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FEBRUARY 2010

www.TheOncologyPharmacist.com

VOL 3, NO 1

er d a Le and e h T ews in N eeting e M erag Cov CANCER CENTER PROFILE

West Michigan Cancer Center:

PAIN MANAGEMENT

Addressing Concerns about Opioid Use for Cancer Pain An Interview, with Judith A. Paice, PhD, RN

A Cancer Center Innovator

By Karen Rosenberg

By Dawn Lagrosa

O

pioids remain a mainstay of treatment for moderate-tosevere cancer pain. In this interview, Judith A. Paice, PhD, RN, director, Cancer Pain Program, Division of Hematology-Oncology, Northwestern University, Feinberg School of Medicine, Chicago, discusses the issues surrounding the use of opioids for the management of cancer pain.

The main campus in Kalamazoo offers medical oncology, radiation oncology, a neurooncology clinic, a breast cancer clinic, and a thoracic clinic, along with laboratory and support services.

W

est Michigan Cancer Center (WMCC) has increased the quality of patient care while updating its business model for today’s economic times. In recognition of this achievement, WMCC received a 2009 Cancer Center Innovator Award. The award was presented by Foley & Lardner at the third annual Cancer Center Business Summit in Dallas, Texas. The Oncology Pharmacist recently spoke with Terry McKay, president and CEO, about how WMCC accomplished these goals as well as its plans for future improvements. Cost-savings WMCC was chosen, in part, because of its aggressive stance on expense Continued on page 26

Despite their demonstrated efficacy, there is still some resistance among healthcare providers, patients, and caregivers to use of opioids for cancer pain. What are the concerns?

For those of us working with people who have cancer, the primary barriers from the patients’ perspective are the fear of side effects, particularly constipation and cognitive blunting, and the perceived meaning of taking an opioid. For many patients, taking morphine, in particular, means that their disease has advanced. From a professional perspective, we are concerned about the side effects. Also, many prescribers are concerned about the regulatory issues involved in prescribing opioids. They are fearful that the Drug Enforcement Administration is watching their practice, especially because there

have been several high-profile cases, not in oncology, that have gotten a lot of publicity. At what point should use of opioids be considered in patients with cancer pain? According to the World Health Continued on page 28

ASH 2009

CONFERENCE NEWS

Nilotinib: First-line Treatment Option for Chronic-phase CML?

The 44th American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition

By Wayne Kuznar

I

n the first head-to-head comparison of targeted oral tyrosine kinase inhibitors as initial treatment for early-stage chronic myeloid leukemia (CML), molecular and cytogenetic remissions were more common with nilotinib compared with imatinib, the previous standard for treating early-stage CML, said Giuseppe Saglio, MD. The finding could elevate nilotinib to first-line treatment in early CML. Currently, nilotinib is approved for the treatment of patients with Phila-

delphia chromosome–positive (Ph+) CML in the chronic and accelerated phases who are resistant to prior therapy. “The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML,” said Saglio, University of Turin, Italy, and lead investigator of the comparison. In the open-label study, 846 patients with newly diagnosed Continued on page 12

Actor Dennis Quaid presented the keynote address at the 44th American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition in Las Vegas. See page 6 for meeting highlights.

Inside REMS Review

SABCS

Risk management: a new era of patient safety

Anthracyclines may not be necessary Based on a presentation by Dennis Slamon, MD, PhD

between pages 16 and 17

page 17

Complimentary CE Credit

Financial Planning

Cancer treatment–related bone loss and osteoporosis: a concern for women with breast cancer

Manage debt through financial planning

page 18 ©2010 Green Hill Healthcare Communications, LLC

page 30

r fo ay E d To e C om r e Fre m.c t is ur oex g Re Yo ww.c w


TOP_Jan_Feb2010_v3_TON 2/5/10 11:33 AM Page Cov2

You prepare anthracyclines, but are you prepared for an anthracycline extravasation? NEW LOWER PRICE OPTION Now Available

Totect® (dexrazoxane for injection) is indicated for the treatment of extravasation resulting from IV anthracycline chemotherapy.

First and only FDA approved treatment for anthracycline extravasation. Supplied as a convenient and accessible complete three day emergency treatment kit, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation. Demonstrates 98% overall efficacy based on two biopsy-confirmed clinical trials1,2 in preventing the need for: o Surgical debridement, plastic surgery and related healthcare costs o Postponement of a patient’s chemotherapy treatments o Rehabilitation, follow-up and avoidance of long-term consequences

For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors: ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply (800) 746-6273 (866) 677-4844 (800) 482-6700 (800) 633-7555

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Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. All images and captions are copyright © Photo Researchers, Inc. They may not be copied, reproduced or used in any way without permission from Photo Researchers, Inc. Use without permission is a breach of copyright under national and international laws.

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TopoTarget USA. All rights reserved. TOT0075/3-09 Totect and its logo mark are registered trademarks of TopoTarget USA, Inc., Rockaway, NJ, USA.

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TOP_Jan_Feb2010_v3_TON 2/5/10 11:33 AM Page 1

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-

www.totect.com

TOT0075/03-09 ©2009 TopoTarget USA

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-

Rx only Totect® is a registered trademark of TopoTarget A/S US Patent No. 6,727,253B2

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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.

Manufactured for: TopoTarget A/SSymbion Science Park Fruebjergvej 3 DK-2 100 Copenhagen Denmark

Marketed by: TopoTarget USA Inc. 100 Enterprise Drive Rockaway, New Jersey 07866 (866) 478-8274


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Editorial Board CO-EDITOR-INCHIEF

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

CO-EDITOR-INCHIEF Patrick Medina, PharmD, BCOP

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, OH

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

RJ Health Systems International, LLC Wethersfield, CT

Betty M. Chan, PharmD, BCOP USC/Norris Cancer Hospital Los Angeles, CA

Desert Regional Medical Center Palm Springs, CA

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

John M. Valgus, PharmD, BCOP

Indiana University Simon Cancer Center Indianapolis, IN

Novant Health Winston-Salem, NC

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Jefferson School of Pharmacy Philadelphia, PA

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

Gary C. Yee, PharmD, FCCP, BCOP

David C. Gammon, BS Pharm

Laura Boehnke Michaud, PharmD, BCOP, FASHP

Oklahoma University College of Pharmacy Tulsa, OK

John F. Aforismo, BSc Pharm, RPh, FASCP

Timothy G. Tyler, PharmD, FCSHP

University of Massachusetts Memorial Hospital Worcester, MA

University of Nebraska College of Pharmacy Omaha, NE

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

The University of Texas M. D. Anderson Cancer Center Houston, TX

Marlo Blazer, RPh, PharmD James Cancer Hospital & Solove Research Institute Columbus, OH

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

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

2

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Steve Stricker, PharmD, MS, BCOP

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Samford University McWhorter School of Pharmacy Birmingham, AL

February 2010 I VOL 3, NO 1

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

www.TheOncologyPharmacist.com


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Looking to trim your “waste” this year? For more than 14 years, the PhaSeal System has been the only clinically proven closed-system drug transfer device on the market. And now the same System that has been uniquely proven to protect your employees from hazardous drug exposure can also help you realize an economic benefit using the Drug Vial Optimization (DVO) Model. Here’s how it works: • PhaSeal provides a physical barrier that helps maintain microbiological integrity 1 • Maintaining the microbiological integrity of the drug vial enables your facility to extend the use of the drug until the chemical expiration date to create cost savings 2 • Savings attributed to Drug Vial Optimization can lower your overall oncology spend and offset the cost of PhaSeal It’s a unique combination of safety and savings. For more information on how Drug Vial Optimization can help you save, call 866-487-9250 or stop by the Carmel Pharma booth at HOPA. 1. De Prijck K, D’Haese E, Vandenbroucke J et al. Microbiological challenge of four protective devices for the reconstitution of cytotoxic agents. Letters in Applied Microbiology. 2008; 47: 543-548. 2. Vandenbroucke J, Robays H. Economic impact of the preparation scenario for cytotoxic drugs: an observational study. European Journal of Hospital Pharmacy Practice. 2008; 14: 37-42.

Carmel Pharma, Inc. 7029 Huntley Road Suite O Columbus, OH 43229 USA Phone: 614-841-0504 Toll Free: 866-487-9250 Fax: 614-841-0525 E-mail: info@carmelpharmausa.com

DVO


TOP_Jan_Feb2010_v3_TON 2/5/10 11:34 AM Page 4

FROM THE EDITORS

A

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Director, Client Services John W. Hennessy john@greenhillhc.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

GH Green Hill Healthcare Communications

, LLC ™

Your Innovative Partners in Medical Media

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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 8 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 ©2010 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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February 2010 I VOL 3, NO 1

s we enter our third year of publication, we are introducing some changes and new features to better serve your needs. First, you will notice that we’ve updated our appearance. But the changes are not only skin deep. We have also established a new collaboration with Veritas Institute for Medical EdSusan Goodin, ucation, Inc., to provide a seamless way PharmD, FCCP, receive continuing education (CE) to BCOP credit online. One article in each issue of The Oncology Pharmacist will offer complimentary CE credit. After reading the article, readers can apply for CE credits by completing a posttest and registering to receive a statement of completion online. In 2007, Veritas Institute received 6year Accreditation with CommendaPatrick Medina, tion from the Accreditation Council for PharmD, BCOP Continuing Medical Education, one of an elite group of accredited providers to receive this recognition. We look forward to working with Veritas Institute to provide high-quality educational programs that will help enhance your professional development. Also this year, we will expand coverage of major medical conferences with news from international as

CONTENTS FEATURE ARTICLES 6 Conference News: ASHP National Alert Network established to prevent medical errors Underuse of language assistance services

well as US meetings. In her opening address at the American Society of Health-System Pharmacists Midyear Clinical Meeting, president Lynnae Mahaney said, “This is a fabulous time to be a pharmacist.” She spoke of economic and other challenges facing the profession, but she said, “there are so many opportunities to show how we improve patient safety and outcomes through rational medication use.” Keynote speaker Dennis Quaid spoke poignantly of his own firsthand experience with the potentially devastating effects of medication errors when his infant twins received overdoses of heparin. Pharmacists and other healthcare workers are “overworked and underappreciated” and human error is inevitable, he said, but the use of technology to reduce system errors and initiatives such as the National Alert Network for Serious Medication Errors can help ensure patient safety. Also in an effort to reduce medication errors, the US Food and Drug Administration is now requiring manufacturers of opioids and other drugs and biologics with potential safety concerns to develop Risk Evaluation and Mitigation Strategies (REMS) for these products. The REMS Review featured in this issue explains what REMS are and why they are being implemented. As pharmacists, we will play a key role in educating our colleagues and patients about REMS and facilitating their smooth integration into practice. As Lynnae Mahaney said, there are challenges and opportunities ahead. ●

February 2010 • VOL 3, NO 1

18 Continuing Education Cancer treatment–related bone loss and osteoporosis

29 Supportive Care

Managed care pharmacists can improve chemotherapy reimbursement

New strategies for preventing anthracycline cardiotoxicity show promise

Rawley M. Guerrero’s contributions remembered

MAC infections in the elderly

Pharmacists show gaps in skin cancer knowledge Curbing use of unapproved abbreviations Alvimopan cuts hospital stay after bowel resection

12 Conference News: ASH

30 Financial Planning Manage debt through financial planning

DEPARTMENTS 22 Oncology Drug Codes Cervical cancer

Rituximab improves overall survival in CLL patients

30 International Oncology News

Weekly bortezomib effective and less toxic

32 In the Literature

Aprepitant improves emesis control in transplant patients

33 News Notes

16 Conference News: SABCS Adjuvant letrozole relieves rheumatologic symptoms Higher doses of fulvestrant may be preferred Anthracyclines may not be necessary for HER2-positive breast cancer Scalp hypothermia for chemotherapy-induced hair loss

REMS REVIEW Risk management: a new era of patient safety Between pages 18 and 19

www.TheOncologyPharmacist.com


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A pioneer in cancer innovation — exploring new directions

At Genentech BioOncology, we’re leading the fight against cancer with innovative science and are working to transform cancer treatment. A family of firsts — Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States. A robust pipeline — Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

www.BioOncology.com

© 2009 Genentech USA, Inc. All rights reserved. 9708100 Printed in USA.


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Conference News ASHP 2009 The following articles are based on reports at the 44th American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting and Exhibition held in Las Vegas, Nevada, December 6-10, 2009.

National Alert Network Established to Prevent Medical Errors

T

Dennis Quaid and ASHP President Lynnae Mahaney

he launch of the National Alert Network for Serious Medication Errors (NAN) was announced at the opening session of the 44th American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting and Exhibition. ASHP is partnering with the Institute for Safe Medication Practices to develop the alert system in an effort to prevent dangerous and repeated medication errors. The system will be triggered when a seriously harmful or potentially seriously harmful error has occurred. The alert will include a description of the error and recommendations to prevent the same error in the future. ASHP will disseminate e-mail alerts to its network of nearly

35,000 health-system pharmacists and other healthcare practitioners. The event-specific information included in the alerts will be obtained from voluntary reports, news reports, and other channels. The alerts will be archived and posted on the ASHP website (www.ashp. org/iv-summit). Keynote speaker Dennis Quaid expressed his support for NAN in his address. Quaid became an advocate for systems changes in hospitals to protect patients from medication errors when his infant twins received near-fatal overdoses of heparin. That experience led to the establishment of The Quaid Foundation whose mission is to help minimize the impact of human error in patient care. ●

Applications Sought for Medication Safety Award Applications for the 2010 Award for Excellence in Medication-Use Safety are being accepted through April 29, 2010. The $50,000 award, supported by a grant from Cardinal Health Foundation, recognizes pharmacy professionals who have assumed a leadership role in promoting safe medication use. Two finalists will each receive $10,000. The application is available on the ASHP website (www.ashp.org).

Pharmacists Underuse Language Assistance Services By Jill Stein

D

espite the frequent need for language assistance services (LAS) at community pharmacies and the widespread availability of such services, LAS are underused by community pharmacists, results of a recent survey show. “Patients who are not proficient in English and who do not know that LAS are available at their pharmacy will not be able to understand the purpose, dosage, and possible side effects of their medications,” said Kevin Clauson, PharmD, associate professor of pharmacy practice at Nova Southeastern University in Palm Beach Gardens, Florida. “Sadly, patients are at increased risk of poor outcomes if they are not proficient in English and don’t have prescription information in their own language.” Clauson and his co-investigators analyzed responses to questionnaires completed by 296 chain and independent community pharmacists nationwide. According to US census figures, a language other than English is spoken in 19.7% of homes in the United States. Of those speaking a language other than English at home, 8.6% have limited English proficiency (Census 2000: Language Use. www.census.gov/ population/www/socdemo/lang_use. html). “My colleagues and I were increasingly concerned about possible inaccuracies on some of the prescriptions we were dispensing,” Clauson explained. “For example, some of the native Spanish speakers and Russian speakers

6

February 2010 I VOL 3, NO 1

were saying that the translations did not exactly match what was being inputted into the system.” LAS include interpreters as well as translated written materials, such as a medication package insert. The results show that although LAS are available in up to 73.8% of pharmacies nationwide, 49.8% of pharmacists who worked at a phar-

that should be easy to address,” Clauson said. To improve the workflow, pharmacies may want to consider reexamining the “duties” performed by pharmacy personnel at each workstation. Focus groups may also help identify ways to reduce the time it takes to process prescriptions and make more efficient use of personnel.

