CME Consultants designates this program for 1 contact hour. Participants should claim only those contact hours actually spent in the educational activity. In order to receive credit for this program, each participant must complete the evaluation form, posttest, and certificate request form. Certificates will be mailed to program participants in approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.

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Page 12

Cancer Center & Research Institute Photo courtesy of The Moffitt Cancer Center

W

hen H. Lee Moffitt, then a Florida State Representative conceived of the center that now bears his name back in 1978, he had no idea that 30 years later his name would be synonymous with innovative and comprehensive cancer care. Moffitt, a cancer survivor, was alarmed by Florida’s high rate of cancer. The state needed a center that would help eradicate cancer as a public health threat through patient care, education, and research. Florida ranks second in the nation for its rates of cancer incidence and mortality. Initially, Moffitt’s vision was met with resistance—where would the funding come from? But with the help of the Floridian government, he was able to raise $70 million dollars initially. In 1981, the Florida legislature passed a bill to secure the planning for the H. Lee Moffitt Cancer Center & Research Institute on the Tampa campus of the University of South Florida. Notably, funding for the initial $70 million needed for construction of the center came mainly from the state’s cigarette tax. In 1983, the center celebrated its groundbreaking, and by 1986, the center started admitting patients. The success was inspiring, and the center continued to grow, in physical size and in reputation. In 1998, the center expanded its research and clinical areas thanks to a $100 million grant from the Florida legislature. This was followed by earning the status of a National Cancer Institute Cancer Center. Earning this highly regarded distinction has translated into doubled research funding and a 130% increase in patient referrals. Moffitt has also earned the honor of being named in US News & World Report as one of America’s Best Hospitals. In addition to its main campus in Tampa, the center has 15 affiliates in Florida, one in Georgia, and two in Puerto Rico. The Moffitt Cancer Center provides the most marrow and blood transplants in the Southeastern United States.

CANCER CENTER PROFILE

Photo courtesy of The Moffitt Cancer Center

12

Personalized cancer care In its vision to “be the leader in scientific discovery and translation into compassionate care, cures, and prevention of cancer,” the center is constantly growing, expanding, and evolving to keep current and remain innovative. The center’s latest initiative is to expand its personalized oncology research. The center started collaborating with Merck & Co in 2006 to develop more personalized treatment for different types of cancers that affect individuals. This Total Cancer Care initiative was started to test every tumor and 30,000 genes of patients with cancer. The goal is to create personalized individual cancer care through genetics and to help save more lives by 2010. Working in conjunction with the University of Florida and Shands Healthcare, the partnership will encompass the spectrums of patient care, research, and education. The goals of this collaboration include quality improvement in cancer care, helping to address the needs of surviving family members, and, lastly, tissue/data collection to create more custom-tailored therapies for each patient. Executive Director, Willian S. Dalton, MD, PhD, stated at a media conference, “Total Cancer Care is intended to streamline pathways to cancer care and to follow the patient through screening, diagnosis, and treatment of cancer, incorporating translational research at each step along this continuum of care.”

Photo courtesy of The Moffitt Cancer Center

CANCER CENTER PROFILE

H. Lee Moffitt

patients and their families are glad to be at Moffitt, she says, and this creates a positive environment. She admits, however, that her job can be emotionally strenuous and is grateful for the support that Moffitt provides for its staff. Not only are ongoing professional workshops provided, but there is an extensive mentoring program for new nurses. In recognition of its efforts to encourage staff nurses to seek oncology certification, the Moffitt Cancer Center received the 2008 Employer Recognition Award from the Oncology Nursing Certification Corporation. —Amy Johansson

Caring for the caregiver One of the initiatives of note at Moffitt is a program called Caring for the Caregiver, which provides stress management training, nutritional counseling, and advice on problem-solving techniques and communication strategies to family members of patients who live at home. Another unique service on offer is Cancer Answers, a toll-free telephone service staffed by registered nurses, who answer queries on such matters as cancer detection, prevention, risk, diagnosis, treatment, and research. Robert Bradbury, RPh, the clinical coordinator of the pharmacy has been a pharmacist since 1975, and has been on staff at Moffitt for 20 years. There are 65 pharmacists on staff at the center, and they work in various areas, such as the central pharmacy, retail pharmacy, and on clinical trials. There are also rounding pharmacists integrated into different areas and different roles. All are board-certified in oncology. According to Bradbury, Florida has the most boardcertified pharmacists in the nation. He says, “We take pride in being integrated with the patient care model at Moffitt so the patients have an advocate for their drug therapy.” Bradbury enjoys his interaction with patients, saying, “No one is more pleasant to work with than cancer patients. They’re very thankful for our interaction. It’s a great opportunity to be of comfort and to improve outcomes for our patients. One person can really make a difference.” Nurse Serena Moody has been on staff at Moffitt for a little over a year, and gives rave reviews of her professional experience there, with both other staff members and patients. She speaks warmly about her patients and their families, saying how grateful she is to be able to provide care and comfort for them, and how positive their interactions are. Many cancer

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Moffitt Facts: Number of beds: 162 Number of inpatients: 726 Number of outpatients: 264,523 Number of staff: 3800 employees (800+ research faculty, 300+ physicians)

Executive Director: William S. Dalton, MD, PhD

Publication: Cancer Control Journal (peer-reviewed journal with a readership of 13,000)

Funding: For 2008, Moffitt received approximately $66 million in grants.

