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MEDICAL MINUTES Novel drug may combat chemoinduced hearing loss.

NEWS NOTES HPV researcher wins Nobel Prize

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Courtesy of Cleveland Clinic

NOVEMBER/DECEMBER 2008 • VOL. 1, NO. 5

The

HEMATOLOGIC CANCERS Pleural effusions costly in patients with CML

www.theoncologypharmacist.com

Oncology

The Official Newspaper of Record for the Hem/Onc Pharmacist

Pharmacist PHARMACY PRACTICE

INTERVIEW

The “Growing Pains” of Oncology Specialty Pharmacy

Anderson Brings Pharmacist’s Perspective to ACCC Leadership An interview with Ernest R. Anderson, Jr, MS, RPh

E

rnest R. Anderson, Jr, MS, RPh, who became president of the Association of Community Cancer Centers (ACCC) at its 34th annual meeting last April, is the first pharmacist to serve in this position. Previously, he was the first pharmacist on ACCC’s Board of Directors and helped establish the Oncology Pharmacy Education Network (OPEN) within the organization. Anderson is director of pharma-

cy at the Lahey Clinic, Burlington, Mass., and the Lahey Clinic North in Peabody, Mass. Anderson is also associate clinical professor of pharmacy at Northeastern University College of Pharmacy and Allied Health Profession and adjunct associate professor of pharmacy at Massachusetts College of Pharmacy and Health Sciences in Boston. The Oncology Pharmacist recently spoke with him about his views on the role of phar-

macists in oncology practice and what he hopes to accomplish in his term as ACCC president.

Please tell us about your education and training and how you got into oncology pharmacy. My present position is director of pharmacy at the Lahey Clinic. I’ve

H

ealthcare payers are seeking greater control over the billions of dollars spent in treating cancer. The focus of their effort is pharmaceuticals, the escalating cost of which—thanks to advances in biotechnology—was unfathomable a decade ago. Specialty pharmacies emerged as a way to save cost and monitor patient compliance and safety in other disease states—initially, hemophilia. These entities brought a degree of expertise regarding niche drugs, and offered a Continued on page 14

Complimentary CE Credit

Continued on page 10

SKIN CANCERS

SAFE HANDLING

Advanced Melanoma Targeted by Newer Molecular Therapies

Work Surface Sampling Reveals High Rates of Drug Contamination

ANAHEIM—Molecular pathways involved in the pathogenesis of malignant melanoma are the targets of an emerging group of therapies that may revolutionize the treatment of this disease, said Jamie Poust, PharmD, University of Colorado Hospital, Aurora. In the United States, melanoma is the most common

ANAHEIM—A large-scale study of the feasibility of antineoplastic drug contamination testing by wipe sample monitoring has revealed high levels of drug contamination on work benches, refrigerator doors, and other surfaces in multiple pharmacies. The findings, reported in a poster session at the 2008 Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners

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Program #CIK9976: Finasteride and Prostate Cancer Prevention: The Latest Chapter

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PRESORTED STANDARD

U.S. POSTAGE

PAID LEBANON JUNCTION, KY

PERMIT #651

PRACTICAL APPLICATIONS Management of VTE in patients with cancer

Between pages 14 and 15 © 2008 Green Hill Healthcare Communications, LLC

PHARMACY CAREERS Job opportunities for pharmacists at the FDA

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For more information, visit www.sancuso.com or call 1-800-SANCUSO.

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MEDICAL MINUTES

Medical Minutes BY JOHN SCHIESZER

Common Pain Relievers May Affect Prostate Cancer Biomarker Men with prostate cancer should be alerted that common pain killers such as aspirin and ibuprofen may affect their prostate-specific antigen (PSA) levels and could artificially mask their risk of prostate cancer. “More than anything, these findings underscore the importance for doctors to know what medications their patients are on,” said study investigator Eric Singer, MD, who is a urology resident at the University of Rochester Medical Center, New York. “We showed that men who regularly took certain medications like aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) had a lower serum PSA level.” Singer’s team studied the records of 1319 men older than 40 years of age who took part in the 2001-2002 National Health and Nutrition Examination Survey (NHANES). The team looked at the men’s use of NSAIDs and the painkiller acetaminophen and their PSA levels. The investigators found men who used NSAIDs regularly had PSA levels about 10% lower than men who did not. The results were similar with acetaminophen, but

the difference was not statistically significant because of the lower number of men in the study taking the medication. While it might be easy to assume that a lowered PSA level automatically translates to a lowered risk of prostate cancer, the authors of the study stress that it is too soon to draw that conclusion. Singer pointed out that a man’s PSA level can be elevated for reasons unrelated to cancer. Sometimes, inflammation is part of a cancer process and sometimes it is not, and so it is possible that a lowered PSA reflects reduced inflammation without affecting a man’s risk of prostate cancer. Another possibility is that a PSA level lowered by NSAIDs might artificially mask a man’s risk for getting prostate cancer. The medications might lower the PSA, but a man’s risk might stay precisely the same. “The data are very interesting, but it will take more research to determine how to interpret the findings. In the meantime, this shouldn’t change men’s behavior or prompt them to take these medications to try to prevent prostate cancer,” Singer explained. ©iStockphoto.com/ObservePhoto

John Schieszer is an award-winning national journalist and radio broadcaster of The Medical Minute. He can be reached at medminutes@aol.com.

©iStockphoto.com/MorePixels

©iStockphoto.com/BustjanT

Researchers in Germany The German researchers found that methadone was as effective as have discovered that metha- standard chemotherapies and radiation treatments against nonresisdone has surprising killing tant leukemia cells and that nonleukemic peripheral blood lymphopower against leukemia cells. cytes survived after methadone treatment. To their surprise, they also They have just published a found that methadone effectively killed leukemia cells that were study that suggests methadone resistant to multiple chemotherapies and to radiation. holds promise as a new therapy Probing the mechanism of methadone’s action, the researchers for leukemia, especially in found that it activates the mitochondrial pathway within leukemia patients whose cancer no cells, which activates enzymes called caspases that prompt a cell into longer responds to chemother- apoptosis. Chemotherapy agents use the same approach, but apy and radiation (Friesen C, methadone activated caspases in sensitive leukemia cells and also et al. Cancer Res. 2008;68: reversed deficient activation of caspases in resistant leukemia cells. 6059-6064). In this study, the single doses used to kill leukemia cells were “Methadone kills sensitive greater than the doses used to treat opioid addiction, but the leukemia cells and also breaks treatment resistance, but without any researchers have since found that they can use a daily low dose of toxic effects on nonleukemic blood cells,” said study senior author methadone to achieve the same effect. Friesen notes that while Claudia Friesen, PhD, a research scientist at the Institute of Legal methadone may become addictive, it is much easier to break Medicine at the University of Ulm, Germany. “We find this very methadone addiction than true opioid addiction. “Addiction should exciting, because once conventional treatments have failed, which not be an unsolvable problem if methadone is ever used as an antioccurs in old and also in young patients, they have no other options.” cancer therapy,” she said. Methadone, developed in Germany in the 1930s, is a lowcost agent that acts on opioid Novel Drug May Help Prevent receptors, and is used as an opioid substitute to treat addiction. Chemotherapy-Induced Hearing Loss Scientists have found that opiResearchers at the Oregon Health and carboplatin-induced hearing loss was widely oid receptors also exist on the Science University in Portland are testing a underestimated because of inadequate testing or surface of some cancer cells for promising new agent to prevent chemothera- a lack of reporting. reasons that are not fully underpy-induced hearing loss in patients with In several preclinical studies, researchers stood. One research group testadvanced head and neck and non–small-cell found that a novel chemoprotectant drug proded the agent in human lung lung cancer. uct being developed by Sound cancer cells lines and found that Hearing loss due to ototoxic medPharmaceuticals in Seattle, Wash. it can induce cell death. ications such as chemotherapy, helps prevent ototoxicity while In this study, Friesen and her antibiotics, or loop diuretics often not interfering with the chemocolleagues tested methadone results in permanent and progrestherapy treatment. The drug, in leukemia cells in laboratory sive disability. Furthermore, the which is a small molecule that culture because this cancer combined use of these ototoxic mimics and induces glutathione also expresses the opioid recepagents is contraindicated, often limperoxidase activity, is being tested tor. This is the first study to iting their clinical utility. Symptoms in a phase 2 trial that includes 80 look at use of this agent in of ototoxicity include hearing loss, cancer patients. In one animal leukemia, specifically in lymtinnitus, dizziness, vertigo, and diffistudy, this agent was also found to phoblastic leukemia T-cell culty understanding speech. Historienhance the tumoricidal activity lines and human myeloid cally, the incidence of cisplatin- or of cisplatin. leukemia cell lines.

November/December 2008

G REEN H ILL H EALTHCARE C OMMUNICATIONS

1

MEDICAL MINUTES

Methadone May Help Combat Leukemia


Vol. 1, No. 5

November/December 2008

Feature Articles

Departments

CONTENTS

9 Hematologic Cancers

1 Medical Minutes

Pleural effusions costly in patient with CML

4 Editor’s Letter

13 Supportive Care Zoledronic acid prevents chemo-induced bone loss in breast cancer patients

6 News Notes 28 FDA Report

16 Pharmacy Careers Job opportunities for pharmacists at the FDA

29 Meetings

21 Continuing Education Finasteride and prostate cancer prevention

26 Skin Cancers Ipilimumab helps late-stage melanoma patients

Practical Applications Management of VTE in Patients with Cancer Between pages 14 and 15

Reach us online at www.theoncologypharmacist.com

EDITORIAL BOARD

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Managing Editor Lara J. Reiman Senior Production Manager Stephanie Laudien Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com Business Manager Blanche Marchitto blanche@greenhillhc.com Circulation circulation@greenhillhc.com

GH Green Hill Healthcare Communications

, LLC ™

Your Innovative Partners in Medical Media

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

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

Helen McFarland, PharmD, BCOP

Cleveland Clinic Taussig Cancer Center Cleveland, OH

Union Memorial Hospital Baltimore, MD

Christopher Fausel, PharmD

Emily Mackler, PharmD, BCOP

Indiana University Simon Cancer Center Indianapolis, IN

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

Rebecca S. Finley, PharmD, MS

Patrick Medina, PharmD, BCOP

EDITOR-IN-CHIEF

Jefferson School of Pharmacy Philadelphia, PA

Susan Goodin,

David C. Gammon, BSPharm

Oklahoma University College of Pharmacy Tulsa, OK

PharmD, FCCP, BCOP

University of Massachusetts Memorial Hospital Worcester, MA

Laura Boehnke Michaud, PharmD, BCOP, FASHP

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

The University of Texas MD Anderson Cancer Center Houston, TX

Sandra Horowitz, PharmD, RPh

Deborah Moradi, PharmD

The University of Texas MD Anderson Cancer Center Houston, TX

The Angeles Clinic and Research Institute Los Angeles, CA

Lew Iacovelli, BS, PharmD, BCOP, CPP

South Carolina College of Pharmacy Columbia, SC

Cancer Institute of New Jersey New Brunswick, NJ

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

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

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

Marlo Blazer, RPh, PharmD

Moses H. Cone Health System Greensboro, NC

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

Cindy Ippoliti, PharmD

CONTENTS

James Cancer Hospital & Solove Research Institute Columbus, OH

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

Bryna Delman Ewachiw, BS, PharmD

Jim Koeller, MS

Johns Hopkins Bayview Medical Center Baltimore, MD

University of Texas at Austin San Antonio, TX

Anjana Elefante, PharmD, BSc, BScPhm, RPh

Helen L. Leather, BPharm

Roswell Park Cancer Institute Buffalo, NY

University of Florida Gainesville, FL

Christopher J. Lowe, PharmD

LeAnn Best Norris, PharmD, BCPS

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

Steve Stricker, PharmD, MS Samford University McWhorter School of Pharmacy Birmingham, AL

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

Novant Health Winston-Salem, NC 2

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November/December 2008


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.

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All rights reserved.

8111602


Letter from the Editor EDITOR’S LETTER

T SUSAN GOODIN, PHARMD, FCCP, BCOP

EDITOR-IN-CHIEF

he election of my friend and colleague Ernest R. Anderson as president of the multidisciplinary Association of Community Cancer Centers (ACCC) this year says a lot about the status of oncology pharmacy as a specialty. Oncology pharmacists have an organization of our own—the Hematology/Oncology Pharmacy Association. But we also need to work closely with physicians, nurses, and other healthcare professionals, and Anderson’s election signifies the increasingly central role pharmacists now play in cancer care. Anderson believes that pharmacists working together with other healthcare professionals can be a strong voice in healthcare policy making, and he emphasizes the importance of leadership skills to be effective as clinicians, administrators, and as advocates for our profession and our patients. One issue that has generated considerable debate is the role of oncology specialty pharmacies. The article entitled “The ‘Growing Pains’ of Oncology Specialty Pharmacy” explores this issue, presenting the views of representatives of specialty pharmacies, healthcare management and consulting firms, and insurance companies on the need for and value of these pharmacies. The continuing education article this month raises interesting questions about risks versus benefits of prostate cancer chemoprevention. Initial results of the large Prostate Cancer Prevention Trial (PCPT), which were reported in 2003, showed that treatment with finasteride significantly reduced the risk of prostate cancer but with

Coming Soon CE article: Quality of Life in Metastatic Renal Cell Carcinoma Setting Up a Chemotherapy Prep Area in a Community Practice Using Nanoparticles to Deliver Chemotherapy New Technologies in HER2 Testing

EDITOR’S LETTER

Reports from ASHP Midyear Clinical Meeting, ASCO Breast Cancer Symposium, European Society for Medical Oncology

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

G REEN H ILL H EALTHCARE C OMMUNICATIONS

an apparent increase in the risk of high-grade disease. A new analysis of the PCPT data indicates that this concern was unfounded and suggests the drug be offered as an option for men concerned about the risk of prostate cancer. The new analysis received much media attention, so it is important for oncology pharmacists to be prepared to answer patients’ questions about the potential use of finasteride or other measures for prostate cancer prevention. The Practical Applications review on management of venous thromboembolism (VTE) addresses another major issue in oncology practice. In September, the Acting Surgeon General issued a Call to Action to reduce the incidence of deep vein thrombosis and pulmonary embolism in the United States. VTE is of particular concern to patients with cancer because it is a frequent complication in this population and adversely affects prognosis and quality of life. With the introduction of the low-molecular-weight heparins, clinicians now have a new option for preventing and treating VTE. One way oncology pharmacists can have a say in public health issues is government service. The article on careers with the US Food and Drug Administration provides detailed information on the types of jobs available within that agency for pharmacy students and graduates. If you would like to share your views on these and other important issues affecting oncology practice, please write 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 #1944-9607. 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.