“We believe that making sure that patients are aware of such services can help improve outcomes in this particularly at-risk population with limited English proficiency.” —Kevin Clauson, PharmD

macy where such services were available acknowledged that they do not notify their patients about the availability of such services. Not surprisingly, Spanish was the language most often requested for verbal interpretation or translation nationwide. French, Vietnamese, Chinese, and Russian were also commonly requested. More than half of pharmacists who did not use LAS said their hesitation stemmed from concern about inaccuracies in translation/interpretation. Nearly one third said that the provision of LAS was too time-consuming. “This is undoubtedly a workflow issue

About one fourth of respondents cited concern about legal issues. “Pharmacists said they were worried that they would be liable if the prescription label was printed in a language they did not know and included inaccurate translations,” he explained. Pharmacists said that LAS were most often needed at prescription drop-offs (56.2%), during counseling (39.2%), and when prescriptions were picked up (36.1%). “The takeaway message is that LAS are available, but they are currently being used suboptimally,” Clauson observed. “And we believe that making sure that patients are aware of

such services can help improve outcomes in this particularly at-risk population with limited English proficiency.” For example, posting notices in conspicuous areas that inform patients about the availability of interpreters and how to contact an interpreter may be helpful, he said. Finally, he noted that interventions may need to take into account cultural barriers. “Some patients who come from cultures where they are taught not to question authority figures because it’s perceived as disrespectful may simply nod in agreement when the pharmacist explains how to use a medication,” he said. “However, they may not understand, and they then go home and draw up 5 tablespoons of cough syrup for their child instead of 5 mL, which is a preventable error.” Clauson mentioned a case where a pharmacist tried to explain to the Spanish-speaking parents of a 10month-old girl how to give the prescribed dose of an iron supplement by showing them the dropper and vial. The pharmacist did not speak Spanish, and an interpreter was not used. Although the parents nodded that they understood the pharmacist’s directions, instead of using the dropper, they gave a tablespoon of iron to the infant. As a result, the child received a 12.5-fold overdose and had to be hospitalized (Morbidity and Mortality Rounds on the Web. April 2006). ● Conference News continued on page 8

www.TheOncologyPharmacist.com


TOP_Jan_Feb2010_v3:TON 2/6/10 11:36 AM Page 7

# Teva is 1 in Oncology Products

View Teva’s complete line of oncology products at www.tevausa.com/oncology

Data derived from the use of information under license from the following IMS Health Information Service: IMS NSP Audit, MAT 9/08. Data is proprietary to IMS Health. ©2009, Teva Pharmaceuticals USA

8349 A

19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com


TOP_Jan_Feb2010_v3_TON 2/5/10 11:34 AM Page 8

Conference News ASHP 2009

Continued from page 6

Managed Care Pharmacists Can Improve Chemotherapy Reimbursement

M

anaged care pharmacists, through implementation of a clinical authorization process, can play a pivotal role in securing payer reimbursement of chemotherapy agents at a cancer hospital, according to recently released data. What’s more, by developing a clinically staffed chemotherapy authorization department, managed care pharmacists can also help increase the procurement of replacement chemotherapy drugs. Those conclusions were reported by Shetal S. Desai, PharmD, who was hired 2 years ago as the director of the Clinical Authorization Center at the University of Southern California (USC) Norris Cancer Hospital in Los Angeles. “My study is actually my job,” said Desai, who has worked extensively in managed care. “This is what I was hired to do.” Specifically, her job required that she examine the issues surrounding financial reimbursement of chemotherapy drugs. Afterward, she was responsible for implementing procedures that were intended to decrease disputed claims and improve drug replacement through enrollment in pharmaceutical manufacturer–driven programs. The USC Norris Cancer Hospital is a private, 60-bed research and teaching hospital with an onsite outpatient

chemotherapy infusion center that services between 20 and 45 patients daily, Desai noted. The payer mix includes primarily commercial insurers and Medicare. When Desai was brought onboard, the facility was having problems with

and the one most frequently disputed; the main reason why the claims were disputed was that payment was being requested for off-label use of bevacizumab (eg, treating metastatic breast cancer before it had been approved for that indication)

“A staff that is clinical is crucial, because they can actually speak the language of the insurance companies.” —Shetal S. Desai, PharmD payer reimbursement of chemotherapy agents. “In fact, monthly total disputed claims dollars averaged between $600,000 and $1 million,” she said. The hospital administration was unclear about the reasons for unpaid or disputed claims, she added. Desai who is also an assistant professor at the USC School of Pharmacy, found that: • The main reasons for disputed or unpaid claims were a lack of authorization before treatment was administered and the use of an agent for unapproved indications • Bevacizumab was the most commonly used chemotherapy agent

• Roughly 40% of all visits for chemotherapy administration were not scheduled in advance • Physician chemotherapy orders were not routinely sent to the authorization department prior to a scheduled appointment • Third-party payers requested from 3 to 5 days to respond to an authorization request • Authorizations were requested by nonclinical hospital personnel, who did not have the clinical knowledge to be able to respond to clinical questions prospective payers needed answered before authorizing payment

• It was difficult to request payment from payers when authorizations for chemotherapy were not accurately obtained or appropriately documented • Clinical criteria for authorization varied by payer and coverage plan. After reporting her results to the hospital administration, Desai recommended that a new clinically staffed chemotherapy authorization department be developed. “A staff that is clinical is crucial, because they can actually speak the language of the insurance companies and they can obtain the proper authorization before treatment,” she said. “In addition, they can supply the insurance companies with any peerreviewed journal articles that might provide enough evidence for treatment in unapproved indications.” Ideally, a managed care pharmacist should serve as the director of the chemotherapy authorization department, and nurses with a case-management background should be hired as clinical authorization specialists, Desai observed. Medical staff, she said, should submit orders 3 to 5 days before treatment to allow sufficient time to obtain authorization. The hospital’s chemotherapy authorization department should also deterContinued on page 14

Rawley M. Guerrero Remembered for Contributions to Pharmacy Education and Training By Karen Rosenberg

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he late Rawley M. Guerrero, ASHP Commission on Credentialing PharmD, MBA, FASHP, was from 1994 to 2000, as vice chair from remembered for his many con- 1997 to 1998, and as chair from 1999 tributions to pharmacy education and to 2000. His two terms of service on training at a reception for winners of the the commission “speak well not only of 2009 ASHP Research and Education his commitment to postgraduate eduFoundation’s Pharmacy Residency cation but also to the respect that his Excellence Awards held during the peers had for his background and comMidyear Clinical Meeting in Las Vegas. mitment,” Dr deLeon said. Dr Guerrero was deeply At the time of his death committed to postgraduate last year, Dr Guerrero was a training and was instrusenior marketing manager mental in establishing the with Pharmacy Affairs, residency awards program. part of Segment Marketing “It is quite conceivable that at Amgen, Inc., Thousand the awards program might Oaks, California. Earlier not exist without Rawley’s in his career, he was assoinput,” said friend and colciate pharmacy director at league Richard deLeon, the University Hospital in PharmD, director of pharSalt Lake City, pharmacy macy affairs at Amgen, Inc. Rawley M. Guerrero, director at the University Dr Guerrero served on the PharmD, MBA, FASHP of Virginia Health System

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in Charlottesville, Integris Health in Oklahoma City, and the University of Miami/Jackson Health System, and medical education and research liaison for TAP Pharmaceuticals in Miami. While at Jackson Memorial, a municipal hospital, he established a clinical residency program despite the limited funding available for the program, Dr deLeon said. “He did what he needed to get it done.” Dr Guerrero received his undergraduate degree from the University of California, San Diego, his doctor of pharmacy degree from the University of the Pacific, and his master of business administration degree from the University of Miami. With his combination of academic and industry experience, Dr Guerrero was uniquely qualified to advise students about career opportunities. At

Amgen, he worked with other staff members to create internships for students at nearby schools of pharmacy. “He was full of ideas and had a lot of energy to devote to students, residents, and fellows. We routinely referred students to him for career counseling,” Dr deLeon recalls. “He will be greatly missed.” ● Conference News continued on page 10

Did You Know? The Bureau of Labor Statistics projects that the number of physicians, other healthcare professionals, and administrators employed by physicians practices will increase substantially from 2008 to 2018, with 109,300 new jobs for physicians, 106,500 new jobs for registered nurses, and 248,700 office and administrative staff support positions.

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STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapyyinduced nausea and vomiting (CINV) during their eir first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6* Can be used with multiple-day chemotherapy regimens mens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL448-A 08/09

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Conference News ASHP 2009

Continued from page 8

Pharmacists Show Gaps in Skin Cancer Knowledge

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rizona pharmacists are not particularly well-informed about skin cancer and need to take steps to improve their knowledge, a survey of pharmacists working in a variety ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS 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 reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

of settings found. Ashley VanAllen, PharmD, and her colleagues at the University of Arizona College of Pharmacy in Tucson, reported the results of questionnaires completed General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, 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.

by 110 Arizona-based pharmacists who worked in community pharmacies, longterm care facilities, hospital outpatient pharmacies, managed care pharmacies, and other settings. Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

“With a maximum possible score of 10, their mean score was only 5.8,” said VanAllen, who is currently a pharmacy resiAshley VanAllen, dent at Health PharmD Point in Kent, Washington. “We would have liked to have seen better results, given that Arizona has the highest rate of skin cancer in the United States and ranks number two in skin cancer incidence worldwide, after Australia.” Only 41% of pharmacists were able to identify the active ingredient in sunscreen that provides the best coverage against both ultraviolet-A (UVA) and ultraviolet-B (UVB) spectrums of light. The correct answer is zinc oxide. Additional findings: • 51% gave a correct response when asked how often a waterproof sunscreen needs to be reapplied after swimming or sweating. The correct answer is every 80 minutes. • 54% gave a correct response when asked what the ABCD acronym stands for. The correct response is that “A” stands for asymmetry (one half of a mole is different from another), “B” is for border irregularity (the mole has an irregular, notched, and indistinct border), “C” is for color variations (a mole changes in color or shade such as blue, white, brown, black, or a combination of these colors and shades), and “D” is for diameter (a mole is larger than a pencil eraser, a diameter greater than 6 mm). • 60% answered correctly when asked to identify the minimum recommended sun protection factor (SPF) for adults. The minimum SPF for adults is 15. • 62% answered correctly when asked about the main factor that determines prognosis/survival with malignant melanoma. The correct response is the depth of the mole in the skin, based on penetration measurement in millimeters. • 80% knew that the most appropriate time to apply sunscreen containing avobenzone and homosalate for outdoor sunlight exposure. It should be applied 30 minutes before exposure to the sun. Fewer than half of respondents were able to identify the risk factors for basal and squamous cell carcinoma. Also, although nearly half said they believe that pharmacists can be effective in Continued on page 11

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Conference News ASHP 2009

Pharmacists Can Help Curb Use of Unapproved Abbreviations

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he pharmacist can play a key role in ensuring that healthcare practitioners avoid using medical abbreviations that have been deemed “off-limits” by The Joint Commission (TJC), according to a new study. In the study, the researchers sent monthly e-mail reminders to individual practitioners who they had identified as being repeat violators. The e-mails detailed their unapproved abbreviations and the reason(s) why the abbreviations were prohibited. “We found that the pharmacist-led e-mail strategy led to a rapid, significant decrease in the number of practitioners using unapproved abbreviations as well as the total number of unapproved abbreviations,” said Juliana Chan, PharmD, assistant director of pharmacy clinical services at the University of Illinois Medical Center (UIMC) in Chicago. As a condition for accreditation by TJC, all healthcare organizations are required to comply with a mandate by the organization prohibiting them from using selected abbreviations for all med-

ication-related documentation. The abbreviations must be avoided whether the documentation is handwritten or entered as free-text on a computer or on preprinted forms. The list was “implemented” in 2005 with the intention of standardizing abbreviations, acronyms, and symbols as part of the TJC’s requirements for meeting National Patient Safety Goals. The official “Do Not Use” list includes, for example, “U,” which refers to “unit.” “U” should not be used because it can be mistaken for “0” (zero), the number “4” (four) or “cc.” Instead, healthcare practitioners should write the word “unit.” “IU,” which refers to “international unit,” is also included in the list of banned abbreviations because “IU” can be mistaken for “IV” (intravenous) or the number “10” (ten). Instead, healthcare practitioners should write “international unit.” The list also includes “QD” (every day), “QOD” (every other day), “MS” or “MSO4” (morphine sulphate), “MgSO4” (magnesium sulphate), deci-

mal doses without leading physicians, 8.4% were zeros, and trailing zeros after a medical students, and the decimal point. rest were a mix of pharmaSeveral additional abbreviacists, social workers, and tions, acronyms, and symbols dietitians. Notably, medare being considered for incluical residents and attendsion in the official “Do Not ing physicians accounted Use” list. These include the for more than three quarsymbol “@,” which may be ters of the total number of mistaken for the number “2” abbreviations. (two), and the abbreviation Juliana Chan, PharmD Since the implementa“µg,” which may be mistaken tion of follow-up e-mails, for “mg” (milligrams) resulting in a one the total number of practitioners using an thousand–fold overdose. unapproved abbreviation has decreased Chan and colleagues reviewed elec- 13.7% from 1317 to 1136. The total tronic medical records at UIMC over a number of unapproved abbreviations was recent 9-month period to identify non- reduced by 32.3% from 8147 to 5517. compliant practitioners and then to test “We were surprised at how effective the usefulness of personal follow-up e- e-mails were in making our institution mails from a pharmacist in improving more TJC-compliant,” Chan said. “We compliance. E-mails were only sent to knew that it would be time-consuming, practitioners who had used at least six but it paid off.” banned abbreviations in a single month. She also noted that her group is conDuring the study period, 1663 practi- sidering using e-mails for other TJC tioners used a total of 13,663 unapproved initiatives, such as medication reconabbreviations. Of the 1663 practitioners, ciliation. ● 37.3% were resident physicians, 21.4% —JS were nurses, 15.3% were attending

Alvimopan Cuts Hospital Stay after Bowel Resection

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lvimopan, a peripherally acting opioid antagonist, reduces the length of hospital stay after a bowel resection, a new study indicates. Linda W. Banares, PharmD, currently a postgraduate year two (PGY2) ambulatory care pharmacy resident at Parkland Health and Hospital System in Dallas, Texas, presented results of a 2009 medication-use study she and her colleagues conducted while she was a PGY1 pharmacy resident at the Moses Cone Health System (MCHS) in Greensboro, North Carolina. The MCHS is a multihospital, community-based system that performs roughly 500 bowel resections annually. Alvimopan speeds recovery of bowel function after partial bowel resection. In

August 2008, alvimopan was added to the health system’s formulary with restrictions. At the request of the MCHS Pharmacy & Therapeutics Committee, Banares and her group performed a 6month evaluation to assess the appropri-

Alvimopan speeds recovery of bowel function after partial bowel resection. ate use of alvimopan and to track clinical outcomes in 142 patients who either did or did not receive alvimopan. Most patients undergoing abdominal

Pharmacists Show Gaps... Continued from page 10 reducing a patient’s risk of skin cancer, fewer than 10% said they were very comfortable with counseling patients about sun safety. “We would hope that Arizona-based pharmacists would be more comfortable counseling patients about sunscreens, given the high incidence of skin cancer in Arizona,” VanAllen said. She also pointed out that although most questions about sunscreen use

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are from adults with children, she thinks that pharmacists should take a more proactive role in counseling about sunscreen for both adults and children. But first, she added, pharmacists need to be better informed, and there are continuing medical education programs available where they can improve their knowledge. ● —JS

or pelvic surgery experience delayed gastrointestinal recovery, including postoperative ileus, Banares noted. Postoperative ileus is characterized by lack of passage of flatus and an absence of bowel movements along with abdominal pain, distension, nausea, vomiting, and accumulation of gas or fluids in the bowels. Postoperative ileus may occur for a variety of reasons, including surgical trauma, inflammation, and the use of exogenous opioids to manage pain. Although metoclopramide, erythromycin, and other drugs have some gutstimulatory effect, none of these agents have demonstrated efficacy in reducing the duration of postoperative ileus, Banares noted. Alvimopan is currently the only US Food and Drug Administration–approved medication indicated to accelerate the time to gastrointestinal recovery following partial large or small bowel resection with primary anastomosis. Phase 3 clinical trials demonstrated reduced time to recovery by up to 1 day. In the present study, all patients were scheduled for partial large or small bowel resection with primary anastomosis via an open or laparoscopic technique. The main indication for surgery was colon cancer. Patients in the alvimopan group

received 12 mg preoperatively and twice daily postoperatively until hospital discharge or for a maximum of 7 postoperative days. Patients in the control group underwent surgery before the drug was commercially available. The study found that after adjustment for sex and age, the mean postoperative length of stay was 1.2 days shorter in the alvimopan group undergoing open resection and 0.9 days shorter in the group undergoing laparoscopic resection, for a cost-saving of $1042 and $338, respectively, per patient. Alvimopan tended to have a more pronounced effect in patients 70 years of age or older, but the difference between older and younger patients was not significant. There were no cases of myocardial ischemia or sudden death in the alvimopan group. In the United States, approximately 350,000 patients undergo colorectal or small bowel resection each year, Banares observed. “Based on the efficacy, safety, and economic benefit seen in this study, alvimopan appears to have a role in clinical care pathways for open and laparoscopic bowel resection,” she said. ● —JS

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Conference News ASH 2009 The following articles are is based on reports at the 51st Annual Meeting and Exposition of the American Society of Hematology (ASH), held in New Orleans, December 5-9, 2009.

Nilotinib: First-line Treatment... Continued from cover Ph+ CML in chronic phase were randomized to either 400 mg of imatinib once daily or 300 mg or 400 mg of nilotinib twice daily. Follow-up lasted about 5 years. At 12 months, the rates of major molecular response (the primary end point of the study) were 44% with 300 mg nilotinib, 43% with 400 mg of nilotinib, and 22% with 400 mg of imatinib. The median time to a major molecular response was faster by about 2.5 months in the nilotinib groups compared with the imatinib group. Saglio noted that molecular monitoring is the most sensitive measure of CML disease burden. “Major molecular response is associated with an extremely low rate of disease progression,” he said. Of the patients who experienced progression of disease in this study, none achieved a major molecular response, he said. Complete cytogenetic responses at 12 months were also significantly better in the nilotinib recipients: 80% with nilotinib 300 mg; 78% with nilotinib 400 mg; and 65% with imatinib 400 mg. Rates of progression to accelerated

phase or blast crisis were 3.9% in the imatinib group compared with less than 0.7% and 0.4% in the patients treated with 300 mg and 400 mg of nilotinib, respectively.

Saglio noted that molecular monitoring is the most sensitive measure of CML disease burden. According to Bayard L. Powell, MD, chief, Section of Hematology and Oncology at Wake Forest University, Winston-Salem, North Carolina, the difference between nilotinib and imatinib in rates of progression to accelerated phase or blast crisis is the most meaningful finding of the study, “because people who go into accelerated phase or blast phase don’t really have the opportunity for second-line therapy.” Nilotinib was superior to imatinib on efficacy end points across all risk groups of patients based on their Sokal score (a risk index based on six criteria).