Research programs: Molecular oncology, immunology, drug discovery, experimental/therapeutic, genetic immunotherapy, behavior oncology, cancer screening, prevention, and detection, digital imaging, tobacco research and intervention, molecular screening

July/August 2008


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Leadership and Communication Skills for Pharmacists

Are You REALLY Listening? By Jim Barnoski

I

interview many professionals in all walks of life every week, and one question that always comes up is: How do you find out what your patient really needs when they don’t communicate well. The answer I often hear is “by listening.” Professionals in pharmacy, nursing, or any other business often forget that listening is a two-part exercise, neither of them passive. The first part of the exercise is planning and asking a variety questions that will get your patient thinking about his needs. After all, patients and clients are often busy people who, contrary to our perceptions, don’t spend a lot of time thinking about how our services might help them. They need some help getting started. So we have to ask the questions that will provoke thought and uncover the real problems. The second part is listening. Asking your patient all the correct questions is wasted if you don’t hear what he or she is saying, either in words, or more subtly, in tones or partial hints. Being a good listener requires more than just keeping quiet while the other person is talking. Sometimes we’re even thinking about our next question while they are answering our last question! Do you hear everything that is being said? Do you understand it completely? Here are some tips on how to become a more effective listener:

Focus in on the basic message Try to pinpoint the main ideas the person is expressing. Ask yourself what the speaker is trying to say. If you’re not sure, ask. “Mr. Jones, I believe what I heard is . . . Am I on track?” Understand what is being said Keep asking yourself if you understand what is being said. If you don’t, ask for clarification—and keep asking until you are sure you fully understand. “Mr. Jones, I’m not sure I understand how this relates to that. Can you help me out?” What you don’t understand, you can’t recall. Additionally, if you don’t understand what is being said, your mind is more likely to wander, and your listening effectiveness diminishes. Don’t get distracted Don’t let trivial things like the speaker’s appearance or random noises divert your attention from what he or she is saying. Listen to the speaker’s whole sentence. Listen not only for content, but context. Anytime you catch yourself being distracted by something that draws your attention away from the speaker’s words, make a conscious effort to focus back on the words. Do that by creating word images that match the speaker’s words. July/August 2008

Listen with your “gut” The speaker’s tone and body language will impart meaning. Body language accounts for 55% of communication and tonality 38%. The words are only 7% of the process. These subtle clues are quickly picked up by the unconscious mind and leave us with a particular feeling about the speaker. When you are left with a “feeling” about someone after a conversation— that they are sincere, they are hiding something, they can’t be trusted, etc— it is a sign that your unconscious mind has put two and two together and come up with an evaluation.

The

on what is being said. Ask a question or relate a relevant story that reinforces what the person is saying, or represents a different point of view. Ask yourself if what the person is saying relates to other situations or experiences. Third-party stories are an excellent way to confirm that you’ve got it right.

Become personally absorbed in what is being said. You can’t listen effectively if you are only “going through the motions.” Every subject has some interesting angle, some impact on you, or something you can learn. To uncover those elements, you must first abandon your prejudiced or preconceived ideas. If you enter into a conversation with the notion that the other person has nothing of interest or importance to say, you will miss what is important. An attitude of curiosity about a patient’s or coworker’s concerns and needs is flattering and can become both a bonding experience and a communications tool.

Get Involved To keep your active attention on what is being said, offer comments. If the situation permits, offer your own perspective

In summary, listen proactively There is more to listening than just passively hearing the words someone is speaking. Remember, neither questioning or listening is a passive activity. ©2008 Sandler Training, Inc. The Sandler Sales Institute is an international sales and management training/consulting firm since 1967. For more information go to www.sandler.com

Jim Barnoski is a trainer with Sandler Training Center.

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MANAGED CARE PHARMACY Continued from cover

MANAGED CARE PHARMACY

aged care setting were discussed from a consultant’s viewpoint and a health plan’s viewpoint at the 20th Annual Meeting and Showcase of the Academy of Managed Care Pharmacy held in San Francisco in April.

Off-label use of oncology drugs Debbie Stern, RPh, vice president of Pharmacy Rxperts, Inc, a managed care consulting firm, observed that there is a trend to require prior authorization and to manage off-label use. Data from the EMD Serono Injectable Digest, a Web-based market research survey conducted in the first quarter of 2008, show that many respondents are now requiring peerreviewed published studies to support off-label use: 51% require at least one peer-reviewed published study to support off-label use and 63% require two or three. Approximately 67% do not support off-label use, and 72% require compendia listing for off-label drug use. Challenges in managing oncology drugs One of the greatest challenges associated with oncology drugs has been trying to move oncologists from the “buy-and-bill” mentality in addition to lack of survival benefit data, lack of published guidelines on drug use, and lack of outcomes data. Ms Stern noted that, despite approval by the US Food and Drug Administration, oncology drugs are perceived as lacking clarity on outcomes and survival benefit. Another challenge arose with regard to how cancer care has evolved in some cases from acute to chronic, resulting in long-term patient exposure to medications. This has required adjusting the care mentality from cure to maintenance, similar to managing patients with hypertension, asthma, and diabetes, she said. Managing specialty drugs There are third-party vendors now who specialize in assisting with medical benefit management of specialty drugs, medical costs in particular. Vendor services include converting J-codes to National Drug Codes, managing oral oncology and/or infused oncology agents, adjudicating some or all medical benefit specialty drugs, and performing clinical and utilization management of specialty drugs. Although the vast majority of respondents to the survey did not plan to use any of these vendors, Ms Stern predicted that attitudes are likely to change in time, and use of the vendors will increase.

MANAGED CARE PHARMACY

Future management strategies in the marketplace There is a growing recognition that with the number of products that have come into the marketplace, oral oncology products will now be considered specialty drugs and require the use of specialty pharmacy. Instituting a first fill for oral oncology agents is fairly new. This was instituted to see whether patients could tolerate the agent prescribed for them. The Great-West Healthcare experience Kerri Miller, PharmD, vice president pharmacy services, Great-West Healthcare, provided the health plan perspective on oncology management. Dr Miller noted that Great-West’s pharmacy side is growing as a result of the use of oral oncology drugs. They collaborate with network management, pricing, quality management, and case management to maintain a balanced approach. Collaboration is more critical in oncology than with other specialties, Dr Miller said. The challenges Great-West has faced include finding and using drugs with the lowest cost from a vari14

Photo courtesy of AMCP

ety of vendors rather than through typical retail contracts; having varying regional reimbursement schedules; keeping up with the volume of new drugs and indications; managing unit costs, quantities, and indications; and preventing inconsistency or duplication in their pharmacy and disease management programs. By contracting with multiple vendors, GreatWest has been able to minimize impact from limited-distribution drugs and ensure appropriate coverage and the best drug prices. This arrangement has also helped them leverage between vendors. They were further able to define their specialty drugs list, among which are the oncology drugs. They commonly see fourth-tier coinsurance, with 20% prescription maximums and a cap on a per-prescription basis. Fewer than 10% of their groups are using this benefit. In 2005, they implemented a retail lock-out of specialty drugs. Members could then get their first specialty drug at a retail pharmacy, and subsequent prescriptions would have to be filled by one of Great-West’s preferred vendors. Having multiple vendors helps to retain a sense of healthy competition in the field while providing access to nearly all limited-distribution drugs, according to Dr Miller. The specialty list has provided consistency, and, over time, lessened member complaints. More than 85% of their specialty drug utilization goes to one of their preferred vendors for pharmacy claims, resulting in $2 to $3 million per year in additional savings beyond what they would have saved had the prescriptions been processed at the retail rate.