November/December 2008


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News Notes NEWS NOTES

■ HPV Researcher Receives Nobel Prize in Physiology and Medicine German virologist Dr Harald zur Hausen has been awarded the 2008 Nobel Prize in Physiology and Medicine for his discovery that certain types of human papillomavirus (HPV) cause cervical cancer. He shares the prize with French virologists Dr Françoise Barré-Sinoussi and Dr Luc Montagnier, who discovered the human immunodeficiency virus, which causes AIDS. Dr zur Hausen’s research contributed to the development of vaccines that protect against cervical cancer. ■ Chemotherapy May Delay Need for Radiation in Children with Brain Tumors Using chemotherapy alone and delaying or even avoiding radiation may be an effective alternative approach for children with unresectable or progressive low-grade glioma, a Children’s Oncology Group study suggests. The results of the multi-institutional study “confirmed the ability of chemotherapy to control the disease,” said Joann Ater, MD, professor of pediatrics at the Children’s Cancer Hospital at M.D. Anderson Cancer Center, Houston, Tex., speaking at the 40th Annual International Society of Pediatric Oncology meeting in Berlin, Germany. The 401 patients enrolled in the trial were treated with one of two different chemotherapy regimens— carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). The TPCV regimen was more effective than the CV regimen and resulted in a 5-year event-free survival rate of nearly 50%. “If we can delay radiation, then we can allow more time for our youngest pa-

peutic Radiology and Oncology. Medicare HMOs cover the 20% difference between Medicare reimbursement and the cost of care, but patients who enroll in “qualifying” clinical trials lose that extra coverage. This could increase their out-of-pocket costs by as much as $3000 a month, Lin and colleagues found in a study of patients with new cancer diagnoses treated at five Pennsylvania hospitals. In 2007, 103 cancer patients screened for clinical trials at these cancer centers declined to participate because of costs, the re-

searchers reported. (Lin CJ, et al. Int J Radiat Oncol Biol Phys. 2008;72[1 suppl]: A1055.)

■ Survival Increasing for Children with Hematologic Malignancies Five- and 10-year survival rates continue to increase for US children diagnosed with three of the most common childhood hematologic malignancies— acute lymphoblastic leukemia (ALL), acute nonlymphoblastic leukemia, and non-Hodgkin’s lymphoma (NHL)—a

new report shows. Hermann Brenner, MD, of the German Cancer Research Center in Heidelberg and his colleagues found that between 1990-1994 and 2000-2004, 5- and 10-year survival increased from 80.2% to 87.5% and from 73.4% to 83.8%, respectively, for children 15 years of age or younger with ALL; from 41.9% to 59.9% and from 38.7% to 59.1%, respectively, for those with acute nonlymphoblastic leukemia; and from 76.6% to 87.7% and from 73.0% to 86.9%, respectively, for those with NHL. Survival rates for children

For Anemic Cancer Patients With Metastatic, Non-myeloid Malignancies Receiving Chemotherapy…

CONTROL THE RESPONSE MANAGE HEMOGLOBIN AND REDUCE TRANSFUSIONS When Treating Your Patients: • Evaluate for other treatable etiologies of anemia (iron, folate, or B12 deficiency, hemolysis, or bleeding) to treat appropriately • PROCRIT therapy should not be initiated at hemoglobin (Hb) levels 10 g/dL • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest Hb level sufficient to avoid the need for red blood cell (RBC) transfusion • The rate of Hb increase should not exceed 1 g/dL in any 2-week period • Monitor Hb weekly until stable, and then regularly during therapy

If we can delay radiation, then we can allow more time for our youngest patients to develop physically.

NEWS NOTES

tients to develop physically, which could decrease some of the long-term effects from treatment,” Ater said in a press release. Long-term effects of radiation include mental impairment, hormonal deficiencies, and increased rate of stroke late in life, causing some physicians and families to avoid radiation treatment.

■ Medicare HMO Rules May Be Barrier to Clinical Trial Participation Enrollment in a Medicare HMO may limit the number of older people participating in clinical trials, said Chyongchiou Lin, PhD, at the annual meeting of the American Society for Thera6

G REEN H ILL H EALTHCARE C OMMUNICATIONS

November/December 2008


■ New Website Matches Breast Cancer Patients with Trials Information on breast cancer clinical trials taking place at more than 1100 medical facilities nationwide is available

on a website recently launched by the University of California, San Francisco Center of Excellence for Breast Cancer Care. BreastCancerTrials.org, a free, nonprofit, clinical trials matching service, matches patients with or at risk for breast cancer with trials that are specific to their personal health situation. The site provides contact information for the trial and criteria for enrollment. Individuals can use the website on a one-time basis or store their health history on secure servers for continual matching to newly listed trials.

■ Alison Martin, MD, to Head Melanoma Research Alliance Alison Martin, MD, has been named

PROCRIT Indication

Additional Important Safety Information

PROCRIT is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT increases mortality or decreases progression-free/recurrence-free survival are ongoing. • PROCRIT is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. • PROCRIT is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence). • PROCRIT is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response). • PROCRIT use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

• Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events (including myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis) when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies; these risks also increased in controlled clinical trials of patients with cancer. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks. • PROCRIT therapy should not be initiated at hemoglobin levels 10 g/dL. • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion. • When the hemoglobin reaches a level needed to avoid transfusion or, increases by more than 1 g/dL in a 2-week period, the PROCRIT dose should be reduced by 25%. Withhold the dose of PROCRIT if the hemoglobin exceeds a level needed to avoid transfusion. Restart dose at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required. Discontinue if after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required. • Monitor hemoglobin regularly during therapy, weekly until hemoglobin becomes stable. • Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT; predominantly in patients with chronic renal failure receiving PROCRIT by subcutaneous administration. If any patient develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins. Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT should be permanently discontinued and patients should not be switched to other erythropoietic proteins. • The safety and efficacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). • In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. • Prior to and regularly during PROCRIT therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT. • Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended. • During PROCRIT therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease. • Seizures in PROCRIT-treated patients have been reported in the context of a significant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology. • The most commonly reported side effects (>10%) for PROCRIT in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection.

Important Safety Information WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1). • To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. • Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications • PROCRIT is contraindicated in patients with uncontrolled hypertension or with known hypersensitivity to albumin (human) or mammalian cell-derived products.

President and Chief Executive Officer of the Melanoma Research Alliance (MRA), an international, cross-disciplinary group of biomedical researchers seeking better treatments and a cure for melanoma. Martin, a medical oncologist, has held various positions within the National Cancer Institute, most recently as head of Genitourinary Cancers and Melanoma Therapeutics in the Clinical Investigations Branch of the Cancer Therapy Evaluation Program. The MRA is a public charity formed in 2007 under the auspices of the Milken Institute. It recently announced the recipients of $8 million in grants to fund 17 innovative melanoma research proposals worldwide.

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on adjacent page.

Manufactured by: Amgen Inc., Thousand Oaks, California 91320-1789 Distributed by: Ortho Biotech Products, L.P., Bridgewater, New Jersey 08807-0914 © Ortho Biotech Products, L.P. 2008 11/08 08PCTC2487B 308470

November/December 2008

G REEN H ILL H EALTHCARE C OMMUNICATIONS

NEWS NOTES

■ Bone Cancer Foundation Provides Information to Healthcare Professionals, Patients The newly formed Bone Cancer Foundation (BCF) provides information on cancer that affects the bone to healthcare providers and cancer pa-

tients on its website (http://www.bone andcancerfoundation.org) and in its publications, all of which are free. Six patient publications are now available in print and on the website, covering bone metastases and treatment-related bone loss in breast, prostate, lung cancer, and myeloma as well as osteonecrosis of the jaw and vitamin D deficiency. More information about the BCF can be obtained by phone (888862-0999) or e-mail (bcfdn@aol.com).

NEWS NOTES

with Hodgkin’s lymphoma did not change substantially over the study period. For children diagnosed in 20052009, the estimated survival rate was 88.0% for ALL, 63.9% for acute nonlymphoblastic leukemia, 90.6% for NHL, and 94.3% for Hodgkin’s lymphoma. (Pulte D, et al. J Natl Cancer Inst. 2008;100:1301-1309.)

7


BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT® (Epoetin alfa) FOR INJECTION

Radiotherapy Alone Cancer Study 5 Head and neck cancer (n=351)

≥15 g/dL (M) ≥14 g/dL (F)

Not available

Locoregional progression-free survival

Decreased 5-year locoregional progression-free survival Decreased overall survival

14-15.5 g/dL

Not available

Locoregional disease control

Decreased locoregional disease control

Not available

Quality of life

Decreased overall survival

10.6 g/dL 9.4, 11.8 g/dL

RBC transfusions

Decreased overall survival

FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE® WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1). • To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. • Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis. (See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.) INDICATIONS AND USAGE PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing. • PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. • PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence). • PROCRIT ® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response). • PROCRIT ® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being. CONTRAINDICATIONS PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human). WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal. Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks. In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03). Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents. In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on KaplanMeier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and ‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients. An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information). Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery. Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8). Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Adverse Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing Study / Tumor / (n) Target (Median Q1,Q3) Endpoint Arm Chemotherapy Cancer Study 1 Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-month cancer (n=939) 12.2, 13.3 g/dL survival survival Cancer Study 2 Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overall malignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival a hemoglobin response Cancer Study 3 Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and overall survival Cancer Study 4 Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free and locoregional and overall survival control and locoregional control

Cancer Study 6 Head and neck cancer (n=522)

No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell 12-14 g/dL lung cancer (n=70) Cancer Study 8 Non-myeloid 12-13 g/dL malignancy (n=989)

Decreased overall survival: Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82). Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04). Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57. Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfa-treated arm compared to the control arm. Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42). Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02). Decreased locoregional control: Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08). Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT® by subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies. PROCRIT® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity). Albumin (Human) PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergic reactions). The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®. However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with caution in patients with known porphyria. In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®. Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter. Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia). Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT®. Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of clinical trials. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation). Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT®-related effects on the F2 generation fetuses. It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® is administered to a nursing woman.

Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients in full Prescribing Information). Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects. Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home, instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of PROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container. Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease. Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which may have been related to seizure activity. In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safety-evaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology. Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safety-evaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study. The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence of thrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%. ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience. There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT®, in controlled clinical trials. Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading. Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were as indicated below: Percent of Patients Reporting Event Patients Treated Placebo-treated With PROCRIT® Patients Event (n = 63) (n = 68) Pyrexia 29% 19% Diarrhea 21%* 7% Nausea 17%* 32% Vomiting 17% 15% Edema 17%* 1% Asthenia 13% 16% Fatigue 13% 15% Shortness of Breath 13% 9% Parasthesia 11% 6% Upper Respiratory Infection 11% 4% Dizziness 5% 12% Trunk Pain 3%* 16% * Statistically significant Although some statistically significant differences between patients being treated with PROCRIT® and placebo-treated patients were noted, the overall safety profile of PROCRIT® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® was consistent with the progression of advanced cancer. Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with PROCRIT® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms. OVERDOSAGE The expected manifestations of PROCRIT® overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving an overdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information. DOSAGE AND ADMINISTRATION IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events. Prior to initiating treatment with PROCRIT® a hemoglobin should be obtained to establish that it is >10 to ≤13 g/dL. The recommended dose of PROCRIT® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery. An alternate dose schedule is 600 Units/kg PROCRIT® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery. All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with PROCRIT® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS). PREPARATION AND ADMINISTRATION OF PROCRIT® 1. Do not shake. It is not necessary to shake PROCRIT®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive. 2. Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration. 3. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing PROCRIT®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution. 4. Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions. Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8°C after initial entry and between doses. Discard 21 days after initial entry. 5. Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free PROCRIT® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of PROCRIT® containing benzyl alcohol. Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 Distributed by: Ortho Biotech Products, L.P. Raritan, New Jersey 08869-0670 Revised 08/2008 © OBPLP 2000

10112802BC


Table. Clinical Management options in 48 Dasatinib-treated Patients with Pleural Effusions Severity All levels (n = 48)

Level 1-2 (up to 25% of one lung volume, n = 29)

Level 3 (26%-50% of one lung volume, n = 16)

Level 4-5 (>51% of one lung volume, n = 3)

Clinical Management Physician evaluation Echocardiogram and computed tomography scans Chest x-ray Treatment interruption (median, 27 days) Dose interruption (median, 27 days) in 83% Dose reduction in 71% All episodes resolved on dasatinib discontinuation, treatment with loop diuretics, or both Short course of oral prednisone in 24% Invasive procedures in 7% Dasatinib interruption and treatment with loop diuretics in 81% Oral prednisone in 44% Invasive procedures in 25% All interrupted dasatinib and required invasive procedures

Source: Jennifer Stephens, PharmD.

were determined for medications, diagnostics, office visits, and invasive procedures. Patient management costs were based on published literature, treatment fee schedules, and drug wholesale price sources. Of the pleural effusions examined, 29 (60%) were mild in severity and man-

aged medically at a cost of $750 per episode. The remaining 19 (40%) pleural effusions were more clinically significant, and half of the patients required invasive procedures. The cost of inpatient invasive procedures ranged from $3807 for placement of a shunt to $15,344 for placement of a

Strict Adherence to Indications Strongly Recommended for ESAs CHICAGO—Given the uncertain effect on symptoms associated with anemia and the potential harm of using erythropoiesis-stimulating agents (ESAs) to treat anemia, indications for treating chemotherapy-induced anemia should be strictly adhered to, said Fadlo R. Khuri, MD, at the 44th annual meeting of the American Society of Oncology. Khuri, associate director for clinical and translational research, Winship Cancer Institute, Emory University, Atlanta, Ga.; chaired a session on negotiating the conflicting demands of ESAs and pointed to evidence that tumor cells may use the erythropoietin system for growth, prolonging the tumor’s sur-

vival. Randomized clinical trials of sufficient size in patients with treated head and neck cancer and breast cancer showed higher locoregional progression of cancer and worse overall survival in recipients of ESAs compared with placebo. Although the data are incomplete, “we have three studies in the curative setting that suggest harm,” he said. Further, randomized, placebo-controlled clinical trials in which ESAs were studied in untreated patients with cancer-related anemia confirmed worse overall survival and worse disease-free survival in those assigned to ESAs. Further study suggests that erythropoietin receptors on cancer cells may

explain the worse prognosis observed with ESAs in cancer patients. In radiotherapy-treated patients with head and neck cancer, those with erythropoietinreceptor–positive disease did significantly worse when treated with epoetin beta versus placebo, Khuri noted. The US Food and Drug Administration (FDA) has taken note of these studies and issued black box warnings and safety-related changes to package inserts. In March 2008, the FDA issued a safety advisory, stating that ESAs were not to be used in the context of curative therapy. —Wayne Kuznar