Seven percent to 11% of patients in each group discontinued their study drug because of adverse events or abnormalities in laboratory values, with no significant differences between groups. Four percent of patients in the imatinib group discontinued because of treatment failure, 4% discontinued because of disease progression, and 2% because of suboptimal response. Edema and weight gain occurred more often with imatinib therapy. Grade 3 or 4 toxicities were rare in any group. In commenting on the study, Rick Van Etten, MD, PhD, director of the Tufts Medical Center Cancer Center, Boston, agreed that the finding “could be used to argue for nilotinib as first-line therapy.” More potent agents lead to impressive complete cytogenetic responses Additional studies of nilotinib and dasatinib, another oral tyrosine kinase inhibitor that is several times as potent as imatinib, show favorable efficacy on major molecular response in patients with newly diagnosed CML. Both sets of

data were reported by Jorges E. Cortes, MD, professor and deputy chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston. The two studies he presented were identical in the nature of their design. In the open-label, single-agent trials, the efficacy of either nilotinib, 400 mg twice daily, or dasatinib, 100 mg/day (given as either 50 mg twice daily or 100 mg once daily), was investigated as first-line therapy in chronic-phase CML. In the nilotinib study, 32 (63%) of 51 patients who were followed for at least 3 months achieved a complete molecular response and 98% achieved a complete cytogenetic response. In the dasatinib study, major molecular response was achieved in 70% and a complete cytogenetic response was achieved in 98% of the 50 patients who were followed for at least 3 months. Cortes noted that the cytogenetic response rates with nilotinib and dasatinib in these studies compare favorably with that observed in imatinibtreated patients. ●

Rituximab Improves Overall Survival in Previously Untreated CLL Patients

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dding rituximab to fludarabine and cyclophosphamide chemotherapy improves overall survival (OS) in patients with advanced, symptomatic chronic lymphocytic leukemia (CLL) compared with chemotherapy alone, according to a study by German researchers. In a randomized study, 87.2% of patients with previously untreated CLL who received rituximab plus chemotherapy were alive after follow-up of more than 3 years compared with 82.5% who received chemotherapy alone, said Michael Hallek, MD, University of Cologne, Germany, lead investigator. This marks the first time that an induction therapy has been shown to improve survival in a randomized trial in patients with advanced CLL, he said. Rituximab binds to the CD20 antigen on the surface of normal and malignant B cells. It recruits the body’s natural defenses to attack and kill the marked B cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B cells to regenerate after

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treatment and return to normal levels within several months. “This is the first randomized trial to demonstrate that the choice of first-line therapy improves the natural course of CLL,” said Hallek. “The results support

The first analysis showed that patients receiving rituximab in combination with chemotherapy as first-line treatment lived an average of 40 months without cancer progression, compared with an average of 32 months for

This marks the first time that an induction therapy has been shown to improve survival in a randomized trial in patients with advanced CLL.

the recommendation to use fludarabine, cyclophosphamide, and rituximab as standard therapy in physically fit patients with CLL.” He presented the second analysis of a study conducted in 191 study sites across 11 countries, in which 817 patients with untreated active CLL who were physically fit were randomized to treatment with either chemotherapy (fludarabine and cyclophosphamide) alone or rituximab plus chemotherapy, and followed for a median of 37.7 months.

patients receiving chemotherapy alone. The primary end point of the study was progression-free survival (PFS). Patients who received rituximab plus chemotherapy had a median PFS of 51.8 months, compared with 32.8 months for those who received chemotherapy alone. The median survival has not yet been reached. At 3 years, PFS was achieved by 64.9% of patients in the rituximab/ chemotherapy arm versus 44.7% of those in the chemotherapy alone arm.

OS was superior in the patients with Binet stage A or B who received rituximab, but not Binet stage C. Hallek explained that treatment intensity may not have been sufficient to demonstrate a significant survival benefit in Binet stage C patients because of their higher tumor load. A complete response (CR) was observed in 44.1% of rituximab/chemotherapy recipients compared with 21.8% of patients receiving chemotherapy alone. Patients who achieved CR had better OS than those without CR. Safety was consistent with previous studies of rituximab. The most common adverse events that occurred more often in the rituximab/chemotherapy arm included blood and lymphatic system disorders, infections, and neoplasms. Grade 3 or greater events that occurred more often in the rituximab/chemotherapy arm were hematologic toxicity, neutropenia, and leukocytopenia. ● —WK Conference News continued on page 14

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Conference News ASH 2009

Continued from page 12

Weekly Bortezomib Effective and Less Toxic By Caroline Helwick

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ess intensive treatment with bortezomib—giving the drug weekly rather than twice weekly —appears to have comparable efficacy but less toxicity, according to a study by Spanish researchers. Good results were reported with the less-intensive regimen in newly diagnosed older patients. “We were trying to optimize the treatment of elderly patients, so we tried a less intensive weekly administration for induction, followed by maintenance doses given every 3 months,” said lead researcher Maria-Victoria Mateos, MD, PhD, from University Hospital in Salamanca, Spain. The study included 260 elderly patients, who were treated with either bortezomib with melphalan and prednisone (VMP) or bortezomib with thalidomide and prednisone (VTP),

both given for six cycles. In the first cycle patients received bortezomib twice weekly, but in subsequent cycles just once weekly. For maintenance, patients received bortezomib plus either thalidomide or prednisone for up to 3 years.

during maintenance. There was a clear difference, however, in the toxicity profiles of the induction regimens, Mateos reported. The VMP regimen was associated with more grade 3 neutropenia and more grade 3 infections, which can

“We asked whether we could achieve similar efficacy with a less intensive bortezomib regimen, and the answer is that clearly we can.” —Maria-Victoria Mateos, MD, PhD Both induction approaches were highly effective, producing response rates of about 80%; both approaches were also effective in the maintenance setting, increasing the rate of complete response from 23% to 42%

be managed with growth factor support, she noted. The VTP regimen was associated with more serious cardiovascular events and more severe peripheral neuropathy, which she considered more important.

“We found that melphalan is probably the best partner for bortezomib in elderly untreated myeloma patients because the efficacy is similar to VTP, but the toxicity profile is different. There are more neutropenias but less cardiotoxicity and peripheral neuropathies with VMP,” she said. “We asked whether we could achieve similar efficacy with a less intensive bortezomib regimen, and the answer is that clearly we can,” she concluded. She added that perhaps the most important finding was that the poor prognosis of high-risk elderly patients could be overcome with either regimen. The investigators are now evaluating whether thalidomide can be replaced with lenalidomide for both induction and maintenance therapy, with the hope of further reducing toxicity. ●

Aprepitant Improves Emesis Control in Transplant Patients with No Adverse Effect on Clinical Outcomes

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atients receiving the neurokinin 1 antagonist aprepitant as part of a preparative regimen prior to stemcell transplant had improved control of acute and delayed nausea and vomiting, and the drug did not interfere with antitumor efficacy, according to investigators

from a prospective, randomized, doubleblind, phase 3 trial. “Everyone would have guessed that aprepitant would be effective as antiemesis, but we did not know whether it might negatively impact long-term survival,” explained Mary Fox-Geiman,

ASHP 2009

Managed Care Pharmacists... Continued from page 8

mine whether patients being considered for off-label treatments are eligible for pharmaceutical manufacturer–sponsored patient-assistance programs. That way, if an insurance company denies reimbursement because a drug is to be used off-label, the authorization department will routinely contact the pharmaceutical company that manufactures the drug to determine whether the patient is eligible for drug replacement through the pharmaceutical manufacturer–sponsored patient-assistance program, she added. One year after the implementation of a clinical-based authorization center, more than $1.1 million in total drug replacement has been recovered, Desai reported. Also, claims were processed more rapidly and in some cases on the same day the request was made. There was also a reduction in the number of claims

14

February 2010 I VOL 3, NO 1

denied due to lack of authorization. An additional benefit of the new clinically staffed authorization department is improved communication between the authorizations department and medical and nursing staff. Desai was unable to determine the extent of improvement in reimbursement to the hospital for chemotherapy with the new authorization process, because her hospital changed ownership earlier this year and retrospective data thus became unavailable. “The main message is that if hospitals want to improve their reimbursement, they need to have a managed care pharmacist in charge of this area,” Desai said. “Otherwise you’ll have someone who will not know how to get around some of the obstacles the insurance companies put up.” ● —JS

PharmD, of the Department of Pharmacy at Loyola University, Maywood, Illinois. The study’s principal investigator was Patrick Stiff, MD, of Loyola’s College of Medicine. Aprepitant is known to interact with cytochrome P450 isoenzymes involved in the bioactivation of highdose cyclophosphamide and may also interfere with etoposide pharmacokinetics. Its impact on long-term survival as well as regimen-associated toxicity after hematopoietic stem-cell transplantation is unknown, she explained. “Once you increase the cyclophosphamide in these regimens, you saturate the enzymes that normally metabolize the drug, and these enzymes are the same ones that are inhibited by aprepitant,” she said, “so there is a theoretical possibility that aprepitant could inhibit the production of the active metabolites and thus decrease the effectiveness of the chemotherapy.” This possibility had to be conveyed to potential trial enrollees as part of informed consent, and this made it difficult to recruit patients to the trial. “We got 181 patients, but the study was begun in 2004 and we expected it to be completed within 15 months,” she said. “The study population is highly skewed in favor of men, as they were more likely to consent.” As part of an ablative preparative

regimen, patients scheduled for hematopoietic stem-cell transplant were randomized to placebo or aprepitant 125 mg orally on day 1, then 80 mg daily during the administration of chemotherapy and for 3 days after the regimen was completed. They all received oral ondansetron 8 mg every 8 hours plus intravenous dexamethasone daily during and for 1 day after the preparative regimen. Only as-needed lorazepam was permitted for nausea. The aprepitant arm demonstrated a significant improvement in complete response rate, the primary end point. Complete responses (no emesis and no or mild nausea) were observed in 81.9% of patients taking aprepitant versus 65.8% receiving placebo, and 48.9% and 14.6%, respectively, met this end point for the entire study period, Fox-Geiman reported. In addition, 73.3% of the aprepitant group never experienced a single episode of emesis during the study, versus 22.5% of the placebo group. The greatest benefit was observed in the reduction of delayed vomiting, she emphasized. Reassuringly, clinical outcomes were similar between the two groups, including days to engraftment (white blood cell or platelets), 30-day survival, progression-free survival, and overall survival, she reported. ● —CH

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Conference News SABCS 2009 The following articles are based on presentations at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, Texas, December 9-13, 2009.

Adjuvant Letrozole Relieves Rheumatologic Symptoms in Patients with Breast Cancer By Jill Stein

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ostmenopausal women with hormone receptor–positive (HR+) early breast cancer who stop treatment with adjuvant anastrozole because of grade 2 to 3 arthralgia and/ or myalgia (A/M) may benefit from switching to letrozole therapy, new data suggest. The results are drawn from the Rheumatologic Evaluation of Adjuvant Letrozole in Postmenopausal Women with Breast Cancer (REAL) study, which found that women who experienced grade 2 or higher A/M while receiving anastrozole have fewer rheumatologic symptoms while taking letrozole. Denise A. Yardley, MD, director of breast cancer research at the Sarah Cannon Research Institute in Nash-

ville, Tennessee, presented results in 261 women who received letrozole therapy after stopping anastrozole therapy due to A/M. “Adjuvant nonsteroidal aromatase inhibitors (AIs) are the treatment mainstay in postmenopausal women with HR+ early breast cancer,” Yardley observed. “However, musculoskeletal pain is a feature common to all AIs and has been found to occur in 7% to 40% of women receiving AI therapy.” Symptoms, which usually occur within 6 months of starting AI therapy, lead to premature treatment withdrawal in up to 20% of patients, she said. The present study was conducted to determine whether switching to another AI could improve A/M and allow patients to remain on AI therapy.

Women were deemed eligible for letrozole treatment (2.5 mg/day for 6 months) if they were postmenopausal, HR+, had early-stage breast cancer, and experienced grade 2 to 3 A/M on anastrozole resulting in therapy discontinuation. Grade 2 pain referred to moderate pain; grade 3 pain denoted severe pain. Patients tolerating letrozole therapy at 6 months had the option of continuing letrozole for their prescribed course of 5 years. At enrollment, 107 (41.0%) women and 70 (26.8%) women had grade 2 A/M or higher A/M, respectively, versus 61 (23.6%) and 46 (17.8%) at 6 months. Overall, 228 (87.4%) women remained on letrozole therapy until the end of the 6-month study. This rate is

similar to the 71.5% rate reported in the Articular Tolerance of Letrozole (ATOLL) study, which also examined the effect of a switch to letrozole in women on anastrozole who had joint pain that was severe enough to require discontinuation, Yardley observed. Only 25 (9.6%) of 261 women discontinued treatment due to A/M; another 8 (3.1%) women discontinued for other reasons. Significant improvements in several quality-of-life measures were documented at 6, 12, and 24 weeks. “Our results suggest that patients who are intolerant of and have discontinued anastrozole due to A/M may better tolerate AI therapy and avoid discontinuation when switched to letrozole,” Yardley said. ●

Higher Doses of Fulvestrant May Be Preferred By Caroline Helwick

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atients with breast cancer may derive greater treatment benefit by doubling the dose of the estrogenreceptor antagonist fulvestrant according to results from the international random-

ized, double-blind, phase 3 Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial. Results from the trial, presented by Angelo DiLeo, MD, of the Hospital of

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY

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February 2010 I VOL 3, NO 1

Prato, Prato, Italy, showed that fulves- 20% reduction in the risk of progrestrant 500 mg (F500) was significantly sion. Disease progression was observed more effective than fulvestrant 250 mg in 82% versus 85.8%, respectively, and (F250) in increasing time to disease pro- the differences were consistent across gression in women with advanced estro- all predefined subgroups. gen receptor–positive breast cancer. “We “It is clear that the 500-mg dose is anticipate that the 500-mg regimen will more effective than 250 mg,” DiLeo become the established dose for fulves- observed, emphasizing that the higher trant,” he said. dose did not result in more The approved dose is 250 toxicity and there was no mg/month, but investigaevidence of dose-depentors hypothesized that outdence for adverse events. comes might be further This was an interim analyimproved by increasing the sis and only 50% of the dose to 500 mg (two 250patients have died. Although mg injections on days 1, 14, there was a trend for imand 28, and every 28 days proved overall survival with thereafter). They designed F500, it did not reach statisa phase 3 trial to determine tical significance. Death Angelo DiLeo, MD whether the higher dosage occurred in 48.3% of the might induce a more proF500 group and 54.3% of found downregulation of the estrogen the F250 group, corresponding to a receptor without worsening side effects. 16% nonsignificant reduction in morCONFIRM compared F250 with F500 tality risk with the higher dose. in postmenopausal women with estrogen “It is not statistically significant, but receptor–positive advanced breast can- our impression is that patients on 500 mg cer recurring or progressing after prior are surviving longer,” he added. endocrine therapy. The study recruited An exploratory analysis is currently 736 women from 128 centers in 17 coun- seeking to identify a subgroup that may tries, and randomized them to one of the derive the most benefit from dose escalatwo doses until disease progression. tion and from hormonal therapy in genThe primary end point, time-to-pro- eral. “It is important to target the popugression, was significantly prolonged lation that will benefit most from with F500—6.5 months versus 5.5 downregulation of the estrogen recepmonths with F250, corresponding to a tor,” he said. ●

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Conference News SABCS 2009

Anthracyclines May Not Be Necessary for HER2-positive Breast Cancer

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ebate continues as to whether all patients with early human epidermal growth factor receptor type 2 (HER2)-positive breast cancer need an anthracycline with trastuzumab. Updated data from the Breast Cancer International Re search Group (BCIRG)-006 trial suggest that eliminating the anthracycline will have comparable efficacy and be less toxic. Dennis Slamon, MD, PhD, of the University of California, Los Angeles, announced that a nonanthracyclinebased regimen with trastuzumab was not associated with significantly more breast cancer recurrences or deaths at 5.5 years, and no subgroup demonstrated special benefit from the anthracycline-based regimen. Furthermore, by eliminating the anthracycline, risk of heart failure and leukemia was significantly reduced, he said. “We should no longer think that the high-risk patient needs anthracyclinebased chemotherapy,” Slamon commented at a press briefing. “The data do not support that.” The trial included 3222 HER2-positive patients who were randomized to one of three arms: standard anthracycline-based therapy with doxorubicin, cyclophosphamide, and docetaxel (ACT), the same regimen plus trastuzumab (AC-TH), or the nonanthracycline regimen of docetaxel and carboplatin plus trastuzumab (TCH). Findings from the third planned analysis, based on 65-month follow-up, led to the following main conclusions: • Trastuzumab provides a similar and significant advantage for both disease-free survival (DFS) and overall survival (OS) when used with either anthracycline-based chemotherapy (AC-TH) or a nonanthracycline

regimen (TCH), in both low-risk and high-risk patients. • The acute and chronic toxicity profiles of TCH are better than those seen with the AC-TH regimen in almost all parameters measured. • There is no statistical advantage of AC-TH over TCH, but there is a 29-event numerical advantage in DFS events with AC-TH. • This numerical advantage comes at a cost: increases in congestive heart failure and leukemias, all in patients receiving AC as part of the treatment.

spectively, he reported. Anthracycline-based therapy was expected to benefit the high-risk patients the most, Slamon added; however, even in patients with four or more positive lymph nodes, the two trastuzumab regimens resulted in identical DFS outcomes. BCIRG-006 also demonstrated that incremental benefit conferred by AC in HER2-positive patients is restricted to the 35% of patients whose tumors coamplify the topoisomerase II alpha (TOP2A) gene, a close genetic neighbor of HER2. Slamon advocated the nonan-

“At this point, when we see an HER2-positive patient, we have elected to treat those patients with a nonanthracyclinecontaining regimen to get close to equivalent efficacy but considerably better safety, in particular, not for the acute toxicity but more important for the life-changing toxicities.” —Dennis Slamon, MD, PhD

DFS at 65 months was 84% with AC-TH compared with 81% for TCH and 75% for AC-T. With the AC-T regimen as the reference (control), AC-TH reduced risk by 36%, whereas TCH reduced risk by 25%. These differences were less robust at this time point than at the first analysis, when risk was reduced by 51% and 49%, respectively. OS was 92% with AC-TH, 91% with TCH, and 87% with TCH, with risk reduced by 37% and 23%, re-

thracycline regimen for patients regardless of TOP2A status, to “avoid the longterm and life-altering toxicities seen with anthracycline-based regimens.” He emphasized the toxicity of the AC-TH regimen, which led to 21 cases of congestive heart failure, compared with four cases in the TCH arm. Additionally, 194 patients had sustained reductions in left ventricular ejection fraction, compared with 97 with TCH, and eight versus zero developed leukemia.