Utilization management Great-West has expanded their policies beyond oncology support drugs and is now focusing on oncology itself, Dr Miller explained. This requires partnering with disease management vendors to assist with policy development and review. They are currently using multiple resources, such as the National Comprehensive Cancer Network, to develop policies. Dr Miller noted that input from oncologists was critical for making decisions about off-label use. Great-West also found it expeditious to use the “grandfathering” approach when implementing prior authorization on existing therapies. Great-West has had a relatively low rate of denials (less than 5%), partly resulting from an increase in awareness from their provider network. They have increased communication with their case management team, improved coordination with their disease management vendors, and were able to provide feedback to their provider network department.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Oncology disease management Disease management was outsourced to Matria Healthcare, formerly Quality Oncology. Great-West uses an internal referral process through its customer services division. All members currently undergoing active treatment are case managed. An oncology nurse is assigned to each patient, and a team of case managers and oncology nurses is available 24 hours a day, 7 days a week. Nurses take an active role in helping patients and their family members understand their disease and treatment. Dr Miller said this approach has helped patients avoid unwarranted emergency department visits and unplanned admissions. All the information gathered is shared with the treating oncologist. Although cancer prevalence among plan members has increased from 8.4 per 1000 members per year in year 1 to 9.3 per 1000 members per year in year 3, Great-West has seen a 16% reduction in acute hospital days per 1000 members and a 10% reduction in readmissions. Their complication-related admissions are 20% below the national average, and 49% of their eligible patients participate in hospice programs. On the whole, Dr Miller observed, there is a high level of patient and provider satisfaction. On the medical benefit side, she noted that Great-West’s reimbursement approach has lowered the impact on individual providers. Their J-codes, for example, are linked to specific drugs for easy identification and medical management. GreatWest is considering initiating a higher percent reimbursement rate for generic drugs to prevent providers from using higher cost drugs to reap a higher reimbursement rate. On the medical benefits side, Dr Miller noted there is a 35% to 45% discount off the billed amount for oncology drugs, an increased awareness within the provider network department with regard to contracting strategies, an increased opportunity to redirect to specialists when possible, minimal provider complaints and no network dis-enrollments, and, finally, improved negotiation opportunities not only with providers but also with home health vendors. Great-West hopes to expand its prior authorization and collaborate more extensively with internal partners, disease management, and case management. Finally, Dr Miller said there is a need to align provider incentives for quality and cost-efficiency and to meet the continual challenge to find better ways to collect and analyze data and provide optimal oncology care. —Sandy Paton July/August 2008


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Complimentary

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

Calculating the Dosage of Anticancer Drugs in Obese Patients: A Clinical Challenge BY SHARYN D. BAKER, PHARMD, PHD, AND DAVID GREGORNIK, PHARMD, BCNSP Pharmaceutical Sciences, St. Jude’s Children’s Research Hospital, Memphis, Tennessee HOW TO RECEIVE CREDIT To receive continuing education credit, learners must: • Read the article in its entirety. • Take the CE self-assessment test and complete the evaluation test: 1. Log onto www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number CIK 9828. • The learner must answer at least 70% of the questions on the post-test correctly. • The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test and evaluation. TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients.

D

osing recommendations for cancer drugs are ordinarily drawn from studies in patients thought to best represent those who are most likely to receive the drug in clinical practice. Unfortunately, the obese patient is usually not considered the typical candidate for the drug. Thus, at least for now, dosing recommendations for obese patients are less grounded in science than for nonobese patients. In the absence of standardized dosing guidelines for cancer drugs in obese patients, dosing recommendations are often extrapolated to this population arbitrarily when the dose must be standardized to a particular patient variable such as body surface area (BSA) to minimize the risk of toxicity. The problem is compounded by the lack of information on the effect of obesity on the pharmacokinetics and pharmacodynamics of anticancer drugs. In the clinical setting, drug doses for obese patients are calculated using a variety of empiric dosing regimens, ranging from using the patient’s BSA up to an arbitrary cut-off or relying on an alternate estimate of the patient’s weight, such as predicted normal weight, among others. Because these dosing regimens are untested, patients are at significant risk of being underdosed, which introduces the potential for suboptimal treatment outcomes. With a growing number of obese adults with cancer, it becomes increasingly important to identify reliable means of calculating dosages of anticancer drugs in this population. To address this question, we need to better understand the physiologic effects of obesity on drug disposition. My coworkers and I re-evaluated data from published studies of eight anticancer drugs FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.