Baseline Hemoglobin Level Predicts Transfusion Risk in Patients Receiving ESAs ANAHEIM—The hemoglobin (Hb) level at which treatment with erythropoiesis-stimulating agents (ESAs) is initiated predicts the subsequent risk of red blood cell (RBC) transfusion in patients with chemotherapy-induced anemia (CIA), according to a meta-analysis. The findings were presented in a poster session held during the 2008 Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners joint annual conference. A recent national coverage decision (NCD) issued by the Centers for MediNovember/December 2008

care & Medicaid Services recommends initiating ESA therapy in patients with CIA and Hb <10 g/dL and discontinuing ESAs when Hb reaches 10 g/dL. The impact of the NCD on transfusion risk and other clinical outcomes in patients with CIA has not been established. A meta-analysis of six randomized, double-blind, placebo-controlled studies of darbepoetin alfa in patients with CIA was conducted by Jeffrey Crawford, MD, and colleagues, Duke University Medical Center, Durham, N.C. The analysis included 1200 patients treated

with darbepoetin alfa and 912 patients in the placebo group. In these studies, ESA therapy was withheld according to different criteria: Hb >13 g/dL or >1 g/dL increase in 14 days; Hb >14 g/dL; and Hb >14 g/dL in women and Hb >15 g/dL in men. The end points of the meta-analysis included the percentage of patients with at least one RBC transfusion from week 5 to the end of the treatment period and the incidences of death and disease progression. In both the darbepoetin alfa and placebo groups, the incidence of RBC transfusion tended to be higher in

pericardial window. The cost of outpatient invasive procedures ranged from $713 for ultrasound thoracentesis to $4598 for placement of a pleural catheter. The placement of a pleural catheter instead of repeated thoracentesis or chest tube placement increased total costs by about 30%. No recurrence of pleural effusion decreased total average costs by about 20%. The total average cost per patient overall was about $2000 to $2700 depending on the types of management interventions provided. The total average cost per patient for pleural effusions requiring invasive management procedures was about $6400 to $9000 depending on the interventions provided. “Development of pleural effusions in patients with imatinib-resistant or -intolerant CML poses a significant challenge to physicians, as they cannot be predicted, the time of onset is variable, and management may require invasive procedures and possible complications,” the researchers wrote. “Despite challenging adverse events, the kinase and Abl inhibitors have been shown to improve outcomes for patients in various phases of CML.” —DSM

patients with lower baseline Hb levels. Overall and across all baseline Hb groups, the transfusion incidence was lower for the darbepoetin alfa group than for the placebo group. The hazard ratio for RBC transfusion ranged from 0.5 in patients with baseline Hb 9 to 19 g/dL to 0.32 in patients with baseline Hb >12 g/dL. Treatment with darbepoetin alfa decreased the transfusion risk compared with placebo both overall and across all baseline Hb subgroups. Overall, the risk for venous thromboembolism (VTE) was higher in the darbepoetin alfa group than in the placebo group and was not strongly influenced by the baseline Hb level at which treatment with ESAs was initiated. “This finding is in accordance with the well-characterized VTE risk associated with ESA use in cancer patients,” the researchers stated. Overall and across baseline Hb groups, the risk of death and the combined end point of death or disease progression was similar in the darbepoetin alfa and placebo groups. In a time-dependent covariate analysis, patients with transfusions in both treatment groups had a higher risk for death and for death or disease progression. In the ESA group, patients with transfusions had increased risk for VTE. “This meta-analysis suggests that the NCD recommendations will increase transfusion rates,” the researchers concluded. “Initiating ESA therapy at Hb levels >11 to 12 g/dL resulted in the lowest absolute risk for transfusions.” —DSM

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HEMATOLOGIC CANCERS

ANAHEIM—The management of pleural effusion in patients with chronic myeloid leukemia (CML) is costly and requires intensive resource utilization, a new study shows. Pleural effusion is relatively common in patients with CML and may emerge up to 2 years after the start of therapy. The hallmark symptoms of pleural effusion are significant cough and dyspnea. The economic burden of pleural effusion was determined in a literaturebased analysis of 138 patients with CML treated with dasatinib at a single institution. The findings were reported by Jennifer Stephens, PharmD, and colleagues, Pharmerit North America, Bethesda, Md., in a poster session held during the 2008 Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners joint annual conference. The study included an analysis of treatment patterns and the probabilities of events or procedures based on the observed medical resource utilization reported for the 48 dasatinib-treated patients (35%) who developed pleural effusion. The clinical management of these 48 patients is summarized in the Table. Total average and item-specific costs

HEMATOLOGIC CANCERS

Pleural Effusions Costly in Patients with CML


ANDERSON INTERVIEW Continued from cover

INTERVIEW

been here for 15 years. Before this, I was at a downtown Boston teaching hospital for 17 years. Iâ&#x20AC;&#x2122;ve always been involved in pharmacy administration, particularly as it relates to operations and financial processes. The reason that I got involved in oncology as a particular area of interest really didnâ&#x20AC;&#x2122;t have to do so much with the drugs in terms of their clinical application, but more in terms of the cost. When I look at a budget here at Lahey and at the inpatient and outpatient drug costs, I find that about 70% of our total drug costs are actually in the outpatient clinics in the ambulatory area. Then, as I look at the ambulatory area as a subcomponent, itâ&#x20AC;&#x2122;s mostly oncology products. So, I developed an interest in oncology products as well as some of the other high-cost drugs, such as the biotech drugs. I was very interested in the reimbursement for these products and whether we were in fact covering our costs or whether we should be considering this a cost center or revenue center. On the inpatient side, when you look at drug expenses, you really need to look at it from the perspective that itâ&#x20AC;&#x2122;s an expense and revenue is pretty fixed. When you look at the outpatient side of things, on the other hand, revenue is not fixed. As much as Medicare has tried to develop a prospective system on the outpatient side, when I look across all of our payers, and across all of the ambulatory injectable drugs in particular, I find that we do, in fact, make sufficient money to cover the cost of the drugs. So, as our budgets increase on the expense side, so do our budgets for revenue.

How did your interests lead to your involvement in ACCC? I lectured a fair amount around the country on these particular topics beginning in the late 1990s and developed an expertise in understanding reimbursement issues, even before the Medicare Modernization Act of 2003, and I developed some cost models that have been used around the country. I tried to educate people on how to look at reimbursement in the outpatient sector, particularly for high-cost ambulatory drugs. The ACCC was very interested in the work I was doing, and they were instrumental in getting me before the Ambulatory Payment Classification System (APCS) panel, which makes recommendations to the Centers for Medicare & Medicaid Services (CMS). So, my involvement in ACCC really goes back to my interest in looking at this whole financial perspective to determine whether we should consider ourselves, from the ambulatory side, a cost center or a revenue center.

INTERVIEW

Could you tell us about ACCCâ&#x20AC;&#x2122;s goals and the services it provides? ACCC is a multidisciplinary organization representing physicians, nurses, pharmacists, social workers, oncology clinic administrators, people involved in finance, and others who are focused on oncology, and it has two basic missions. One is advocacy, and the other is education. 10

physician office practices and hospitalbased practices. On the physician practice side, reimbursement is different on the inpatient side from the outpatient side. One of the things that we do, from an advocacy standpoint, is to point out those differences to CMS. In terms of the second objective, which is education, ACCC does a lot in terms of education. We have two major conferences each year, the ecoLeadership is incredibly nomics conference in the fall and the annual meeting in the important to be effective as spring. At the economics conference last week, there were clinicians, administrators, or sessions on issues like the compendia, general access to care, and changes in reimbursement. in other roles.

ACCC has representation and a good reputation within the government, both in CMS and Congress, and we meet with government representatives to tell the story of whatâ&#x20AC;&#x2122;s happening out in the real world of practice. One of the concerns that we have always had in terms of advocacy is access to care. ACCC represents both

Thereâ&#x20AC;&#x2122;s a lot of information for practitioners on the ACCC website [http:// www.accc-cancer.org]. We encourage hospitals as well as private physician practices to become members of ACCC, which gives them access to all of the information on both the public and private sections of the website. Each Monday, members receive an email newsletter called This Week at ACCC, which provides the most recent information available on any number of topics that affect oncology care.

You were instrumental in establishing OPEN within ACCC. What services does it provide for pharmacists?

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

November/December 2008


Some of the reimbursement information that I talked about earlier and some of the spreadsheets that I created are posted on the website as tools to help pharmacists do a cost analysis of particular drugs to determine if there is a margin on that drug across all of their payers. We also hold OPEN seminars during the ACCC annual meeting focused on topics that are particularly relevant to oncology pharmacists. Sometimes these sessions later get incorporated in ACCC general sessions because the information is of interest to the global membership, such as a presentation a few years ago about the role of the pharmacist in the private practice setting.

How does OPEN differ from the Hematology/Oncology Pharmacy Association (HOPA)? We certainly do not see ourselves as competing organizations. HOPA is made up of just pharmacists, and we work very closely with them. The president of HOPA and I have made a commitment to work in concert with one another and make sure that we have a message that is very cohesive. Weâ&#x20AC;&#x2122;ve developed a stakeholder group, and every year when weâ&#x20AC;&#x2122;ve gone before the APCS panel of CMS, weâ&#x20AC;&#x2122;ve gone as a stakeholder group and come to agreement on exactly what we are going to present. The American Society of Health-System Pharmacists (ASHP) is

a part of that too as well as dedicated cancer centers, the Biotechnology Industry Organization, and even some group purchasing organizations.

What does having for the first time a pharmacist as president of ACCC say about the organization and about the role of pharmacists in cancer care? It shows the diversity of the group, the multidisciplinary approach it takes, and the value that every discipline brings to the table. One of my objectives early on in getting involved with ACCC was to bridge not only to HOPA, but also to bridge to ASHP. I saw a lot of synergy between what

INTERVIEW

The executive director and I decided to make ACCC more appealing to pharmacists because there was not a lot of pharmacy activity within ACCC. One of my objectives was to try to get more pharmacists involved because I thought that we could bring great value to the table and to help ACCC as an organization. At the same time, we wanted to show that ACCC has value to oncology pharmacists. So, we created OPEN with a board that consisted of pharmacists from around the country who either had clinical expertise in oncology or were pharmacy administrators like myself, and we started the OPEN website, a subsection of the ACCC website.

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INTERVIEW



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G REEN H ILL H EALTHCARE C OMMUNICATIONS

11


INTERVIEW

ACCC was doing and what ASHP was doing, and one of my goals when I became a member of the ACCC board of trustees was to get more pharmacists involved in the organization. The fact that now we have a pharmacist as president of ACCC means that has come to fruition. We anticipate a continuation of this type of involvement of pharmacists in ACCC.

What are your goals for your term as president? One, as I just mentioned, is to acknowledge the fact that by bringing other organizations into the fold that there is great synergy, and it presents a powerful statement to the regulatory agencies and to Congress. Another

focus this year is the theme of leadership. Leadership is incredibly important to be effective as clinicians, administrators, or in other roles. If we want to have a well-run oncology practice that takes good care of patients, we need good leadership within that. One example of leadership is to try to bring together ACCC and other stakeholders within the oncology community such as HOPA, ASHP, and the National Comprehensive Cancer Network to educate CMS on issues of reimbursement. Another component of leadership has to do with valuing every person within the organization. I recently wrote an editorial called â&#x20AC;&#x153;Leading with Emotional Intelligenceâ&#x20AC;? (Oncology

Issues. Sept/Oct 2008. Page 5). Emotional intelligence is a topic that is very important within any organization. Leading with emotional intelligence requires that the leader, first of all, knows himself or herself and then that the leader knows how to relate in a very positive and constructive way with all of the employees within that group. One of the terms that I like a lot is that the leaders need to be servant leaders. The concept here is that by serving the people who work for you, you value them, and help them be successful at what they do. If Iâ&#x20AC;&#x2122;m successful at making them successful, overall the whole organization is going to grow and to flourish. â&#x20AC;&#x201D;Karen Rosenberg

Did you

Know? 49% of adults who have ever taken a prescription medication report that they are only â&#x20AC;&#x153;fairly confident,â&#x20AC;? â&#x20AC;&#x153;somewhat confident,â&#x20AC;? or â&#x20AC;&#x153;not at all confidentâ&#x20AC;? in their knowledge about these medications. Source: www.harrisinteractive.com.

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INTERVIEW

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12

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November/December 2008


Leukemia Group B (CALGB) trial 79809 at the American Society of Clinical Oncology 2008 Annual Meeting showed that zoledronic acid (ZA) preserves bone mineral density (BMD) in this population. The trialâ&#x20AC;&#x2122;s primary hypothesis was that ZA would prevent bone loss measured at the lumbar spine at 12 months in women with chemotherapy-induced ovarian failure. Eligible women had histologic evidence of invasive stages I-III breast cancer, were >40 years of age, were not pregnant, and were actively menstruating or had their last menstrual period within the past 6 months.

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November/December 2008

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trols (P <.0001). Among women receiving ZA with or without tamoxifen, BMD percent change increases were similar (+2.0/+2.2, respectively), but BMD losses in the control group were larger without tamoxifen (â&#x20AC;&#x201C;4.3/ â&#x20AC;&#x201C;9.5, respectively). Higher-grade toxicities were minimal in ZA groups. Shapiro concluded, â&#x20AC;&#x153;Zoledronic acid prevents bone loss in women with chemo-induced ovarian failure, adding minimal toxicity to adjuvant chemotherapy.â&#x20AC;? He noted further that given every 6 months, ZA prevents bone loss in premenopausal women receiving GnRH agonists and would probably be effective in chemo-induced ovarian failure as well. Results for the secondary hypothesis, that â&#x20AC;&#x153;earlyâ&#x20AC;? ZA would be more effective than â&#x20AC;&#x153;lateâ&#x20AC;? ZA, remain pending.