“The acute and chronic toxicity profiles of TCH are better than those seen with the AC-TH regimen in almost all parameters measured,” he told the press. “At this point, when we see an HER2-positive patient, we have elected to treat those patients with a nonanthracycline-containing regimen to get close to equivalent efficacy but considerably better safety, in particular, not for the acute toxicity but more important for the life-changing toxicities,” he said. Questions remain Eric Winer, MD, of Dana-Farber Cancer Center, Boston, however, is not convinced that anthracyclines can be safely eliminated. He told The Oncology Pharmacist, “Ultimately, the most important thing is survival. The differences shown between the arms in the trial are not statistically significant [versus each other], and the two arms were, in fact, never intended to be compared with each other, and the study is therefore not powered to show equivalence between anthracycline- and nonanthracycline-based regimens,” he said. “I don’t have a problem with using TCH to avoid cardiac problems. It is an acceptable regimen, but I am not of the view that it should be a preferred regimen,” he said. “There are some patients for whom TCH might be appropriate, based on the need to avoid the side effects. But in someone at low risk for developing cardiac problems, I think one has to think long and hard before opting for a regimen that might be slightly less effective. And I think we must be very cautious before adopting new standards.” ●

—CH

Scalp Hypothermia Shows Promise for Chemotherapyinduced Hair Loss

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calp hypothermia seems to be effective in minimizing alopecia in some women with breast cancer who develop the condition as a result of their chemotherapy regimen, according to the results of a pilot study. “Alopecia, though temporary, is one of the most distressing side effects of chemotherapy in breast cancer patients,” said Shannon Wills, PhD, clinical research associate at Beaumont Hospitals in Royal Oak, Michigan. “In fact, up to

www.TheOncologyPharmacist.com

8% of women reportedly refuse chemotherapy because of the potential for this side effect.” She added, women who refuse chemotherapy and “go with” just surgery and radiation increase their risk of recurrent disease, because systemic chemotherapy is sometimes necessary to prevent recurrence. Several scalp-cooling techniques have been tried, including ice packs consisting of crushed ice, but results

have been mixed, she said. The technique used in the trial involves the continuous application of a cold cap to the scalp before, during, and after chemotherapy. The method is thought to work via cutaneous vasoconstriction, which decreases blood flow to the hair follicles during chemotherapy and thus reduces the cellular uptake of chemotherapeutic agents. Wills and colleagues reported data using a cold cap in 34 women with stage

I to III breast cancer who were receiving standard adjuvant chemotherapy regimens with or without doxorubicin. Participants in the trial had agreed to wash their hair no more than two times per week during chemotherapy and for 4 months after the completion of chemotherapy. They were instructed to use a mild shampoo and tepid water. The use of hair color as well as hot rollers, curling irons, and Continued on page 26

February 2010 I VOL 3, NO 1

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CONTINUING EDUCATION EDITORIAL BOARD

PROGRAM TOP1 • RELEASE DATE: FEBRUARY 15, 2010 • EXPIRATION DATE: FEBRUARY 15, 2011

Laura B. Michaud, PharmD, BCOP, FASHP Manager, Clinical Pharmacy Services The University of Texas M. D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX 77030

ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Rita Wickham, PhD, RN, AOCN Assistant Professor Rush University College of Nursing 600 S. Paulina Street Armour Academic Center Suite 1080 Chicago, IL 60612

PLANNING COMMITTEE Gloria Mui Medical Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Julie Ann Tagliareni CME Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Anne L. Finger President Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drvie Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drvie Monroe Twp, NJ 08831

Cancer Treatment–related Bone Loss and Osteoporosis: A Concern for Women with Breast Cancer By Rita Wickham, PhD, RN, AOCN Rush University College of Nursing, Oncology and Palliative Care Consultant, Chicago, Illinois STATEMENT OF NEED

As women treated for breast cancer are living longer, their bone health is a major concern. Healthcare providers should be able to identify risk factors for bone loss to determine who may benefit from current management options. TARGET AUDIENCE

Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients LEARNING OBJECTIVES

After completing this activity, the reader should be better able to: • Explain normal bone physiology and the effects of cancer therapies on bone health

leading to low bone mass (formerly called osteopenia) or osteoporosis.1 The effects of CTIBL can occur independently of bone metastases and pathologic fractures. Because women treated for localized or metastatic breast cancer are living longer, their bone health is a major concern. Healthcare providers must have an understanding of normal bone turnover, patientand treatment-related risk factors for bone loss, measurement of bone mineral density (BMD), and implications for clinical practice. Patients at risk for bone loss should be identified early so that care interventions can be planned to decrease risks for osteoporosis, maintain or restore normal BMD, sustain functional independence, and prevent potentially fatal low-impact (fragility) fractures.

• Identify risk factors for bone loss • Discuss current recommendations for pharmacologic and nonpharmacologic interventions to prevent and treat bone loss in patients with cancer

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reast cancer is a disease of women: only 1% of cases occur in men. Risk for breast cancer increases with age, and 95% of new cases are diagnosed in women aged 40 years or older.1 The median age at diagnosis is 61 years,1 so half of all cases occur in younger women—who may be premenopausal. Women are more likely than men to develop osteoporosis, because they have smaller bones with proportionally less bone volume and density. In addition, women with breast cancer may be at high risk for cancer treatment–induced bone loss (CTIBL),

Normal bone turnover Bones are stiff, flexible, lightweight, and strong to aid in body movement, support and protect vital organs, produce blood cells, and serve as rapid stores for body minerals. Sixty percent of bone is mineralized as calcium hydroxyapatite in a collagen matrix. There are two types of bone: the outer compact (or cortical) bone that makes up most of the long bones (femur, tibia, humerus) and pelvis, as well as the outer covering of flat bones (ileum, vertebrae, ribs), and the inner trabecular (cancellous or spongy) bone found near the ends of the long bones and within flat bones.2 Bone turnover continues over a lifetime to maintain strength and integrity, and all bone undergoes remodeling depending on the

CONTINUING PHARMACY EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT

This activity is provided free of charge to participants.

Veritas Institute for Medical Education, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program (UPN 0394-0000-10-001-H01-P) is acceptable for 1.0 Contact Hours. Initial release date: February 15, 2010. A statement of credit will be available online to participants who successfully complete the program, learning assessment (>70%), and program evaluation form. There is no registration or processing fees.

FINANCIAL DISCLOSURES

METHOD OF PARTICIPATION

1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Click on “CE Credits” 4. Click on “Click here to complete the posttest and obtain a CE certificate online” 5. Register to participate 6. Enter program number TOP1 7. Complete and submit the CE posttest and CE Activity Evaluation and Request for Credit Form online 8. Print your statement of credit

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forces placed on it. Only a small portion of total bone is remodeled at a given time; areas of greatest stress—vertebral bodies, femoral head and hip, and long bones—are the sites of most frequent remodeling. Turnover is greater in trabecular than in compact bone. Bone homeostasis is tightly regulated and, in general, bone resorption and bone synthesis are coupled. During childhood and after fractures, more bone is synthesized than resorbed, but in young adults, bone resorbed equals bone made. After about age 30 to 35 years, slightly less bone is formed, and gradual bone density loss continues into old age. This uncoupling in bone turnover increases dramatically in women during menopause because of the sudden loss of estrogen. This pronounced uncoupling wanes after 5 to 10 years, and bone loss in postmenopausal women and men older than 55 years is equivalent (about 0.5%-1% per year).3,4 There are three types of bone cells: osteocytes, osteoclasts, and osteoblasts. Osteocytes are the functional bone cells, osteoclasts (c for bone consuming) break down bone, and osteoblasts (b for bone building) synthesize new bone cells and differentiate into osteocytes. Each bone cell influences the activity of the other cell types, which are also influenced by hormones, cytokines, and local growth factors, as well as the central and peripheral nervous system.5,6 For example, osteoclasts and osteoblasts of women and men express estrogen receptors and androgen receptors. Estrogen is more important and may prevent bone loss by regulating cytokine

February 2010 I VOL 3, NO 1

Veritas Institute for Medical Education, Inc. is required to disclose to the activity audience the relevant financial relationships of the planners and faculty involved in the development of CE content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CE activity content over which the individual has control. In addition, all faculty are expected to openly disclose any unlabeled/unapproved/investigational uses of drugs or devices discussed in this activity. Disclosures are as follows: • Laura B. Michaud, PharmD, BCOP, FASHP, has nothing to disclose. • Rita Wickham, PhD, RN, AOCN, has nothing to disclose. The staffs of Veritas Institute for Medical Education, Inc. and Green Hill Healthcare Communications, LLC have nothing to disclose. DISCLAIMER

The opinions expressed in this activity are those of the presenters and do not necessarily reflect the opinions or recommendation of Veritas Institute for Medical Education, Inc. Copyright © 2010 Veritas Institute for Medical Education, Inc. All rights reserved.

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www.TheOncologyPharmacist.com production, maintaining coupled bone turnover, and suppressing the rate of turnover.3 Loss of estrogen increases and intensifies osteoclast activity and may impair osteoblast activity, thereby uncoupling bone homeostasis with more bone resorbed than formed and decreasing bone mass.7,8 Bone remodeling occurs over 3 to 6 months in phases of initiation, transition, and termination. Initiation begins when micro cracks in bone, loss of mechanical loading (as caused by prolonged inactivity), or altered hormones or cytokines cause monocytes to gather and differentiate into preosteoclasts. These subsequently fuse into large, multinucleated osteoclasts that have powerful proteases to demineralize and resorb damaged bone. Resorption lasts about 3 weeks.7,9 During transition (or reversal), osteoclasts stimulate local mesenchymal stem cells to differentiate into preosteoblasts and then osteoblasts, at which point osteoclasts undergo apoptosis and stop resorbing bone. During termination (or formation), osteoblasts begin to form new bone. Layering of osteoblasts continues until the resorbed cavity fills in over 3 to 4 months. Osteoblasts ultimately flatten and differentiate into osteocytes and become encased in hydroxyapatite. New bone is not as mineralized (or strong) as older bone.

Ovarian damage and premature menopause occur in 63% to 96% of premenopausal women within 1 year after adjuvant chemotherapy that includes cyclophosphamide. Risk factors for BMD loss Bone strength depends on BMD and bone quality (mineralization, hydroxyapatite matrix, altered repair, and microdamage).3 Only BMD can be measured, and evaluation of BMD is recommended in individuals at high risk for osteoporosis and low-intensity fractures. These fractures can result from a fall from a height no more than the person’s standing height or occur spontaneously with coughing, sneezing, or abrupt movement.10 Aging inevitably leads to bone loss, so elderly women and men have less bone strength than young adults. Some risk factors for osteoporosis, such as genetic predisposition and early menopause (<45 years of age) are unchangeable; however, other factors, including sedentary lifestyle, low calcium and vitamin D intake, cigarette smoking, and alcohol intake, can be changed.10,11 Bone architecture is altered with bone loss, and osteoporotic compact bone is

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Table 1. T-scores and BMD Category

Definition

T-score

Normal

• BMD within 1 SD of young normal adult

–1.0 and above

Low bone mass (osteopenia)

• BMD between 1 and 2.5 SDs below that of young normal adult

Between –1.0 and –2.5

Osteoporosis

• BMD is 2.5 SD or more below that of young normal adult

Below –2.5

Severe osteoporosis

• BMD is 2.5 SD or more below that of young normal adult • Has had ≥1 low-impact (fragility) fracture

Below –2.5

BMD indicates bone mineral density; SD, standard deviation. Source: Reference 11.

Table 2. ASCO Recommendations for Patients with Nonmetastatic Breast Cancer DXA Hip ± Spine

Management

Monitoring

Not recommended

Lifestyle advice; calcium and vitamin D

Annual history for risk status

T-score: –1.0 and above Recommended

Lifestyle advice; calcium and vitamin D

Annual BMD

T-score: –1.0 to –2.5

Lifestyle advice; calcium and vitamin D

Annual BMD

Lifestyle advice; calcium and vitamin D; begin bisphosphonate or raloxifenea

Annual BMD

Low risk High risk

Recommended

T-score: –2.5 and below Recommended

Raloxifene, a selective estrogen-receptor modulator, is not recommended in patients who have taken tamoxifen. ASCO indicates American Society of Clinical Oncology; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry. Source: Reference 15.

a

thin and brittle, whereas cancellous bone loses many trabeculae; both loss of trabeculae and compact bone greatly weaken bone.12 Cancer medications that can cause CTIBL, autologous bone marrow/stemcell transplantation, and multiple myeloma are all high-risk factors for patients with cancer. Chronic corticosteroid treatment (eg, 5 mg prednisone per day for ≥3 months) can also induce bone loss and osteoporosis. Chemotherapy and hormones may indirectly cause bone loss by leading to loss of estrogen. Ovarian damage and premature menopause occur in 63% to 96% of premenopausal women within 1 year after adjuvant chemotherapy that includes cyclophosphamide, and older women receiving higher cumulative doses are at greatest risk for bone loss.7 More than two thirds of breast cancers are estrogen receptor–positive, and hormones—particularly selective estrogen-receptor modulators (SERMs) and aromatase inhibitors (AIs) that are given to treat or prevent breast cancer by inducing menopause or further reducing estrogen levels—also affect bone remodeling.13 Tamoxifen, a SERM, is an estrogen antagonist on

bone and increases bone loss in premenopausal women, but is an agonist on bone and spares bone in postmenopausal women.7,14 AIs block the action of aromatase, the enzyme that converts adrenally produced androgens into estrogen in postmenopausal women. Anastrozole, letrozole, and exemestane increase bone loss and fracture rates, but this effect is reversible shortly after the AI is stopped. It is not known, however, whether lost bone is regained or over what period. Similarly, a gonadotropin-releasing hormone agent such as goserelin dramatically decreases circulating estrogen, as does oophorectomy or sudden menopause. Detection and management of osteoporosis It is critical to identify patients at risk for bone loss because osteoporosis is asymptomatic until a fracture occurs. The best single test for BMD is central dual-energy x-ray absorptiometry (DXA or DEX), which provides two-dimensional views of the hip and spine, or total body bone.7,10 DXA results, reported as T-scores, represent the differences in standard deviations (SDs) in the patient’s BMD and a standard compari-

son group of young adult women. BMD may be normal, low bone mass (osteopenia), osteoporosis, or severe osteoporosis (Table 1).11 Fracture risk is inversely correlated with BMD and increases by 1.6 to 2.2 times for each fall in T-score SD.15 In 2003, the American Society of Clinical Oncology published updated guidelines for management of bone health in women with breast cancer (Table 2). The guidelines stress the importance of early detection and therapy for osteoporosis.16 Management involves both nondrug and pharmacologic therapies.10-12 First, healthcare providers must identify at-risk patients who may benefit from lifestyle changes that can decrease bone loss. For example, current recommendations from the National Osteoporosis Foundation for daily intake of calcium and vitamin D are 1200 mg/day and 800 IU/day to 1000 IU/day, respectively, and many individuals will need supplements to attain these levels.11 Supplemental calcium should not exceed 1500 mg/day (in divided doses), however, because of risks for kidney stones and cardiovascular problems. Patients should also be counseled on strategies to stop smoking and limit alcoContinued on page 20

February 2010 I VOL 3, NO 1

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CONTINUING EDUCATION Continued from page 19

Cancer Treatment–related Bone Loss and Osteoporosis...