16

COST This program is complimentary for all learners. DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education. While the University of Nebraska Medical Center, Center for Continuing Education is an ACPE accredited organization, this does not imply endorsement by the UNMC or ACPE of any commercial products affiliated with this activity. LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Describe current methods of calculating dosage of anticancer drugs for obese patients • Summarize the findings of studies of eight anticancer drugs in lean and obese patients • Evaluate the potential utility of alternative weight descriptors in dose calculation for obese patients

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

Findings • The disposition of some, but not all, drugs is significantly altered in obese patients. • The absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly increased in obese patients. However, this was not seen with carboplatin, docetaxel, irinotecan, or topotecan. • With doxorubicin, systemic clearance was significantly reduced by approximately 30% in obese women but not in obese men. Recommendations • For most of the drugs we evaluated, weight scalars used to calculate BSA should take into account ABW, irrespective of size. In fact, ABW is the most accurate and precise descriptor for calculating anticancer drug doses for obese patients. For example, a

The following authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity: • Lois Colburn • Brenda Ram, CMP • Karen Rosenberg • Lara J. Reiman • Cass Hammond, RN, MSN, CRNP • Sharyn D. Baker, Pharm, PhD • David Gregornik, PharmD, BCNSP • Kimberly S. Hamilton, RN, BSN • Robert J. Ignoffo, PharmD, FASHP

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EDITORIAL BOARD Sharyn D. Baker, PharmD, PhD Department of Pharmaceutical Sciences St Jude Children’s Research Hospital Memphis, TN 38105-2794 David Gregornik, PharmD, BCNSP St Jude Children’s Research Hospital Memphis, TN 38105-2794 Kimberly S. Hamilton, RN, BSN Chronic Leukemia and Myeloma Program Cleveland Clinic Cleveland, OH 44195 Robert J. Ignoffo, PharmD, FASHP Touro University Vallejo, CA PLANNING COMMITTEE Lois Colburn Executive Director Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Brenda Ram, CMP Coordinator Center for Continuing Education University of Nebraska Medical Center 986800 Nebraska Medical Center Omaha, NE 68198-6800 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Lara J. Reiman Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Cass Hammond, RN, MSN, CRNP Avid Education Partners 18071 Crampton Lane Sharpsburg, MD 21782 REVIEWER Gary C. Yee, PharmD, FCCP, BCOP Professor Department of Pharmacy Practice University of Nebraska Medical Center 986405 Nebraska Medical Center Omaha, NE 68198-6045

ACCREDITATION The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-08-150-H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of August 1, 2008. The expiration date is July 31, 2009. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.

July/August 2008


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Continuing Education Program #CIK 9828 • RELEASE DATE: August 1, 2008 • EXPIRATION DATE: July 31, 2009 C O M M E N TA R Y

Table. Antineoplastic Chemotherapy Protocol Weeks 0, 3, 6, and 26 • Ifosfamide 2650 mg/m2 on days 1 to 3 of the course • *Carboplatin target area under the curve (AUC) = 8 mg* min/mL on day 1

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

Weeks 14, 23, and 32 • Ifosfamide 2650 mg/m2 on days 1 to 3 • Doxorubicin 25 mg/m2 on days 1 and 2

Weeks 17 and 26 • *Carboplatin target AUC = 8 mg* min/mL on day 1* • Ifosfamide 2650 mg/m2 day 1 to 3

Weeks 20, 29, and 35 • *Carboplatin target AUC = 8 mg* min/mL on day 1 • Doxorubicin 25 mg/m2 days 1 and 2 *Glomerular filtration rate (GFR) was estimated by assessment of 99Tc-DTPA renal clearance and used to target the carboplatin AUC using a modified Calvert formula: Dose of carboplatin (mg/m2) = AUC × [(GFR (in mL/min/m2) × 0.93) + 15]

BSA that uses ABW seems to be the best strategy for calculating the dose for cisplatin, paclitaxel, and troxacitabine. • The use of lean body mass or IBW is probably the best dosing scalar for doxorubicin in obese women and docetaxel in both men and women. • For carboplatin, the average of ABW and IBW is the best predictor of carboplatin clearance within the Bénézet/Chatelut formula that uses serum creatinine to calculate dose.

When choosing an alternate size descriptor for dose calculation in the obese, it is important to consider the particular agent and the patient’s sex. • When choosing an alternate size descriptor for dose calculation in the obese, it is important to consider the particular agent and the patient’s sex. • The data do not support arbitrary dose capping in obese patients for any of the eight drugs studied. • The data do not support the practice of empiric dose reduction because of obesity. • Prospective studies are needed to refine dosing strategies in obese patients for individual chemotherapeutic agents. • Pharmacokinetic studies are needed to clarify whether different subgroups of obese patients have different drug dispositions. July/August 2008

Calculating the Dosage of Anticancer Drugs in Obese Patients: A Clinical Dilemma: A pharmacist’s perspective BY ROBERT J. IGNOFFO, PHARMD, FASHP Touro University, Vallejo, California, and the University of California, San Francisco

O

f all the therapeutic challenges facing the oncologist, the dosing of anticancer drugs in the obese cancer patient is one of the most difficult. Only a few studies have addressed this issue in a systematic fashion. This research has resulted in dosing guidelines for specific drugs but not a generalized standard dosing guideline that can be applied to all anticancer drugs. No one patient variable stands out as a key factor in the dosing of these agents. The use of body surface area (BSA), a standard (although unproven in a clinical study) for dosing of anticancer drugs in the nonobese patient, does not correlate with the pharmacokinetics or pharmacodynamics of these toxic agents. A study by Baker and colleagues1 attempts to address the issue of reliable dosing of anticancer drugs in the obese cancer patient. They used alternative weight descriptors (lean body weight, geometric mean between actual and lean body weight, ideal body weight, and predicted normal weight) in the calculation of a patient’s BSA and then monitored drug area under the curve (AUC) to determine differences in obese and nonobese cancer patients. Unfortunately, their results varied by individual agent and even individual class (the taxanes in particular). While absolute clearance was increased for all drugs studied in obese patients (cisplatin, paclitaxel, and troxcitabine were significantly increased), there was no difference in clearance when values were standardized to BSA. The use of actual body weight in the BSA formula for dosing docetaxel and doxorubicin resulted in AUCs that were 33% and 25% significantly higher than 1.0, respectively. This was apparently due to changes in disposition of these drugs in women, because men did not have significantly higher AUC ratios. Using lean body weight in both men and women resulted in no difference in AUC ratios. Capping the BSA to 2.0 m2 resulted in a significantly higher AUC ratio only for women receiving doxorubicin, but the authors did not specifically discuss this. BSA capping, however, produced lower AUC ratios for other agents and, in general, is discouraged by the authors. This is consistent with the study of Joerger and colleagues,2 who showed that for each increase in BSA of 0.2m2, paclitaxel elimination was increased by almost 10%, suggesting that capping the BSA would result in lower drug exposure for this agent. With regard to carboplatin, they confirmed

