http://www.theoncologypharmacist.com/docs/issues/November-December-2009

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Photo courtesy of American Society of Clinical Oncology.

CONFERENCE NEWS No link found between cancer and bisphosphonate use

Re f o gis M u sec r te lti ond Yo p le a ww My nnu ur r To w. elomaal Con Fre day page 28 co new side e ex s le r a t i C E m tte r o n s www.theoncologypharmacist.com .co ser in m ie s .

CANCER CENTER PROFILE University of Pittsburgh Medical Center Cancer Centers and Cancer Institute provide high-quality care

Based on research by John Bilezikian, MD

page 9 November/December 2009 • vol. 2, No. 7

er d a Le and e h T ews in N eeting e M erag Cov conference news

suPPortive care

Systems Approach Can Improve Cancer Pain Management Based on research by Barbara A. Murphy, MD SAN DIEGO—A systems approach to pain and symptom management can boost the overall well-being of patients with cancer, according to Barbara A. Murphy, MD, a medical oncologist who works with a multidisciplinary healthcare team to improve patients’ quality of life (QOL) and ensure coordinated care.

Speaking at the Scripps Cancer Center’s 29th annual conference on clinical hematology and oncology, she said it is “a moral imperative” to alleviate suffering in cancer patients.

Murphy is director of the Pain and Symptom Management Program, Cancer Supportive Care Program; director of the Head and Neck

Pharmacy Practice

W

Continued on page 8

COMPLIMENTARY CE CREDIT AT WWW.THEONCOLOGYPHARMACIST.COM

Planning for a Great Residency Project

PROGRAM #CIK10278

By Lisa Lohr, PharmD, BCOP, BCPS Department of Pharmacy Services, University of Minnesota Medical Center, Fairview, Minneapolis

By Michele Woods, PharmD, BCOP hen you are ready to start designing your oncology clinic, you need to consider some of the “soft” requirements of clinic setup as well as the equipment issues discussed in Part 2 of this series (September/October 2009). In this category, I

Continued on page 6

DENVER—Bone loss is a growing concern among breast cancer survivors, because aromatase inhibitors are increasingly being prescribed as adjunctive hormonal therapy for estrogen receptor–positive breast cancer.

Research shows significant decline in bone mineral density (BMD) and increased risk of fracture among women who receive aromatase inhibitors.

However, researchers are now reporting that bone loss can be prevented in breast cancer survivors undergoing hormonal therapy if secondary causes of bone loss (vita-

Pharmacy careers and education

Challenges of Oncology Pharmacy Practice in the Community Setting. Part 3 Illinois Cancer Center, Peoria

Research Program; associate professor of medicine (hematology/oncology) and VICC member, VanderbiltIngram Cancer Center, Vanderbilt University, Nashville, Tennessee.

She told the audience it would require planning on their part to

New Study Shows Importance of Treating Secondary Causes of Bone Loss in Breast Cancer Patients

Chemotherapy-induced Peripheral Neuropathy: Prevention and Treatment

C

onducting a practice-based major project can be one of the most rewarding experiences for a pharmacy resident. It provides opportunities to learn real-world skills in project management, process improvement, and practice-based practice-based research. Working together to reach a common goal

Continued on page 12

Continued on page 13

PAGE 16

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# 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

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

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A SUSAN GOODIN, PHARMD, FCCP, BCOP

PATRICK MEDINA, PHARMD, BCOP

s this issue goes to press, heated debate continues about healthcare reform and the possible implications for oncology practice if the reforms are passed.

But even without broader healthcare reform, actions being taken by the US Food and Drug Administration (FDA) could have an immediate impact on oncology practitioners and their patients. The FDA has announced the Safe Use Initiative, intended to reduce preventable adverse events due to abuse or misuse of prescription drugs. This initiative signals an expanding role of the agency. “We’re moving beyond our traditional role of regulator of the industry and reaching beyond to make sure we’re impacting use in the real world,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research at a news conference.

The FDA is also considering implementation of one of its Risk Evaluation and Mitigation Strategies (REMS) for opioids.

These agents are mainstays of pain management in patients with cancer, and, although it is necessary to ensure that they are used safely and appropriately, it is also important that any restrictions on their use are not prohibitive and they remain available to patients who need them. As discussed in the article on pain management in this issue, however, good management of pain goes beyond drug therapy, and a multidisciplinary approach can improve symptom control and patients’ quality of life.

Good bone health is also essential in maintaining a patient’s mobility and quality of life. New reports from the American Society for Bone and Mineral Research demonstrate the importance of preventing bone loss in patients with cancer and provide

reassurance that treatment with bisphosphonates does not appear to promote development of cancer, which some earlier reports had suggested.

In addition to responsibilities to our patients, many of us are involved in practice management decisions and training of residents. Lisa Lohr provides excellent suggestions for designing and implementing a residency project. For pharmacists practicing in community cancer centers, Michele Woods continues her series providing suggestions on organizational issues and hardware and software requirements for setting up a clinic in this setting.

We are planning for our third year of publication and look forward to hearing your views on healthcare reform and other issues of importance to pharmacists and other members of the cancer care team. ●

News Notes News Updates of Relevance to Everyday Oncology Practice ■ Metastatic Lobular Breast Cancer Tumor DNA Sequenced Canadian researchers, in an attempt to precisely characterize all somatic coding mutations that occur during the development and progression of an individual cancer, have sequenced all 3 billion letters in the DNA sequence of one estrogen receptor α–positive metastatic lobular breast cancer tumor. With the recent advances in next-generation sequencing, the researchers were able to sequence the genome in just weeks. They found 32 somatic nonsynonymous coding mutations in the metastatic tumor. On comparison with the patient’s primary tumor from 9 years prior, five of those mutations were prevalent, six were

present at lower frequencies, 19 were not present, and two were undetermined. The five prevalent mutations were not previously known to researchers as being involved in cancer, thus identifying avenues to pursue for the development of personalized medicines for patients (Nature. 2009;461:809-813).

■ PV-10 Compassionate Use Program Extended to United States PV-10, an investigational agent being developed as a therapeutic for a broad spectrum of cancers, is now available to patients under the US Food and Drug Administration’s compassionate use guidelines. The agent will be available for indications that do not

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 7 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 ©2009 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.

November/December 2009

involve visceral organs and are not subject to enrollment in ongoing clinical trials. Cancers that meet these indications include certain breast cancers, basal cell carcinoma, squamous cell carcinoma, certain head and neck cancers, and melanoma. The agent is currently available through St. Luke’s Hospital & Health Network, Bethlehem, Pennsylvania, and will be extended to more sites in the upcoming months (Provectus Pharmaceuticals).

■ UnitedHealthcare Offers Free Access to NCCN Drugs & Biologics Compendium UnitedHealthcare now provides its in-network physicians and their staff free access to the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium. The Centers for Medicare & Medicaid Services recognizes the NCCN compendium as a mandated reference for oncology coverage policy. In January 2008, UnitedHealthcare began basing its benefit coverage for chemotherapy drugs used in outpatient settings on the compendium as well. The free access reflects the company’s ongoing commitment to ensuring physicians and patients have access to evidenced-based care. The access will also help save time by eliminating time spent on phone calls for coverage confirmation (UnitedHealthcare).

■ 2010 Medicare Physician Fee Schedule The Centers for Medicare & Medicaid Services (CMS) announced the final policies and payment rates for services rendered during the 2010 calendar year by practitioners who are paid under the Medicare Physician Fee Schedule (MPFS). In a success for radiation oncology, CMS will not implement its proposed 19% cut; instead radiation oncology payments will be reduced by only 5% over the next 4 years. CMS will also continue to use specialty supplemental survey data to determine practice expenses for medical oncology. In a statement, American Society of Clinical Oncology CEO Allen S. Lichter, MD, expressed: “We are deeply concerned that these cuts will continue to erode access to cancer care in the United States. ●

G REEN H ILL H EALTHCARE C OMMUNICATIONS

1

EDITORS’ LETTER

A Letter from the Editors

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Vol. 2, No. 7

November/December 2009 Departments

Feature Articles 9

Conference News

CONTENTS

No link found between cancer and bisphosphonate use

14

Breast Cancer Cardiac toxicity and breast cancer: prevention, monitoring, and treatment

16

Continuing Education

1

News Notes

4

Viewpoint

7 23

Cancer Center Profile University of Pittsburgh Medical Center Cancer Centers and Cancer Institute

28

Editors’ Letter

Editorial Director Karen Rosenberg karen@greenhillhc.com

How the US Government rations health care

Chemotherapy-induced peripheral neuropathy: prevention and treatment

28

1

PUBLIsHING sTAFF Publisher Philip Pawelko phil@greenhillhc.com

Clinical Pharmacy Specialist Spotlight James Natale, PharmD

International Oncology News Oncology Drug Codes

26

Recent FDA Approvals

32

In the Literature

33

Meetings

Associate Editor Dawn Lagrosa Production Manager Lynn Hamilton Director, Client services John W. Hennessy john@greenhillhc.com Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston

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Circulation Department Circulation@greenhillhc.com

GH Green Hill Healthcare Communications

, LLC ™

Your Innovative Partners in Medical Media

™

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

steven L. D’Amato, RPh, BCoP

Jim Koeller, Ms

Maine Center for Cancer Medicine Scarborough, ME

University of Texas at Austin San Antonio, TX

Bryna Delman Ewachiw, Bs, PharmD

Helen L. Leather, BPharm

Johns Hopkins Bayview Medical Center Baltimore, MD

University of Florida Gainesville, FL

Anjana Elefante, PharmD, Bsc, BscPhm, RPh

Christopher J. Lowe, PharmD

Roswell Park Cancer Institute Buffalo, NY

Novant Health Winston-Salem, NC

Co-EDIToRs-IN-CHIEF

Beth Faiman, RN, MsN, APRN, BC, AoCN

Helen McFarland, PharmD, BCoP

susan Goodin, PharmD, FCCP, BCoP

Cleveland Clinic Taussig Cancer Center Cleveland, OH

Union Memorial Hospital Baltimore, MD

Cancer Institute of New Jersey New Brunswick, NJ

Christopher Fausel, PharmD

Emily Mackler, PharmD, BCoP

Indiana University Simon Cancer Center Indianapolis, IN

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

Patrick Medina, PharmD, BCoP

Rebecca s. Finley, PharmD, Ms

Laura Boehnke Michaud, PharmD, BCoP, FAsHP

EDITORIAL BOARD

Oklahoma University College of Pharmacy Tulsa, OK

John F. Aforismo, BsC Pharm, RPh, FAsCP RJ Health Systems International, LLC Wethersfield, CT

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

sylvia Bartel, RPh, MPH

Jefferson School of Pharmacy Philadelphia, PA

The University of Texas MD Anderson Cancer Center Houston, TX

David C. Gammon, BsPharm

Deborah Moradi, PharmD

University of Massachusetts Memorial Hospital Worcester, MA

The Angeles Clinic and Research Institute Los Angeles, CA

Heidi D. Gunderson, PharmD, BCoP

LeAnn Best Norris, PharmD, BCPs, BCoP

Mayo Clinic Cancer Center Rochester, MN

South Carolina College of Pharmacy Columbia, SC

sandra Horowitz, PharmD, RPh

Debra L. Phillips, PharmD

The University of Texas MD Anderson Cancer Center Houston, TX

East Carolina University Greenville, NC

Lew Iacovelli, Bs, PharmD, BCoP, CPP

steve stricker, PharmD, Ms

Dana-Farber Cancer Institute Boston, MA

Moses H. Cone Health System Greensboro, NC

Samford University McWhorter School of Pharmacy Birmingham, AL

Deborah Blamble, PharmD, BCoP

Andrea A. Iannucci, PharmD, BCoP

Timothy G. Tyler, PharmD, FCsHP

The University of Texas MD Anderson Cancer Center Houston, TX

University of California Davis Medical Center Sacramento, CA

Desert Regional Medical Center Palm Springs, CA

Marlo Blazer, RPh, PharmD

Cindy Ippoliti, PharmD

John M. Valgus, PharmD, BCoP

James Cancer Hospital & Solove Research Institute Columbus, OH

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

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Betty M. Chan, PharmD, BCoP

Dwight Kloth, PharmD, FCCP, BCoP

Gary C. Yee, PharmD, FCCP, BCoP

USC/Norris Cancer Hospital Los Angeles, CA

Fox Chase Cancer Center Philadelphia, PA

University of Nebraska College of Pharmacy Omaha, NE

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November/December 2009

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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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Viewpoint VIEWPOINT

How the US Government Rations Health Care The agency that would likely run the “public option� was slow to pay for implantable cardiac defibrillators.