CASE REPORT

M

T was diagnosed with stage IIB breast cancer at age 42 years. After lumpectomy and axillary node dissection, she underwent chemotherapy (followed by radiotherapy). She received four cycles of intravenous (IV) doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) every 3 weeks, followed by four cycles of IV paclitaxel 175 mg/m2 every 3 weeks. Her menstrual periods stopped after her second cycle of AC and never resumed. At her 18-month follow-up visit, MT reported vaginal dryness and discomfort with intercourse. She told her advanced practice nurse about an article she had read regarding osteoporosis and wondered about her risk, because of her chemotherapyinduced menopause and her mother’s osteoporosis, which resulted in a hip fracture at age 72 years. Her other risk factors included a history of cigarette smoking (down to six to seven cigarettes/day from one pack/day at diagnosis) and relative thinness (5’6” tall, 119 lb). MT underwent a base-

line dual-energy x-ray absorptiometry (DXA) scan, and her T-scores were –2.4 (spine) and –2.0 (hip). MT’s diagnosis was low bone mass, but the oncologist decided MT should start bisphosphonate therapy to prevent further bone mineral density loss. MT was already taking a daily vitamin containing vitamin D 400 IU and calcium 600 mg, so the nurse advised her to take an additional 600 mg of calcium each evening. MT’s creatinine clearance was 110 mL/min and her serum calcium level was 8.6 mg/dL. She was given IV zoledronic acid over 30 minutes. The plan is to repeat DXA and zoledronic acid in 1 year. Three days after receiving zoledronic acid, MT phoned the nurse and reported “jerky” muscles, cramps in her legs, and tingling in her fingers and toes. She returned for laboratory tests, which showed the following: serum calcium, 7.5 mg/dL, and serum vitamin D (calcidiol), 15 ng/mL. She was given IV vitamin D 50,000 U and instructed to increase her supplemental vitamin D to 1000 U/day. Laboratory tests will be repeated in 2 days, and IV vitamin D

treatment repeated if her calcidiol is <30 ng/mL. Discussion Vitamin D deficiency is common in the United States because of sun avoidance and few dietary sources. Calcidiol levels of 32 ng/mL to 100 ng/mL are considered normal, and deficiency impairs absorption of dietary calcium and parathyroid hormone metabolism.1 Internists would likely check calcidiol before starting a bisphosphonate for osteoporosis, but oncologists less commonly do so.2 Bisphosphonate administration in the face of vitamin D deficiency can cause calamitous hypocalcemia (neuromuscular irritability evidenced by tetany [positive Chvostek’s or Trousseau’s sign], confusion, cardiac arrhythmia, seizures) and worsen secondary hyperparathyroidism, low bone mass, and the risk for fracture. References 1. Heaney RP. Vitamin D endocrine physiology. J Bone Miner Res. 2007;22(suppl 2):V25-V27. 2. Wang-Gillam A, Miles DA, Hutchins LF. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. Oncologist. 2008;13:821-827.

hol intake, and the benefits of regular weight-bearing exercise (walking or jogging, stair climbing, Tai-Chi) and muscle-strengthening exercise (weight training, resistive exercises), which may decrease the risk of falls and modestly increase BMD, should be emphasized.11 Raloxifene, estrogen (not used in patients with breast cancer), calcitonin, parathryroid hormone, and some bisphosphonates have US Food and Drug Administration approval to treat postmenopausal osteoporosis (Table 3).10,11 Bisphosphonates, which suppress osteoclast activity to slow bone resorption, are the most commonly used agents in patients with cancer. An evidence-based review of bisphosphonates for CTIBL in breast cancer patients confirmed that clodronate, ibandronate, pamidronate, risedronate, and zoledronic acid have protective effects against bone loss secondary to chemotherapy-induced menopause, ovarian ablation with goserelin, or treatment with an AI.13 When using pamidronate and zoledronic acid, it is important to remember that the doses used to treat osteoporosis are lower than those commonly used for hypercalcemia. It is also important to

COMMENTARY

A Pharmacist’s Perspective Laura B. Michaud, PharmD, BCOP, FASHP Manager, Clinical Pharmacy Services, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

B

one loss and osteoporosis are significant clinical issues facing many cancer patients but often go unrecognized by oncology professionals. Until recently, benign bone disease (not due to metastases) had been referred to primary care or family physicians to manage. Despite these referrals, many cancer patients did not receive adequate screening or monitoring for bone loss, which placed them at risk for fractures and increased mortality. With national and international recognition of the problem, oncologists and other healthcare professionals in cancer care are beginning to recognize the ramifications of cancer treatments on bone and are proactively addressing these problems using modern tools to assist them. Pharmacists in many different practice settings are in a position to facilitate awareness and improve adherence with monitoring and medication administration. This requires that all pharmacists have a working knowledge of bone physiology, an understanding of the risk factors for bone loss and the

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February 2010 I VOL 3, NO 1

national guidelines for monitoring and treating bone-related diseases in patients with cancer, and an intimate knowledge of the pharmacology of the available drugs for osteoporosis as well as how best to help patients adhere to these medications’ regimens. The National Comprehensive Cancer Network has published recommendations from their task force on bone health in cancer care.1 These recommendations review the available evidence, identifying risk factors unique to patients with cancer, establishing monitoring guidelines for cancer patients, and outlining the data supporting the use of bone-targeting agents for the management of cancer treatment– induced bone loss (CTIBL) and cancer-related bone loss. Readers are strongly encouraged to review these recommendations and incorporate what they learn into their daily encounters with patients. Pharmacists are uniquely poised to interact with breast cancer patients when they are filling prescriptions for

drugs (eg, aromatase inhibitors) or having injections administered in the clinic, infusion center, or hospital (eg, luteinizing hormone-releasing hormone agonists) that will increase their risk for bone loss. When these patient encounters occur, pharmacists can inquire about risk factors, monitoring, and adherence. The World Health Organization has developed a riskassessment tool—FRAX, which pharmacists can use and share with patients to increase awareness of their individual risk for fractures and potentially to encourage follow-up with their oncologist or other healthcare providers.2 These pharmacist–patient interactions may directly impact clinical outcomes for patients, increasing awareness of bone health in general and influencing adherence to monitoring and therapeutic interventions. Most of the bone-targeting agents available for management of CTIBL (or osteoporosis in general) are fraught with insurance coverage issues. Many insurance carriers have preferred agents that have associated lower outof-pocket expenses for patients.

Some will have unique preauthorization requirements for intravenous agents or require documentation of a failed attempt to use an oral agent before approval of an intravenous agent. These details are often difficult to determine ahead of time, and optimizing these aspects of a therapeutic intervention often falls on the pharmacist. One positive aspect is that most of the pharmaceutical companies marketing these agents have some type of patient-assistance program, which can be accessed if needed. Hopefully, through diligent research and investigation, a patient will not have to go without appropriate bone therapy because of financial constraints, and the pharmacist can be a vital resource in this aspect of prescribing. References 1. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force report: bone health in cancer care. J Natl Compr Cancer Netw. 2009; 7(supp 3):1-32. 2. World Health Organization Collaborating Centre for Metabolic Bone Diseases. FRAX: WHO fracture risk assessment tool. www.shef.ac.uk/FRAX. Accessed January 7, 2010.

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www.TheOncologyPharmacist.com Table 3. Agents that Might Be Used in Patients with Breast Cancer and Osteoporosis Class/Agent

Indications Prevention

Bisphosphonates Alendronate (Fosamax, Fosamax D)

Postmenopausal osteoporosis

Dosing Treatment

Tablet: 5 mg/day or 35 mg/week

Tablet or liquid: 10 mg/day or 70 mg/week

Comments

Take upon rising in AM with 8 oz water, empty stomach; do not eat or drink and stay upright for 30 minutes

Tablet: 70 mg/week with 2800 IU or 5600 IU of vitamin D Ibandronate (Boniva)

Postmenopausal osteoporosis

Tablet: 2.5 mg/day or 150 mg/month

Tablet: 2.5 mg/day or 150 mg/month IV: 3 mg every 3 months

Take upon rising in AM with 8 oz water, empty stomach; do not eat or drink and stay upright for 60 minutes

Risedronate (Actonel, Actonel with calcium)

Postmenopausal osteoporosis; increase bone mass in men with osteoporosis; prevent, treat osteoporosis in men and women starting or taking glucocorticoid

Tablet: 5 mg/day or 35 mg/week or 75 mg on two consecutive days or 150 mg once a month

Take upon rising in AM with 8 oz water, empty stomach; do not eat or drink and stay upright for 30 minutes

Zoledronic acid (Reclast)

Postmenopausal osteoporosis

IV: 5 mg once a year

Administer over at least 15 minutes

Women at least 5 years postmenopausal

Single daily intranasal spray 200 IU

Alternate nares

Postmenopausal women at high risk for fracture

Daily subcutaneous injection: 20 μg

Contraindicated: patients receiving skeleton or bone radiotherapy to metastases, history of skeletal malignancy, hypercalcemia

Calcitonin Salmon calcitonin (Miacalcin, Fortical) Parathyroid hormone PTH (1-34) Teriparatide (Forteo)

IV indicates intravenous. Sources: References 10 and 11.

assess vitamin D levels in patients who are prescribed a bisphosphonate for osteoporosis, because vitamin D insufficiency, which is common in patients with cancer, can worsen hypocalcemia and lead to secondary hyperparathy-

less than 1 year.18 Ibandronate and zoledronic acid can be administered intravenously. This may enhance adherence but can also cause acute flulike symptoms, which can be alleviated by acetaminophen.

When using pamidronate and zoledronic acid, it is important to remember that the doses used to treat osteoporosis are lower than those commonly used for hypercalcemia. roidism, low bone mass, and fractures.17 Patients with low vitamin D levels thus require instruction about vitamin D supplementation during bisphosphonate therapy. To take an oral bisphosphonate, patients must be able to take it with tap water on an empty stomach and to sit or stand for 30 minutes after taking it because of the potential for reflux, esophageal irritation, and gastritis. Some oral bisphosphonates are given weekly or monthly to simplify administration, but adherence is problematic, and up to 50% of patients stop taking oral agents after

www.TheOncologyPharmacist.com

Conclusion Osteoporosis is likely to become an increasingly important issue in survivorship care plans for patients with breast cancer. Early identification of patients at risk—particularly as they age—and counseling about maintaining healthy weight, regular exercise, calcium and vitamin D intake, moderate alcohol use, and avoidance of smoking are essential for preventing this complication. Some patients will also require pharmacologic management of CTIBL, which will require nurses, pharmacists, and others caring for these patients to maintain up-to-date knowl-

edge about current recommended therapies to teach patients about drug benefits and burdens and aid patient adherence. ● References 1. Breast Cancer Facts and Figures 2007-2008. Atlanta, GA: American Cancer Society; 2008. 2. Datta HK, Ng WF, Walker JA, et al. The cell biology of bone metabolism. J Clin Pathol. 2008;61:577-587. 3. Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007;282:27285-27297. 4. Lønning PE. Endocrine therapy and bone loss in breast cancer: time to close in the RANK(L)? J Clin Oncol. 2008;26:4859-4861. 5. Borovecki F, Pecina-Slaus N, Vukicevic S. Biological mechanisms of bone and cartilage remodeling—genomic perspective. Int Orthop. 2007;31:799-805. 6. Elefteriou F. Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys. 2008;473:231-236. 7. Michaud LB, Goodin S. Cancer-treatment-induced bone loss, part 1. Am J Health Syst Pharm. 2006;63:419-430. 8. Zallone A. Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci. 2006;1068:173-179. 9. Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys. 2008;473:201-209. 10. Institute for Clinical Systems Improvement. Health Care Guideline: Diagnosis and Treatment

of Osteoporosis. September 2008. www.icsi.org/ osteoporosis/diagnosis_and_treatment_of_osteo porosis__3.html. Accessed November 20, 2009. 11. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008. http://nof.org/professionals/NOF_ clinicians_guide.pdf. Accessed November 20, 2009. 12. Turner Biomechanics Laboratory. Osteoporosis/ biomechanics. 2005. www.engr.iupui.edu/~tur nerch/biomech.htm. Accessed November 20, 2009. 13. Saad F, Adachi JD, Brown JP, et al. Cancer treatment-induced bone loss in breast and prostate cancer. J Clin Oncol. 2008;26:5465-5476. 14. Bjarnason NH, Hitz M, Jorgensen NR, Vestergaard P. Adverse bone effects during pharmacological breast cancer therapy. Acta Oncol. 2008; 47:747-754. 15. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20:1185-1194. 16. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:4042-4057. 17. Wang-Gillam A, Miles DA, Hutchins LF. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. Oncologist. 2008;13:821-827. 18. Boonen S, Vanderschueren D, Venken K, et al. Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced compliance. J Intern Med. 2008;264:315-332.

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

Medications Used for the Treatment of Cervical Cancer Cervical cancer forms in tissues of the cervix (the organ connecting the uterus and vagina). It is usually a slow-growing cancer that may not have symptoms but can be found with regular Pap tests. Cervical cancer is almost always caused by human papillomavirus (HPV) infection. The following sections will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of cervical cancer.

In the November/December issue, the Oncology Drug Codes for the Medications Used for the Treatment of Leukemias inadvertently did not note which agents are FDA-approved or included in the NCCN Drugs & Biologics Compendium for off-label use. The complete codes can be viewed at www.theoncologypharmacist.com.

Associated ICD-9-CM Codes Used for Cervical Cancer

The following sections include: • Associated ICD-9-CM codes used for the classification of cervical cancer • Drugs that have been FDA-approved in the treatment of cervical cancer. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in cervical cancer. NCCN is recognized by CMS (Centers for Medicare & Medicaid Services) as a referencing source • Corresponding HCPCS/CPT Codes and Code Descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication

generic (Brand) name

HCPCS code: code description

bevacizumab (Avastin) bleomycin (Blenoxane) carboplatin (Paraplatin) cisplatin (Platinol AQ) cisplatin (Platinol AQ) docetaxel (Taxotere) doxorubicin HCl liposome (Doxil)

J9035: injection, bevacizumab, 10 mg J9040: injection, bleomycin sulfate, 15 units J9045: injection, carboplatin, 50 mg J9060: cisplatin, powder or solution, per 10 mg J9062: cisplatin, 50 mg J9171: injection, docetaxel, 1 mg J9001: injection, doxorubicin hydrochloride, all lipid formulations, 10 mg J9178: injection, epirubicin HCl, 2 mg

epirubicin (Ellence)

180 Malignant neoplasm of cervix uteri Includes: invasive malignancy [carcinoma] Excludes: carcinoma in situ (233.1) 180.0 Endocervix Cervical canal, not otherwise specified Endocervical canal Endocervical gland 180.1 Exocervix 180.8 Other specified sites of cervix Cervical stump Squamocolumnar junction of cervix Malignant neoplasm of contiguous or overlapping sites of cervix uteri whose point of origin cannot be determined 180.9 Cervix uteri, unspecified 233 Carcinoma in situ of breast and genitourinary system 233.1 Cervix uteri Adenocarcinoma in situ of cervix Cervical intraepithelial glandular neoplasia, > grade III < Cervical intraepithelial neoplasia III [CIN III] Severe dysplasia of cervix Excludes: cervical intraepithelial neoplasia II [CIN II] (622.12) cytologic evidence of malignancy without histologic confirmation (795.06) high-grade squamous intraepithelial lesion (HGSIL) (795.04) moderate dysplasia of cervix (622.12)

FDAapproved for cervical cancer

NCCN Drugs & Biologics Compendium off-label use for cervical cancer

Current code price (AWP-based pricing), effective 1/10/10

Medicare allowable (ASP + 6%), effective 1/10/10-3/31/10

CPT administration codes

$66.99

$57.46

96413, 96415

$45.30

$28.47

96401, 96409

$85.10

$4.84

96409, 96413, 96415

$4.33

$2.08

96409, 96413, 96415

$21.66

$10.41

96409, 96413, 96415

$23.23

$17.62

96413

$559.32

$471.38

96413

$8.16

$2.65

✓ ✓ ✓ ✓ ✓ ✓

✓ 96409, 96413

✓ Continued on page 24

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February 2010 I VOL 3, NO 1

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Presents the Third Annual Curriculum for

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

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

★ Earn Continuing Education Credits ★ 8-part newsletter series

CASE STUDY DISCUSSIONS: • Front-line therapy

• Non-Transplant Patients

• Maintenance Settings

• Cytogenetics

• Transplant Settings

• Side Effect Management

• Retreatment Settings

• Bone Health

Each newsletter will feature: • Contributions from thought-leading physicians, nurses, and pharmacists

• Continuing Education credits available to physicians, nurses, and pharmacists

PARTICIPATE TODAY at www.COEXM.com For complete learning objectives and accreditation information, please refer to each activity.

Target Audience These activities were developed for physicians, nurses, and pharmacists.

These activities are jointly sponsored by

These activities are supported by an educational grant from Millennium Pharmaceuticals, Inc.