that the use of the mean of actual and lean body weight in the Bénézet-Chatelut formula leads to the most accurate prediction of drug exposure. The authors noted that this result was similar to that in the study performed by Bénézet and colleagues.3 This is further supported by a case report by de Jonge and colleagues,4 who reported extremely high drug exposures in a 130-kg patient receiving highdose cyclophosphamide, thiotepa, and carboplatin. They used adjusted body weight for carboplatin, which lowered the AUC into the normal range. The study by Baker and colleagues is an important addition to the scientific literature and brings to light many of the issues that should be considered in the dosing of anticancer drugs, including sex, type of body weight to incorporate into dosing formulas, flat dosing, dose capping, and empiric dose reduction. It appears that physiochemical properties of the particular drug do not significantly affect the pharmacokinetic parameter of drug exposure for the drugs studied.

Recommendations • I agree with Drs Baker’s and Gregornik’s bulleted recommendations in their review. I would add further that ideal body weight is not a good weight scalar for any of the drug studies, and it led to a significant decrease in drug exposure for cisplatin and paclitaxel. • Because the world is experiencing a global epidemic in obesity, extensive further research on dosing strategies along with the evaluation of pharmacokinetics of anticancer drugs is needed in obese patients. This work should be linked to the pharmacogenomics of anticancer drug effects. • Studies should be performed on other commonly used anticancer drugs, including cyclophosphamide, thiotepa, capecitabine, other anthracyclines, and hormonal agents. References 1. Sparreboom A, Wolff AC, Mathijssen RH, et al. Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol. 2007;25:4707-4713. 2. Joerger M, Huitema AD, van den Bongard DH, et al. Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel patients with solid tumors. Clin Cancer Res. 2006;12:2150-2157. 3. Bénézet S, Guimbaud R, Chatelut E, et al. How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol. 1997;8:607-609. 4. de Jonge M, Mathôt RA, Van Dam SM, et al. Extremely high exposures to in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin. Cancer Chemother

Continued on page 18

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Continuing Education Program #CIK 9828 • RELEASE DATE: August 1, 2008 • EXPIRATION DATE: July 31, 2009 Continued from page 17

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

Case Report A 21-year-old obese white woman (height, 160.7 cm; weight, 106.6 kg; body mass index, 41.3 kg/m2; BSA, 2.22 m2) presented with osteosarcoma of the left femur.1 The patient reported that approximately 1 year before diagnosis she began to experience disturbances in her gait, when her left leg involuntarily began to “swing out” while walking. Six months before diagnosis, she experienced intermittent left leg pain localized to her femur. This continued for 4 months until she was examined by her general practitioner, who prescribed anti-inflammatory medications. The patient returned to her general practitioner after 18 days, complaining of worsening pain, mild night sweats, and a decrease in appetite. Her general practitioner referred the patient to an orthopedic specialist, who ordered a radiograph of the left leg followed by magnetic resonance imaging and a bone scan. The results of the diagnostic imaging studies led to referral to our institution.

Carboplatin was dosed based on the patient’s individual GFR, which would account for obesity-related changes in renal function. After the diagnosis of osteosarcoma was confirmed, the patient was enrolled on the front-line investigational protocol for osteosarcoma (Table). As stipulated in the protocol, IBW was used to calculate all chemotherapy doses. This patient’s IBW was estimated to be 57.5 kg. Using IBW in the Gehan-George BSA equation, the patient’s dosing BSA was calculated to be 1.6 m2, a decrease of 28%. Despite this conservative approach to dosing her chemotherapy, the patient experienced appreciable toxicity during her therapy, including two admissions to the intensive care unit for hypotension and sepsis, prolonged thrombocytopenia resulting in delayed therapy, and significant nausea and emesis. Carboplatin was dosed based on the patient’s individual glomerular filtration rate, which would account for obesity-related changes in renal function. Based on the analysis by Sparreboom and colleagues,2 the use of lean body mass or IBW was recommended when calculating a doxorubicin dose for obese women; information on ifosfamide dosing in the obese patients was not included in this analysis. The patient completed her final course of therapy approximately 40 weeks after the original diagnosis. A computed tomography scan of the chest immediately after completion of her chemotherapy was positive for a new small lung nodule. A followup image 2 months later revealed new nodules in the right lung and a slight increase in size of the original nodule. The patient underwent thoracotomy with resection of the nodules. Gross residual disease involving the diaphragm remained after sur18

gery. Pathologic examination of the nodules showed metastatic osteosarcoma. The patient received salvage chemotherapy with several different regimens. Unfortunately, her disease progressed through this therapy, and she died 2 years after her original diagnosis. References 1. Gehan EA, George SL. Estimation of human body surface area from height and weight. Cancer Chemother Rep. 1970;54:225-235.

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

To receive complimentary CE credit: 1. Log onto www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number CIK 9828.

C O M M E N TA R Y

Calculating the Dosage of Anticancer Drugs in Obese Patients: A nurse’s perspective BY KIMBERLY S. HAMILTON RN, BSN Cleveland Clinic Foundation, Cleveland, Ohio

A

study of US adults in 2002 showed that 31% were obese (with a body mass index [BMI] of ≥30 kg/m2) compared with 23% in 1 1994. Studies have shown that cancers of the colon, breast (postmenopausal), endometrium, kidney, and esophagus are associated with obesity. Links between obesity and cancers of the gallbladder, ovaries, and pancreas have also been found, and obese adults may be at increased risk for other types of cancer as well.2 With the increasing incidence of obesity among US adults, it is imperative to find ways to treat these individuals effectively and safely when they do develop cancer. Historically, appropriately conducted clinical trials have provided information on drug efficacy, safety, and tolerability through several phases, which then translates into clinical practice, before a drug is considered for approval by the US Food and Drug Administration. Phase 1 trials include a smaller group of patients, and the drug is dosed based on preclinical research in nonhuman models. Drugs given to patients enrolled in a phase 1 study may be used for several tumor types, with the goal of determining the maximum tolerated dose of the drug in humans. Phase 2 trials provide data on efficacy and tumor response in a larger group of patients. Information gathered from phase 2 trials suggests effective dosing in a specific tumor type. Finally, phase 3 trials often include a randomized design, comparing the new therapy with a standard therapy, to prove superiority of one treatment over the other. In my own experience in treating patients enrolled in clinical trials, I have found that often patients are not excluded from clinical trials because of their obesity, but rather because of the comorbidities associated with obesity. Exclusion criteria for many clinical trials include uncontrolled hypertension, cardiovascular disease, and an Eastern Cooperative Oncology Group performance status ≥2. Although several patients that I have treated would be considered obese with a BMI >30 kg/m2, it is not clear how different response to treatment is in this special population compared with those with a lower BMI.