P

resident Barack Obama deflects criticism that his health-care plan will bring on government rationing of medical care by arguing that insurance companies ration care.

Everyone knows private payers limit access to some health care. But government does it in far more byzantine and arbitrary ways.

Consider the $450 billion Medicare program. It provides a model for— indeed its bureaucracy could well end up running—the “public option� health plan that Mr. Obama wants to offer all Americans under the age of 65. In recent years, Medicare’s staff has been aggressively restricting coverage for costly treatments. Looking for ways to control spending on medical products— and preserve the illusory “trust fund� that pays Medicare claims—is what shapes the culture of the organization and motivates the agency’s staff.

This often means limiting access to the costliest technologies. To do this Medicare relies on its rationing and pricing systems. National coverage decisions (NCDs) are assessments issued by Medicare’s medical staff that define who is eligible for new but often expensive treatments. Medicare then assigns medical products and procedures with

“codes� that determine which regulated category they fall into. Finally, price “schedules� are developed by Medicare’s staff each year to assign each unique code with its own updated payment rate. The process for getting a favorable code on a new product is a source of intense lobbying. It can make or break a technology.

For a remote agency like Medicare, far removed from clinical practice, it’s easier to try and manage the use of a high-cost but specialty treatment than a much lower-cost but very widely used product. Yet cheaper, more commonly used products can still be mispriced and account for more total cost to the agency. For example, low-tech orthotic devices and other “durable medical equipment� are a known source of wasteful spending. These medical products often evade Medicare’s attention in favor of less used but more expensive items such as a biological cancer drug.

Take the agency’s tortured decisions concerning the use of implantable defibrillators that jump-start stopped hearts during cardiac arrest. Medicare sharply restricted their use in the 1990s. Mounting research proved that the $30,000 devices could be saving many more lives. So in 2003 Medicare

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

adopted a novel theory to expand coverage to some, but not everyone, who needed one. The agency said only patients with certain measures on their electrocardiograms (called “wide QRS�) seemed to benefit.

It was an easily measurable but ultimately imprecise way to allocate the devices. After another major study firmly refuted the QRS theory, Medicare expanded coverage again in 2005, potentially saving 2,500 additional lives according to a press release issued with that decision.

That experience wasn’t unique. From 1999 to 2007, Medicare denied access in a third of the treatments it evaluated through its coverage process, taking an average of eight months to complete its reviews. When coverage was granted, in 85% of cases the treatments were restricted, usually to patients with more advanced illnesses.

Medicare is lately increasing its use of the national coverage process and is becoming more tightfisted. Since 2008, according to my review of Medicare data, it conditioned access in 29% of its reviews and denied new or expanded coverage in fully 53% of cases.

Medicare’s methods can also be arbitrary. Take the travails of the pharmaceutical company Sepracor and its drug Xopenex, an innovative respiratory medicine that competes with the chemically distinct and much cheaper generic albuterol. Both are inhaled aerosols used to treat asthma and chronic obstructive pulmonary disease. Xopenex has the same benefits as albuterol, but some believe fewer of its cardiac side effects. Medicare didn’t agree.

The agency tried to make a “national coverage decision� on Xopenex but couldn’t come up with a clinical justification to limit the drug’s usage. So Medicare manipulated its payment process, saying it would pay Xopenex a price equivalent to the “least costly alternative� form of generic albuterol, 10 cents a treatment compared to about $2.50 for Xopenex. Then Medicare was sued by a patient, and a Federal court recently ruled the agency exceeded its authority.

Medicare finally succeeded in reigning in the use of Xopenex with its coding system. By issuing Xopenex the same classification as generic albuterol, it was able to pay both products the same “blended� price—an average of the cost of each individual drug. That

lowered the price on Xopenex, but ironically increased what Medicare paid for the generics.

It’s not a stretch to say that Medicare spent hundreds of cumulative man-hours focusing on Xopenex while other priorities languished. The question is why?

There weren’t safety concerns. Xopenex may have been used in lieu of a cheaper alternative, but at peak Medicare sales of about $300 million it represented far less than one one-thousandth of the agency’s budget. Simply put, a few staffers inside Medicare were consumed with the drug and its higher price—revealing a process that is capricious and often disconnected from science.

Worse still is how impenetrable these programs have become. Drug and device companies spend millions of dollars trying to influence Medicare decisions. The hundreds of consultants they hire to advise them typically command $20,000-a-month retainers.

Formal patient and provider appeals to Medicare took an average of 21 months, according to a report issued in 2003 by the Government Accountability Office (using 2001 data), with delays in “administrative processing� due to “inefficiencies and incompatibility� of data systems eating up 70% of the time spent processing appeals.

There’s nothing inherently wrong with a program like Medicare seeking value for taxpayers. But it shouldn’t make up the rules as it goes. When private plans ration care, patients can appeal directly to an insurer’s medical staff. Only a small fraction of Medicare’s denied claims—about 5%—are ever formally appealed because its process is so impenetrable. People can also switch insurers, and in many cases patients chose a policy because it matched their preferences in the first place. These options don’t exist in a government health program. � —Scott Gottlieb Dr. Gottlieb is a resident fellow at the American Enterprise Institute and a former senior official at the Centers for Medicare & Medicaid Services. He is partner to a firm that invests in healthcare companies, and he advises health plans.

Reprinted with permission. Š Scott Gottlieb. Originally printed in Opinion Journal. The Wall Street Journal.

September 30, 2009.

November/December 2009

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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

www.ALOXI.com

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Improving Cancer Pain Management SUPPORTIVE CARE

Continued from cover launch an assertive, proactive communication program and to manage dose requirements of opioids.

Improving QOL The holistic program used in her practice is committed to improving the patients’ QOL by addressing not only 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.

6

their physical cancer issues, but their emotional and spiritual issues as well.

“I’m not just talking about drugs,” she said. “Pain is a problem, and we have had the tools to deal with that part of the problem.”

The purpose of Murphy’s oncology supportive care program, she said, is to: 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.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

• Improve patients’ overall wellbeing and thus the QOL • Enhance symptom control and functional outcome • Modify health behaviors.

The global construct, Murphy said, includes patients’ perceptions of wellbeing, as influenced by their experiences, 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

points of view, expectations, and beliefs.1 She reminded clinicians that healthrelated issues are only one factor when considering QOL. Commonly assessed QOL domains include well-being on several fronts: physical, functional, social, emotional, spiritual, and financial.

Patients underreport psychological distress Murphy said numerous studies use self-report questionnaires to conclude that cancer patients do not have a lower QOL than healthy people.

Murphy quoted the work of Breetvelt and Van Dam2 who wrote about the so-called response shift: “Under the influence of a highly significant life event, such as getting a life-threatening disease…there will be a concurrent change in the internalized standard on which the patient bases their perceptions.”

In other words, patients in these studies were underreporting their psychological distress; on their own, they had made the decision to move the bar.

Breetvelt and Van Dam warned that the true nature of cancer and the resulting decrease in QOL could be “obscured totally.” They said these “I’m OK” studies were in contrast with other research that documented the de rigueur experience of treating physicians, nurses, and other caretakers.

They advised physicians not to put a lot of stock in questionnaires.

Education of patients, physicians, and their staffs: what works?

Murphy said patient education can help overcome barriers to improved QOL. “But patient education by itself will not improve their outcome,” she said. Barrier reduction can have more of an effect on the outcome if it focuses on such end points as knowledge, attitudes, practice patterns, and pain control, but, in studies, it has not been sufficient by itself.

“We hoped education would improve patient outcome, but you can change knowledge and attitude and that has not made a significant difference in the outcome,” said Murphy. A study by Wells and associates found that a pain education program could improve knowledge and beliefs of the patient and their primary caregiver, but that continued access to pain-related information did not affect long-term pain outcomes.3 Moving beyond education “We need to move beyond education—but where next?” asked Murphy.

“More interventions are needed that can be easily adopted by clinicians in various settings.” She suggested a “pain hotline” where patients could communicate their

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A model for adequate pain control would include patient reporting of pain levels, an assessment titration communication, and the physician’s cooperation. pain to their providers. “This had been used in a postoperative setting where it was found to be effective, but when studied in the oncology setting, it was not.”

Murphy suggested that a model for adequate pain control would include patient reporting of pain levels, an assessment titration communication, and the physician’s cooperation.

Patients, she suggested, could keep a pain diary and a brief pain index. She noted her current investigation of a nurse-managed narcotic-titration drugorder sheet,4 as a way to improve pain control. This phase 3 study is sponsored by the National Cancer Institute.

Critical steps for adequate pain outcome Murphy listed the critical steps that should be considered for adequate pain outcome: 1. Patient report of pain (and medical staff recognition of problem) 2. Assessment of pain by the provider 3. Pain treatment plan 4. Review of plan with patient 5. Document assessment and plan

6. Patient follows treatment plan.

To elucidate the critical steps in a specific plan, Murphy discussed a study by Cleeland and colleagues, who examined a computerized telephone monitoring and alert system (with an interactive voice-response system) that alerted clinic staff via e-mail when cancer patient pain levels exceeded a specified threshold.5 Telephone calls primarily reinforced the patient’s use of prescribed medication, provided information for the management of symptoms, or addressed the need for and arranged a change of medication. The researchers found that this method reduced symptom severity and lowered symptomrelated interference for the monitored group compared with the control group.

“The e-mail alert would go to a nurse, and she could react; we found this phone call intervention worked really well,” said Murphy.

VHA study An earlier report by Cleeland and associates described a joint collaborative (Veterans Health Administration [VHA] and Institute for Healthcare Improve-

ment) that used a rapid-cycle improvement model to improve pain management within the VHA Health System.

Each patient–healthcare provider dyad worked within a system to affect a better outcome.6 The study’s goals were to improve delivery of pain management to VHA patients and to compare team process and patient report data on key goals from selected study units; 70 teams from 22 Veterans Integrated Service Networks participated.

Findings were that the number of patients experiencing moderate or severe pain on study units dropped from 24% to 17% while pain assessment increased from 75% to 85%; pain-care plans for patients with mild pain increased from 58% to 78%; and the number of patients provided pain education increased from 35% to 62%. “This study highlights the critical issue of patients needing a plan of care,” said Murphy.

IT could address complex problem Murphy said that combining electronic medical records with a systems approach gives data at a glance. The two basic components of a systems approach —elements and processes—can be applied in the medical records setting.