TOP_Jan_Feb2010_v3_TON 2/5/10 11:35 AM Page 24

ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 22

generic (Brand) name

HCPCS code: code description

fluorouracil (Adrucil) gemcitabine (Gemzar) ifosfamide (Ifex) irinotecan (Camptosar) mesna (Mesnex) mitomycin (Mutamycin) mitomycin (Mutamycin) mitomycin (Mutamycin) paclitaxel (Taxol, Onxol) pemetrexed (Alimta) topotecan (Hycamtin) vinorelbine (Navelbine)

J9190: injection, fluorouracil, 500 mg J9201: injection, gemcitabine hydrochloride, 200 mg J9208: injection, ifosfamide, 1 gram J9206: injection, irinotecan, 20 mg J9209: injection, mesna, 200 mg J9280: mitomycin, 5 mg J9290: mitomycin, 20 mg J9291: mitomycin, 40 mg J9265: injection, paclitaxel, 30 mg J9305: injection, pemetrexed, 10 mg J9350: injection, topotecan, 4 mg J9390: injection, vinorelbine tartrate, per 10 mg

FDAapproved for cervical cancer

NCCN Drugs & Biologics Compendium off-label use for cervical cancer

Current code price (AWP-based pricing), effective 1/10/10

Medicare allowable (ASP + 6%), effective 1/10/10-3/31/10

CPT administration codes

$3.30

$1.60

96409

$169.46

$144.93

96413

$56.40

$30.08

96413, 96415

$84.71

$6.94

96413, 96415

$10.44

$4.64

96409

$67.20

$17.15

96409

$218.40

$68.60

96409

$300.00

$137.19

96409

$17.70

$9.43

$59.25

$50.59

96409

$1264.99

$1031.91

96413

$42.60

$11.59

96409

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 96413, 96415

✓ ✓ ✓

References • HCPCS Level II Expert 2009 • CPT 2010; 2009 • ICD-9-CM for Professionals Volumes 1 & 2; 2010 • The Drug Reimbursement Coding and Pricing Guide, Vol 7, No 1; RJ Health Systems International LLC; 1st Quarter 2010 • FDA-approved indication (from products’ prescribing information) • NCCN Drugs & Biologics Compendium; 2010; National Cancer Institute; www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 1st Quarter 2010 (effective dates 1/1/10-3/31/10). Prices listed herein are effective as of January 1, 2010. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

2010 UPDATES OF THE HEALTHCARE COMMON PROCEDURE CODING SYSTEM (HCPCS)

This information was supplied by:

Effective: January 1, 2010 New C9257: injection, bevacizumab, 0.25 mg (Avastin) J9155: injection, degarelix, 1 mg (Firmagon) J9171: injection, docetaxel, 1 mg (Taxotere) J9328: injection, temozolomide, 1 mg (Temodar) Deleted Q2024: injection, bevacizumab, 0.25 mg (code deleted effective 1/1/10; see C9257 and J9035) J9170: injection, docetaxel, 20 mg (code deleted effective 1/1/10; see J9171) C9253: injection, temozolomide, 1 mg (code deleted effective 1/1/10; see J9328)

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February 2010 I VOL 3, NO 1

PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 F: (860) 563-1650 www.RJHealthSystems.com

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Cancer Center Profile West Michigan Cancer Center... Continued from cover reduction and revenue enhancement, which is evident by its consolidation and affiliation efforts, according to Foley & Lardner. McKay explained how technology cut overall spending: “The single most important endeavor we pursued for efficiency and cost-effectiveness was to implement an electronic medical record [EMR]. We have had an EMR since 2004, and it has taken half a million dollars out of operating expenses each year. We saved in medical records, the charts themselves, the paper, the copying of the paper, and the filing of the paper. We saved in goods and services and personnel.” Benchmarks were also used to ensure that staff need and staff numbers aligned. Since 2000, WMCC has placed all of its employees, both clinical and nonclinical, on productivity benchmarks. “We use those benchmarks to monitor the employees’ productivity, but also to determine if an additional employee is needed,” McKay explained. “Managers no longer request additional staff unless they can substantiate the need through additional benchmarks, which is a pretty concrete number.” WMCC also tracks the American Society of Clinical Oncology’s Quality Oncology Practice Initiative (QOPI) indicators for clinical quality. Each year, one or two indicators are tracked. To date, WMCC has tracked the QOPI guidelines in chemotherapy, clinical staging, and appropriate conversation and referral to hospice, according to McKay. In 2010, WMCC is tracking chemotherapy treatments in the last 14 days of life. “I think when you start to examine your processes and you can measure them and you compare them, you can always see room to improve,” said McKay. “What we did was general

awareness with physicians. Just by them knowing that we are tracking a guideline, it becomes more top of mind.” WMCC also tracks patient satisfaction through satisfaction surveys. Twice a year, staff meet to determine what they can change to make the patient experience better. As an example, in 2009, the center’s goal was to see patients within

patients and their families. WMCC also has six satellite locations where its medical oncologists treat patients. The center employs a multidisciplinary approach with thoracic, breast, and neurooncology. Although not as large as the breast clinic, the thoracic and neurooncology teams are “aggressive and progressive.” WMCC has recently

“The single most important endeavor we pursued for efficiency and costeffectiveness was to implement an electronic medical record.” —Terry McKay President and CEO 15 minutes, 65% of the time. This year, that goal has been increased to 70% of the time, according to McKay. “We track [satisfaction] very carefully. If any other issues are brought up in our satisfaction survey, we address those very quickly and head-on to make sure that we continuously strive for high patient satisfaction,” McKay explained. Patient-focused WMCC, a joint venture of Borgess Medical Center and Bronson Methodist Hospital, is its region’s only truly comprehensive cancer treatment facility. In its main campus in Kalamazoo, WMCC offers medical oncology, radiation oncology, a neurooncology clinic, a breast cancer clinic, a thoracic clinic, laboratories, x-ray technology, positron-emission tomography/computed tomography, pharmaceutical services, social and psychological counseling, nutrition counseling, and key allied support services for

expanded the multidisciplinary approach to gynecologic cancers, with a new team onboard. The center’s current goals include adding additional clinics for palliative care and survivorship. This year, “we are going to start laying the groundwork for them,” said McKay. WMCC has always had the philosophy of treating the entire person, not just the disease. To this end, the center offers many services: social workers, psychologists, dietitians/nutritionists, on-site pharmacy and personal coaches. It also offers Tai Chi, meditation, Pilates, yoga, and massage therapy. In addition, the center provides financial counseling, transportation assistance, and lodging. WMCC’s focus on its patients and their families has afforded it high standing in its community. “Our programs—the psychological counseling, the nutrition, the Tai Chi, the medi-

tation, the Pilates, the yoga, everything we have—extend to the caregiver as well. We are very encompassing of what the family member is going through caring for the patient,” said McKay. The old medical records room did not go to waste. WMCC has converted it into a fitness center. “The fitness center is open all day for patients and their caregivers, as well as our staff during specific hours. Patients are actively involved in living a healthier lifestyle even if it is for the first time in their life that they decided to exercise, because of the cancer diagnosis,” explained McKay. Many decide to continue after cancer. “We have a lot of patients who still use our facilities after cancer; we don’t put a time limit on it,” McKay said. Nationally affiliated WMCC receives timely results of National Cancer Institute (NCI) clinical trials of advanced cancer treatment drugs and techniques. For the right patient, participation in a trial of a new medication or procedure is available at the center or in his or her home. “We have a very robust clinical trial program funded by the NCI, and we put on about 112 to 115 patients a year,” said McKay. “That is a doubledigit percentage of new patients who go on clinical trials, which is rather impressive.” WMCC also works closely with regional physicians and healthcare professionals, and with cancer specialists throughout the United States. In addition, WMCC is professionally affiliated with the NCI, Susan G. Komen Race for the Cure, and the American Cancer Society. ●

SABCS 2009

Scalp Hypothermia... Continued from page 17 hot air blow dryers was not permitted. Caps were typically cooled and maintained between –5°C and –15°C for 24 hours prior to the start of chemotherapy. Two caps were worn for 20 minutes each before the infusion to initiate the scalpcooling process. Afterwards, caps were changed every 30 minutes throughout chemotherapy and for an additional 3 hours after chemotherapy. Patients were monitored throughout the cooling process for hyperpigmentation of the scalp, headache, and intolerance to cold temperature. Chemotherapy regimens used in the trial were regimens commonly used in breast cancer patients, all of which nearly always cause alopecia. Regimens included doxorubicin/cyclophospha-

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mide for four cycles; dose-dense, doxorubicin/cyclophosphamide followed by paclitaxel for eight cycles; docetaxel/ doxorubicin/cyclophosphamide for six

“The treatment, by allowing patients to retain their hair, gave patients a sense of being normal when their life was not normal.” —Shannon Wills, PhD cycles; docetaxel/cyclophosphamide for four cycles; and docetaxel/carboplatin/ trastuzumab for six cycles. Overall, 22 patients received an anthracycline-based

regimen, and 12 patients received a nonanthracycline-based regimen. A validated assessment tool known as Dean’s scale was used for alopecia grading. Overall, alopecia was significantly more likely to occur in women who got an anthracycline-based regimen. Also, 83% of women in the nonanthracycline-containing group and 47% of women in the anthracycline-containing group felt that they did not need either a wig or scarf. Hair thinning for most patients in both groups was even and not patchy. Treatment was well tolerated in most cases. Overall, three patients dropped out of the study because of either scalp discoloration during treatment or dis-

comfort related to cooling. “What’s particularly gratifying for practitioners is that the treatment, by allowing patients to retain their hair, gave patients a sense of being normal when their life was not normal,” Wills pointed out. “It’s important to keep in mind that concern about alopecia is not really a question of vanity,” she added. “You’re going through all of this, you’ve been told you may lose your breast, you have surgery, and by the time you’re almost done, your physician now tells you that you may need chemotherapy and that you’ll lose your hair. The prospect of hair loss is like the last jab.” ● —JS

www.TheOncologyPharmacist.com


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Metastatic Colorectal Cancer: Sound Strategies for Selecting First-Line Therapies

LOG ON TODAY TO PARTICIPATE www.coexm.com/ace01.asp FACULTY

Release Date: November 25, 2009 Expiration Date: November 24, 2010

Neal P. Christiansen, MD Assistant Professor of Medicine Medical University of South Carolina Division of Hematology/Oncology Charleston, South Carolina

TARGET AUDIENCE This activity is intended for hematologists, oncologists, oncology nurses, oncology/specialty pharmacists, and others who are involved with the care of patients with metastatic colorectal cancer (mCRC).

STATEMENT OF NEED Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the United States. Approximately 149,000 new cases are diagnosed each year. At the time of presentation, about 20% of patients with CRC will have metastatic disease. Cure at this stage is rarely possible, although some patients whose metastases are limited (especially if to the liver or lung) may be “cured” by surgical means. For most sufferers of mCRC, however, treatment is palliative, offering prolonged survival, improvement in symptoms, and enhanced quality of life.

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • Evaluate and assess current findings in the management of mCRC • Identify current first-line therapies, both chemotherapeutic and biologic agents, and practices in mCRC • Tailor a therapeutic regimen to meet the needs of the individual patient with mCRC • Employ select strategies to minimize exposure to ineffective therapies and their toxicities

INSTRUCTIONS To receive a statement of credit, you must: • Review the content of the activity • Successfully complete the post-test (70% or higher) • Complete the evaluation at the end of the activity Your statement of credit will be issued immediately upon successful completion of the post-test and submission of the evaluation

ACCREDITATION STATEMENT 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 the University of California, Irvine School of Medicine (UCI) and Center of Excellence Media, LLC. The University of California, Irvine School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT The University of California, Irvine School of Medicine designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity is complimentary.

FACULTY INFORMATION AND DISCLOSURES Dr Christiansen has received consultancy fees from sanofi-aventis and Genentech. Off-label use of cetuximab (in patients in whom irinotecan has not failed) and bevacizumab (continuing after first-line therapy) will be discussed in this presentation. Conflict resolution: This presentation has been peer reviewed for evidence base and fair balance.

GENERAL DISCLOSURE STATEMENT It is the policy of the University of California, Irvine School of Medicine and the University of California CME Consortium to ensure balance, independence, objectivity, and scientific rigor in all CME activities. Full disclosure of conflict resolution will be made in writing via handout materials or syllabus. Bonnie Carroll, Director, CME, UC Irvine School of Medicine, has no financial or other relationship to products or devices with commercial interests related to the content of this CME/CE activity. Center of Excellence Media, LLC: The planners and managers have nothing to disclose related to the content of this activity. Erica Johansson, RN, Astute CE, LLC, has nothing to disclose related to the content of this activity. Dr. Randall F. Holcombe, University of California, Irvine School of Medicine, peer-reviewed the content for evidence base and fair balance. Dr Holcombe has no real or apparent conflicts of interest related to this activity. Conflict resolution: This presentation has been peer reviewed for evidence base and fair balance. This activity is in compliance with California Assembly Bill 1195, which requires continuing medical education components to include curriculum in the subjects of cultural and linguistic competency. For specific information regarding Bill 1195 and definitions of cultural and linguistic competency, please visit the CME web site at http://www.cme.uci.edu. This activity is supported by an educational grant from Genentech BioOncology.

In collaboration with


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Pain Management Addressing Concerns about Opioid Use for Cancer Pain Continued from cover Organization’s pain ladder, when a patient has moderate-to-severe pain it makes sense to introduce an opioid. That correlates to patient-rated pain, using a 0 to 10 scale, of 4 and above. Also, when patients have milder pain, we might start very low doses of an opioid. This would apply in patients who may not be candidates for a nonopioid because of adverse effects or because their pain would not necessarily be responsive to adjuvant analgesics. What assessments should be done before introduction of opioids? It’s critical that we do a comprehensive pain history, which includes a pain assessment. The pain rating is a small piece of that assessment. We also want to know where all the pain sites are and the quality of the pain, because these factors help in selection of pharmacologic and nonpharmacologic interventions. We determine if the pain is constant, intermittent, or both, and we look at aggravating and alleviating factors. The combined data along with a physical examination and, in some cases, computed tomography scans, xrays, or other tests help clarify the underlying etiology of the pain. If we know the etiology, we can do a better job of identifying pharmacologic and nonpharmacologic therapies, and, in some cases, anticancer therapies that might be helpful. For example, someone with back pain who has a malignancy may have back pain because of an unrelated herniated disc. But a person who has back pain due to vertebral body metastases might benefit from radiotherapy or, in some cases, vertebroplasty or kyphoplasty. By knowing the underlying cause of the pain, we can be much more precise in our management. Are there medical conditions that are contraindications to use of opioids? We do want to know about related medical history and diseases, but these are not generally a contraindication for opioid therapy. These conditions are more likely to be contraindications for nonsteroidal anti-inflammatory drugs (NSAIDs). If the patient has chronic renal disease, for instance, then you wouldn’t choose an NSAID. If the patient has liver failure or chronic liver disease, you wouldn’t want to use anything containing acetaminophen. If the patient has narrow-angle glaucoma, you would be very cautious about using certain tricyclic antidepressants. If the patient is taking a particular chemotherapeutic or hormonal agent, you wouldn’t want to use a drug that interferes with the action of that agent; for example, you wouldn’t want to use duloxetine in a person who is taking

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tamoxifen because it might interfere with the metabolism of tamoxifen. It’s critical that we have a sense of each patient’s current medical diseases and medical history as well as his or her current medication list. In addition, we like to take a thorough psychosocial history, which includes asking patients about their current and past use of cigarettes, alcohol

ic around the clock for the first day or two, and then we can wean down the antinausea drug. Most patients become tolerant of the nauseating effect of the opioid by that time. Other side effects include itching and urinary retention, but for most people, these tend to go away over time. We might switch to a different opioid if they occur. Some of these adverse effects are

We also want to know where all the pain sites are and the quality of the pain, because these factors help in selection of pharmacologic and nonpharmacologic interventions. use, and recreational drug use. Recently, we’ve begun asking people about the history of addictive diseases in firstorder family members. A history of addictive diseases in any of their family members will make it more challenging in terms of prescribing opioids, but it isn’t a contraindication. We also like to ask patients about the things that give them strength, such as family, work, their religious affiliation, or spiritual belief. Often, we can use those to help devise nonpharmacologic approaches to help patients with cancer cope with chronic pain and their other symptoms. How can constipation and other common side effects of opioids be prevented or managed? The best strategy is to prevent the constipation, but the measures that are generally useful in preventing constipation are not particularly helpful when it’s opioid-induced constipation. We generally encourage patients to take a laxative in combination with a softener. Most patients need to take these agents regularly, so it requires a lot of education. When it has been more than 2 days since their last bowel movement, we become more aggressive and prescribe tablets, liquids, suppositories, or enemas, depending on the patients’ preference and whether they have any contraindications. What about other common side effects? Cognitive blunting is probably the second most problematic side effect that patients describe. We help people to understand that during the first day or two of opioid therapy they are likely to be sedated, but that for many people sedation dissipates over time. For some, however, it persists, and we will use psychostimulants such as methylphenidate. Nausea also can occur, often early in the course of opioid use in people who are opioid-naïve. We typically have them take an antiemet-

more common in a postoperative setting or with spinal drug delivery. Are there any special considerations in treating pain in the elderly? The elderly tend to have some borderline renal dysfunction, so NSAIDs are dangerous in a certain population of the elderly. In an older cancer patient with cachexia, the patient isn’t eating well, which further exacerbates the adverse effects associated with acetaminophen. There is a sense that acetaminophen is safe in lower doses, and yet people who are in a wasting syndrome should not take acetaminophen. So in the elders, it is safest to use opioids. The biggest issue we have found is the need to start very slowly and increase the dose very gradually. Over time, the patients end up at a similar dose to what might be used for a middle-aged person; it just takes longer to get there. Probably the biggest challenge we face when working with an older patient who has cancer is caregiver issues, such as remembering when to take medication. A caregiver can remind the patient to take a pain medication, but if the patient doesn’t have that kind of encouragement or support, he or she may not get good pain relief. In addition, obtaining schedule II opioids is very difficult. The neighborhood pharmacy may not have that medication, and getting to another pharmacy may be difficult. Again, it comes down to having caregiver support. Are there issues concerning reimbursement for opioids for cancer pain? It has gotten very complicated. Even for patients who have insurance, many insurance companies place caps on the numbers of tablets that a patient may obtain, not just for opioids but on any drug/compound used for pain control. For example, a lot of insurance companies have issued refusals for pregabalin, which is newer and slightly more expen-

sive than gabapentin. The insurance companies want the patient to first fail on gabapentin before obtaining pregabalin even though pregabalin has better bioavailability and is easier to titrate. Another example is lidocaine patches. There is very little if any systemic uptake of the drug. So for patients who are having side effects to some of the oral agents, this is a useful addition to their treatment regimen, but some insurance companies are refusing to pay for these unless the patient has postherpetic neuropathy. In addition, I have found lately that some insurance companies have placed a maximum on how many oxycodone tablets they will pay for. Different insurance companies will allow only a limited number of tablets of oxycodone in any given dose, but they’ll allow a patient to order 90 tablets of the 60-mg dose, 90 tablets of the 40-mg dose, and 90 tablets of the 20-mg dose. This becomes very confusing for the patient. What’s happening for professionals is we are spending an enormous amount of time on the telephone and filling out paperwork for prior authorization when the insurance companies refuse to pay. ●