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To deliver the appropriate and effective treatment dose to patients, especially when calculating the dosage of most intravenous therapies, the patient’s weight is somewhat accounted for by dosing per the body surface area or area under the curve calculations, given the current model. There are dose limits and precautions to prevent against the toxicity associated with many anticancer drugs. It is very interesting that the findings reported by Baker and colleagues showed differences in the disposition and absolute clearance of some of the drugs that were studied in the obese patients. It is evident that more clinical trials are needed to decipher how body weight, sex, and other characteristics of individual patients affect the dosing of their treatment regimen. Although these questions may be answered by a clinical trial, it would be specifically challenging in any given trial, depending on the study end points, to do subset analyses of patients with a BMI >30 kg/m2 or to randomize patients who have a greater BMI to different dose levels. In addition, many tumor types are rare, and larger trials are difficult to conduct for these tumor types. Another aspect to consider would be the flat dosing of many novel oral agents for obese patients. Several oral anticancer therapies are dosed at a specific standard amount for a disease process based on doses determined in the clinical trial setting. For example, lenalidomide at the 25-mg dose is prescribed for patients with multiple myeloma. We adjust the dose for renal impairment, but seldom make dose adjustments based on the weight of the patient. The study by Baker and colleagues will raise awareness of the need for more clinical trials with an emphasis on the effects of obesity and other factors that may influence the appropriate dose of anticancer drugs for each patient. References 1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA. 2002;288:17231727. 2. Vainio H, Bianchini F. IARC Handbooks of Cancer Prevention. Vol. 6: Weight control and physical activity. Lyon, France: IARC Press; 2002.

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

July/August 2008

suppressive,” said study coinvestigator Steven Kaplan, MD, a professor of urology at Weill Cornell Medical College, New York. “We know that it reduces PSA levels, which are indicative of prostatic disease. Finasteride appears to be particularly adept at suppressing the more indolent cancer. So in the future, it might be useful to use the drug to determine just how aggressive and needful of treatment a particular tumor is. If the patient takes finasteride and his PSA levels quickly drop, he probably has a less-threatening tumor that may just require watchful waiting. But if PSA levels rise, that tumor may need more active treatment.”

He said, in the meantime, researchers need to keep prostate volume in mind whenever they conduct trials assessing the anticancer properties of prostate-shrinking medications. “Right now, the drug maker GlaxoSmithKline is testing out a similar drug, dutasteride, as a possible agent against prostate cancer. We hope that they will incorporate prostate volume in their analysis to help avoid the confusion that dogged PCPT,” explained Dr Kaplan. The PCPT trial was funded by the US National Cancer Institute and Merck, which is the maker of finasteride.

Did you

Know? Men who eat at least 14 ounces of broccoli each week have a reduced risk of prostate cancer. Broccoli, British researchers found, may affect gene expression by changing cell-signaling pathways associated with inflammation and carcinogenesis. Source: PLoS One. July 2008.

—John Schieszer

Trends in Prostate Cancer >>>Men with High-risk Prostate Cancer at Low Risk of Cancer-specific Mortality A substantial proportion of patients with high-risk prostate cancer by currently available definitions do not have a uniformly poor prognosis after radical prostatectomy (RP), according to a study of 5960 men with clinically localized or locally advanced prostate cancer who underwent RP. Among the study group, eight different high-risk subsets, each comprising 4% to 40% of the study population, were identified. Each of the identified high-risk criteria was associated with increased hazard ratio (HR) for secondary cancer therapy (HR, 1.3–5.2; P <.05) and metastatic progression (HR, 2.1–6.9; P <.05). Depending on the definition of increased risk, the probability of freedom from additional therapy 10 years after RP ranged from 35% to 76%. The 10-year cumulative incidence of prostate cancer–specific mortality in high-risk patients ranged from 3% to 11% (HR, 3.2–10.4; P <.0005) (Yossepowitch O, et al. Eur Urol. 2008;53:950-959).

>>> Parenteral Estrogen Efficacy Similar to Combined Androgen Deprivation in Metastatic Prostate Cancer

The anticancer efficacy of high-dose polyestradiol phosphate (PEP) is equivalent to that of combined androgen deprivation (CAD) in patients with prostate cancer and skeletal metastases, but the adverse effects profiles of these treatments are markedly different. These findings emerged in a study of 910 patients with T0-4, NX, M1, G1-3 prostate cancer and an Eastern Cooperative Oncology Group performance status of 02 who were randomized to treatment with either PEP or CAD (flutamide in combination with either triptorelin or bilateral orchidectomy). There were no differences between the treatment groups in terms of biochemical or clinical progression-free survival or overall or diseasespecific survival. Cardiovascular mortality was similar in both groups, but the incidence of nonfatal cardiovascular events was significantly higher in the PEP arm than in the CAD arm (P <.05), predominantly due to

an increase in ischemic heart and heart decompensation events in the PEP group. There were 18 grave skeletal events in the CAD group and none in the PEP group (P = .001) (Hedlund PO, et al. Scand J Urol Nephrol. 2008;42:220-229).