SUPPORTIVE CARE

CHICAGOâ&#x20AC;&#x201D;Ovarian failure is induced in 50% to 70% of premenopausal women receiving chemotherapy. Bone loss in the lumbar spine attributed to estrogen deficiency in these women is similar to that seen with gonadotropinreleasing hormone (GnRH) agonists and is roughly threefold higher than that seen with aromatase inhibitor therapy, said Charles L. Shapiro, MD, Ohio State University, Columbus. â&#x20AC;&#x153;This rapid bone loss should be prevented, because it may increase the risks of osteoporosis in some breast cancer survivors,â&#x20AC;? Shapiro said. His report of first results from the Cancer and

They received adjuvant chemotherapy with/without tamoxifen, 1000 mg calcium, and 400 IU of vitamin D. Intravenous ZA (4 mg) was given every 3 months for 2 years starting immediately in one group (â&#x20AC;&#x153;earlyâ&#x20AC;?) and after 12 months in the other (â&#x20AC;&#x153;lateâ&#x20AC;?). Controls did not receive ZA. Among 439 women randomized, ovarian failure, defined as amenorrhea >3 months, occurred in 166 women. Mean age was 47 years, and mean lumbar spine BMD was 1.14 g/cm2. Seventy-five percent of women in the ZA group (n = 81) and 62% of women in the control group (n = 85) planned to take tamoxifen. Mean percent change in BMD was +2.2 in the ZA group and â&#x20AC;&#x201C;6.6 in con-

â&#x20AC;&#x201D;Walter Alexander

Synchronizing ESA and Chemotherapy Treatments Potential Opportunity for Convenience and Cost-savings KANSAS CITY, MOâ&#x20AC;&#x201D;More than 30% of treatments with erythropoiesisstimulating agents (ESAs) were given during separate visits from chemotherapy treatments, according to a retrospective study of a large database of more than 185,000 patients with cancer reported at the 2008 Educational Conference of the Academy of Managed Care Pharmacy (AMCP). The authors suggest that synchronization of ESA therapy and chemotherapy is an opportunity for cost-savings and greater patient convenience compared with separate visits to the clinic for each form of therapy. Of available ESAs, epoetin alfa was associated with significantly more nonchemotherapy clinic visits than darbepoetin alfa, presumably because of a more rigid dosing schedule for epoetin alfa. Recent studies have shown that darbepoetin alfa can be given every 3 weeks, whereas epoetin alfa requires more frequent office visits. â&#x20AC;&#x153;Synchronization of therapy should reduce travel to and from the clinic and reduce patientsâ&#x20AC;&#x2122; costs and time allotted for additional visits,â&#x20AC;? said lead author Beth L. Nordstrom of United BioSource Corporation in Lexington, Mass. Nordstrom noted that a prospective study is needed to confirm the safety and cost-savings of synchronization of these two forms of therapy. The study utilized a database provided by Varian Medical Oncology comprising electronic medical records from outpatient oncology clinics in the United States. The study population included 8044 adult patients with breast, lung, colorectal cancer, or lymphoma treated with systemic antineoplastics, including at least one conventional myelosuppressive agent, on a regular schedule. All patients received at least two ESA treatments during conventional chemotherapy (4484 on darbepoetin alfa and 3560 on epoetin alfa) between January 1, 2002, and June 30, 2007. Compared with patients who received Continued on page 15

G REEN H ILL H EALTHCARE C OMMUNICATIONS

13

SUPPORTIVE CARE

Zoledronic Acid Prevents Chemo-induced Bone Loss in Breast Cancer Patients


GROWING PAINS Continued from cover

PHARMACY PRACTICE

number of services that particularly benefited managed care organizations and their members. Driven by their success in other disease areas, specialty pharmacies then expanded to oncology. Under the bestcase scenario, oncology specialty pharmacies may be contributing to patient care and affordability. Under less ideal circumstances, however, there may be concerns.

PHARMACY PRACTICE

Why the need for oncology specialty pharmacies? Approximately 9 million Americans are living with cancer, and the need for payers to control the cost of their treatment is the prime rationale. Payers have issues with the “buy and bill” model, that is, the system in which a large share of an oncologist’s income is derived from buying drugs at wholesale and selling them at retail. The perception is one of inconsistency and variation in drug use, excessive off-label drug use, and wasteful management strategies by physicians, says Dawn G. Holcombe, FACMPE, ACHE, MBA, president of DGH Consulting, South Windsor, Conn., and executive director of the Oncology Network of Connecticut. Elan Rubinstein, PharmD, MPH, principal of EB Rubinstein Associates, a healthcare consulting firm in Oak Park, Calif., says, “It comes down to dollars, and payers are driving all this. It costs payers much less to have the drug go through pharmacy [benefits program] than for the doctor to give it.” The cost-control mandate also happens to converge with the emergence of oral therapies, which has opened the door for specialty pharmacies, since direct-to-patient shipping is a key part of the business model. Some 30% or more of new pipeline products are oral formulations, and some states actually forbid oncologists from dispensing oral agents in their offices. Lee Newcomer, MD, senior vice president of oncology for UnitedHealthcare, adds that oral oncology drugs can be seen as a “second chance to get some things right,” such as “correcting the strategic errors from buy and bill in the physician’s office.” Advocates of specialty pharmacy say that this system can best adapt to the handling and storage requirements of oncolytics and to the field’s complex Medicare reimbursement issues. The provision of value-added services is also a selling point to payers, including educational resources, patient safety and compliance tracking, and reimbursement assistance. When carried out successfully, these features provide a strong rationale for oncology specialty pharmacy, says Mark Neville, vice president of sales and marketing for Diplomat Specialty Pharmacy, the largest independently owned pharmacy in the country. “Oral oncolytics is our core model because of limitations in distribution, the cost, the need for assistance with patient copays, and the difficulties in keeping patients on the drug to achieve proper outcomes,” he says. Oncology specialty pharmacy, he notes, helps to combat the “perfect storm of cost and 14

complexity” in the treatment of cancer. In the current environment, cost control is clearly an area where oncology specialty pharmacy can have an impact, and not just in the form of discounts and rebates for payers, according to Neville. “Oncology is probably in a class by itself with regard to the magnitude of the cost of treatment.” “We talk to patients daily who are deciding between filling their prescription and refinancing their house or selling their car. The Medicare Part D ‘doughnut hole’ is $4050. Once patients get past this, they are still responsible for 5% of the total prescription cost. We arrange copay assistance for them, and if funds are left over, we apply these to future pharmacy costs,” he said. “We do all this for patients behind the scenes. Many patients have no idea that resources like this exist.”

Value-added services Other value-added services also set oncology specialty pharmacies apart. “The 24-hour availability of the pharmacist or nurse helps ensure treatment safety, reduces the expense of poorly managed side effects, and helps to control complications associated with drug interactions,” says Bob Crutchfield, vice president and general manager of US Oncology’s pharmaceutical services division. Pharmacy staff also provides regular reports to the patients’ physicians. “Outside retailers often lack the oncology expertise necessary to provide counseling, follow-up, or compliance support, so much of that responsibility falls to the physicians who are already timeconstrained. We help extend the care while keeping physicians involved.” Neville agrees. Speaking of Diplomat’s value-added service, he describes the management of patients receiving erlotinib, which causes rash. “We provide education, cream for the potential rash, and outbound nursing calls a couple of days after the first drug shipment, midway through the first treatment cycle, and at the time of the first refill [by phone], to proactively manage the rash and assure there is no gap in treatment,” he says. Not so fast Some oncology healthcare consultants are not completely sold, however. “Managed care still doesn’t quite know how to handle oncology and its rising costs, and they are looking for answers. But there are a lot of opinions and disconnects among parties,” says Holcombe. She maintains that oncology is different from other fields in which specialty pharmacy has demonstrated benefits and therefore may not be compatible with the specialty pharmacy model. “Specialty pharmacy has done a good job in other settings where physicians are not as involved in symptom management,” she said, alluding to one of the greatest areas of concern—safety and toxicity. Other concerns include monitoring for compliance, issues of liability, waste of drug, and, the potential loss of revenue derived by in-office infusions. While specialty oncology pharmacy currently distributes only oral agents and self-injectables, discussions about specialty pharmacy–operated

G REEN H ILL H EALTHCARE C OMMUNICATIONS

infusion centers have begun, she says. While oral drugs may seem to be safer and also perhaps easier for patients to take, they are still toxic, and compliance with oral therapy has not been demonstrated, she points out. Furthermore, since oral agents are often delivered as part of a regimen that includes intravenous agents as well, separating the two treatments seems irrational to some. Chemotherapy treatments are often delayed or dose-reduced because of conditions that are identified just before treatment, and under these circumstances, there are concerns about wasting drug under the direct shipment model, Holcombe notes. Under the specialty pharmacy model, drug delivery is no longer a “triangle” formed by oncologists, patients, and payers. Oncologists, therefore, are skeptical and hesitant. Many view specialty oncology pharmacists as “middlemen” to whom they are relinquishing control of patient care, according to Holcombe. “Many doctors are fighting this, not just because they want to keep the revenue in their own hands but because separating the drugs from the treatment seems counter to the natural delivery of patient care,” she comments.

Not all specialty pharmacies created equal Oncologists have reason to be wary, acknowledges Neville. “There is truly a spectrum of service. On one end, there is a ‘lick, stick, and ship’ model that is payer-driven and that lacks the built-in financial margin with which to provide value-added services to the patient. At the other end is a very ‘high-touch’ model that takes all-comers, finds copay assistance (beyond providing a website address), provides patient education and support, offers special compliance packaging, and so forth,” he explains. Diplomat falls into the latter category, he adds. “We have a full team that is very drug- and disease-specific, who do everything they can on behalf of the patient, the oncologist, the nurse, and the case manager at no additional charge.” Rubinstein agrees that value-added services are not a given with all specialty pharmacies. “It depends on the margin for the drug. A recent survey found that payers are compensating for the cost of oncology drugs by transitioning to an average sales price (ASP)-based payment system with different markups. The thinner the markup, the less money there is to play with,” he says.1 “Services are nice, but pharmacies get paid for filling prescriptions. As margins come down, it gets harder to justify extra services,” he notes. “The concern is that with payers going to the [ASP] model, will there be margin left for specialty pharmacies to do these things, or will they turn into fancy mail-order companies that frankly don’t provide much?” Addressing the issues Whether these issues can be satisfactorily resolved is unclear, as no clear model for oncology specialty pharmacy has been established, says Holcombe. “When you drill down and look at where specialty pharmacy is being used in oncology, it is predominantly in areas where Medicaid has required it and the

physician cannot afford to provide drugs any other way,” she observes. And don’t look for issues to be settled on the policy level, she adds. For instance, the competitive acquisition program—“the federal experiment in using specialty pharmacy to provide oncology drugs”—had only one bidder, BioScrip, which has not renewed its 2009 contract. “The smarter thing,” she says, “would be for all parties to sit down together and look at the realities of patient care.” —Caroline Helwick

Reference 1. Lin C, et al. Monitoring the changing oncology environment: lessons for managed care pharmacy from a national study. Presented at the Academy of Managed Care Pharmacy 20th Annual Meeting. April 16-19, 2008; San Francisco, CA. Poster PRR27.

It All Started with Biologics In 1994, Biologics, headquartered in Cary, N.C., became the country’s first oncology specialty pharmacy and remains the only one dedicated solely to oncology. President Robin Smith, who launched the company, told The Oncology Pharmacist, “We concentrate on what we know best, and that’s cancer care. We have the flexibility to address all 300 types of cancer since our model is not ‘one size fits all.’ Our laser-like focus on cancer gives us the opportunity to build out various business units within the cancer umbrella,” Smith said. Besides serving the prescription needs of 18,000 cancer patients, Biologics is an oncology management company and, for the past 12 years, has run a clinical trials unit that not only distributes drugs but is involved in trial design, budgeting, patient enrollment, database development, placebo management, protocol review, and so forth. Having insight into drugs in the pipeline gives her company a heads-up before new drugs transition into clinical use, Smith added. Biologics also has a proprietary information technology platform, ClinImpact, which helps define and customize clinical metrics data for payer clients. The data include, for example, outcomes and pharmacogenomics information that clients use to “track and trend” such things as laboratory values and comorbidities based on demographics, disease state and stage, sex, and so forth. This service fills a need for informatics within the industry, Smith maintained. “Return on investment will be huge going forward. We are talking about expensive therapies, and payers want to see some return on their dollars,” she said.

November/December 2008


Continued from page 13

epoetin alfa, those who received darbepoetin alfa had a lower minimum hemoglobin level during the chemotherapy episode of care; were more often on every-2-weeks chemotherapy regimens and less often on weekly chemotherapy regimens; and were more often on every2-weeks or every-3-weeks ESA schedules and less often on weekly ESA schedules. Because darbepoetin’s every-3-weeks schedule was approved in 2006, the authors studied chemotherapy and ESA schedules during two different periods: 2002-2005 and 2006-2007. Patients on an every-3-weeks chemotherapy schedule received darbepoetin alfa every 2 weeks more often in 2002-2005, but the every-3-weeks schedule for darbepoetin alfa was used more frequently in 20062007. Epoetin alfa was dosed weekly in all patients more often during both time periods. More frequent synchronization of chemotherapy and ESA therapy was associated with darbepoetin alfa compared with epoetin alfa, more frequent chemotherapy schedules, hospitalbased clinics compared with community clinics, Northeast and Midwest regions of the United States compared with South and West regions, lower minimum hemoglobin levels during the regimen, and colorectal and breast cancer compared with lung cancer and lymphoma.

About 20% to 25% of all breast cancers are HER2 positive. The survival benefit of trastuzumab, directed against the HER2 protein, is confined to HER2-positive patients. Thus, HER2 testing should be standard before initiating trastuzumab. The study was based on 405 members who filed at least one medical claim for trastuzumab from November 2006 through October 2007. Claims for HER2 testing were identified for 106 (26.2%) members. Medical records were requested for 299 members (72.3%) with no medical claims billed for a HER2-related laboratory test. The type of HER2 test, date of the test, and test results were recorded. HER2 testing was performed or assumed to be performed in 375 (92.3%) of 405 members.