Breakthrough Cancer Pain Survey The American Pain Foundation has released a first-of-its-kind survey, which explores the impact breakthrough cancer pain has on a patient’s quality of life, medical treatment, and finances. The survey, polled 545 adults who have been diagnosed with cancer, are currently living with cancer-related pain, are taking medication to manage the pain, and experience breakthrough pain. Among the findings: • 44% said their pain was not adequately controlled • 91% believed their quality of life would “greatly improve” if they could get breakthrough pain under control • 51% are visiting their healthcare provider more often • 67% said they experienced medical-related financial issues as a result of their pain • 95% have discussed their pain with their healthcare provider at some point • 52% said their healthcare provider has described breakthrough cancer pain as a normal side effect of cancer or its treatment. The complete survey can be viewed at www.painfoundation.org.

www.TheOncologyPharmacist.com


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Supportive Care

New Strategies for Preventing Anthracycline Cardiotoxicity Show Promise By Daniel M. Keller

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iven the increasing number of older patients with both cancer and cardiovascular disease and the potential cardiotoxic effects of many cancer therapies, creation of a new specialty called cardio-oncology or onco-cardiology has been suggested (Albini A, et al. J Natl Cancer Inst. 2010;102:14-25). New strategies for protecting against cardiotoxicity in patients treated with anthracyclines were reported at the American Heart Association Scientific Sessions 2009. A study by researchers at the University of Cagliari in Cagliari, Italy, showed that the angiotensin II receptor blocker telmisartan can counteract the cardiotoxic effect of epirubicin, presumably by limiting inactivation of cardiac antioxidant defenses. Using conventional echocardiography and tissue Doppler in previous studies, the researchers, led by Christian Cadeddu, MD, demonstrated impairment of left ventricular function at epirubicin doses as low as 200 mg/m2, even in the absence of changes in biochemical markers denoting oxidative stress. The researchers had also shown that free radicals and the reninangiotensin-aldosterone system play a role in the pathogenesis of epirubicin cardiotoxicity. Telmisartan limits the production of oxygen free radicals by inhibiting the activation of superoxide sources, such as nicotinamide adenine dinucleotide phosphate-oxidase, mitochondria, and xanthine oxidase. In the present phase 2, placebo-controlled study, the authors investigated

whether telmisartan could prevent preclinical myocardial damage induced by epirubicin. The trial enrolled 36 patients (26 women, 10 men; mean age, 56 years) who were free of cardiac disease, were previously untreated for a variety of solid tumors, and were to receive an epirubicin-based regimen. They were randomized to receive telmisartan 40 mg/day or placebo, starting 1 week before chemotherapy. Cardiac function was assessed by conventional echocardiography, tissue Doppler, and strain rate (SR) imaging, which depicts regional myocardial contractility. The researchers also measured plasma levels of reactive oxygen species (ROS; free radicals) and the capacity for antioxidative defenses, the latter by detecting glutathione peroxidase activity. These parameters were assessed at baseline and 7 days after each new 100mg/m2 dose of epirubicin. At the 200-mg/m2 epirubicin dose, the SR peak was significantly impaired compared with baseline for both the telmisartan and placebo groups, with no statistical difference between the two groups. As epirubicin cumulative doses increased, however, SR impairment became significantly less pronounced in the telmisartan group compared with the placebo group (P <.001 at both 300 mg/m2 and 400 mg/m2). At the 200-mg/m2 epirubicin dose, telmisartan limited the production of ROS (463 free oxygen radicals test units [FORT-U] vs 455 FORT-U at baseline; P = not significant), whereas ROS increased in the placebo group

compared with baseline (525 FORT-U vs 406 FORT-U, respectively; P <.05) [1 FORT-U corresponds to 0.26 mg/L H2O2]. Glutathione peroxidase activity decreased significantly in both groups at the 200-mg/m2 dose. The researchers said that these data confirm their earlier findings that epirubicin cardiotoxicity is largely related to inactivation of cardiac antioxidant effects. They concluded that telmisartan can decrease the amount of epirubicininduced free radicals and counteract the early myocardial impairment. They intend to continue the study on a larger cohort of patients. Another group of researchers reported that granulocyte colonystimulating factor (G-CSF) can protect myocardium and preserve systolic function in patients receiving anthracycline-based chemotherapy. That was the finding of a retrospective cohort study involving patients admitted to the oncology floor of Jackson Memorial Hospital of the University of Miami in Florida between October 2007 and September 2008. Of 597 patients admitted, 107 had transthoracic echocardiograms prior to the first dose and following the last dose of G-CSF, thereby allowing assessment of baseline and posttreatment left ventricular ejection fractions (LVEFs). Seventy patients received GCSF, and the 37 who did not served as a control group. There were no statistically significant differences in age (mean, 44-48 years), sex, use of beta blockers or angiotensin-converting

enzyme inhibitors, proportion receiving cardiotoxic chemotherapy, or number of days between echocardiograms between the two groups. Lead author Raphael Cires, MD, said that “the patients who received filgrastim have protection in their ejection fraction compared with the patients who did not receive filgrastim.” Considering all 107 patients, those who received filgrastim had a posttreatment mean LVEF of 55.8% versus 56.2% at baseline (P = .83). Without filgrastim, the mean LVEF decreased to 55.2% versus 59.7% at baseline (P = .02). Among the group who received cardiotoxic chemotherapy, specifically doxorubicin, “We found that the difference is even bigger,” he said. “The patients who received filgrastim had…almost no variation in the ejection fraction [57.6% vs 59% at baseline, P = .55], and the patients who did not receive filgrastim had a drop of almost 10 points in the ejection fraction [48.8% vs 58.3% at baseline, P = .04].” Some of the limitations of the study include its small sample size, lack of randomization to treatment with GCSF, and lack of standardization of the G-CSF doses. Cires said a future study will better monitor the amount of GCSF delivered and will use magnetic resonance imaging, the gold standard, to assess LVEF. He speculated that G-CSF could potentially be used in the future for its cardioprotective effects with anthracycline-based chemotherapy. ●

Mycobacterium avium Complex Infections in the Elderly: To Treat or Not?

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iven elderly patients’ frequent intolerance of the multidrug regimen needed to treat Mycobacterium avium complex (MAC) infections, some patients with solid tumors may do better and survive for prolonged periods with observation compared with pharmacotherapy. Watchful clinical and radiographic monitoring may alert physicians if the infection progresses to a point of requiring treatment. Reporting at the 47th annual meeting of the Infectious Diseases Society of America, researchers from The M. D. Anderson Cancer Center in Houston, Texas, characterized the natural history of MAC infection in cancer patients who were intolerant of antimycobacter-

www.TheOncologyPharmacist.com

ial therapy or elected not to receive it. Their study was a retrospective review of the medical records of 10 such patients at their institution between 2004 and 2009. All had laboratory-confirmed MAC infection. Patients had a median age of 70.8 years, 90% were women, and all were afebrile and asymptomatic for MAC. Four were receiving antineoplastic therapy, five elected not to receive therapy for MAC, and an additional three discontinued standard triple-drug therapy (ethambutol and a macrolide plus either rifampin or moxifloxacin) at 3 to 12 weeks because of intolerance. Two patients completed 18 months of therapy but had persistent

positive cultures and radiographic changes. All 10 patients were followed for a median of 28 months (range, 9-57 months) without MAC therapy. Coralia Mihu, MD, an assistant professor at the cancer center, reported that all the patients remained minimally symptomatic or asymptomatic, although there was some waxing and waning of pulmonary opacities in all 10 patients. None developed progressive infection of the lung requiring therapy. Mihu told The Oncology Pharmcist that active chemotherapy for cancer in four patients did not appear to put them at higher risk for worsening of MAC infection. She noted that her findings are important because of the many patients

with MAC infection, a group that tends to be older, on polypharmacy, and often has comorbidities. “Therefore, three drugs added on their already complicated medication regimen makes things worse in terms of tolerability,” she said. Also, MAC therapy may require 12 to 18 months. In the absence of MAC treatment, Mihu advised following asymptomatic patients closely with frequent chest imaging, and said “[MAC] is worth treating in patients who do have clinical signs of worsening infection...like low-grade fevers or productive cough, which our patients did not.” ● —DMK

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Financial Planning

Manage Debt Through Financial Planning @Copyright iStockphotos.com/Réne Mansi

By Eileen Koutnik-Fotopoulos

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raduating pharmacy school and finding a job in the profession is a major accomplishment. As many pharmacists begin their career, they are faced with the financial responsibilities of student loans, living expenses, rent, etc. Nationally, the retail staff pharmacist’s median total cash compensation (including base salary and annual bonus) was $108,700 in 2008, according to the 2008 US Pharmacy Compensation Survey—Spring Edition. Although this is an excellent salary and will increase during a pharmacist’s career, managing debt while paying off student loans and other expenses can be overwhelming. FinAid estimates that 82.2% of graduating pharmacists have an average of $63,412 in student loan debt (www.finaid.org/ loans).

Derek R. Williams, CFP, president of Williams Wealth Management Group Inc, recently spoke with student pharmacists about financial planning during his “Dollars and Good Sense” presentation at the 44th American Society of Health-System Pharmacists Midyear Clinical Meeting. He defines financial planning as “the process of meeting your life goals through a ‘big picture’ approach to managing your finances.” Williams proposes a four-step process for financial planning. Step 1: determine financial status To determine financial status, pharmacists need to look at debts (liabilities) and factor in student loans, car payment, credit card debt, and other expenses. They also need to look at their income (assets) and calculate their net worth (assets minus liabilities). Does this figure mean you are living within your means? Step 2: set goals Pharmacists need to identify their unique goals (ie, type of car and house they envision, vacations, and if they are planning an early retirement). This leads to many questions: What is a budget? Should I start saving and how much?

Should I consolidate my student loans? Should I buy or lease a car? Do I need life insurance?

to change with your circumstances throughout the major and minor life events that you experience.”

Step 3: develop and implement plan Pharmacists need to plan for the short-, medium-, and long-term future. The short-term includes creating a budget, establishing an emergency fund (3-6 months’ fixed expenses), paying off credit cards and consumer debt, and starting a savings plan. For the medium-term, pharmacists should pay off student loans and educate themselves on the terms of the loans and if consolidation is feasible. Also, they should start to invest their money and purchase life insurance. The long-term future is planning for retirement. Williams recommends pharmacists look into traditional individual retirement accounts (IRAs) and Roth IRAs. Tax deferrals and tax savings are considerations with both types of IRAs. In addition, pharmacists need to contribute to their employers’ 401(k) or 403(b) plans. Pharmacists should factor in how much the company will match their contribution and how many years until they are fully vested in the plan. Williams said that flexibility is crucial. “You need a plan that is flexible enough

Step 4: monitor progress After coming up with a plan, pharmacists need to assess if their financial goals have changed, if they are staying within their budget, and if they are earning the investment rates of return anticipated. Pharmacists can seek help with financial planning through an accountant, stockbroker, or insurance agent, as well as online sources. Williams encourages individuals to work with Certified Financial Planner (CFP) professionals. Established in 1985, The CFP Board of Standards Inc is a nonprofit, professional regulatory organization. For more information, visit www.cfp.net. For additional resources on financial planning, visit: • The Financial Planning Association to help find a CFP (www. fpanet.com) • Mint.com to set and track your budget (www.mint.com) • Morningstar Inc to research investments (www.morningstar.com) • Fidelity Investments to monitor investments (www.fidelity.com). ●

@Copyright iStockphotos.com/Günay Mutlu

INTERNATIONAL ONCOLOGY NEWS

Reports from International Meetings and Researchers By Jill Stein

Palliative Care for Children with Cancer Is Suboptimal MELBOURNE, AUSTRALIA—Healthcare workers need to pay more attention to children with cancer to better manage common end-of-life symptoms, a group from the Children’s Cancer Center at the Royal Children’s Hospital has advised. John A. Heath, PhD, FRACP, clinical associate professor at the hospital, and his coworkers analyzed responses to questionnaires completed by parents of children who had died of cancer roughly 5 years earlier. Overall, 89 parents were surveyed. Their findings showed that 84% of parents of these children maintained that their child had suffered “a lot” or “a great deal” from at least one symptom in their last month of life. These symptoms included pain in 46% of children, fatigue in 43%, and poor appetite in 30%. The study also found that current treatments for these symptoms were often inadequate. In fact, fewer than half of all symptoms were successfully treated

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using presently available treatments. The symptoms that were the most difficult to treat were fatigue, poor appetite, constipation, and diarrhea. In Australia, cancer is the leading cause of nonaccidental deaths in children, and children represent the majority of those who receive end-of-life care, the authors wrote in their article. The study was published in the January 2010 issue of The Medical Journal of Australia.

Drivers Should Wear Gloves to Cut Skin Cancer Risk WELLINGTON, NEW ZEALAND— The Cancer Society of New Zealand is recommending that drivers wear gloves to avoid developing skin cancer. Contrary to popular opinion, closed car windows do not protect hands that are on the driving wheel against ultraviolet radiation, the charity said in a statement. In fact, standard glass windows block only 37% of ultraviolet-A radiation.

Ultraviolet radiation is known to increase the risk of malignant melanoma and other skin cancers. The drivers with the greatest risk are those who are exposed to the sun through side windows on long trips or frequent trips, a charity spokesman said.