>>> Treatment Choice Determines Overall Satisfaction in Prostate Cancer Survivors

Prostate cancer treatments are each associated with a distinct pattern of change in quality of life (QOL) domains, and these changes influence satisfaction with treatment outcomes among patients and their spouses or partners. The determinants of health-related QOL after primary treatment of prostate cancer and the effects of such determinants on satisfaction with treatment outcomes were prospectively examined in 1201 patients and 625 spouses or partners before and after radical prostatectomy, brachytherapy, or external-beam radiotherapy. Among patients receiving brachytherapy or radiotherapy, adjuvant hormone therapy was associated with worse outcomes across multiple QOL domains. Patients in the brachytherapy group reported having prolonged urinary irritation, bowel and sexual symptoms, and transient problems with vitality or hormonal function. Nerve-sparing procedures helped mitigate the adverse effects of prostatectomy on sexual function. Urinary incontinence was observed after prostatectomy, but urinary irritation and obstruction improved, particularly in patients with large prostates. No treatment-related deaths occurred, and serious adverse events were rare. Treatment-related symptoms were worsened by obesity, larger prostate size, a high prostate-specific antigen score, and older age. Black patients reported lower satisfaction with the degree of overall treatment outcomes. QOL changes were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners (Sanda MG, et al. N Engl J Med. 2008;358:1250-1261). Continued on page 20

G REEN H ILL H EALTHCARE C OMMUNICATIONS

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PROSTATE CANCER

ORLANDO—A reanalysis of data from the landmark Prostate Cancer Prevention Trial (PCPT) suggests that finasteride may reduce the risk for prostate cancer without boosting the odds of aggressive tumors. PCPT, which involved 18,822 men who received either a placebo or finasteride for 7 years, was stopped early in June 2003. The reason was that researchers noted that although finasteride reduced the incidence of prostate cancer in men by up to 25%, men taking this agent appeared to have more aggressive prostate tumors if and when they did develop the disease. These findings caused concern that finasteride may be promoting higher-grade cancer. Now, a new analysis of PCPT presented at the 103rd Annual Scientific Meeting of the American Urological Association (AUA) has concluded that finasteride actually reduced the risk of developing prostate cancer more than researchers had originally thought and does not increase the risk of aggressive tumors. For their new analysis of PCPT data, the investigators used advanced statistical modeling techniques and a complete assessment of prostate tissue biopsies. They found that finasteride did not increase development of more aggressive cancers and that the majority of tumors prevented were those that could spread and cause death. These new findings suggest that men should take an individualized approach to prostate cancer prevention, according to the researchers. “Because we now know that men with even low PSAs [prostate-specific antigens] can develop prostate tumors, if a man is worried about his risk, regardless of PSA score, he can take an agent that is now proven to be effective in lowering that risk,” commented study investigator Ian Thompson, MD, who is chairman and professor of urology at the University of Texas Health Sciences Center, San Antonio. Dr Thompson said finasteride actually shrinks the prostate gland. So, in the initial study it appeared that more cancer was being found in biopsy specimens of men who took the drug. In the re-analysis, the researchers looked once more at PCPT data on biopsies taken from the 18,882 men in the study. They adjusted for treatment type, age, race, family history of prostate cancer, baseline PSA levels, and the individual patient’s prostate volume. The investigators found no evidence that the drug increased the rate of aggressive tumors, but instead actually decreased their rate by 27%. “I believe that the drug is chemo-

PROSTATE CANCER

Prostate Cancer


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TRENDS

Trends in Lung Cancer

Continued from page 19

TRENDS

>>>18F-fluoro-2-deoxy-glucose Uptake Predicts Outcomes in NSCLC

Low 18F-fluoro-2-deoxy-glucose uptake at presentation predicts a favorable prognosis in patients with gefitinib-treated non-small-cell lung cancer (NSCLC). The finding is based on a retrospective analysis of 84 positron emission tomography/computed tomography findings from patients with gefitinib-treated NSCLC. Patient characteristics, response rates, and survival rates were evaluated according to the maximum standardized uptake value (SUV) of the primary tumor. The response rates (RRs) were higher in never-smokers than in ever-smokers (41% vs 9%; P = .001), and patients with adenocarcinoma had higher RRs than those with other tumor histopathologies

(35% vs 9%; P = .009). The SUV was significantly lower in patients who were never-smokers (P = .005), patients with adenocarcinoma (P <.001), and women (P = .017). Patients with a low SUV had higher RRs compared with those with a high SUV (53% vs 18%; P = .003). Median progression-free survival was significantly greater in patients with low SUVs compared with those with high SUVs (33.1 weeks vs 8.6 weeks; P = .003). A low SUV was associated with improved overall survival in univariate (P = .011) and multivariate (P = .043)

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

>>>Gemcitabine, Cisplatin, and UFT is Effective First-line Regimen in Advanced NSCLC The combination of gemcitabine, cisplatin, and uracil-tegafur (UFT) is an active and well-tolerated first-line regimen in patients with advanced nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC), according to the findings of a phase 2 study. A group of 37 chemotherapynaive patients (median age, 60 years) with histologically or cytologically

Trends in Hematologic Cancer >>> High GM-CSF Autoantibody Titers Predict Active Disease in Patients with Myeloid Leukemia

Antibodies to granulocyte-macrophage colony-stimulating factor (GMCSF) are present in patients with active myeloid leukemia and may be useful markers of disease activity. The finding is based on a study of 69 patients with acute myeloid leukemia, chronic myeloid leukemia, or myelodysplastic syndrome, including 19 patients who received GM-CSF with peptide antigen and incomplete Freundâ&#x20AC;&#x2122;s adjuvant in a vaccine trial for the presence or induction of anti-GM-CSF antibodies. AntiGM-CSF IgG antibodies were present in 52% of the patients with myeloid leukemia compared with 3% of healthy controls (P = .008) and none of 6 patients with lymphoid leukemia (P = .0001). Antibody titers were unaffected by vaccination. Anti-GM-CSF IgA and IgM antibodies were found in 33% and 20% of the patients with myeloid leukemia, respectively. Anti-GM-CSF IgG titers were significantly higher in patients with active disease than in those in complete remission (P = .0009), but GM-CSF expression was not increased in either group (Sergeeva A, et al. Leukemia. 2008;22:783-790).