She explained it this way: In a car, the dashboard gives the driver a glimpse of all the information needed to make decisions while operating the vehicle.

Dashboards in IT are essentially the

same. “You can look at the display and say, ‘What am I doing well, or not well?’

It allows you to search databases and identify outcome issues at the patient level, the clinic level, and the provider level,” said Murphy, who pointed out that, based on the patient’s report of pain, the provider could match the level of pain to the regimen prescribed. She said that a lot of data could be organized with this system so that providers could offer adequate pain control for the many stakeholders. She added, “Pain control is complex, but using information systems and technology may hold the key to this complex problem.” ● —Kristina Rebelo

References

1. Murphy BA, Gilbert J, Cmelak A, Ridner SH. Symptom control issues and supportive care of patients with head and neck cancers. Clin Adv Hematol Oncol. 2007;5:807-822.

2. Breetvelt IS, Van Dam FS. Underreporting by cancer patients: the case of response-shift. Soc Sci Med. 1991;32:981-987.

3. Wells N, Hepworth JT, Murphy BA, et al.

Improving cancer pain management through patient and family education. J Pain Symptom Manage. 2003;25:344-356.

4. Kane MN, Hamlin ER 2nd, Hawkins WE. Measuring preparedness to address patient preferences at the end of life. Am J Hosp Palliat Care. 2004;21:267-274.

5. Cleeland CS, Vaporcian A, Shi Q, et al. A computerized telephone monitoring and alert system to reduce postoperative symptoms: a randomized trial. J Clin Oncol. 2008;26(15S): Abstract 9536.

6. Cleeland CS, Reyes-Gibby CC, Schall M, et al.

Rapid improvement in pain management: the Veterans Health Administration and the Institute for Healthcare Improvement collaborative. Clin J Pain. 2003;19:298-305.

InternatIonal oncology news Reports from International Meetings and Researchers Intranasal Fentanyl Is Superior to Oral Formulation for Breakthrough Cancer Pain LISBON, PORTUGAL—Intranasal fentanyl spray (INFS) confers meaningful relief of breakthrough cancer pain faster than transmucosal fentanyl citrate (OTFC) in most patients, according to data released at the 6th Congress of the European Federation of Chapters of the International Association of the Study of Pain.

Sebastiano Mercadante, MD, director of the Palliative Care Unit at La Maddalena Hospital in Palermo, Italy, presented results in 139 patients who had been randomized to treatment with INFS or OTFC titrated to doses of 50, 100, or 200 µg and 200, 400, 600, 800, 1200, or 1600 µg fentanyl, respectively.

Trial participants were adult inpatients or outpatients with cancer who

November/December 2009

were experiencing at least three episodes of weekly breakthrough cancer pain but no more than four daily episodes. All patients were using a stable chronic opioid treatment for background pain.

Overall, 25% of episodes showed meaningful pain relief at 5 minutes after treatment with INFS versus 7% with OTFC. In addition, 51% of INFS-treated patients had meaningful pain relief at 10 minutes versus 24% with OTFC. The analysis also revealed that patients found INFS easier to administer. Overall, 90% of patients said that INFS was “easy” or “very easy” to use versus 40% for OTFC. “The pharmacodynamic profile of INFS fits very closely with the temporal characteristics of breakthrough cancer pain,” Mercadante observed.

The study also found that INFS was well tolerated.

More than 90% of patients with cancer pain experience breakthrough pain, which is inadequately controlled in two thirds of cases, Mercadante pointed out.

Increased Public Awareness of Head and Neck Cancer Needed AMSTERDAM, THE NETHERLANDS—New data demonstrate a lack of knowledge among Europeans about the risk factors and symptoms of head and neck cancer.

The findings were reported by researchers who analyzed responses to online questionnaires completed by about 7500 people in France, Denmark, Italy, the Netherlands, Spain, Sweden, and the United Kingdom.

The “About Face” survey revealed that only 23% of participants were aware of the term “head and neck can-

cer,” and less than half were able to correctly identify symptoms of head and neck cancer. Sixty percent of respondents thought that brain tumors are a type of head and neck cancer.

Most participants knew that there is a link between head and neck cancer and smoking or high alcohol intake, but few patients knew of the role of the human papilloma virus (HPV) infection or excessive sun exposure in disease etiology.

“Efforts need to address the gaps in knowledge among the general public in head and neck cancer,” according to C. Rene Leemans, MD, co-director of the VUMC Cancer Centre in Amsterdam, the Netherlands. This is particularly important since knowledge gaps can lead to a delay in seeing a physician, which translates into a delay in diagnosis, he added. ● —Jill Stein

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Bone Loss in Breast Cancer Patients CONFERENCE NEWS

Continued from cover min D deficiency, idiopathic hypercalciuria, primary hyperparathyroidism, hypocalciuria, and normocalcemic hyperparathyroidism) are corrected and bisphosphonate therapy is used appropriately.

Primary causes of osteoporosis are menopause and aging. Secondary causes are diseases or conditions that exacerbate bone loss.

“Doctors evaluating breast cancer patients for possible bone loss should look further than cancer drugs,” said Pauline Camacho, MD, an associate professor of medicine at Loyola University School of Medicine, Chicago.

It is well documented that aromatase inhibitors can decrease BMD and increase the risk of fractures in postmenopausal women. These medications can decrease the body’s production of estrogen. Although estrogen feeds cancer, the hormone also protects against osteoporosis.

Camacho and colleagues reviewed charts of 81 consecutive breast cancer patients who were referred for treatment or prevention of osteoporosis. The researchers found that 51 patients had secondary causes of bone loss, including vitamin D deficiency (65%), excessive calcium excretion in urine (16%), or an overactive parathyroid gland (13%).

Thirty patients did not have secondary causes of bone loss.

All the patients received similar treatment with osteoporosis medications, such as alendronate and ibandronate.

Women with secondary bone loss, however, also received additional treatments.

For example, vitamin D deficiency was treated with prescription doses of vitamin D supplements, and excessive calcium excretion was treated with a diuretic.

After 1 year, the breast cancer patients with secondary causes of bone loss had stable BMD in their spines and necks. BMD improved in the breast cancer patients who did not have secondary causes of bone loss. BMD is the amount of calcium and other minerals packed into a segment of bone and it predicts osteoporosis.

Camacho said the study demonstrated that bone loss “can be prevented in women undergoing hormonal therapy if secondary causes of bone loss are corrected and bisphosphonate osteoporosis drugs are appropriately used.” She said the mean age of the women with secondary causes of bone loss was 58 years, and the mean age of the women without secondary causes of bone loss was 63 years.

These study findings, which were presented at the 31st annual meeting of the American Society for Bone and Mineral Research, suggest that healthcare providers should discuss the importance of treating secondary causes of bone loss with women undergoing

8

breast cancer therapy.

“This study is good news for breast cancer survivors, because they are worried about their bones and so are their oncologists. We showed that with proper workup and appropriate treatment they do quite well in terms of bone health. So

E RBITUX

G REEN H ILL H EALTHCARE C OMMUNICATIONS

®

our findings are quite reassuring,” said Camacho in an interview with The Oncology Pharmacist. “I think the most important take-home point here is that aromatase inhibitors are being used increasingly in breast cancer patients and so these patients need to be thoroughly

evaluated and evaluated for secondary causes of bone loss, such as calcium deficiency. We found vitamin D deficiency was the most common problem. We saw it in 65% of the patients.”

—John Schieszer

(cetuximab): FOR PATIENTS WITH HEAD AND NECK C ANCER*

ERBITUX + RT: 26% reduction in Risk of Death from SCCHN1,2

Important Safety Information Including Boxed WARNINGS Infusion Reactions I Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions I Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest I Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity I Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities I In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin I The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

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No Link Found between Cancer and Bisphosphonate Use DENVER—There appears to be no relationship between the use of bisphosphonates and the development of cancer, according to researchers at Columbia University College of Physicians and Surgeons.

A letter to the editor in the January 1, 2009, issue of the New England Journal of Medicine cited reports of esophageal cancer following treatment with alendronate as well as alendronate combined with other oral bis-

phosphonates. Since then, controversy has surrounded this issue.

“We need to rectify this issue. There is no relationship between the use of bisphosphonates and esophageal cancer,” said John Bilezikian, MD, professor of

ERBITUX + RT (%) (n = 208)

medicine at Columbia University College of Physicians and Surgeons, New York.

In a study presented at the 31st annual meeting of the American Continued on page 10

RT Alone (%) (n = 212)

No. (%) of Patients ERBITUX + RT (n = 211)

Grades 1-4

RT Alone (n = 213)

Delivery of planned RT dose Adequate delivery per protocol Inadequate delivery per protocol

184 (87.2) 27 (12.8)

187 (87.8)

Grade 3/4

Grades 1-4

Grade 3/4

Mucositis/stomatitis

93

56

94

52

Dysphagia

65

26

63

30

Xerostomia

72

5

71

3

Radiation dermatitis

86

23

90

18

26 (12.2) I

† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2

The incidences of grades 3/4 xerostomia, mucositis/stomatitis, and radiation dermatitis were more frequent in the ERBITUX plus RT arm

*INDICATIONS I ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck IERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

Electrolyte Depletion I Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary Late Radiation Toxicities I The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy I In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events I The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus I The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection I The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

References: 1. ERBITUX® (cetuximab) Package Insert. ImClone LLC, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ 08543; July 2009. 2. Bonner JA, Harari PM, Giralt J, et al.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001.

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent page.

© 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, Princeton, New Jersey 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC.

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Cancer and Bisphosphonate Use CONFERENCE NEWS

Continued from page 9 Society for Bone and Mineral Research, Bilezikian and his colleagues examined clinical and postmarketing data regarding risedronate. This agent has been studied in placebo-controlled phase 3 trials for up to 3 years and in more than 19,000 patients. Risedronate has also

been studied in active-controlled studies with 4000 additional patients.

Patients in the placebo-controlled studies were randomized to receive risedronate 2.5 mg daily (N = 4998), risedronate 5 mg daily (N = 5395), or placebo daily (N = 5363). The inci-

dence of esophageal cancer in these combined risedronate studies was 0.04% (two patients) in the 2.5-mg group, 0.02% (one patient) in the 5mg group, and 0.04% (two patients) in the placebo group.

Overall, the researchers found that

ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

10

G REEN H ILL H EALTHCARE C OMMUNICATIONS

the incidence rate for esophageal cancer was 19 per 100,000 patient-years of observation in placebo patients, 22 per 100,000 in the 2.5-mg, daily patients, and 9 per 100,000 in the 5-mg-daily patients. In the active-control studies, no cases of esophageal cancer were

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=212) (n=208) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 1 13 1 29 Fever1 19 <1 8 <1 Headache 15 3 2 0 Infusion Reaction2 13 1 9 1 Infection Chills1 16 0 5 0 Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 3 43 2 21 1 Alanine Transaminase, high 38 1 24 1 Aspartate Transaminase, high3 Alkaline Phosphatase, high3 33 <1 24 0 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneform Rash4 Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3

4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

November/December 2009

TOPNov_Dec09 11/17/09 10:15 AM Page 11

dent with risedronate use was very rare or less than 0.1 per 100,000 patientyears of exposure.

“Many clinicians and their patients are confused about this issue,” said Bilezikian in an interview with The Oncology Pharmacist. “After the New

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy

Body System Preferred Term Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

Erbitux plus BSC (n=288) Any Grades Grades2 3 and 4 % of Patients

BSC alone (n=274) Any Grades Grades 3 and 4

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

4

0

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

35

13

17

6

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

2 Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

November/December 2009

England Journal report, patients started calling their physicians and saying ‘I am not going to take that medicine,’ but it wasn’t true and they were misled.