Women Who Don’t Vote Are More Likely to Skip Pap Smear LONDON, UK—Women who don’t vote in elections are less likely to undergo screening for cervical cancer, according to data released in the December 2009 issue of the Journal of Medical Screening. Jo Waller, PhD, MSc, BA Hons, senior research associate at Cancer Research UK Health Behaviour Research Centre, and colleagues interviewed 580 women ranging from 26 to 64 years of age. The results showed that women who reported that they rarely or never voted in elections were more likely to have postponed having a Pap smear. The find-

ings were most pronounced in women who ranged from 26 to 44 years of age. The investigators said that the results undermine the widespread notion that low screening rates are largely due to emotional factors such as embarrassment or fear. Instead, it appears that practical barriers may play a greater role—for example, difficulty in scheduling an appointment that is convenient. “In terms of the correlation between voting and screening attendance, it may be that both activities require a degree of organization, and women who do not manage to vote because of busy and chaotic lives might also be unlikely to attend screening,” they wrote in their article. Waller and her colleagues maintain that their findings are actually encouraging in that practical barriers are easier to manage than emotional ones. One such option is holding evening or weekend clinics to capture women who are unable to attend appointments during weekday clinic hours. ●

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In the Literature

Concise Reviews of Studies Relevant to Cancer Care 10-year Follow-up: Chemoradiotherapy for Locally Advanced Head and Neck Cancer Background: The UK Head and Neck Cancer Trialists’ Group was established in 1990 to determine the effectiveness of chemotherapy used in conjunction with radiotherapy and surgery. The effect of timing and duration of chemotherapy was also investigated. Design: Patients with locally advanced head and neck cancer who had not previously undergone surgery were randomized to radical radiotherapy alone (n = 233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n = 166); or 14 and 28 days after completing radiotherapy (SUB alone, n = 160); or both (SIM + SUB; n = 154). Chemotherapy was either methotrexate alone or vincristine/bleomycin/methotrexate/fluorouracil. Patients who had previously undergone radical surgery to remove their tumor were only randomized to radiotherapy alone (n = 135) or SIM alone (n = 118). The primary end points were overall survival (OS) and event-free survival (EFS; recurrence, new tumor, or death; whichever occurred first) among patients who were diseasefree 6 months after randomization. Analyses were by intention to treat. Summary: All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median OS was 2.6 years (99% CI, 1.9-

4.2) in the radiotherapy alone group, 4.7 (99% CI, 2.6-7.8) years in the SIM alone group, 2.3 (99% CI, 1.6-3.5) years in the SUB alone group, and 2.7 (99% CI, 1.64.7) years in the SIM + SUB group (P = .10). The corresponding median EFS rates were 1.0 (0.7-1.4), 2.2 (1.1-6.0), 1.0 (0.6-1.5), and 1.0 (0.6-2.0) years (P = .005), respectively. Among the patients who had previously undergone surgery, median OS rates were 5.0 (99% CI, 1.88.0) and 4.6 (99% CI, 2.2-7.6) years in the radiotherapy alone and SIM alone groups (P = .70), respectively, with corresponding median EFS rates of 3.7 (99% CI, 1.1-5.9) and 3.0 (99% CI, 1.2-5.6) years (P = .85), respectively. Toxicities included mucositis and xerostomia. Takeaway: Patients with head and neck cancer who do not undergo surgery benefit from concurrent nonplatinum chemoradiotherapy. This regimen reduced recurrences and deaths, even 10 years after starting treatment. Those who undergo surgery do not benefit from the addition of chemotherapy to adjunctive postoperative radiotherapy. Chemotherapy given after radiotherapy is ineffective. Tobias JS, et al. Lancet Oncol. 2009 Oct 27. Epub ahead of print. CT Morphologic Criteria Associated with Pathologic Response to Bevacizumab Treatment Background: Pathologic response to

preoperative chemotherapy has been shown to correlate with improved survival; however, a noninvasive method of predicting pathologic response to chemotherapy in colorectal liver metastases, particularly in patients treated with biologic agents, is lacking. Novel tumor response criteria based on morphologic changes observed on computed tomography (CT) require validation. Design: Two hundred thirty-four colorectal liver metastases from 50 patients who underwent hepatic resection after preoperative bevacizumabcontaining chemotherapy from 2004 to 2007 were evaluated. All patients underwent routine contrast-enhanced CT at the start and end of preoperative therapy. Three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. These criteria were validated with a separate cohort of 82 patients with unresectable colorectal liver metastases. Response determined using morphologic criteria and Response Evaluation Criteria in Solid Tumors (RECIST) was correlated with pathologic response in resected liver specimens and with patient survival. Summary: Interobserver agreement for scoring morphologic changes was good (kappa, 0.68-0.78; 95% CI, 0.51-

0.93). In resected tumor specimens, the median (interquartile range [IQR]) percentages of residual tumor cells for optimal morphologic response was 20% (10%-30%); for incomplete response, 50% (30%-60%); and no response, 70% (60%-70%; P <.001). With RECIST, the median (IQR) percentages of residual tumor cells were for partial response 30% (10%-60%); for stable disease, 50% (20%-70%); and for progressive disease, 70% (65%70%; P = .04). Among patients who underwent hepatic resection, median overall survival was not yet reached with optimal morphologic response and 25 months (95% CI, 20.2-29.8 months) with incomplete or no morphologic response (P = .03). In the validation cohort, patients with optimal morphologic response had median overall survival of 31 months (95% CI, 26.8-35.2 months) compared with 19 months (95% CI, 14.6-23.4 months) with incomplete or no morphologic response (P = .009). RECIST did not correlate with survival in either the surgical or validation cohort. Takeaway: Morphologic response was significantly associated with the percentage of residual tumor cells, as well as with pathologic response. Optimal morphologic response to preoperative chemotherapy translated into a survival benefit after hepatic resection. Chun YS, et al. JAMA. 2009;302: 2338-2344. ●

Cancer Vaccine May Mop Up Leukemia Cells Imatinib Leaves Behind By John Schieszer

A

vaccine made with leukemia cells may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia (CML) patients taking imatinib mesylate, according to researchers at Johns Hopkins Kimmel Cancer Center. In a pilot study published in Clinical Cancer Research, the investigators used a vaccine made from CML cells irradiated to halt their cancerous potential and genetically altered to produce an immune system stimulator called granulocyte-macrophage colony-stimulating factor. The treated cells also carry antigens specific to CML cells, which prime the immune system to recognize and kill circulating CML cells. Imatinib is one of the first targeted cancer therapies with wide success in patients with CML, and it destroys most leukemic cells in the body. In most CML patients, however, some cancerous cells

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February 2010 I VOL 3, NO 1

remain and are measurable with sensitive molecular tests. The Hopkins researchers say these remaining cells are a source of relapse, especially if imatinib therapy is stopped. The study vaccine was given to 19 CML patients with measureable cancer cells, despite taking imatinib for at least 12 months. A series of 10 skin injections were given every 3 weeks for a total of four times. After a median of 72 months of follow-up, the number of remaining cancer cells declined in 13 patients, 12 of whom reached their lowest levels of residual cancer cells. In seven patients, CML became completely undetectable. “We want to get rid of every last cancer cell in the body, and using cancer vaccines may be a good way to mop up residual disease,” says Hyam Levitsky, MD, a professor of oncology, medicine, and urology at Johns Hopkins University, Baltimore, Maryland. He

noted that the study was conducted in a limited number of patients, and the vaccine was not compared with other therapies. Therefore, he said more studies are needed with larger numbers of patients. Currently, the investigators are testing blood samples taken from the study participants to identify the precise antigens that the immune system is recognizing. With this information, they will tailor their vaccine for additional studies that monitor immune response more precisely. Patients receiving the vaccine experienced relatively few side effects, mainly injection-site pain and swelling. Some patients reported occasional muscle aches and mild fevers. Most CML patients will need to remain on imatinib therapy for the rest of their lives, according to the Hopkins researchers. More than 90% of them will achieve remission, but about 10% to

15% of CML patients cannot tolerate the drug long term. “Often patients have low blood-cell counts, fluid retention, significant nausea, and other gastrointestinal problems,” said study investigator B. Douglas Smith, MD, an associate professor of oncology at Johns Hopkins University. “Patients often tell me that they feel about 80% to 90% of what they should, and over time, this may have a big impact on their quality of life.” He said secondary therapies, such as dasatinib and nilotinib, also have many side effects. Imatinib cannot be taken during pregnancy. Because one third of patients with CML are in their 20s and 30s, many patients hoping to start families would like to discontinue taking it. “Ultimately, should this vaccine approach prove to be successful, the ability to get patients off lifelong imatinib therapy would be a significant advance,” Levitsky added. ●

www.TheOncologyPharmacist.com


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News Notes ASCO and ONS Release Chemotherapy Administration Safety Standards The American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) have released standards for safe chemotherapy administration to adult cancer patients in the outpatient setting. The document lists 31 standards encompassing seven domains: • Review of clinical information and selection of a treatment regimen • Treatment planning and informed consent • Ordering a treatment • Drug preparation • Assessment of treatment compliance • Administration and monitoring • Assessment of response and toxicity monitoring. Over the past 5 years, recommendations to improve safety in chemotherapy administration have been developed in response to reports of chemotherapy administration errors. These recommendations have included standardizing approaches, developing policies and procedures for system improvements, and having errors reviewed by interdisciplinary professional staff. The new standards also incorporate the need for extravasation management procedures and accessible antidote order sets and antidotes. Oral chemotherapy agents come with their own challenges, most notably medication adherence. Although the need for increased patient education and for processes to monitor adherence and adverse effects is great, few standards have been developed. The new standards incorporate providing patients on oral chemotherapeutic agents written or electronic education materials that include the preparation, administration, and disposal of the chemotherapy. Including family members, caregivers, or others in the education plan is also highlighted. In addition to the standards, ASCO and ONS recognize that the increased use of electronic medical record systems may improve the safety and quality of outpatient chemotherapy administration. For example, some systems prompt clinicians to specify standard, evidence-based regimens to be used for specific diagnosis. The standards are available at www. asco.org and www.ons.org.

COMPLETE International Registry for Patients with PTCL Allos Therapeutics has launched a new international registry designed to help understand treatment patterns and outcomes for patients with peripheral Tcell lymphoma (PTCL). The Com-

www.TheOncologyPharmacist.com

prehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a global observational study that will enroll patients with newly diagnosed PTCL and obtain data regarding longitudinal treatment patterns and outcomes. COMPLETE is expected to add much needed information on PTCL disease management across various

treatment regimens to existing registries collecting data on incidence and prognosis at diagnosis. Ap proximately 75 sites are projected to participate, including academic, hospital, and community practices in the United States and Europe. Physicians interested in participated or learning more can visit www.mednetregistry. com/mednet/allos. ●

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), institute appropriate treatment for complaints of abdominal pain, especially early in the SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of LEUKOENCEPHALOPATHY (PML) immunization with live viral vaccines following Rituxan therapy has not been studied and Infusion Reactions: Rituxan administration can result in serious, including vaccination with live virus vaccines is not recommended. Laboratory Monitoring fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have Because Rituxan binds to all CD20-positive B lymphocytes (malignant and nonoccurred. Approximately 80% of fatal infusion reactions occurred in malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals association with the first infusion. Carefully monitor patients during during Rituxan therapy and more frequently in patients who develop cytopenias [see infusions. Discontinue Rituxan infusion and provide medical treatment for Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse beyond the treatment period. ADVERSE REACTIONS The most common adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, Reactions: Severe, including fatal, mucocutaneous reactions can occur in mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other patients receiving Rituxan [see Warnings and Precautions, Adverse viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are infection resulting in PML and death can occur in patients receiving Rituxan 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 [see Warnings and Precautions, Adverse Reactions]. drug and may not reflect the rates observed in practice. The data described below reflect INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up indicated for the treatment of patients with: Relapsed or refractory, low-grade or to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non–progressing DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after given as a single agent weekly for up to 8 doses, in combination with chemotherapy for first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, including fatal, infusion reactions. Severe reactions typically occurred during the first myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and reactions typically occurred within 30 to 120 minutes of beginning the first infusion and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, resolved with slowing or interruption of the Rituxan infusion and with supportive care pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate reactions was highest during the first infusion (77%) and decreased with each patients with an antihistamine and acetaminophen prior to dosing. Institute medical subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than reactions as needed. Depending on the severity of the infusion reaction and the required 5% of patients with NHL in the single-arm studies. The overall incidence of infections interventions, consider resumption of the infusion at a minimum 50% reduction in rate was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and after symptoms have resolved. Closely monitor the following patients: those with pre- Precautions.] In randomized, controlled studies where Rituxan was administered existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary following chemotherapy for the treatment of follicular or low-grade NHL, the rate of adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/ infection was higher among patients who received Rituxan. In diffuse large B-cell mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor lymphoma patients, viral infections occurred more frequently in those who received Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences administer supportive care, including dialysis as indicated. [See Boxed Warning.] of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of outcome, can occur in patients treated with Rituxan. These reactions include patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan who experience a severe mucocutaneous reaction. The safety of readministration of 375 mg/m2 weekly for 4 doses. Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Table 1 Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b patients with hematologic malignancies or with autoimmune diseases. The majority of All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) patients with hematologic malignancies diagnosed with PML received Rituxan in Any Adverse Events 99 57 Respiratory System 38 4 as a Whole 86 10 Increased Cough 13 1 combination with chemotherapy or as part of a hematopoietic stem cell transplant. The BodyFever 53 1 Rhinitis 12 1 Chills 33 3 Bronchospasm 8 1 patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Infection 31 4 Dyspnea 7 1 Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Asthenia 26 1 Sinusitis 6 0 Headache 19 1 Metabolic and Nutritional Consider the diagnosis of PML in any patient presenting with new-onset neurologic Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 manifestations. Discontinue Rituxan and consider discontinuation or reduction of any Back Pain 10 1 Hyperglycemia 9 1 concomitant chemotherapy or immunosuppressive therapy in patients who develop Throat Irritation 9 0 Peripheral Edema 8 0 5 0 LDH Increase 7 0 PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation HemeFlushing and Lymphatic System 67 48 Digestive System 37 2 Lymphopenia 48 40 Nausea 23 1 Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death Leukopenia 14 4 Diarrhea 10 1 can occur in patients with hematologic malignancies treated with Rituxan. The median Neutropenia 14 6 Vomiting 10 1 Thrombocytopenia 12 2 Nervous System 32 1 time to the diagnosis of hepatitis was approximately 4 months after the initiation of Anemia 8 3 Dizziness 10 1 44 2 Anxiety 5 1 Rituxan and approximately one month after the last dose. Screen patients at high risk of Skin and Appendages Night Sweats 15 1 Musculoskeletal System 26 3 HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for Rash 15 1 Myalgia 10 1 Pruritus 14 1 Arthralgia 10 1 clinical and laboratory signs of active HBV infection for several months following Rituxan Urticaria 8 1 Cardiovascular System 25 3 therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who Hypotension 10 1 Hypertension 6 1 develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Infections Rituxan is NCI-CTC criteria. not recommended for treatment of patients with severe active infections. The following In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to additional serious viral infections, either new, reactivated, or exacerbated, have been 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy identified in clinical studies or postmarketing reports. The majority of patients received Adverse reactions information below is based on 1250 patients who received Rituxan in Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell combination with chemotherapy or following chemotherapy. Rituxan in Combination transplant. These viral infections included cytomegalovirus, herpes simplex virus, With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, experienced a higher incidence of infusional toxicity and neutropenia compared to the viral infections occurred as late as one year following discontinuation of Rituxan and patients in the CVP arm. The following adverse reactions occurred more frequently have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan including fatal, renal toxicity can occur after Rituxan administration in patients with following CVP compared to patients who received no further therapy: fatigue (39% vs. hematologic malignancies. Renal toxicity has occurred in patients with high numbers of 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), lysis syndrome and in patients with NHL administered concomitant cisplatin therapy rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. during clinical trials. The combination of cisplatin and Rituxan is not an approved 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more treatment regimen. Use extreme caution if this non-approved combination is used in frequently (≥2%) in the Rituxan arm compared with those who received no further clinical trials and monitor closely for signs of renal failure. Consider discontinuation of therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Studies 6 and 7, the following adverse reactions, regardless of severity, were reported Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to to death, can occur in patients receiving Rituxan in combination with chemotherapy. In CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder

Did You Know? More than 40% of office-based physicians responding to a National Center for Health Statistics survey reported using electronic health records (EHRs) in 2008, and preliminary data for 2009 show a continuing increase with 44% reporting use of EHRs. Only 4.4%, however, said they had a “fully functional” EHR.

(29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 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 R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a 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, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving singleagent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval 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. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. 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. 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 oral ingestion of 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 frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan, or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. Because caution should be exercised in administering Rituxan to patients with active infections, it is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy.

Revised 10/2009 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2009 Biogen Idec Inc. and Genentech, Inc. 7140918 November 2009

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Across approved NHL indications

DRIVING BETTER OUTCOMES IN NHL PROVEN OUTCOMES ACROSS MULTIPLE ENDPOINTS1-3

In the GELA trial1‡

In the Marcus trial 1

In the E1496 trial 1

At 5 years, OS increased from 46% with CHOP alone to 58% with R-CHOP

At 1.5-year median follow-up, there was a 71% improvement in median PFS (2.4 years R-CVP vs 1.4 years CVP alone)

At 2.3-year median follow-up, there was a 51% reduction in the risk of relapse, progression, or death with CVP→R vs CVP alone (p≤0.05)

Indications 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 Weekly ×4

Weekly ×8

Bulky disease

Retreatment

Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy Across DLBCL trials in patients ≥60 years of age, the following Grade 3 or 4 adverse reactions were reported 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 and neutropenia. In the Marcus trial of first-line follicular NHL, patients in the R-CVP arm had higher incidences of infusional toxicity (71% vs 51%) and Grade 3–4 neutropenia (24% vs 14%) as compared with those in the CVP arm. In the E1496 trial of low-grade NHL, neutropenia was the only Grade 3 or 4 adverse event that occurred more frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%).

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

©2009 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.

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Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. For additional safety information, please see following page for brief summary of prescribing information, including BOXED WARNINGS and Medication Guide. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *In the ECOG 4494 and MInT DLBCL trials, 2-year OS was R-CHOP 74% vs CHOP 63% (p<0.05) and R-CHEMO 95% vs CHEMO 86% (p<0.05), respectively.1 † Improvement in overall PFS was calculated using the formula (1–HR)/HR. ‡ R-CHOP improved the primary endpoint of median event-free survival by 164% (2.9 years vs 1.1 years) vs CHOP alone.1 NHL=non-Hodgkin’s lymphoma; DLBCL=diffuse large B-cell lymphoma; R=RITUXAN; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; OS=overall survival; GELA=Groupe d’Etude des Lymphomes de l’Adulte; CVP=cyclophosphamide, vincristine, and prednisone; PFS=progression-free survival; HR=hazard ratio; ECOG=Eastern Cooperative Oncology Group; MInT=MabThera® (Rituximab) International Trial; CHEMO=CHOP, CHOEP (CHOP+etoposide), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) biweekly, or PMitCEBO (prednisolone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, and vincristine) biweekly. References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2009. 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. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 3. Marcus R, Imrie K,Solal-Céligny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579-4586.

December 2009

http://www.theoncologypharmacist.com/docs/issues/February-2010  

http://www.theoncologypharmacist.com/docs/issues/February-2010.pdf

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