Review of medical records showed that 97.8% of patients taking trastuzumab were HER2 positive. Using medical claims history as the sole method for determining drug utilization may be insufficient, Chang commented. In this study, medical claims accounted for only 26% of members receiving HER2 testing. Medical records of the population without claims data showed that HER2 testing was actually performed in 92% of those receiving trastuzumab (more than the estimated 26% reflected in claims data). She noted that the inaccuracy of medical claims may be due to bundling of claims with no specific codes in the hospital setting, testing done outside the date span of the study, and providers’

inconsistent use of Current Procedural Terminology codes for HER2 testing. Chang said that medical records review is the best way to confirm HER2 testing. A cost analysis showed that prior authorization review for HER2 testing for members receiving trastuzumab would have yielded a low return on investment, ranging from 1.7% (best case) to 14.2% (worst case). “This drug utilization review reveals that oncologists are following the standard of care, and suggests that implementing a prior authorization on trastuzumab is unnecessary and places a burden on the physician, patient, and health plan,” Chang stated. —AG

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KANSAS CITY, MO—The majority of oncologists under the Regence Group (an affiliation of BlueCross BlueShield health plans in the Pacific Northwest) are following American Society of Clinical Oncology and National Comprehensive Cancer Network recommendations for human epidermal growth factor receptor 2 (HER2) testing for patients with invasive breast cancer before initiating trastuzumab (Herceptin), according to a drug utilization review for trastuzumab from its pharmacy benefit management, RegenceRx. More than 90% of health plan members who were taking trastuzumab had confirmed HER2 testing, suggesting that prior authorization is not necessary for patients prescribed trastuzumab. “The study suggests that prior authorization review of all trastuzumab claims to review for HER2 testing may yield a low return on investment. More efficient use of health plan resources may be directed towards educational outreach to prescribers to encourage HER2 testing of breast cancer patients before starting trastuzumab,” according to Crystal Chang, who conducted the review for RegenceRx. Chang, who is a fourth-year Doctor of Pharmacy degree candidate at University of Southern California School of Pharmacy, presented her poster on HER2 testing at the 2008 Educational Conference of the Academy of Managed Care Pharmacy. November/December 2008

Current activities at www.COEXM.com include: • Considerations in Multiple Myeloma: Health Economics • Perspectives on the Treatment of Colorectal Cancer • Perspectives on the Treatment of CTCL and PTCL • Developments in the Treatment of Metastatic Breast Cancer • Perspectives on the Treatment of Lung Cancer FREE CE newsletters at www.COEXM.com

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HER2 Testing Done on Majority of Patients Prescribed Trastuzumab in BlueCross BlueShield Plan


PHARMACY CAREERS

Opportunities for Pharmacists at the US Food and Drug Administration By B. Vicky Borders-Hemphill, PharmDa; Rebecca Saville, PharmD, MSb; Louis Flowers, PharmD, MSc Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Epidemiology, Silver Spring, MD. Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Office of Antimicrobial Products, Division of Special Pathogen and Transplant Products, Silver Spring, MD. c Food and Drug Administration, Center for Drug Evaluation and Research, Office of Executive Programs, Division of Training and Development, Silver Spring, MD. a

b

PHARMACY CAREERS

A vast array of career opportunities for pharmacists is available, making it a worthy and marketable healthcare profession to pursue. This array of opportunities is accompanied by the need for plenty of background research to find the career path that fits a desired lifestyle. While changes in the direction of one’s career can occur at any time, one should become aware of all opportunities available as a licensed pharmacist. Strategic career planning should begin as early as possible and is imperative to allow for the development of knowledge and skills for advancement and to avoid career pitfalls. Many pharmacy students and residents are not aware of the numerous public health opportunities for pharmacists. A variety of public health opportunities for pharmacists are available at the US Food and Drug Administration (FDA). The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation. The FDA helps the public obtain accurate, science-based information needed to use medication and foods to improve and manage their health. The FDA has a complex organizational structure composed of offices and centers. The centers are composed of offices, which are further structured into divisions. This complexity attests to the FDA’s substantial growth since its 1862 inception as the Bureau of Chemistry, in the US Department of Agriculture. Additional information about the FDA’s history can be found at http://www.fda.gov/oc/history/history offda/default.htm. Links to charts displaying the FDA organizational structure are located at http://www.fda.gov/ opacom/7org.html. The FDA employs more than 300 pharmacists in more than 150 cities nationwide. Pharmacists are employed in various positions within the FDA and have gained employment at various points in their careers. However, the majority of pharmacists hired have had at least 2 years of experience in clinical or community practice. Pharmacists are employed in the Office of the Commissioner, the Office of Regulatory Affairs, and within the six centers of the FDA. Depending on experience and education, a pharmacist may work as a reviewer in clinical pharmacology, pharmacokinetics, pharmacology/toxicology, regulatory, or radiopharmacology. Also, pharmacists may work as regulatory health project managers, also known as consumer safety officers, in one of the offices under the Center for Drug Evaluation and Research (CDER) Office of New Drugs. The consumer safety officer position is an excellent starting 16

Table. Examples of Pharmacist Positions and Duties at the FDA, Center for Drug Evaluation and Research Location

Title

General summary of duties

Office of New Drugs

Regulatory project manager/ consumer safety officer

Office of New Drugs

Clinical analyst reviewer

OSE/Division of Pharmacovigilance or Division of Medication Error Prevention and Analysis

Safety evaluator

OSE/Division of Epidemiology

Drug utilization data analyst

Provide regulatory oversight and advice to multidisciplinary teams and pharmaceutical industry during the NDA approval process, coordinate the review of drug applications, serve as liaison between industry and FDA, facilitate internal FDA meetings and external meetings with industry Conduct reviews of clinical study protocols, review and evaluate reports and data from clinical trials submitted in INDs, NDAs, and BLAs to verify safety and efficacy of drug products. Provide advice on design of clinical studies, recommend approval of applications, and evaluate product labeling Review and evaluate spontaneous adverse event reports submitted by manufacturers, healthcare professionals, and consumers; review medication error reports; participate in risk management program development and monitor the impact of the program; participate in preapproval safety conferences between the FDA and drug sponsors and in FDA advisory committee meetings Analyze national drug utilization data obtained from specialized database searches as related to public health and safety concerns, collaborate with other divisions in OSE to evaluate the magnitude of adverse drug events and drug risk Review and evaluate promotional materials for prescription drug products to ensure compliance with the federal Food, Drug, and Cosmetic Act and various regulations pertaining to the advertising of prescription drug products Advise and assist the director, Division of Training and Development, the Committee for Advanced Scientific Education, appropriate CDER coordinating committees, and related industry and academic organizations, scientific experts, and scientific staff throughout CDER, as well as FDA officials on the program planning, evaluation, and conduct of CDER’s science-based educational activities. Prepare documents, including program management data, and correspondence related to the accreditation of CDER’s continuing medical education and continuing pharmaceutical education programs. Assure compliance with criteria for administration, conduct, and evaluation of these programs Verify that sponsor has submitted labeling in compliance with Code of Federal Regulations, serve as liaison between industry and FDA on issues related to label requirements, critically assess proposed labeling of approved abbreviated NDAs and supplements in terms of appearance, content, regulatory compliance, and safety Conduct reviews of clinical pharmacology and biopharmaceuticals data and use technical tools (eg, modeling and simulation) in support of CDER’s IND, NDA, and BLA review program to determine relevant clinical issues and exposure–response, drug–drug interactions, pharmacokinetics, effect of clinical pharmacology on dosing and administration, dosing regimen adjustments, and issues that impact labeling Conduct inspections of pharmaceutical manufacturing facilities to evaluate current good manufacturing practices (cGMPs) compliance, review inspection reports from other FDA investigators to determine need for regulatory or administrative action, initiate regulatory or administrative action ensuring corrected deficiencies, answer (cGMP) inquiries, provide oversight and advice to FDA staff and pharmaceutical industry on cGMPs and conducting pharmaceutical inspections, draft and review cGMP guidance documents, and train FDA field investigators

Office of Medical Policy/Division of Regulatory review officer Drug Marketing, Advertising, and Communication Office of Training and Communications/Division of Training and Development

Director, health promotion officer

Office of Pharmaceutical Science/ Labeling reviewer Office of Generic Drugs/Division of Labeling and Program Support, Labeling Review Branch Office of Translational Sciences/ Office of Clinical Pharmacology

Clinical pharmacology reviewer/pharmacometrician

Office of Compliance

Compliance officer

FDA indicates US Food and Drug Administration; IND, investigational new drug; NDA, new drug application; BLA, biological licensing application; OSE, Office of Surveillance and Epidemiology; CDER, Center for Drug Evaluation and Research.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Continued on page 18

November/December 2008


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JOB OPPORTUNITIES Continued from page 16

PHARMACY CAREERS

point for a pharmacist’s career in the FDA. Pharmacists are commonly hired for these positions not only for their scientific knowledge, but also for their attention to detail, communication, and organizational skills. In addition, pharmacists may work as safety evaluators, drug utilization analysts, labeling reviewers, field inspectors, compliance officers, or on expert advisory committees and review panels. Additional information on opportunities for pharmacists at other Department of Health and Human Services (DHHS) agencies can be found at http://www.hhs.gov/ pharmacy/agencies.html#FDA. The Table provides a list of examples of various positions and duties performed by pharmacists for the FDA in the CDER. This list is not inclusive of all potential opportunities for pharmacists at the FDA. Pharmacy students interested in a career at the FDA should participate in the FDA Pharmacy Student Experiential Program. This program provides an opportunity for pharmacy students in their last year of pharmacy school to learn about FDA laws, regulations, and guidance governing drugs, biologics, and devices for human use during a 4- to 6- week rotation. Participating students

WORK SURFACE SAMPLING Continued from cover

joint annual conference, raise important questions about pharmacy workplace safety and the effectiveness of routine pharmacy cleaning and decontamination procedures. Strategies for the protection of pharmacy employees against the carcinogenic, mutagenic, and reprotoxic effects of antineoplastic drugs have been implemented and improved during the last decades, but contamination of personnel and the workplace with these compounds still occurs. Regular monitoring of antineoplastic drug contamination in pharmacies may be a useful means of determining the effectiveness of decontamination strategies and provide input for the development of

Table. Antineoplastic Drugs

PHARMACY CAREERS

Investigated in the MEWIP Study Cyclophosphamide Etoposide 5-Fluorouracil Ifosfamide Gemcitabine Methotrexate Paclitaxel Docetaxel MEWIP indicates Monitoring Effect Study of Wipe Sampling in Pharmacies.

18

may attend FDA advisory committee meetings and congressional hearings. Additionally, the program provides academic credit hours required for the Doctor of Pharmacy degree. More information about this program can be located at http://www.fda.gov/Cder/Offices/ DDI/pharmstudent.htm.

are assisted financially during their final year of pharmacy school in return for an agreement to work for the USPHS after graduation. The student is appointed as an active-duty USPHS officer during the senior year and receives monthly pay and allowances as an Ensign (0-1) grade officer. The stu-

Pharmacy students interested in a career at the FDA should participate in the FDA Pharmacy Student Experiential Program. Pharmacy students should consider the United States Public Health Service (USPHS) extern programs as an opportunity for experiential training at various DHHS agencies, including the FDA. This program offers paid employment and other excellent benefits. There are two opportunities to participate while still in pharmacy school. The Junior Commission Officer Student Training and Extern Program (COSTEP) is available to students who are enrolled in a professional accredited school of pharmacy. Junior COSTEP allows students to serve in assignments at any time during the year for 31 to 120 days. In Senior COSTEP, students

dent agrees to work for the program that provided the financial support for twice the time supported following graduation. For more information about COSTEP, contact the Office of Commissioned Corps Operations at 800-279-1605. Ask to speak to the Commissioned Officer Student Training and Extern Program Coordinator. Pharmacy residents or graduating pharmacy students considering a career in public health should apply for a commission in the USPHS. The USPHS is the principal component of the DHHS. USPHS Commissioned Corps pharmacists are employed in various DHHS agencies, including the FDA. A career

thresholds and guidelines for the safe handling of antineoplastic and other hazardous drugs. As part of an effort to achieve compliance with workplace safety regulations recently implemented in Germany, researchers from the Institute of Energy and Environmental Technology, Duisburg, identified the antineoplastic drugs most commonly handled by pharmacies in that country. For 17 of the 25 most frequently handled compounds, sampling and analytical methods for routine contamination monitoring have been established and validated. The identification of suitable sampling strategies for these drugs included the selection of media to be monitored (eg, ambient air, work surfaces, textiles), sampling techniques and locations, and the timing and frequency of sampling. For the remaining eight drugs (Table), a program of workplace surface wipe sampling and testing (Monitoring Effect Study of Wipe Sampling in Pharmacies [MEWIP]) was developed and implemented in 130 pharmacies (78 hospital and 52 public pharmacies) in Germany in 2006. The goals of the MEWIP program were to establish the feasibility of wipe sample monitoring, baseline levels of work surface contamination, and the long-term effects of routine ambient monitoring on pharmacy contamination levels. The participating pharmacies were divided into two groups: the monitoring group (55 pharmacies) performed work surface wipe sampling every 3 months and received the results of contamination testing (and thus had the opportunity to take targeted actions to decrease contamination levels), and the control group (75 pharmacies) performed sam-

pling only at baseline and the conclusion of the 15-month program. The designated pharmacy work surface sampling locations were the floor in front of the most intensively used safety cabinet, the most intensively used countertop, and the refrigerator door and handle. Wipe samples were obtained using standardized materials and procedures and were taken from 900 cm2 areas by pharmacy personnel at the end of the work day but before cleaning of the respective surfaces. A total of 1272 wipe samples were obtained during the course of the program, resulting in 10,176 measured values. Overall, 61% of the sampled surfaces revealed contamination with at least one of the eight investigated drugs, reported T.K. Kiffmeyer and colleagues. The highest percentage of contaminated wipe samples (73%) came from the pharmacy floors. Contamination with at least one drug was detected in 61% of the samples from countertops and 49% of the samples from refrigerator doors. Cyclophosphamide was the drug most frequently detected (37% of the surfaces), followed by gemcitabine (32%), 5-fluorouracil (31%), and ifosfamide (21%). The four remaining drugs were detected on a maximum of only 5% of the work surfaces sampled. Little correlation was observed between work surface contamination levels and the responses to questionnaires regarding pharmacy work practices. In particular, the levels of work surface contamination were not influenced by the amounts of drug processed or the frequency of cleaning of the respective work surface.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

in the USPHS Commissioned Corps provides both career and quality-of-life benefits. While protecting, promoting, and advancing the public health of the nation, Commissioned Corps pharmacists can enjoy benefits including an accession bonus, 30 days of paid annual leave, medical and dental benefits, access to military bases around the world, use of the GI bill to advance education, and access to the Veterans Administration loan program. Additional information on the USPHS Commissioned Corps can be found at http://www.usphs.gov/ or contact the Office of Commissioned Corps Operations at 800-279-1605. Licensed pharmacists seeking employment at the FDA, whether as a Commissioned Corps pharmacist or a civil servant pharmacist, should apply online at http://jobsearch.usajobs.gov. USAJOBS is the official job site of the United States Federal Government, and pharmacists should apply to the pharmacist recruitment bulletin, which includes pharmacists’ positions for various FDA offices and centers.