We are now trying to make the point by using data to argue that the report was not well founded.”

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.

Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2009 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A5 ER-B0001A-07-09

Rev July 2009

He said healthcare providers should reassure their patients that there is no link between bisphosphonate use and esophageal cancer. According to the National Cancer Institute Surveillance, Ep- John Bilezikian, MD idemiology and End Results (SEER) database, the incidence of esophageal cancer in American men and women 65 years of age is 23.3 per 100,000 per year. In Caucasian women 65 years of age, the incidence is 11.2 per 100,000 per year. Bilezikian said the incidence of esophageal cancer events observed among risedronate or placebotreated patients was consistent with the background rates in the population.

David Prelutsky, MD, associate clinical professor of medicine at Washington University School of Medicine, St. Louis, Missouri, said these finding are very important because they help clarify this area of controversy.

“This study is clinically relevant, as it reassures primary care physicians, who prescribe the bulk of bisphosphonates, that they are doing no harm. No physician wants to prevent one problem and then possibly cause another with a treatment. These data are reassuring,” said Prelutsky in an interview with The Oncology Pharmacist. ● —John Schieszer

NCCN Updates Breast Cancer Guidelines New breast cancer guidelines from the National Comprehensive Cancer Network (NCCN) include three notable updates.

First, despite the increasing number of women with cancer in one breast who choose to have the other breast removed, the updated guidelines discourage prophylactic mastectomy except for women who are at high risk. If prophylactic mastectomy is being considered, according to the NCCN guidelines, its benefits must be balanced with the risk of disease recurrence, the social and psychological issues associated with bilateral mastectomy, and the overall risks of contralateral mastectomy. Another change is that the guidelines now recommend sentinel node mapping and excision rather than full axillary lymph node dissection for women with clinically negative lymph nodes, provided that they are being treated by clinicians with experience in sentinel node biopsy. The guidelines also include a new regimen (fluorouracil/ epirubicin/cyclophosphamide followed by weekly paclitaxel) as an option for adjuvant therapy for invasive breast cancer.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

11

CONFERENCE NEWS

reported in prevention, flexible-dosing, male osteoporosis, or open-label extension studies.

In postapproval surveillance from May 1998 to January 9, 2009, with more than 18 million patient-years of exposure, reported esophageal cancer coinci-

Photo courtesy of American Society of Clinical Oncology.

Cancer and Bisphosphonate Use

TOPNov_Dec09FINAL 11/17/09 12:22 PM Page 12

Challenges of Oncology Pharmacy Practice PHARMACY PRACTICE

Continued from cover would include computer/phone needs, references, the formulary, and your Pharmacy and Therapeutics (P&T) committee.

erence will be needed at multiple sites.

Mobility is also a factor. Consider a PDA/smartphone with loaded references if you will be very mobile.

Computer/phone needs The formulary Data and phone lines often need to There are many good reasons to have be requested early in the planning a written formulary in an outpatient process, so you need to clinic. You will use it every decide what your computer time you develop or update needs are as early as possisystems in the clinic. This ble. Will you work from a would include when switchdesktop or laptop computer? ing wholesalers, implementWhat are the data requireing automated dispensing ments of your automated systems, adopting electronic dispensing system? Does medical records, and designyour refrigerator monitoring ing preprinted chemotherapy system require a dedicated order sheets, just to name a phone line? You may need few. A written formulary also to request these things (and Michele Woods, PharmD, comes in handy when develBCOP keep requesting them) at oping guidelines for dose the beginning. rounding, high/low limits, and compatibility/stability charts. In our clinic, I References have also posted the written formulary References are another important on our intranet as a means of communipart of the pharmacy that are often left cation with our clinical and financial to chance. While the clinic is being staff. The formulary answers many freplanned, start a list of preferred refer- quently asked questions, including ences and check for updated versions. those about brand/generic names, manDetermine whether you will use print or ufacturers, single-dose versus multipleonline versions. This decision might be dose vials, and vial size availability. It made based on personal preference or also makes staff aware of what we keep overall cost. Ease of use might be in stock and what requires notice for another factor, if multiple personnel ordering (Table). will be using the reference or if the refRegarding treatment drugs, we make

Table. Sample Posted Formulary Generic

Brand

24*

Paclitaxel Abraxane protein-bound particles (albumin-bound)

Type

Vial sizes

SDV

100 mg

line development. For the sake of simplicity, I will refer to this process as the P&T committee.

Ideally, the clinical pharmacist should coordinate the P&T committee. To get started, choose a physician champion who is the most likely to be both sympathetic to standardization and (if possible) inspire buy-in from other physicians. The physician champion can help determine how to choose other physician members and how they will rotate through the committee. Next, interested nonphysician members should be invited. These members will vary depending on the practice, but may The P&T committee include midlevel practitioners, a Depending on the size of your clinical nurse specialist or nurse edupractice, you may benefit from start- cator, and financial counselors/busiing a P&T committee. Even smaller ness office staff (voting or nonvotpractices may be able to standardize ing). It is also important to decide their clinical services using a clinical how decisions will be implemented committee of some kind. Either way, and enforced. pharmacists should take an active The next step is the preparation of role in obtaining physician agree- the agenda. The pharmacist/coordinator ment for standardization and guide- prepares each meeting’s agenda by soliciting topics from committee members and other physicians.

Topics may also be suggested by Manufacturer Representative Contact other members of the clinical staff. I often present new drug Abraxis John Doe XXX-XXXinformation at this time, make XXXX formulary reviews, or clarify confusing drug policies. If I have students, they present drug utiGenzyme/Bayer John Doe XXX-XXXlization reviews or interesting XXXX drug information questions that may change practice. Agendas MedImmune John Doe XXX-XXXshould be sent out about 3 to 4 XXXX days before each meeting, and AstraZeneca Jim Smith XXX-XXXshould include a standard format of objective, summary, XXXX and references, so that comCephalon Jim Smith XXX-XXXmittee members can prepare XXXX for meetings. few formulary decisions in the classic sense. Mainly, we choose whether to keep a drug in stock or order when needed based on utilization. Keeping inventory of low-volume drugs to a minimum reduces waste. Making vial size information readily available to staff facilitates dose rounding. The supportive care aspect of treatment offers more opportunities for traditional formulary management. More agents in a class, for example, antiemetics, allows for selection between clinical equivalents based on cost. Posting your formulary can keep everyone informed of the current choices.

Alemtuzumab

Campath

•

SDV

30 mg

Amifostine

Ethyol

•

SDV

500 mg

Anastrozole

Aridimex

PO

PO

Arsenic trioxide

Trisenox

SDV

10 mg

Azacitidine

Vidaza

SDV

100 mg

Celgene

Betty Jones

XXX-XXXXXXX

Bevacizumab

Avastin

SDV

400 mg, 100 mg

Genentech

Ann Taylor

XXX-XXXXXXX

SDV

30 U, 15 U

Generic

Ann Taylor

XXX-XXXXXXX

•

Bleomycin Bortezomib

Velcade

SDV

3.5 mg

Millennium

Tim Anderson

XXX-XXXXXXX

Capecitabine

Xeloda

PO

PO

Roche

Sally Jennings

XXX-XXXXXXX

*May need at least 24 hours’ notice to order drug.

12

Pharmacists should take an active role in obtaining physician agreement for standardization and guideline development.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Conclusion Setting up or remodeling an oncology clinic in the community practice setting presents many challenges. The articles in this series have discussed selection of equipment, software needs, and organizational issues to be considered. Careful planning and coordination with other members of the healthcare team are essential to maintaining a safe, efficient oncology clinic and providing high-quality care for patients. ●

November/December 2009

Planning for a Great Residency Project Continued from cover can provide many learning opportunities for the resident and preceptor.

Using a structured plan for conducting a residency project will enhance the educational experiences as well as allow for project completion during the residency year.

Generating an idea for the project Generating the idea for the project will require a lot of input from the preceptor. Because work on the project should start as soon as possible in the year, many residency programs generate project concepts before the resident even begins the program. Some of the best residency projects arise out of practice-based problems, after looking backward to find the root of the problem.

Project ideas can also be developed out of departmental strategic goals and quality improvement initiatives, as well as national benchmarks, such as Joint Commission requirements and the National Patient Safety Goals.

The best projects are concise, interesting to both the resident and preceptor, and relevant to pharmacy practice.

Projects with a focus that is too broad or that contains too many objectives can be very problematic. The scope of the project must remain contained to provide a quality learning opportunity and to make sure that the project can be completed during the residency year.

Handing projects from one resident to the next does not allow the residents to participate during all phases of the project. “Project drift” can occur when the project’s goals shift because of new obstacles or when newcomers to the project propose a new focus to the project. This should be avoided. In projects based on implementation of a process change, thought should be given to designing the intervention at this stage.

The intervention should be accomplishable given the resources available during the project year and afterward, so that the project will yield useful outcomes, and should rely as little as possible on the availability of outside resources (eg, information technology [IT] support, physician time). The purpose of the study and primary and secondary outcomes of the study should be set, and the resident should be able to state them in one or two simple sentences.

Designing the study The next step in a successful residency project is the creation of a comprehensive timeline. Essentially, this outlines the steps involved in project completion and the estimated time needed. Time spent in this phase will pay off later in increased efficiency. It allows for identification of when resources (eg, resident project time, IT

support) will be needed. Responsibilities and roles of the project team members should also be assigned. Regular meetings should be scheduled to track progress as well as identify and solve roadblocks so that the project can continue successfully. Delays will be encountered in every residency project, and setting an aggressive timeline can allow for unexpected delays and ensure that the project is completed. an intervention, but is prone to tempoAfter setting a timeline, the next step ral bias. Temporal bias occurs when is designing the actual study. Residency something else that could influence the study projects can take many forms. outcome (eg, new lab test methodology, Although it is possible to have residen- new physician staff) happens concurcy projects that do not involve data col- rently with the intervention. The lection, more complex projects that sys- pretest and posttest with control design tematically investigate a is stronger than the posttest situation or confirm accomwith control design because plishment of a goal are preit measures the outcome ferred. Published studies before and after the intergenerally are grouped into vention, both in the experidescriptive reports, observamental group and in a contional studies, and experitrol group that did not have mental studies. Descriptive the intervention. This conreports include case reports trols for some confounders and case series that investibut doubles the resources gate a particular clinical Lisa Lohr, PharmD, needed for data collection. problem. These offer a great BCOP, BCPS Other considerations in introduction into publishdesigning the study are the ing, providing the resident experience definition of the outcome measures, the in formal case presentation and manu- inclusion and exclusion criteria, sample script preparation. Observational stud- size, setting, and data sources. Types of ies include cohort studies, case-control, outcome measures include economic and cross-sectional studies. These stud- (direct costs), clinical (clinical effects, ies do not involve an intervention, but physiologic measures, length of stay), or examine the association between a risk humanistic variables (quality of life, or exposure and the development of an patient satisfaction). The outcome outcome. To gain useful information, measure should be as precise and as relthese studies are usually large, requiring evant as possible given the available substantial time and resources, and are resources. For example, mea suring usually not appropriate for 1-year resi- venous thromboembolisms (VTEs) by dency projects. A randomized clinical venography after hospitalization is more trial will provide the most scientific clinically relevant, but it may only be proof of the research question. In these possible to mea sure the surrogate studies, the investigator actively inter- measure of the provision of appropriate venes and measures the effect of that VTE prophylaxis during hospitalizaintervention. Although it is the gold tion. Inclusion and exclusion criteria standard of research, a randomized clini- should be chosen to best represent the cal trial is very time-consuming and population of interest. A more homoexpensive, making it, most likely, a better geneous sample, chosen with a lot of fit for a research fellowship. exclusion criteria, is less variable but it Quasi-experimental study designs are less likely the data can be extrapolated appropriate for many residency projects. to the general population. A heterogeAlthough scientifically limited in estab- neous sample, chosen with few exclulishing causality, they are able to mea- sion criteria, would be more variable sure the effect of an intervention. The and less likely to yield a specific result, posttest-only analysis simply measures but more representative of the whole. the outcome after an intervention and Comparator groups should be as similar is the weakest of the group. This analy- to the study population as possible and sis type may be used if no data were col- may include patients at a different lected before the intervention. The location, those offered “usual care,” or posttest with control comparison analy- historical controls. sis uses an outcome measurement in the Planning for data collection should experimental group as well as the con- include the source of the data, such as trol group, but does not show that the medical records or billing records. A outcome improved after the interven- common problem in residency projects tion. The pretest and posttest design is is the collection of too much data, just in probably the most commonly used. It case it is needed. This is time-consuming measures the outcome before and after and can discourage the resident. If you