>>> CHOP + Radioimmunotherapy Effective in Elderly Patients with Diffuse Large B-cell Lymphoma

TRENDS

Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus radioimmunotherapy is safe and effective in previously untreated elderly patients with diffuse large B-cell lymphoma (DLBCL). In a prospective, sin20

gle-arm, open-label, nonrandomized phase II trial, 20 elderly patients (age >60 years) with previously untreated DLBCL received a novel regimen consisting of six cycles of CHOP chemotherapy followed 6 to 10 weeks later by 90Y ibritumomab tiuxetan. The overall response rate to the entire treatment regimen was 100%, including 95% complete remission (CR) and 5% partial remission. Four (80%) of the five patients who achieved less than a CR with CHOP improved their remission status after radioimmunotherapy. With a median follow-up of 15 months, the 2-year progression-free survival rate was estimated to be 75%, with a 2-year overall survival rate of 95%. The 90Y ibritumomab tiuxetan toxicities included grade >3 hematologic toxicity in 12 of 20 patients; the most common grade >3 toxic effects were neutropenia (12 patients) and thrombocytopenia (7 patients). One patient received transfusions of red blood cells and/or platelets (Zinzani PL, et al. Ann Oncol. 2008;19:769-773).

100 mg/m2 given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4. Mean peak plasma level after intravenous etoposide was significantly higher compared with oral administration (16.3 vs 12.0 mcg/mL; P = .015). The mean bioavailability of oral etoposide was 58% with an interpatient variability of 26%. Significant differences in bioavailability of oral etoposide were not observed between the used dose levels (350, 400, and 450 mg). Mean area under the curve (AUC) after a 100mg/m2 intravenous and a 200-mg/m2 oral dose of etoposide were 74.0 and 84.9 mcg/h/mL, respectively (P = .481). Interpatient variability in the AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as a percentage of the administered dose was 39.4% after intravenous infusion and 35.4% after oral intake (P = .422). Renal etoposide clearance was similar with intravenous and oral administration (18.5 and 16.7 mL/min, respectively; P = .546) (Kroschinsky FP, et al. Cancer Chemother Pharmacol. 2008;61:785-790).

>>> Oral Etoposide Equal to IV Dosing in Patients with NHL Receiving CHOP

Etoposide doses of 200 mg/m2 administered orally and 100 mg/m2 administered intravenously are pharmacokinetically equivalent, a finding which supports the use of etoposide capsules on days 2 and 3 of the CHOP plus etoposide protocol. The pharmacokinetic equivalency of oral and intravenous etoposide was examined in 10 patients (median age, 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Did you

Know? The survival rate of children with cancer is now nearly 80%. Almost two thirds, however, experience one or more chronic health problems. Source: NCI Cancer Bulletin.

confirmed stage IIIB or IV NSCLC and a performance status of 0 to 2 received gemcitabine on days 1 and 8, cisplatin on day 1, and UFT orally on days 1 to 14. Treatment was repeated every 3 weeks for up to six cycles. Complete response was achieved in one (3%) patient, partial response in 17 (46%) patients, and stable disease in 10 (27%) patients. The overall response rate was 48.6% on an intention-to-treat basis and 54.5% in patients in whom a response evaluation was possible (n = 33). The median survival time was 14.7 months, the 1-year survival rate was 54%, and the median time to progression was 5.4 months. Toxicities were moderate and consisted mostly of hematologic events. Grade 3/4 neutropenia developed in 37% of patients and four patients experienced febrile neutropenia. Grade 3/4 anemia and thrombocytopenia occurred in 19% and 5% of patients, respectively. Nonhematologic toxicities were mild (Shin SJ, et al. Lung Cancer. 2008;60:83-91).

The overall response rate was 48.6% on an intention-to-treat basis. >>> Gemcitabine Plus Irinotecan Combination Effective in Patients with Previously Treated SCLC

Gemcitabine plus irinotecan is effective and well-tolerated in patients with previously treated small-cell lung cancer (SCLC), new data suggest. A total of 31 patients (median age, 64 years) with SCLC who had experienced treatment failure with one prior chemotherapy regimen received gemcitabine and irinotecan on days 1 and 15 of a 28day cycle. All patients were required to have a performance status of 0 to 2 and adequate organ function at enrollment. An objective response was obtained in 36.7% of the patients. The median overall survival time was 14.4 months, and the 1-year survival rate was 51%. The primary grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia and one case of grade 4 thrombocytopenia (Ohyanagi F, et al. Cancer Chemother Pharmacol. 2008;61:503-508). July/August 2008


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Meetings SEPTEMBER 2008 2008 Breast Cancer Symposium www.astro.org

17 – 20 SAN FRANCISCO, CA 25th National Oncology Economics Conference www.accc-cancer.org

19 – 20 MIAMI, FL 9th Annual Perspectives in Colorectal Cancer www.imedex.com

©iStockphoto.com/Tony Tremblay

OCTOBER 2008

16 – 18 MONTREAL, CANADA 9th Meeting of the International Society of Geriatric Oncology www.cancerworld.org/siog

17 – 18 ARLINGTON,VA 2008 ASTRO Translational Advances in Radiation Oncology and Cancer Imaging www.astro.org

NOVEMBER 2008

4 – 8 NEW YORK, NY

Chemotherapy Foundation Symposium XXVI www.chemotherapyfoundation.org

13 – 18 CHICAGO, IL 2008 Multidisciplinary Lung Cancer Symposium www.oncologymeetings.org July/August 2008

50th Annual Meeting and Exposition American Society of Hematology www.hematology.org

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

7 – 11 ORLANDO, FL

American Society of Healthsystem Pharmacists Midyear Clinical Meeting www.ashp.org

11 – 14 SAN ANTONIO,TX San Antonio Breast Cancer Symposium 2008 www.sabcs.org

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 Respiratory System 38 4 Any Adverse Events 99 57 more common among the elderly, including pneumonia and pneumonitis. Low86 10 Increased Cough 13 1 Body as a Whole 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 b Adverse reactions observed up to 12 months following Rituxan. Adverse 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.

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July/August 2008 Vol. 1 No. 3