References 1. US Food and Drug Administration. FDA organization. http://www.fda.gov/opacom/7org.html. Accessed August 12, 2008. 2. Swann JP. History of the FDA. http://www.fda. gov/oc/history/historyoffda/default.htm. Accessed August 12, 2008.

In contrast, a significant correlation was observed between the level of contamination and the procedures for the disinfection of drug vials before they are put into the safety cabinets. Spraying of disinfectant (eg, isopropanol) onto the drug vials resulted in higher levels of cyclophosphamide contamination on all work surfaces sampled than wiping the vials or using no disinfection. A tendency towards higher levels of contamination was observed in pharmacies where the air from the safety cabinet was recirculated into the work room. This configuration was observed in only 21% of the pharmacies studied. No significant decreases in the proportion of contaminated work surfaces were observed in either group during the course of the 15-month program. The overall contamination load decreased in the monitoring group during the study. Most of the MEWIP participants expressed satisfaction with the wipe sampling and monitoring procedures, and two thirds of the pharmacies reported planning consequences based on the monitoring results. Most of the participants agreed to accept or consider ongoing contamination monitoring. The researchers said that safe work surface contamination thresholds have not been established for most antineoplastic drugs. They noted that absolute work surface contamination levels may be less important than levels relative to those in other facilities and changes in levels over time or in response to revised cleaning or decontamination procedures. —DSM November/December 2008


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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent, supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Contraindications: None known. Warnings: Pregnancy Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/ m2 basis) and embryotoxic and teratogenic at 8 mg/kg when given daily during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg were embryotoxic and teratogenic. Terato-

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genic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. There is no adequate information about the use of Totect in pregnant women. 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. Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Reversible elevations of liver enzymes may occur. Blood counts and liver enzymes should be monitored. Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation. Women who have the potential to become pregnant should be advised that Totect might cause fetal harm. There are no known drug interactions. No carcinogenicity studies have been done with Totect in animals. The carcinogenic potential of dexrazoxane has not been investigated. Long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Dexrazoxane is mu-

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tagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs. The effect of dexrazoxane on labor and delivery in humans has not been studied. It is not known whether dexrazoxane or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dexrazoxane, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The safety and effectiveness of Totect in pediatric patients have not been established. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients has been observed. This drug is 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, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse reactions: Adverse reactions of nausea/ vomiting, diarrhea, stomatitis, bone marrow suppression (neutropenia, thrombocytopenia), altered liver function (increased AST/ALT), and infusion site burning have been observed. These adverse reactions have been reversible.

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Continuing Education Program #CIK9976 • RELEASE DATE: December 1, 2008 • EXPIRATION DATE: November 30, 2009

Finasteride and Prostate Cancer Prevention: The Latest Chapter

EDITORIAL BOARD Amy K. Darke, MS Public Health Services Division Fred Hutchinson Cancer Research Center Seattle, WA 98109

BY MARY W. REDMAN, PHD Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Helen McFarland, PharmD, BCOP Clinical Pharmacist—Oncology and Pain Management Department of Pharmacy Union Memorial Hospital Baltimore, MD 21218

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 on to www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number #CIK9976. • 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.

O

ur recently published reanalysis of the Prostate Cancer Prevention Trial (PCPT) appears to settle the issue of finasteride’s role in prostate cancer prevention. My colleagues and I reported that the 5-alpha-reductase inhibitor reduced risk of prostate cancer detection by 30% in healthy men >55 years of age without the increased rate of detecting high-grade tumors (Gleason grade >7) seen in the initial study.1,2 An accompanying editorial supports our findings, stating that “finasteride is a safe and effective prevention option that should be offered to men at risk for prostate cancer.”3 Increased detection of high-grade malignancies in the initial study appeared to primarily reflect improved screening properties of prostate-specific antigen (PSA) testing and digital rectal examination (DRE) as well as an increased sensitivity for detecting such tumors on biopsy in men receiving finasteride rather than any effect of finasteride on the biology of cancer progression.1 The increased biopsy sensitivity most likely resulted from the prostate gland shrinkage associated with finasteride, in line with its approved use in benign prostatic hypertrophy.1,4

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. The following authors, reviewers, and planning committee

November/December 2008

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: • Summarize the initial findings of the Prostate Cancer Prevention Trial. • Explain how finasteride may affect prostate cancer detection by prostate-specific antigen testing or digital rectal examination. • Discuss how the use of a risk calculator may be helpful for patients and their physicians when evaluating prostate cancer risk and making decisions about prevention.

Initial PCPT findings We first studied finasteride as a possible protective agent because it blocks conversion of testosterone to the more potent androgen dihydrotestosterone involved in prostate cancer development. The large (N = 18,882) National Cancer Institute–funded PCPT followed lowrisk men >55 years of age treated with placebo or finasteride (5 mg daily) for 7 years to determine the drug’s effect on prostate cancer detection.2 Men underwent annual PSA testing and DRE. Those with abnormal DRE or annual PSA >4 ng/mL, adjusted for finasteride’s effect, were referred for biopsy. This analysis revealed that: • Finasteride reduced the risk of prostate cancer detection by 24.8% overall (detection rates, 18.4% in the finasteride group vs 24.4% in the placebo group, 95% confidence interval [CI], 18.6%30.6%, P <.001). • Finasteride was associated with a higher risk of detecting highgrade malignancy. Gleason grade >7 tumors were identified in 6.4% of men in the finasteride group compared with 5.1% of men in the placebo group, for a 27% higher risk (95% CI, 1.07-1.50, P = .005).

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 • Jennifer Ludwig, PharmD • Gary C. Yee, PharmD, FCCP, BCOP • Amy K. Darke, MS • Helen McFarland, PharmD, BCOP • Mary W. Redman, PhD • Gary Shelton, MSN, ARNP, AOCN • Eileen McCaffrey The following author has stated that he has the following financial relationships:

Ian M. Thompson, MD, states that he is a consultant for Veridex and Mission. 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 447-000-08-423H04-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 December 1, 2008. The expiration date is November 30, 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.

Mary W. Redman, PhD Public Health Services Division Fred Hutchinson Cancer Research Center Seattle, WA 98109 Gary Shelton, MSN, ARNP, AOCN Clinical Research Program NYU Cancer Institute New York, NY 10016 Ian M. Thompson, MD Department of Urology The University of Texas Health Science Center at San Antonio San Antonio, TX 78229 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 Lara J. Reiman Managing Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 REVIEWERS Jennifer Ludwig, PharmD Oncology Pharmacist University of Nebraska Medical Center Omaha, NE 68198 Gary C. Yee, PharmD, FCCP, BCOP Professor of Pharmacy Practice Associate Dean for Academic Affairs College of Pharmacy University of Nebraska Medical Center Omaha, NE 68198

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Continuing Education Program #CIK9976 • RELEASE DATE: December 1, 2008 • EXPIRATION DATE: November 30, 2009 Because of this apparently elevated rate of aggressive disease, finasteride did not enter common use as a chemopreventive agent.

Continued investigation The impact of finasteride on prostate gland size and PSA levels was known before the PCPT. Therefore, before ruling out finasteride as an effective chemopreventive agent, the study team undertook a series of analyses to investigate finasteride’s effect on detection of prostate cancer and high-grade disease. To determine whether finasteride improved cancer screening, we compared the predictive value of a positive DRE and/or PSA levels between the placebo and finasteride arms with biopsy findings. To determine whether finasteride improved biopsy sensitivity to detect high-grade disease, we compared biopsy findings with radical prostatectomy samples. These studies revealed that: • Finasteride significantly increased the sensitivity of PSA testing for detecting prostate cancer (P <.001) and high-grade (Gleason grade >7) disease (P = .003).5 • Finasteride significantly increased the sensitivity of DRE for detecting prostate cancer (P = .015).6 • Finasteride significantly increased the sensitivi-

ty of biopsy for detect- Figure. Prostate Cancer Detection Rates ing high-grade malignancies, based on comparison of Gleason score at biopsy and prostatectomy. Biopsy detected 69.7% of Gleason grade >7 malignancies that were identified at prostatectomy in the finasteride group versus 50.5% of such cancers in the placebo group (P = .01).4 We proposed that the increased sensitivity for high-grade cancers most likely resulted from the reduction of median prostate gland volume seen with finasteride (25.1 cm3 finasteride vs 34.4 cm3 with placebo; P <.001).1,4 We also suggested that

C A S E S T U DY

Case Study of Five Prostate Cancer Prevention Trial Participants BY MARY W. REDMAN, PHDa; AMY K. DARKE, MSa; IAN M. THOMPSON, MDb a Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington b Department of Urology, The University of Texas Health Science Center at San Antonio, Texas

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he Prostate Cancer Prevention Trial randomized 18,882 men to receive finasteride, a selective inhibitor of type 2 five-alpha reductase or placebo to be followed annually for up to 7 years for prostate cancer. The study, which closed in 2003, showed that finasteride reduced the risk of prostate cancer by at least 25%.1 Based on study data, a calculator for the risk of prostate cancer and high-grade cancer (Gleason score >7) was developed.2 Presented here are five cases from the placebo arm that illustrate the diversity of prostate cancer risk and the use of the risk calculator. The calculator is intended to help inform the decision process for patients and their physicians on the risk of prostate cancer and the possible benefit of finasteride use for prevention of prostate cancer. Case 1 is a white man, 62 years old at study entry, with no family history of prostate cancer. During his 7 years of follow-up in the study, he had no clinical indications for biopsy of the prostate. At his 7-year and final annual study visit, results of his digital rectal examination (DRE) were normal, and his prostate-specific antigen (PSA) level was 1.1 ng/mL. His end-of-study biopsy found no cancer. According to the risk calculator, this patient has a 15% chance of prostate cancer and a 2% chance of high-grade prostate cancer. Case 2 is a white man, 67 years old at study entry, with no family history of prostate cancer. During his 7 years of follow-up in the study, he had no clinical indications for biopsy of the prostate. At his final visit, his DRE results were normal, and his PSA level was 2.5 ng/mL. Prostate cancer was detected on biopsy with a Gleason score of 6, indicating low-grade disease. This man has a 27% and 6% chance of prostate cancer and high-grade can-

cer, respectively. Case 3 is a white man, 68 years old at study entry, with a family history of prostate cancer. At his 2-year visit, his PSA level was 2.4 ng/mL, and his DRE results were abnormal. Results of a biopsy of the prostate were negative. At his 6-year visit, his PSA level was elevated at 4.3 ng/mL, and he again had abnormal DRE results. He underwent a second biopsy, and prostate cancer was detected with a Gleason score of 6, indicating low-grade disease. This man has a 47% and 19% chance of prostate cancer and high-grade cancer, respectively. Case 4 is a white man, 60 years old at study entry, with no family history of prostate cancer. At his 7-year visit, his PSA level was 5 ng/mL, and his DRE results were normal. Results on biopsy of the prostate were negative. This man has a 39% and 11% chance of prostate cancer and high-grade cancer, respectively. Case 5 is a black man, 72 years old at study entry, with no family history of prostate cancer. At his 1-year visit, his PSA level was 0.3 ng/mL, and his DRE results were abnormal. Prostate cancer was detected on biopsy with a Gleason score of 6, indicating low-grade disease. This man has a 13% and 3% chance of prostate cancer and high-grade cancer, respectively.

References 1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224. 2. Comprehensive Center for the Advancement of Scientific Strategies, Fred Hutchinson Cancer Research Center. Cancer Risk Calculator. http://www.compass .fhcrc.org/edrnnci/bin/calculator/main.asp?t=prostate &sub=disclaimer&v=prostate&m=&x=Prostate%20 Cancer. Accessed October 28, 2008.

finasteride may have selectively inhibited low-grade cancers, leaving high-grade tumors constituting a greater proportion of the total cancers detected.4 Counterbalancing these factors, men in the placebo group were more likely to undergo biopsy. This latter finding would bias results toward greater cancer detection in the placebo group.1 We then conducted a series of analyses in an effort to control for these detection biases. We also incorporated 3 months of data not included in the 2003 report. These additional data were gathered from when the data set was frozen after the trial was stopped, up to its unblinding.1

Latest findings Our team recently published the latest findings from these analyses.1 • Increased sensitivity of PSA and DRE did not considerably affect initial findings that finasteride significantly reduced risk of prostate cancer detection. Increased likelihood of biopsy in the placebo group also did not substantially change results. • Specifically, after accounting for these biases, finasteride reduced the risk of prostate cancer detection by 30% (detection rates: 14.7% in the finasteride group vs 21.1% in the placebo group [Figure]; 95% CI, .64–.76; P <.0001) and there was a now-nonsignificant increased risk of high-grade cancer (14%, 95% CI, .96–1.35; P = .12). • Last, we controlled for the heightened biopsy sensitivity for the high-risk malignancies seen with finasteride. This analysis showed that finasteride significantly reduced the rate of both high-grade (Gleason >7) and low-grade (Gleason <6) prostate cancer, by an estimated 27% (95% CI, .56–.96; P = .02) and 34% (95% CI, .55–.80; P <.0001), respectively. We corrected for the increased biopsy sensitivity to high-grade cancer seen with finasteride by attempting to estimate the rate of highgrade prostate cancer that would have been identified if all men with biopsy-detected malignancies had undergone prostatectomy. About 25.5% of study subjects with biopsy-detected malignancies had their prostate removed and had prostatectomy samples and biopsy grade information available for analysis.4 Continued on page 23

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November/December 2008


Continuing Education Program #CIK9976 • RELEASE DATE: December 1, 2008 • EXPIRATION DATE: November 30, 2009 Continued from page 22

Recommendations • Whether healthy men should take finasteride for prostate cancer prevention depends on many factors. These include the risk of prostate cancer, significance of the cancers that can be prevented, and finasteride’s risk/benefit profile. • Prostate cancer is common. Primarily because of frequent screening, the estimated lifetime risk for men in the United States is one in seven.1 • Identification of even low-grade cancer often prompts men to seek treatment. Treatment has its own costs and side effects; it also exacts an emotional toll on patients and their families. • Finasteride significantly reduced the risk of both low- and high-grade cancers. It decreases urinary

symptoms and complications of prostatic hypertrophy. We identified no evidence that finasteride increased the risk of high-grade prostate cancer. • Finasteride’s side effects include reduced sexual function. • Evidence supports offering finasteride to men at risk for prostate cancer. • Studies are needed to determine the optimal duration of therapy to prevent prostate cancer while minimizing risk of side effects.3

References 1. Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA Jr, Thompson IM. Finasteride does not increase the risk of highgrade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res. 2008;1:174-181.

2. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224. 3. Logothetis CJ, Schellhammer PF. High-grade prostate cancer and the Prostate Cancer Prevention Trial. Cancer Prev Res. 2008;1:151152. 4. Lucia MS, Epstein JI, Goodman PJ, et al. Finasteride and highgrade prostate cancer in the Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2007;99:1375-1383. 5. Thompson IM, Chi C, Ankerst DP, et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006;28:1128-1133. 6. Thompson IM, Tangen CM, Goodman PJ, et al. Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection. J Urol. 2007;177:1749-1752.

Eileen McCaffrey contributed to the preparation of this manuscript. Continued on page 24

C O M M E N TA R Y

Finasteride and Prostate Cancer Prevention: The Latest Chapter A Pharmacist’s Perspective BY HELEN MCFARLAND, PHARMD, BCOP Union Memorial Hospital, Baltimore, Maryland

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he Prostate Cancer Prevention Trial (PCPT) was the largest prostate cancer prevention trial ever completed.1 The positive results were tainted by the increased incidence of high-grade tumors found in the finasteride arm, thus muting the enthusiasm of the medical community to use finasteride as a preventive agent. The current reanalysis of the PCPT data presented in the Redman article is one of many attempts to evaluate the PCPT results to determine the real role of finasteride as a preventive agent for prostate cancer. Redman and colleagues used advanced statistical modeling to determine whether finasteride is truly increasing the risk of high-grade tumors or if there are other factors that are lending bias to the interpretation of the data. The authors thoroughly discuss the difference between the original data and their findings and conclude that finasteride does not increase the risk of high-grade prostate cancer after 7 years of therapy. The PCPT investigators suggest that finasteride increases the sensitivity of prostate-specific antigen (PSA) and digital rectal examination (DRE) for detecting prostate cancer.2,3 Finasteride decreases the prostate gland volume, therefore if there was tumor present, it would be easier to detect by DRE or biopsy. Finasteride decreases PSA levels to a greater extent in the setting of benign prostatic hyperplasia, thus those men receiving finasteride with persistently elevated PSA levels are more likely to have prostate cancer, and the risk of high-grade disease increases proportionally with higher PSA levels. When the PCPT data

November/December 2008

were adjusted for prostate gland size, the biopsy results showed there was no increase in highgrade tumors in the finasteride group.2 The amount of data that has been released which contradicts the original conclusion of the 2003 PCPT data certainly has offered some clarification of the risks and benefits of finasteride for prostate cancer prevention. Patients and providers should feel comfortable that finasteride in the preventive setting is not selecting out for high-grade tumors.

Patients and providers should feel comfortable that finasteride in the preventive setting is not selecting out for high-grade tumors.

and decreased over the 7 years of treatment.4 Patients in the PCPT received finasteride 5 mg orally every day for up to 7 years of therapy. Additional studies are required to determine the minimally effective duration of therapy to decrease potential adverse effects. Thompson and colleagues developed a risk calculator taking into account variables such as PSA, DRE, age, race, family history, and history of a prior negative biopsy.5 The calculator predicts a patient’s risk for developing prostate cancer and risk of high-grade disease. Use of these results in combination with consideration of the risks and potential benefits of finasteride therapy should be part of the counseling session with all men older than 55 years of age. This can assist the patient in determining the best course of action based on the potential aggressiveness of his disease and potentially decrease unnecessary systemic therapy in patients with low-risk disease. References

So what is the final recommendation for the use of finasteride in prostate cancer prevention? The American Urological Association and the American Society of Clinical Oncology have yet to make formal recommendations on the subject. The most common side effects reported in the PCPT finasteride group were sexual dysfunction (reduced ejaculate volume, erectile dysfunction, and decreased libido) and gynecomastia. Older age predicts increased sexual dysfunction with finasteride. The increase in adverse effects in the finasteride arm was small

1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224. 2. Yael CC, Liu KS, Heyden NL, et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the prostate cancer prevention trial. J Natl Cancer Inst. 2007;99:1366-1374. 3. Thompson IM, Chi C, Ankerst DP, et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006;98:1128-1133. 4. Moinpour CM, Darke AK, Donaldson GW, et al. Longitudinal analysis of sexual function reported by men in the prostate cancer prevention trial. J Natl Cancer Inst. 2007;99:1025-1035. 5. Thompson IM, Ankerst DP, Chen C, et al. Assessing prostate cancer risk: results from the prostate cancer prevention trial. J Natl Cancer Inst. 2006;98:529-534.

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Continuing Education Program #CIK9976 • RELEASE DATE: December 1, 2008 • EXPIRATION DATE: November 30, 2009 C O M M E N TA R Y

Finasteride and Prostate Cancer Prevention: The Latest Chapter A Nurse’s Perspective BY GARY SHELTON, MSN, ARNP, AOCN New York University Cancer Institute, New York

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ncology nurses tackle new knowledge and balance it against old behavior. Advanced practice nurses embrace this role, allowing them a framework to promote change that influences practice and ultimately improves outcomes. We welcome research like fresh air, hoping that findings will lead to evidence-based care that healthcare providers will accept and promote. Prevention of cancer is of primary interest. A fresh look at the maturing data from the Prostate Cancer Prevention Trial, in which men took finasteride 5 mg daily for 7 years, reveals interesting bias-adjusted data.1 It is now clearer that finasteride not only reduces the incidence of prostate cancer (chemoprevention), but also allows for more accurate grading of the disease when found through screening/early detection. With better understanding of the mechanism of action of finasteride (ie, shrinking the prostate gland and blocking the conversion of testosterone to dihydrotestosterone), we see how finasteride increases the sensitivity of prostate-specific antigen testing and digital rectal examination for detecting prostate. Men with benign prostatic hyperplasia take finasteride as indicated to shrink the prostate gland, thereby lessening urinary obstructive symptoms. For many of these men, this benefit outweighs the sexual side effect of erectile dysfunction. Men without urinary obstructive symptoms may not see themselves as being at risk for prostate cancer, and they may not be ready to hear about medical interventions to prevent the disease. Men without known health problems may not actively be seen in clinics or seek healthcare interventions. As with all attempts at prevention of disease, the proposed intervention must be seen as beneficial and with acceptable side effects. In the case of prostate cancer, there are a number

of questions to consider: Do men see themselves at risk of prostate cancer? Would they consider an intervention to prevent cancer as necessary? Are they aware of these new data? How do we introduce the topic? Are men coming to our offices or are we reaching out to them? An asymptomatic population may not be aware of their risk of prostate cancer. All men deserve the option of an intervention that may either prevent disease or allow for easier detection. Nurses must be knowledgeable about prostate cancer and comfortable about discussing it with their patients. They should discuss both the overall and relative risk for prostate cancer and outline what is known about the disease and its prevention. All men deserve to be informed of ways to improve their quality of life, especially through diet and lifestyle changes.

All men deserve to be

Treatment with finasteride may also allow for more accurate staging when cancer is detected, making it possible to treat more aggressive disease earlier. When men understand the risk/benefit ratio of an intervention, they are more likely to consider the option. Being up front and candid about side effects allows for discussion of possible treatments and approaches to dealing with side effects. Referral to specialists may be necessary at times. Although finasteride cannot currently be promoted for prostate cancer prevention, it is our role and duty to make our patients aware of recent research and their treatment options. Cancer prevention interventions are routinely discussed in all contact moments. Oncology nurses should be up-to-date on research findings and offer education to peers and populations at risk to facilitate decision making and patient advocacy.

Reference 1.Redman MW, Tangen CM, Goodman PJ, et al. Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res. 2008;1:174-181.

informed of ways to improve their quality of life, especially through diet and lifestyle changes. Finasteride is not currently approved for prostate cancer prevention and may not be available to all men; however, evidence supports offering finasteride to men at risk for prostate cancer. The incidence of prostate cancer is high, perhaps due in part to overscreening. By implementing chemoprevention with finasteride, we may be able to stave off the development of prostate cancer in some men.

To receive complimentary CE credit: 1. Log on to www.theoncologypharmacist.com. 2. Click on UNMC logo on homepage. 3. Register to participate. 4. Enter program number #CIK9976.

Reach us online at www.theoncologypharmacist.com

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November/December 2008


Using Upfront Contracts to Cure Mutual Mystification

H

ave you ever thought that your communication with people was crystal clear and then find that the other person didn’t get it? Typically we think, “How could they not understand? They just don’t listen.” But maybe your communication wasn’t as clear as you thought it was. When two or more people engage in communication but the end result is neither person clearly understands what the other expressed, we call that mutual mystification. If this is happening on a regular basis, a system of agreement might help. We call it an upfront contract. People communicate through different methods. Upfront contracts are the mutually agreed upon expectations between individuals, established before moving forward in any endeavor. In any professional setting, whether it is business or the practice of medicine, when you set an upfront contract with a prospect or patient, both of you have agreed on what you want to accomplish and what will happen next, provided a specific set of events occurs. The mechanics are more involved, but the concept is that simple. An upfront contract in a typical discussion might set the parameters for what will be discussed, what information will be provided by both the nurse and the patient, and what the outcome of the action might be at the end of the discussion.

The

Oncology Nurse

The Official Newspaper of Record for the Hem/Onc Nurse

ic set of events occurs. Upfront contracts often ease anxiety that patients have due to the unknown. Think of a child going the dentist. In the old days, the dentist would command the child to get in the chair and keep his mouth open while the dentist poked, picked, and shoveled power tools into his mouth. Today, the dentist knows a little more about upfront contracts and makes the child feel more comfortable. The dentist may explain that he will only be in the chair for 20 minutes and that he is only inspecting and cleaning the child’s teeth. He may also explain that none of the tools he will use will hurt and may even ask the child if he would like to watch a cartoon. Now, the child may still feel a little stress, but it’s much easier than the initial situation. November/December 2008

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contract, you are establishing the ground rules for a working relationship beBarnoski tween yourself and others. The contract describes which behaviors are expected to achieve those aspects of the goal for which they will be responsible. For a computer analyst, the goal could be a component of a software package; for a salesperson, the goal might be expressed as a sales quota; for a nurse, the goal could be a higher level of satisfaction for the patients. By discussing mutual expectations, you establish what is expected of the others and what you need to provide. This may be stated explicitly. For instance, the employee may

need training to achieve a particular outcome. Or, specific coaching may be necessary to keep an employee on behaviors to achieve an outcome. Certain supervisory checkpoints may be described and then established to maintain the flow and pace of work. Upfront contracts require work. First, there is the front-end learning curve—gaining an understanding about how to set upfront contracts. Second, there is the effort involved in actually setting the contract with the other person, a step most people are not currently doing. Third, there is the continual process of improving how you set contracts with others. Contracts make your life easier, but they do require more effort—an investment in time and energy that pays back many times over.

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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.

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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25


ADVANCED MELANOMA

abundance of molecular studies designed to clarify the role of this and other pathways in melanomagenesis. type of cancer in persons aged 20 to 30 Bcl-2, a protein overexpressed in years and the primary cause of cancer about 80% of melanomas, inhibits death in women aged 25 to 30 years, apoptosis and is believed to contribute said Poust at a symposium held during to chemotherapy resistance, Poust said. the 2008 Hematology/Oncology Phar- Oblimersen is a Bcl-2 antisense commacy Association/International Society pound that selectively targets Bcl-2 of Oncology Pharmacy Practitioners RNA for degradation and decreases Bcljoint annual conference. 2 protein production. The risk of malignant melanoma Poust described the findings of a randeveloping in an American in the domized study of 771 patients with United States is now 1 in 87, an increase advanced melanoma treated with dacarof nearly 2000% since the 1930s. The bazine alone or preceded by a 5-day increasing incidence of malignant continuous intravenous infusion of melanoma is actual (ie, not due to oblimersen (J Clin Oncol. 2006;24:4738increased surveillance or changes in 4745). The addition of oblimersen to diagnostic criteria) and expected to con- dacarbazine yielded a trend toward tinue for at least the next 10 to 20 years. improved median survival (9.0 vs 7.8 Current options for the management months; P = .077) and significant of advanced melanoma include surgery, increases in median progression-free radiation, combination antineoplastic survival (PFS; 2.6 vs 1.6 months; P chemotherapy, and systemic therapy <.001), overall response (13.5% vs with dacarbazine, temozolomide, or 7.5%; P = .007), and durable response interleukin-2. “The overall impact of (7.3% vs 3.6%; P = .03). these approaches is minimal, and the RAF proteins are serine/threonine current 5-year survival rate is only 6%,” kinases that regulate cell proliferation, Poust said. differentiation, and survival, Poust explained. BRAF mutations occur in about 70% of melaTargeted inhibition of BRAF noma cell lines, he noted, and targeted inhibition of may be a useful strategy for BRAF may be a useful strategy for the treatment of and other tumors. the treatment of melanomas melanomas Sorafenib is an oral multikinase inhibitor that inand other tumors. hibits RAF serine/threonine kinases and receptor tyrosine kinases involved in Recent discoveries have provided tumor growth and angiogenesis. Soraincreased understanding of the molecu- fenib has been approved in several counlar events leading to melanoma devel- tries worldwide for the treatment of opment and progression and the basis renal cell carcinoma and has demonfor a new generation of molecular-tar- strated preclinical and clinical activity geted therapies, Poust said (Table). In in several tumor types. particular, the identification of prevaIn a randomized study described by lent activating mutations of the BRAF Poust, 101 patients with advanced kinase in melanomas has led to an melanoma received dacarbazine with Continued from cover