Using a structured plan for conducting a residency project will enhance the educational experiences as well as allow for project completion during the residency year. guard against “project drift” and collect only the data to match the outcome measures, this phase will go smoother and faster. The resident should think ahead at this point to how the data will be analyzed and presented. This will help him or her focus on the outcomes of interest. For example, if the proportion of patients with creatinine clearance <30 mL/min is needed, collect that data as a yes/no field, instead of recording all the laboratory values on admission. Sample size in a randomized controlled trial is defined by statistical calculations, but in quasi-experimental designs, the sample size is usually estimated based on the personal experience of the preceptor and available time and resources. The datacollection tool should be prepared at this point, including only the relevant information needed. The data-collection tool should be tested on a few patients before fine-tuning it. A plan for removing patient-specific data should be made, to protect the patients’ privacy. Data-collection tools can range from simple onepage paper forms to complicated database-driven electronic tools, based on the needs of the project.

Getting approval The next step in the process is writing the protocol and the institutional review board (IRB) submission. If all the aspects discussed have been considered, writing the proposal should be fairly simple. A usual proposal outline includes an introduction/justification, purpose/outcomes, methods, plan for analysis, data-handling plan, and references. Obtaining IRB approval ensures that the project is ethical and protects the human subjects and their privacy. It is required for projects that generate data that will be published or presented outside of the institution. Most IRBs classify projects according to the risk they pose to the patients. Many residency projects will qualify for the less intensive “exempt” or “expedited” reviews, because they pose minimal to no risk to the patient.

Implementing the project After approval by the IRB and residency advisory council, the project can proceed. If the project is using a quasiexperimental design, data collection is usually the next step. It is important for Continued on page 30

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Breast Cancer BREAST CANCER

Cardiac Toxicity and Breast Cancer: Prevention, Monitoring, and Treatment ORLANDO—Cardiac toxicity related to chemotherapy is not a new topic but it is an increasingly important one in light of emerging data showing adverse effects from many molecularly targeted agents as well as the older anthracyclines.

Especially for patients with breast cancer, there is keen interest in better understanding the true level of risk and the best means of preventing, monitoring, and treating cardiac toxicity.

Concerns have been raised about trastuzumab, especially when it is given in conjunction with an anthracycline, which is a common practice. But at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO), an international group of investigators from the phase 3 Herceptin Adjuvant (HERA) trial reported that the incidence of cardiac end points remains low even with longer-term follow-up.

Investigators assessed the cardiac

United Kingdom (a nonprofit research foundation).

Cardiac dysfunction in the trastuzumab group after 1 year was 0.6% for severe CHF and 3.0% for confirmed significant LVEF drop. After 3.6 years, the incidence of cardiac dysfunction after trastuzumab remained low: 0.8% for severe CHF and 3.6% for confirmed significant LVEF drop. In the observation arm, there were no cases of severe CHF, but 0.6% had confirmed significant LVEF declines, and one patient suffered a cardiac death, the study found.

Of the 73 patients in the trastuzumab group with a cardiac end point, 59 (80%) recovered after an average of 6 months.

There was evidence of progressive cardiac disease in six of 1682 patients, but the remaining affected patients had a favorable outcome, Procter said.

All occurrences of severe CHF and 85% of the confirmed significant LVEF

Guidelines recommend measuring LVEF periodically, but this is insufficient because more than one third of patients with heart failure have normal ejection fractions. safety of trastuzumab after 3.6 years’ median follow-up among 1682 patients who received adjuvant trastuzumab for 1 year and 1719 patients in the observation arm. Several cardiac end points were evaluated: • Significant drop in left ventricular ejection fraction (LVEF), defined as an absolute decline of ≥10% to <50% • Confirmed significant LVEF drop, defined as an asymptomatic (New York Heart Association [NYHA] class I) or mildly symptomatic (NYHA class II) significant LVEF drop, unless the next LVEF assessment indicated a return to levels that did not meet the definition of significant LVEF drop, or as identified by the treatment-unblinded cardiac advisory board • Severe congestive heart failure (CHF, NYHA class III or IV and significant LVEF drop).

“The cumulative incidence of any type of cardiac end point among patients randomized to 1 year of trastuzumab increased during the scheduled treatment period, but remained relatively constant thereafter,” reported Marion Procter, MSci, of Frontier Science Scotland, Ltd, Kincraig, Kingussie,

14

drops occurred during the scheduled treatment period. In contrast, anthracycline-associated cardiotoxicity can occur years after treatment, the authors pointed out.

“Cardiac dysfunction in the trastuzumab group is consistent with preclinical findings that in trastuzumabassociated cardiac dysfunction, no significant rate of myocardial cell death is observed,” he said. “This is different from the mechanism of anthracyclineassociated cardiotoxicity.”

These findings are consistent with those of a study reported at the Canadian Cardiovascular Congress 2009, which showed that trastuzumabrelated cardiac toxicity is “largely reversible.” In a study by Michael McDonald, MD, of the Heart Function Clinic at Toronto General Hospital and associates, 14 of 18 patients with breast cancer who were treated with trastuzumab had decreases in LVEF of ≥10% and showed signs of heart failure. Trastuzumab therapy was stopped in 13 of these patients, and at 3 months’ follow-up, all had nearnormalization of LVEF and improvement in symptoms. Patients were able to resume trastuzumab therapy and completed the course of treatment.

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Heart disease and breast irradiation In another study presented at the ASCO annual meeting, Harvard investigators examined the cardiac effects of left-sided chest irradiation in breast cancer patients in the Nurses’ Health Study and found risk to be associated with baseline Framingham risk score.

The study population included 3849 women with nonmetastatic breast cancer who were treated with radiotherapy.

They were categorized according to low (n = 1764), intermediate (n = 1495), and high (n = 601) Framingham score, and risk of coronary heart disease (CHD) was determined after adjusting for age and CHD risk factors.

The investigators found that left-sided breast radiotherapy raised the risk of having a CHD event by 80% in women with low baseline cardiac risk, but did not increase risk in the other two cohorts, reported Ronald C. Chen, MD, of the Harvard Radiation Oncology Program, Boston. “With modern radiotherapy techniques,” he suggested, “this difference may be smaller.”

The findings could have implications for treatment decision-making.

“A simple office-based Framingham score can be calculated to assess baseline cardiac risk. Women with earlystage left-sided breast cancer and low baseline cardiac risk should weigh the potential benefits of breast conservation against a small absolute increase in risk of CHD after radiotherapy,” he suggested.

Patients often not referred for care Certainly, one means of managing chemotherapy-related toxicity is to diagnose and treat it early and appropriately; however, Stanford University investigators have shown that cancer patients who “silently” develop left ventricular dysfunction may not be referred to cardiologists. The study was presented at the American College of Cardiology (ACC) annual scientific session in April.

In the retrospective analysis led by Geoffrey Yoon, MD, based on 88 patients receiving anthracyclines or trastuzumab between 2005 and 2007, mean LVEF (60% at baseline) dropped below normal during or after chemotherapy in 41% of patients, of which 25% had no overt symptoms of heart failure. Among the asymptomatic group, only 37% were referred to a cardiologist, 33% received an angiotensinconverting enzyme inhibitor or angio-

tensin-receptor blocker, and 41% received a beta blocker.

Optimal monitoring of chemotherapy patients Also at the ACC session, Daniel J. Lenihan, MD, professor of cardiology at The University of Texas M. D. Anderson Cancer Center, Houston, discussed how best to monitor for cardiac effects. Guidelines recommend measuring LVEF periodically, but this is insufficient because more than one third of patients with heart failure have normal ejection fractions, he pointed out.

Furthermore, as the “mainstay” of diagnosis, symptomatology is insufficient as well, he added, and biomarker testing is not yet recommended, although troponin and brain natriuretic peptide levels have been found useful.

Lenihan’s observations were echoed in a recent article in The Lancet Oncology (2009;10:391-399), which emphasized that LVEF is commonly used for screening for toxic effects but underestimates cardiac damage. Altena and colleagues further maintained that evidence to support current guidelines for monitoring is not robust.

The authors reviewed the current data for the various approaches and concluded: • Echocardiography assesses systolic and diastolic cardiac function.

Especially when it involves contemporary techniques, such as tissue velocity imaging of the early diastole, strain, and strain rate, echocardiography might permit earlier detection of subclinical signs of cardiac dysfunction.

• Multigated acquisition (MUGA) scintigraphy is a reliable method for assessing LVEF but is somewhat insensitive for detecting subtle changes in cardiac function.

MUGA scintigraphy, therefore, has limited value in the early detection of cardiotoxicity.

• Serum cardiac biomarkers are promising as a screening strategy for early cardiovascular damage.

• Cardiac magnetic resonance imaging, combined with gadolinium enhancement, is a promising screening strategy for the detection of subclinical damage. Persistent increases in troponin I or N-terminal pro-brain (B-type) natriuretic peptide concentrations seem to identify patients at risk for cardiotoxicity. ● —Caroline Helwick

November/December 2009

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Continuing EduCation

Complimentary

at www.thEonCologypharmaCist.Com Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010 EDITORIAL BOARD Timothy R. McGuire, PharmD, FCCP, BCOP College of Pharmacy University of Nebraska Medical Center 986000 Nebraska Medical Center Omaha, NE 68198 Rhonda J. Moore, PhD Scientific Review Officer Special Review and Logistics Branch Division of Extramural Activities National Cancer Institute National Institutes of Health 6166 Executive Boulevard Rockville, MD 20852 Virginia Sun, RN, PhD(c) Senior Research Specialist Department of Population Sciences Division of Nursing Research and Education City of Hope 1500 East Duarte Road Duarte, CA 91010 Constance Visovsky, PhD, RN, ACNP-BC Associate Professor University of Nebraska Medical Center College of Nursing 985330 Nebraska Medical Center Omaha, NE 68198-5330

Chemotherapy-induced Peripheral Neuropathy: Prevention and Treatment

BY CONSTANCE VISOVSKY, PhD, RN, ACNP-BC1; RHONDA J. MOORE, PhD2 1University of Nebraska Medical Center, College of Nursing, Omaha, Nebraska; 2National Cancer Institute, National Institutes of Health, Rockville, Maryland HOW TO RECEIVE CREDIT To receive continuing education credit, learners must: • Read the article in its entirety • Take the CE self-assessment test and complete the evaluation test: 1. Log on to www.theoncologypharmacist.com.

2. Click on “CE Credits.”

3. Click on “Click Here To complete the post-test and obtain a CE certificate online.”

4. Click on “CE Credits.”

5. Enter program # CIK10278 • The learner must answer at least 70% of the questions on the post-test correctly.

• The estimated time to complete this activity is 1 hour. Your continuing education certificate can be printed by following the directions online after successful completion of the post-test.

DISCLAIMERS The opinions or views expressed in this continuing education activity are those of the faculty and do not necessarily reflect the opinions or recommendations of the University of Nebraska Medical Center (UNMC), Center for Continuing Education.

C

hemotherapy-induced peripheral neuropathies (CIPNs) present an increasingly common neuropathic and pain syndrome PLANNING COMMITTEE in cancer survivors.1,2 Peripheral neuropathy is the end result Lois Colburn of peripheral, motor, sensory, and autonomic neuron damage secExecutive Director ondary to neurotoxic chemotherapy agents that inactivate the comCenter for Continuing Education ponents required to maintain the metabolic needs of the axon. The University of Nebraska Medical Center damage caused by chemotherapeutic agents can cause subsequent 986800 Nebraska Medical Center and long-term functional abnormalities of structural lesions in the Omaha, NE 68198-6800 peripheral and central nervous systems (CNS).3-5 CIPN is sensory, Brenda Ram, CMP dose-related, and cumulative. It is usually delayed and may appear Coordinator weeks to months after the initiation of therapy. The chemotheraCenter for Continuing Education peutic agents most often associated with CIPNs are the platinumUniversity of Nebraska Medical based compounds, taxanes, vinca alkaloids, thalidomide, and borteCenter zomib.3-10 Although the incidence of peripheral neuropathy resulting 986800 Nebraska Medical Center from a single agent can be significant, the administration of two neuOmaha, NE 68198-6800 rotoxic agents is not uncommon and results in higher grades of overDawn Lagrosa all neurotoxicity.11 At this time, no standard or evidenced-based Associate Editor therapies exist to prevent or treat CIPNs. This article aims to provide Green Hill Healthcare an understanding of CIPNs and to review the evidence for both its Communications, LLC 241 Forsgate Drive prevention and treatment.

While the University of Nebraska Medical Center, Center for Continuing Education is an ACPE-accredited organization, this does not imply endorsement by the UNMC or ACPE of any commercial products affiliated with this activity.

LEARNING OBJECTIVES After completing this activity, the reader should be better able to: • Review the epidemiology of chemotherapy-induced peripheral neuropathy (CIPN) • Explain the causes of CIPN • Describe the symptoms of CIPN • Compare available pharmacologic and nonpharmacologic therapies for CIPN TARGET AUDIENCE Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients COST This program is complimentary for all learners.

Case study A 56-year-old right-handed woman, a 2-year survivor of a stage IIIB adenocarcinoma of the left lung (Pancoast tumor) previously treated with cisplatin-gemcitabine-paclitaxel, presented to the clinic with left shoulder pain radiating into the left arm and hand, grade 3 CIPN, weight loss, hand weakness, poor appetite, and cough. She was clinically diagnosed with stage IV adenocarcinoma. During her previous treatment, she had developed grade 3 CIPN. She articulated the dominance of CIPN and pain on her quality of life (QOL): I no longer remember what it is like to not be in pain. I can’t think of anything else but the pain and I can’t concentrate at all. It has been like this for over 5 months. I have pain all over, under the cuff of my left arm, the doctor calls it subclavicle pain, and on my arm. I have lost time because of pain. I have pain that increases when I have chemotherapy, and I have pain that increases when I don’t have chemotherapy. I am damned. I am so tired, I hurt, and I can’t walk without the pain. I can’t feel my feet anymore or my fingers. I can’t drive, and I have lost my independence.

Pancoast tumors of the lung are relatively rare. The pain associ-

Monroe Twp, NJ 08831

Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831

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FACULTY/PLANNER DISCLOSURES It is the policy of the University of Nebraska Medical Center, Center for Continuing Education that all planners and faculty participating in continuing education activities provided by the University of Nebraska Medical Center, Center for Continuing Education are to disclose to the audience any real or apparent conflicts of interest with providers of commercial products and/or devices relating to the topics of this educational activity and also disclose discussion of labeled/unapproved uses of drugs or devices discussed in their presentation. The planners and faculty have been advised that this activity must be free from commercial bias and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis.

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The authors, reviewers, and planning committee members listed below have stated they have no significant or substantial relationship with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporter of this activity.

• Lois Colburn • Dawn Lagrosa • Rhonda J. Moore, PhD • Brenda Ram, CMP • Karen Rosenberg • Virginia Sun, RN, PhD(c) • Constance Visovsky, PhD, RN, ACNP-BC The following author has stated that he has the following financial relationships:

• Timothy McGuire, PharmD, FCCP, BCOP, has received research support from AstraZeneca.

ACCREDITATION AND CONTACT HOURS STATEMENT The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE provider number is 0447-0000-09-085H04-P. To receive the 1 contact hour of continuing education credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity. Approval is valid from the initial release date of December 15, 2009. The expiration date is December 14, 2010. A statement of credit will be available for printing online upon completion of the post-test with a score of 70% or better and the evaluation instrument.

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at www.thEonCologypharmaCist.Com Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010 ated with a Pancoast tumor can extend along an ulnar nerve distribution of the arm to the elbow and is frequently relentless and unremitting. Although a relatively unique scenario, this case illustrates the potential for severe complications from cancer and CIPN.

Pathophysiology and Epidemiology It has been hypothesized that neurotoxic chemicals directly damage nerve fibers by inactivation of components required to maintain the metabolic needs of the axon. The longer and larger distal axons are affected first and this may result in interruptions of axonal transport and degeneration of myelinated nerve fibers and unmyelinated axons.8-10 In a recent animal-model study of paclitaxel-induced CIPN, abnormalities in the axonal mitochondria of sensory nerves were found to contribute to paclitaxel-induced neuropathic pain.12 Under normal circumstances, large sensory neurons do not conduct noxious stimuli. These large myelinated sensory fibers are preferentially injured by neurotoxic chemotherapeutic agents. Injury or damage to large sensory fibers by chemotherapeutic treatments can also result in the paresthesias, dysesthesias, and decreased proprioceptive abilities. These stimuli can be detected by nerves within the body as well as by the semicircular canals of the inner ear. Thus, CIPNs induce a type of neuropathic pain and represent a serious yet understudied consequence of cancer treatment. The sensory and motor symptoms and signs of CIPNs are potentially disabling and can have a significant impact on QOL for patients with cancer.13,14 Moreover, even when CIPN is not a dose-limiting side effect, its onset may severely affect QOL and cause chronic discomfort and pain.6-11 Prevalence and incidence The prevalence of CIPNs is not known because of a lack of adequate standardized assessment, measurement, and reporting mechanisms.3,9,11 Toxicity-grading scales used to detect CIPN vary widely, and specific guidelines for these instruments are lacking.

The incidence of CIPN varies depending on the drugs, dosage, and treatment schedules used.3-11 The incidence of severe CIPN has been estimated at about 3% to 7% in individuals treated with single agents and upward of 38% in those treated with multiple chemotherapeutic agents.3-11 Risk factors Risk factors associated with worsening CIPN symptoms include prior use of chemotherapies (particularly platinum-based therapies), older age, and female gender. Comorbid conditions that appear to place patients at greater risk for CIPN include diabetes, human immunodeficiency virus infection, alcoholism, preexisting neuropathies (diabetic neuropathy, small fiber neuropathies), and vitamin B deficiencies.3,6,11,13-15 The symptoms associated with CIPNs also vary widely (Table 1), and little is known about other risk factors.

Moreover, even when neurophysiologic methods are used to diagnose CIPNs, there is still wide variation in the resultant symptoms, which enhances the difficulty in predicting and modeling which patients are potentially at the greatest risk.4-11

November/December 2009

Mechanisms The sensory and motor symptoms and signs of CIPNs are potentially disabling and can have a significant impact on QOL.1-11 Yet, the mechanisms and risk factors associated with the development of CIPNs have not been fully elucidated. Several interesting mechanisms have been proposed. For instance, in patients with cancer, the immune response to tumor cells contributes to an already adverse proinflammatory state. One potential consequence is that tumoral invasion at central or peripheral sites can lead to mechanical damage, proteolysis, and the release of inflammatory pain mediators, including proinflammatory cytokines (ie, interleukin-1, interleukin-6, and tumor necrosis factor-a). These may result in damage to surrounding tissues and may also play a prominent role in the initiation, development, and maintenance of chronic pain states, including neuropathic pain.16-26 Other research has examined the impact of platinum-based cancer chemotherapies on mitochondrial function.27 Alterations in mitochondrial function has been noted in cancer cell resistance to chemotherapeutic agents. Cisplatin’s toxic side effects appear to be associated with mitochondrial injury in vivo and in vitro, highlighting the plausible role of mitochondria, including the role of production of mitochondrial electron transport chain reactive oxygen species in models of other forms of painful peripheral neuropathy.27-30 Variation in symptoms: presentation, progression, and resolution The primary effects of CIPN are sensory, occurring in a stocking-and-glove distribution in the toes and fingers. The lack of gold-standard measures for CIPN and the wide variation in symptoms contribute to limitations in symptom management in patients. CIPN can vary in its onset, severity, and length, and its resolution cannot be predicted, as the symptomology can last from a few days to a lifetime.3-11 The symptoms are described briefly below.

• The majority of patients report a gradual onset of neuropathic symptoms, although some develop symptoms more rapidly.3-11 • The primary effects are sensory, occurring in a stocking-and-glove distribution in the toes and fingers.3-11 • Terms such as “burning,” “tingling,” “electric shock sensation,” and “painful numbness” have all been used to describe the sensations.4,8 • Patients may also report increased pain during walking, with descriptions of sensations such as “walking on shards of glass” or “stepping on razorblades.”4,8 • Physical examination may reveal tactile allodynia, cold allodynia, hypersensitivity, and loss of deep tendon reflexes.4,8 • Motor symptoms such as declines in muscle strength can lead to muscle weakness and atrophy, precipitating functional impairment.

• Patients may also experience a loss of proprioception, the unconscious perception of movement and spatial orientation within the body.