SKIN CANCERS

Ipilimumab Helps Latestage Melanoma Patients

SKIN CANCERS

STOCKHOLM—Nearly half of patients with unresectable stage III or IV melanoma who are treated with the investigational monoclonal antibody ipilimumab remain alive after 1 year, researchers announced at the 33rd Congress of the European Society for Medical Oncology. The results are from three phase 2 studies involving a total of 487 previously treated patients who received four doses of 10 mg/kg ipilimumab every 3 weeks for 12 weeks. Patients received maintenance dosing with ipilimumab every 12 weeks starting at week 24. The studies showed a 47% to 51% 1-year survival rate, which includes patients who had progressed while receiving standard treatment or relapsed or failed to respond to other experimental treatments or were unable to tolerate currently approved therapies. According to recent reports, the 1-year survival rate for advanced metastatic melanoma patients who receive approved therapies is approximately 25%. Ruggero Ridolfi, MD, with the Istituto Scientifico Romagnolo per lo Studio e la Cura del Tumori (IRST) in Meldova, Italy, who presented the results from one of the trials, said that the findings on both efficacy and safety corroborate those reported in other phase 2 tri26

Table. Molecular-targeted Therapies for Advanced Melanoma Anticytotoxic T-lymphocyte antigen 4 • Ipilimumab • Tremelimumab B-cell leukemia/lymphoma 2 antisense • Oblimersen RAF kinase inhibitors • Sorafenib • RAF 265 • PLX 4032 MEK inhibitors • AZD 6244 Antiangiogenesis • PI 88 • Bevacizumab • IMC 1121B Elesclomol (STA 4783) YM-155 LY 57636 TST88 (ricin toxin) Source: Jamie Poust, PharmD.

placebo or sorafenib (J Clin Oncol. 2008;26:2178-2185). Median PFS was 21.1 weeks in the sorafenib plus dacarbazine arm and 11.7 weeks in the placebo plus dacarbazine arm (P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months and in time to progression (TTP) in favor of sorafenib plus dacarbazine, but no differences in overall survival were observed between the groups. The addition of sorafenib to paclitaxel and carboplatin provided no additional improvements in overall survival, TTP, or response rate in a randomized

phase 3 study of 270 patients with advanced melanoma, Poust pointed out (J Clin Oncol. 2007:25:8510). Median PFS was 17.4 weeks in the three-drug group and 17.9 weeks in the two-drug group (P = .492), he noted. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a CD28 family receptor expressed primarily on CD4+ T cells, Poust said. CTLA-4 plays a key role in the maintenance of T-cell homeostasis, and blockade of CTLA-4 sustains T-cell activation and proliferation. The monoclonal anti-CTLA-4 antibodies ipilimumab and tremelimumab have shown promising activity and manageable toxicities in early clinical trials in patients with advanced melanoma, Poust noted. The toxicity profiles of these agents involve inactivation of normal immunosuppressive homeostatic mechanisms and manifest as inflammatory bowel symptoms, uveitis, dermatitis, arthritis, and other disorders. Melanoma vaccines are designed to stimulate the formation of antibodies to antigens found on melanoma cells and are produced individually using a patient’s own tumor cells, Poust explained. Examples of types of melanoma vaccines include polyvalent melanoma vaccine, heat shock protein vaccines, antigen-bound vaccines, and dendritic cell vaccines. “Polyvalent melanoma vaccine stimulates cytotoxic T-cell immune responses in the host, resulting in inhibition of tumor cell proliferation and tumor cell death,” Poust said. The results of large clinical trials of melanoma vaccines have been disappointing, Poust noted, and vaccine therapy remains experimental in this population. Future treatment of advanced melanoma may involve a multimodal approach including vaccines, adjuvants, and other targeted molecular therapies, he added. —DSM

als involving ipilimumab. The analysis showed grade 3 immune-related adverse events, including rash, diarrhea, and hepatitis, in 20% to 28% of patients and grade 4 events in 0% to 12% of patients. Adverse events were generally manageable and reversible within days or weeks with the use of supportive care and systemic steroids using established treatment guidelines in the majority of patients.

all skin cancer deaths. According to the American Cancer Society, about 62,000 new cases of melanoma will be diagnosed in the United States this year, and roughly 8000 patients will die of the disease.

Although melanoma accounts

Know?

for only about 4% of all skin cancers, the disease is responsible for 79% of all skin cancer deaths. Phase 3 trials presently under way are examining the role of ipilimumab in tandem with dacarbazine in patients with untreated, unresectable stage III or IV metastatic melanoma as well as ipilimumab administered as adjuvant therapy in patients with high-risk stage III disease. Although melanoma accounts for only about 4% of all skin cancers, the disease is responsible for 79% of

G REEN H ILL H EALTHCARE C OMMUNICATIONS

—Jill Stein

Did you

The incidence of many common cancers is falling, but the incidence of melanoma continues to rise significantly, at a rate faster than that of any of the seven most common cancers. Approximately 62,480 melanomas will be diagnosed this year. Source: www.skincancer.org. November/December 2008


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FDA Report FDA REPORT

FDA Approves New Patch to Treat CINV SEATTLE—The first and only patch to provide up to 5 consecutive days of control of nausea and vomiting for patients receiving a moderately and/or highly nausea-inducing chemotherapy has been approved and is now heading to pharmacy shelves. The Granisetron Transdermal System (Sancuso), which was approved by the US Food and Drug Administration (FDA) in September 2008, is the only 5hydroxytryptamine 3 (5-HT3) patch approved for the prevention of chemotherapy-induced nausea and vomiting (CINV). Granisetron is also available in oral and intravenous (IV) formulations.

setron is given orally or through IV,” said Rogers in an interview with The Oncology Pharmacist. “There is no comparison, but we expect it to be similar or be less of a problem when it comes to constipation. Does a steady flow of the drug from the patch cause more constipation or less? We don’t know. It might be peak effects that cause more of a problem, but we don’t know that. We don’t expect it to be worse as far as more side effects, but it may be less because there is a more steady flow of the drug and no peaks and valleys that may cause constipation.” Use of the patch is contraindicated in patients with known hypersensitivity to granisetron or to any of We should have zero tolerance for CINV. the components of the patch. The makers of the patch say granisetron may mask a progressive ileus and/or gastric distention caused by the underlying A patch that can be applied before condition. In addition, patients should avoid direct of the application site to natural or artifitreatment, releasing medication consis- exposure cial sunlight by covering with clothing while wearing the patch and for 10 days after removing it.

tently into the bloodstream over a number of days, has the potential to impact

—John Schieszer

patient comfort and quality of life.

FDA REPORT

Granisetron is a selective 5-HT3 receptor antagonist with little or no affinity for other serotonin receptors. Similar to other 5-HT3 receptors, granisetron prevents serotonin from binding to 5-HT3 receptors. By preventing activation of these receptors, 5-HT3 antagonists interrupt one of the pathways that lead to vomiting. Studies have shown that by binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after chemotherapy. “We should have zero tolerance for CINV. A patch that can be applied before treatment, releasing medication consistently into the bloodstream over a number of days, has the potential to impact patient comfort and quality of life,” said Barbara Rogers, CRNP, MN, who is an adult hematologyoncology nurse practitioner at Fox Chase Cancer Center, Philadelphia. She said that the approval of this patch should lead to improved management of CINV because it adds a new tool to clinicians’ armamentarium. She said it is imperative that oncology pharmacists are aware of the approval of this patch. Patches contain 34.3 mg of granisetron and release 3.1 mg of the drug every 24 hours for 7 days. In adults, the patch is applied up to a minimum of 24 hours before chemotherapy, but may be applied up to a maximum of 48 hours before chemotherapy. The patch should be removed a minimum of 24 hours after completion of chemotherapy. The FDA approved the patch for the prevention of CINV based on results of a multicenter, phase 3, randomized, double-blind, double-dummy, controlled study. The investigators compared the efficacy, tolerability, and safety of the patch with once-daily oral granisetron (2 mg) in 641 patients receiving moderately or highly nausea-inducing multiday chemotherapy. The trial met its primary end point of achieving complete control of CINV, working as well as oral granisetron. Complete control was defined as no vomiting and/or retching, no more than mild nausea, and no rescue medication from first administration of the patch until 24 hours after the last day of chemotherapy. In clinical trials, the patch was generally well-tolerated. Adverse reactions considered drug-related by investigators occurred in 8.7% of patients receiving the patch. Constipation was the most common drug-related adverse reaction. Application site reactions were reported but were mild and did not lead to drug discontinuation. The incidence of skin reactions was comparable to that with placebo. “It is a drug we know and a route of administration that we already have. Constipation is a common problem. So, the constipation is nothing new that we don’t see when grani28

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Casopitant Bolsters Prevention of Chemotherapy-related Nausea and Vomiting STOCKHOLM—The use of casopitant in combination with standard care is superior to standard care alone for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC), according to phase 3 results released at the 33rd Congress of the European Society for Medical Oncology. Casopitant is a novel neurokinin-1 receptor antagonist. Steven Grunberg, MD, an oncologist at the University of Vermont in Burlington, and coworkers tested the use of a single oral dose or a 3-day intravenous (IV)/oral regimen of casopitant plus standard care (ondansetron plus dexamethasone) in 810 cancer patients who were receiving HEC. Overall, 99% of patients received cisplatin-based HEC regimens for up to six cycles. Patients were randomized to a control arm, single oral dose casopitant arm, or a 3-day IV/oral dosage casopitant arm and continued on the same treatment arm throughout the study. The primary study end point was the proportion of patients achieving a complete response (CR), defined as no vomiting/retching and no use of rescue medications during the first 120 hours. Results showed that patients who received the single oral dose and 3-day IV/oral dosage casopitant regimens had statistically significant improvements in CR rates compared with the control arm (86% and 80% vs 66%, respectively). Significantly more patients in each casopitant arm achieved CR versus patients in the control arms in both the acute phase and the delayed phase. The benefits with casopitant were maintained in the first four cycles of chemotherapy. The study also found that significantly more patients who received casopitant had no significant nausea, no nausea, and no vomiting overall compared with the control group. Both casopitant-based regimens were well tolerated with minimal and manageable side effects. The most commonly observed adverse events were those typically associated with myelosuppressive cisplatin-based chemotherapy.

Recent FDA Approvals • Full Approval for Denileukin Diftitox for CTCL The US Food and Drug Administration (FDA) has approved an efficacy supplemental biologics license application for denileukin diftitox solution (Ontak; Eisai) for intravenous treatment of patients with persistent or recurrent cutaneous Tcell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. The FDA’s action marks the conversion of an accelerated approval indication to full approval based on results of a phase 3 trial.

• New Indications for HPV Vaccine The FDA has approved the human papillomavirus (HPV) quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil; Merck) for prevention of vaginal and vulvar cancer caused by HPV types 16 and 18 in girls and women 9 to 26 years of age. The vaccine was originally approved in 2006 for the prevention of cervical cancer, precancerous genital lesions, and genital warts.

• Receives Third US Approval for Pemetrexed The FDA has granted approval for use of pemetrexed for injection (Alimta; Lilly) in combination with cisplatin as first-line treatment of locally advanced and metastatic non–small-cell lung cancer (NSCLC) in patients with nonsquamous histology. This is the third US approval for the drug, which was approved in 2004 in combination with cisplatin for unresectable malignant pleural mesothelioma and as a single agent for second-line treatment of locally advanced or metastatic NSCLC after prior chemotherapy.

• Device Cleared to Assess Lymphedema ImpediMed has received FDA 510(k) clearance for the L-Dex U400 bioimpedance spectroscopy device to assist physicians and other medical professionals in the clinical assessment of unilateral lymphedema of the arm in women with breast cancer. The device, which uses the characteristics of frequency-dependent current flow to quantify changes in extracellular fluid in the patient’s limb, can be used preoperatively and postoperatively. It provides an immediate result, and accompanying software can be used to track changes in the patient’s L-Dex value over time.

—Jill Stein November/December 2008


JANUARY 2009

DECEMBER 2008

6 - 9 SAN FRANCISCO, CA

10 - 14 SAN ANTONIO, TX 11 - 12 WASHINGTON, DC 15 - 17

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

San Antonio Breast Cancer Symposium www.sabcs.org

©iStockphoto.com/ekash

FEBRUARY 2009

5 - 7 SCOTTSDALE, AZ 4th Annual Community Oncology Conference www.communityonc.com

5 - 7 SAN DIEGO, CA 11th International Symposium on Anti-Angiogenic Agents www.antiangio2009.com

©iStockphoto.com/SCM Studios

MARCH 2009

11 - 15 HOLLYWOOD, FL NCCN 14th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care www.nccn.org

14 - 18 LAS VEGAS, NV 19th Annual National Interdisciplinary Breast Cancer Conference www.breastcare.org

November/December 2008

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

Oncology Forum 2008 www.avalerehealth.net

SAN FRANCISCO, CA 2009 Gastrointestinal Cancers Symposium-ASCO www.asco.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 Any Adverse Events 99 57 Respiratory System 38 4 more common among the elderly, including pneumonia and pneumonitis. LowBody as a Whole Increased Cough 13 1 86 10 Rhinitis 12 1 Fever 53 1 Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in Bronchospasm 8 1 Chills 33 3 low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 numbers of patients aged 65 and over to determine whether they respond Metabolic and Nutritional Headache 19 1 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 Digestive System 48 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 Anxiety 5 1 44 2 Musculoskeletal System 26 3 Night Sweats 15 1 Medication Guide and provided an opportunity to read prior to each treatment Myalgia 10 1 Rash 15 1 session. Because caution should be exercised in administering Rituxan to patients Arthralgia 10 1 Pruritus 14 1 Cardiovascular System Urticaria 8 1 25 3 with active infections, it is important that the patient’s overall health be assessed Hypotension 10 1 Hypertension 6 1 at each visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by months following completion of therapy. Individuals of childbearing potential NCI-CTC criteria. In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and should use effective contraception during treatment and for 12 months after up to 6 months after Rituxan infusion. Rituxan in Combination With Rituxan therapy. Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of Revised 1/2008 (4835504) infusional toxicity and neutropenia compared to patients in the CVP arm. The Jointly Marketed by: following adverse reactions occurred more frequently (*5%) in patients receiving Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (*5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. ©2008 Biogen Idec Inc. and Genentech, Inc. 7140916 March 2008 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (*2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (*5%) in patients age *60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3

G REEN H ILL H EALTHCARE C OMMUNICATIONS

MEETINGS

Meetings


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

When planning a treatment course for DLBCL

Take the essential path toward improved survival RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

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

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5

RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.

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


November/December 2008 Vol. 1 No. 5