In addition, loss of proprioception can lead to significant safety issues.8,9,13 Patients without proprioception are

Table 1. Symptoms of CIPN Sensory symptoms • Paresthesia • Hyperesthesia or hypoesthesia • Dysesthesia • Pain • Allodynia • Numbness and tingling • Electrical sensation (L’Hermitte’s sign) • Hyporeflexia or areflexia • Diminished or absent proprioception • Diminished or absent vibratory sensation • Diminished or absent cutaneous sensation • Diminished or absent sense of sharp/dull discrimination Motor symptoms • Weakness • Gait disturbance • Balance disturbance • Difficulty with fine motor skills (buttoning clothing, writing) Autonomic symptoms • Constipation • Urinary retention • Sexual dysfunction • Blood pressure alterations CIPN indicates chemotherapy-induced peripheral neuropathy.

at a great risk for falls because they also tend to lose all sense of the position of their feet. This raises concerns about their ability to drive safely, particularly when they are unable to feel the brakes or lack the strength to press a pedal adequately.7,9,15 Heterogeneity in CIPN-related symptoms can range from an almost exclusively sensory to a sensory-motor neuropathy, with or without clinical evidence of autonomic impairment.3,11,13-15,24-26 Recent insight from animal and human studies suggests that the great heterogeneity in the underlying mechanism(s) of nerve injury caused by individual agents may partly explain the wide variation in the resultant symptoms.3,11,24,26,31-34 Chemotherapeutic toxicity is also influenced by multiple genetic factors and nongenetic factors, including age, gender, and drug-drug interactions.26,31-38 The manifestations of adverse drug reactions also differ between men and women. Women tend to experience greater toxicity from chemotherapeutic drugs than men.34 Recent studies suggest that the mechanisms underlying the various forms of peripheral neuropathy may actually be different, and therapies have to be tailored in light of these different neurotoxic effects.27 These issues further contribute to the difficulties in Continued on page 18

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Complimentary

Continuing EduCation

at www.thEonCologypharmaCist.Com Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010 Continued from page 17

Table 2. Pharmacologic Prevention and Treatment of CIPN Agent Acetyl L-carnitine

Studies Bianchi G, et al. 200535 Maestri A, et al. 200564

Conclusions • Tested for the treatment of preexisting paclitaxelor cisplatin-induced peripheral neuropathy • Nonrandomized design and small sample sizes are limitations • Randomized clinical trials are necessary before recommendation as a potential treatment for CIPN

Amifostine

Hilpert F, et al. 200542 Leong SS, et al. 200374 Moore D, et al. 200343 Openshaw H, et al. 200444

• Due to negligible toxicity, low cost, and lack of interference with chemotherapy, may be a viable preventive treatment for oxaliplatin-based therapy

Calcium/magnesium infusions

Gamelin L, et al. 200448 Hochster HS, et al. 200775 Hochster HS, et al. 200876 Nikcevich DA, et al. 200877

• Because of negligible toxicity, low cost, and lack of interference with chemotherapy, may be a viable preventive treatment for patients receiving oxaliplatin-based therapy

Carbamazepine

Eckel F, et al. 200251 von Delius S, et al. 200752

• No grade 2 to 4 neuropathy in patients treated with carbamazepine vs 30% in historical controls • In patients with colorectal cancer, no differences in neurotoxicity with carbamazepine • Randomized, placebo-controlled trials are necessary to determine use for prevention or treatment of CIPN

Gabapentin

Rao RD, et al. 200762

• No benefit with gabapentin to treat CIPN symptoms found in phase 3 trial

Glutamine

Stubblefield MD, et al. 200553 Vahdat L, et al. 200154 Wang WS, et al. 200755

• Patients developed less grade 1 to 2 CIPN as compared with controls

Cascinu S, et al. 199559 Cascinu S, et al. 200257 Smyth JF, et al. 199758

• Significantly less CIPN experienced by patients

Nortriptyline

Hammack JE, et al. 200263

• Based on one small pilot study and lack of objective measurements of neuropathy, effectiveness in reducing neuropathy-associated paresthesia is not established

Vitamin E

Argyriou AA, et al. 200547 Argyriou AA, et al. 200678 Bove L, et al. 200145 Pace A, et al. 200346 Pace A, et al. 200779

• Reduced the incidence and severity of cisplatin-related CIPN

Glutathione

• Larger, randomized, placebo-controlled trials are necessary to assess efficacy for the prevention of CIPN

• Randomized clinical trials are needed to test the effectiveness as an intervention for CIPN

• Randomized clinical trials with larger sample sizes are still needed to further evaluate role in prevention and treatment of CIPN

CIPN indicates chemotherapy-induced peripheral neuropathy.

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at www.theonCologypharmaCist.Com Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010 predicting which patients from which populations will exhibit long-term damage from chemotherapeutic treatments.39-41 Some chemotherapeutic agents are known to induce neurotoxicity that extends beyond the discontinuation of therapy, a phenomenon known as coasting.3 It is still quite difficult to predict whether otherwise neurologically normal patients will exhibit susceptibility to the neurotoxic effects of chemotherapy.3-11 The diagnosis, assessment, and management of CIPNs are also complicated by the lack of a reliable and standardized means to diagnose and monitor patients at risk of or who become symptomatic from this complication of treatment.26,31,32 Finally, no wellestablished guidelines exist for dose reduction.8-11 This wide variation in symptoms remains a significant bar-

rier that further contributes to the inadequate pain assessment and management of CIPNs.

Prevention of CIPN Chemoprotectants Chemoprotectants such as amifostine have been tested as a means of detoxifying chemotherapy and facilitating DNA repair while not interfering with the efficacy of chemotherapy (Table 2). In the studies testing the effect of amifostine on peripheral neuropathy associated with taxane-based chemotherapy regimens, no differences were found in sensory or motor neurotoxic symptoms in patients treated with amifostine.

Amifostine was also found to be ineffective in preventing or reducing the neurotoxic effects of highdose paclitaxel.42-44

Vitamin E Vitamin E has been thought to protect against cellular oxidative damage and side effects, such as numbness, tingling, burning, and/or pain in peripheral extremities produced by cisplatin and other cytotoxic drugs. Three studies examined the cytoprotective effect of vitamin E supplementation on the development of CIPN following the administration of cisplatin, paclitaxel, or a combination regimen.45-47 The findings, based on subjective, clinical, and electrophysiologic assessments, showed that the incidence of neurotoxicity was lower in the group that received vitamin E as compared with the control group.

Further randomized clinical trials are needed, however, to evaluate the role of vitamin E in the prevention and treatment of CIPN. Continued on page 20

Commentary Chemotherapy-induced Peripheral Neuropathy: Prevention and Treatment: A Pharmacist’s Perspective

BY TIMOTHY R. MCGUIRE, PHARMD, FCCP, BCOP University of Nebraska College of Pharmacy, Omaha

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hemotherapy-induced peripheral neuropathy (CIPN) is a relatively common and poorly treated adverse effect of several anticancer drug classes, including the taxanes, vinca alkaloids, platinum analogs, and the antimyeloma drugs, thalidomide, lenalidomide, and bortezomib.

Because there are no proven therapies to treat CIPN, methods to prevent CIPN are particularly important. The ability of any given agent to prevent CIPN needs to be weighed against any real or theoretical concern of diminished antitumor effect. Because the mechanisms of CIPN are thought to be at least in part an extension of the drug’s mechanism of antitumor effect (eg, tubulin inhibition, DNA adduct formation), the proposed protective agents (amifostine, calcium/magnesium, vitamin E, glutamine, N-acetylcysteine, glutathione, acetyl L-carnitine, and erythropoietin) need to be used thoughtfully. This is particularly true given that there is no strong evidence that many of these agents lower rates of CIPN. One method of reducing the rates of CIPN is related to advances in drug development and formulation of anticancer drugs. For example, carboplatin was developed by the addition of a more complex and bulky-leaving group to the cisplatin molecule, leading to the production of less reactive platinum species and lower rates of several of the toxicities associated with cisplatin, including CIPN. Oxaliplatin is much more like cisplatin despite its more complex chemical structure, and substantial reduction in CIPN compared with cisplatin has not been realized. Cisplatin may be

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more likely to produce permanent neurologic damage, consistent with the science showing three times more platinum-DNA adduct formation in the dorsal root ganglia with cisplatin compared with oxaliplatin.1 The CIPN associated with docetaxel is less severe than that with paclitaxel. Variation is also seen among the vinca alkaloids, vinblastine and vinorelbine, which are associated with lower rates of CIPN compared with vincristine. The differences between these antimitotic drugs are based on differences in their affinity for axonal microtubules.

In addition to drug selection that can minimize CIPN, a number of new formulations of neurotoxic chemotherapy may improve tolerability. For instance, although nanoparticle albumin-bound paclitaxel is not less likely to produce CIPN than solvent-based paclitaxel, the CIPN that develops may be more reversible.2 The inhibitors of tumor progression commonly used to treat multiple myeloma (thalidomide, lenalidomide, and bortezomib) have differing liability for CIPN. Thalidomide is a common cause of CIPN, which is only slowly or incompletely reversible and related to cumulative dose. In comparison, CIPN is uncommon with lenalidomide and, when present, is usually mild. Bortezomib is associated with neuropathy in approximately one third of patients.3 Bortezomib-induced CIPN, however, is generally more rapidly reversible than that with thalidomide, and resolves in most patients after dose reduction or discontinuation.3,4 Unfortunately, determining the clinical nature of the

CIPN associated with these agents is difficult given that patients with multiple myeloma may have a history of receiving neurotoxic therapy, and the underlying disease itself may be associated with neurologic deficit.4 It is not always possible to switch between drugs of the same class because of either nonequivalence in a given tumor or lack of data demonstrating clinical equipose. In addition, lower rates of CIPN are often at the cost of higher rates of myelosuppression or other toxicities that may create equal or greater clinical issues.

In conclusion, although prevention of CIPN is preferred given the lack of agents to effectively treat CIPN and the potential irreversibility of the damage, there are limited data on the value of preventive agents. In addition, antagonism of antitumor activity with preventive therapies is not a settled issue. The appropriate selection of both analog and formulation may be an effective method of minimizing this important complication of chemotherapy. ●

References 1. McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther. 2009;8:10-16.

2. Schiff D, Wen PY, van den Bent M. Neurological adverse effects caused by cytotoxic and targeted therapies. Nature Reviews.

2009;6:596-603.

3. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

J Clin Oncol. 2006;24:3113-3120.

4. Argyiou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599.

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Calcium and magnesium Infusions of calcium and magnesium have been used as a means of preventing oxaliplatin-associated CIPN. Oxalate, an oxaliplatin metabolite, seeks out and binds to calcium and magnesium.48 In one study, 140 patients were randomly assigned to receive calcium gluconate and magnesium sulfate or placebo before and after oxaliplatin to reduce neurotoxicity. Improvements in the clinical manifestations of acute neurotoxicity were

reported after infusion of calcium and magnesium, and at the end of oxaliplatin therapy, 65% of the patients in the calcium/magnesium infusion group had no symptoms of neuropathy compared with only 37% in the control group.48 There was concern that tumor response rates may be lower in patients who received calcium and magnesium infusions. A subsequent review of computed tomography scans from the trial, however, showed that the antitumor response rates were actually

numerically higher in the group that received the calcium and magnesium infusions compared with those who received placebo. Thus, calcium and magnesium infusions appear to offer a safe, cost-effective means of preventing oxaliplatin-related peripheral neuropathy.49,50

Carbamazepine Carbamazepine, an anticonvulsant drug, appears to protect against oxaliplatin-induced neurotoxicity by

CommEntary Chemotherapy-induced Peripheral Neuropathy: Prevention and Treatment: A Nurse’s Perspective

BY VIRGINIA SUN, RN, PhD(c) City of Hope, Duarte, California

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nowledge of current treatment and supportive care strategies for common cancer-related toxicities is critical to the provision of quality nursing care. Visovsky and Moore provide a comprehensive overview of the epidemiology, prevalence, characteristics, and management of chemotherapyinduced peripheral neuropathy (CIPN). The article will not only serve as an excellent resource for clinical oncology nurses, but also allow them to provide comprehensive education for cancer patients about what to expect with CIPN. The assessment and management of CIPN continues to be a clinical challenge for healthcare professionals for several reasons that are addressed by the authors and others. First, there is great variability in the characteristics of symptoms related to CIPN. This may, in part, be related to the specific class of chemotherapeutic agents that causes CIPN, but currently there is no conclusive evidence that explains this variability. The variability in symptom characteristics also poses a clinical challenge for developing effective assessment and follow-up protocols for CIPN. Second, although research is ongoing, CIPN is still overall a poorly understood phenomenon.

Current evidence related to the underlying neurobiology, actual prevalence rates, and a lack of definitive animal models are factors that affect our overall understanding of CIPN.1 Finally, despite the growing number of clinical trials testing various therapeutic options for CIPN, currently there is no standard, evidence-based treatment for the prevention or treatment of CIPN.2 Understanding the relationship between CIPN and quality of life (QOL) is important not only for patients but also for nurses caring for individuals with cancer. To thoroughly understand how CIPN affects the QOL of our patients, there is a need to capture the overall experience of living with CIPN from the patient’s perspective. Few qualitative studies conducted in recent years have attempted to understand

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CIPN from the subjective perspective. Bakitas conducted an excellent qualitative study that described the CIPN symptom experience and the effect of symptoms on everyday life.3 Patients described CIPN as “background noise” that can be overshadowed by other treatment- and disease-related issues, but CIPN’s unpleasantness can interfere with daily activities and socialization. The awareness of CIPN was often inaccurate and its occurrence surprising because most patients did not recall being educated or advised to anticipate the symptoms. When monitoring CIPN, clinicians primarily focused on how the symptoms affected motor functionality (dexterity, gait) but rarely asked about CIPN’s effect on daily living. CIPN caused disruptions with daily living, leisure, work, and family roles. Patients who reported a pain component to their CIPN often experienced functional difficulties, fatigue, sleep disturbance, and mood disturbances. Patients also described the use of multiple processes in learning to live with CIPN. Similar results have been described in another qualitative study conducted by Closs and colleagues4 as well as in our work at the City of Hope. Our descriptive, mixed methods study explored the impact of peripheral neuropathy on QOL in 53 patients with colorectal cancer. Our qualitative data suggest that although patients did not find the dysesthesias and cold-related allodynia distressing, the acute sensations were surprising when first experienced, and patients made adjustments in life (eating and drinking habits related to cold foods and beverages) to cope with these neuropathic symptoms.5 There are several ways that nurses can contribute clinically and scientifically to the sparse evidence in CIPN prevention and management. By keeping abreast with the most current information on CIPN management, nurses are better equipped to provide quality care and support to cancer patients living with CIPN. The prompt assessment of symptoms related to CIPN is essential for determining appro-

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priate and effective management strategies. The assessment of CIPN should continue throughout treatment and beyond, because chronic CIPN can occur months and even years beyond treatment.6 Most important, nurses must be vigilant in educating patients on what to expect with CIPN. It is evident from some of the current evidence that clinicians are not doing an optimal job of providing patients with timely information on CIPN. Beyond pharmacologic treatments, it may also be helpful for nurses to discuss nonpharmacologic supportive care strategies to cope with CIPN, such as personal safety measures to prevent burns, falls, or other problems that may be related to sensory motor deficits.7 Finally, for nurses who are committed to advancing the science of CIPN management, there is a need for more studies and evidence that focuses on outcomes beyond the efficacy of therapeutic agents.8 Studies that characterize the time of onset, duration, and resolution or persistence of CIPN are needed to develop a more comprehensive and subjective understanding of CIPN.1 ●

References 1. Paice JA. Clinical challenges: chemotherapy-induced peripheral neuropathy. Semin Oncol Nurs. 2009;25(suppl 1):S8-S19.

2. Visovsky C, Collins M, Abbott L, et al. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2007;11:901-913.

3. Bakitas MA. Background noise: the experience of chemotherapy-induced peripheral neuropathy. Nurs Res. 2007;56;323-331.

4. Closs SJ, Staples V, Reid I, et al. Managing the symptoms of neuropathic pain: an exploration of patients’ experiences. J Pain Symptom Manage. 2007;34:422-433.

5. Sun V, Otis-Green S, Shibata S, et al. Symptom concerns and QOL in oxaliplatin-induced peripheral neuropathy. 2008 ASCO Gastrointestinal Cancers Symposium. Abstract 503.

6. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy.

J Peripher Nerv Syst. 2008;13:27-46.

7. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376.

8. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33:15-49.

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at www.thEonCologypharmaCist.Com Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010 slowing the rate of recovery of voltage-activated sodium channels. Carbamazepine was tested in the prevention of CIPN in a single nonrandomized pilot study consisting of 10 previously treated patients with advanced colorectal cancer receiving oxaliplatin, leucovorin, and 5-fluorouracil. Results indicated the absence of World Health Organization grade 2 to 4 neuropathy development in the patients treated with carbamazepine compared with 30% who experienced grade 2 to 4 neuropathy in a historical control group.51 In a randomized controlled trial, von Delius and colleagues tested the efficacy and safety of carbamazepine for the prevention of oxaliplatin-associated neuropathy in 36 patients with advanced colorectal cancer.52 No differences were found between the groups on assessments of neurotoxicity. Further randomized, placebo-controlled trials are necessary to determine if carbamazepine can be used to prevent or treat CIPN.

Glutamine Glutamine, a neutral gluconeogenic nonessential amino acid, is thought to have neuroprotective effects for patients receiving paclitaxel.53 In one study, 12 women with advanced breast cancer were given glutamine 10 g daily for 4 days starting 24 hours after completion of paclitaxel and 33 women did not receive glutamine.

Only 8% of women treated reported dysesthesias in the fingers and toes compared with 40% of the women who did not receive glutamine.54 In another study, Stubblefield and colleagues examined the neuroprotective effect of glutamine on 46 patients scheduled to receive high-dose paclitaxel before stem cell transplant.53 Seventeen patients received glutamine, and 29 patients made up the control group. Responses to questions about neurologic symptoms and results of electrodiagnostic testing indicate that those who received glutamine developed less weakness, loss of vibratory sensation, and toe numbness compared with those in the control group.

In a nonrandomized pilot study, Wang and colleagues tested the efficacy of glutamine for reducing the incidence and severity of peripheral neuropathy in patients receiving oxaliplatin in 86 patients with colorectal cancer.55 Glutamine supplementation significantly reduced the incidence and severity of oxaliplatin-induced neuropathy. The percentage of grade 3 to 4 sensory neuropathy was lower in the glutamine group after four cycles of treatment and remained that way for six cycles. The results suggest that glutamine is a potential neuroprotective agent but must be studied in larger populations in a randomized, placebo-controlled trial. Concerns still exist about glutamine supplements protecting tumor cells from the cytotoxic effects of chemotherapy.55 Glutathione Some evidence shows that glutathione, a naturally occurring thiol tripeptide, may also prevent neurotoxicity induced by platinum compounds by preventing the initial accumulation of platinum adducts in the dorsal root ganglia.56 Three studies testing the potential neuroprotective effects of glutathione have been published.5759 Following all cycles of chemotherapy, the incidence of neuropathy was greater in the placebo-treated arms compared with those who received glutathione. Further randomized clinical trials are needed to test the effectiveness of this agent in CIPN.

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Treatment of CIPN Historically, treatments for CIPNs have been supportive.60 Neuropathic pain management is aimed at the reduction of symptoms, generally by suppressing neuronal activity, not glial cell activation, which has also recently been associated with the development and maintenance of chronic pain states.13,61 At this time, no medications exist that can fully relieve the sensory and motor loss associated with advanced CIPNs. The needs of patients with CIPNs are largely unmet because of the absence of adequate assessment and evidence-based treatments that could be widely applied across clinical CIPN patient populations and could potentially prevent or mitigate this increasingly common clinical problem.11 Gabapentin Gabapentin is an antiepileptic medication that has demonstrated efficacy for the treatment of neuropathic pain, possibly in patients with CIPNs. Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid, but it is not believed to act on the same brain receptors.

Although the exact mechanism of action is unknown, the therapeutic action of gabapentin on neuropathic pain is thought to involve voltage-gated calcium channels. In a phase 3, randomized, double-blind, placebocontrolled, crossover trial, 115 patients with symptomatic CIPN were randomized to receive either gabapentin or placebo over the course of two 6-week phases separated by a 2-week “washout” period. No significant differences were reported between the groups on scores of symptom distress or mood states. The only significant difference between the groups was in the McGill Pain Rating Index, which showed lower pain in the gabapentin group at the end of the first 6-week treatment period. The study failed to demonstrate the benefit of gabapentin to treat CIPN symptoms.62 Nortriptyline Nortriptyline, a tricyclic antidepressant, works by blocking the reuptake of serotonin and norepinephrine in the pain-modulating system within the CNS.63 In a randomized, double-blind, placebo-controlled, crossover study, 51 patients treated with cisplatin received escalating doses of nortriptyline up to 100 mg/day over a 4-week period. Responses to questionnaires concerning pain, sleep, QOL, and neuropathic symptoms also indicate a relatively modest benefit in cisplatin-induced paresthesia over the placebo group. Objective measures of neuropathy were not used in this small pilot study, and thus the effectiveness of nortriptyline in reducing paresthesias related to CIPN cannot be established.

Acetyl L-carnitine Acetyl L-carnitine is an acetylated form of L-carnitine that has shown neuroprotective effects and may be useful in treating peripheral nerve injury. Two small studies examined the use of acetyl L-carnitine in the treatment of preexisting paclitaxel- or cisplatin-induced peripheral neuropathy.64 Patients who received acetyl L-carnitine showed improvement in neuropathy symptoms and in objective measures of sensory and motor neuropathy; however, small sample sizes and nonrandomized onegroup designs limit these studies. Further randomized

clinical trials are necessary before acetyl L-carnitine can be recommended as a potential treatment for CIPN.

Alternative treatments Acupuncture In one case series study testing the use of acupuncture in five patients with CIPN, this modality was found to improve sensation and gait, resulting in decreased analgesic use. Control of symptoms persisted for 6 months for four of the five patients treated.65 Physical activity/exercise Three relatively small studies examined progressive resistance exercise, aerobic exercise, and stretching exercises in the treatment of diabetic peripheral neuropathy and myotonic dystrophy. All three studies found significant improvement in stance, functional reach, and peroneal and sural motor nerve conduction velocity. The findings of these studies should be interpreted with caution, as they have not been replicated in patients who have or are at risk for CIPN.66-68 Pulsed infrared light therapy (PILT) PILT, also called anodyne therapy, consists of delivering infrared light to the feet of patients with diabetes, but it has not been tested as a treatment for CIPN. Following a series of treatments, significant improvement in sensation, neuropathic symptoms, and pain was evident in most patients.69 Prendergast and colleagues found anodyne therapy improved sensory impairments as measured by peroneal nerve function and current perception thresholds in 26 participants after 10 treatments delivered over 2 weeks, each lasting 40 minutes.70 In another study, significant improvements in sensation were found when PILT treatments were given for 30 minutes three times a week over an 8-week period.71 Transcutaneous electrical nerve stimulation (TENS) TENS has been tested in patients with diabetic neuropathy, but not in patient populations with cancer. In a randomized clinical trial of 19 patients with diabetic neuropathy, Forst and colleagues compared TENS with pseudostimulation by an electrically inactive device.72 Significant subjective improvements in neuropathy symptoms, including numbness, pain, and allodynia, were demonstrated in 70% of treatment group participants compared with 29% in the control group.

Capsaicin ointment Capsaicin has been studied for the treatment of peripheral neuropathy in the diabetic population, with inconclusive results that prevent recommendation at this time. Although 10 patients who received capsaicin completed a study with a significant decrease in hypoesthesia, two patients discontinued treatment due to erythema or generalized allergic skin reaction at the application site.73 Conclusions Evidence supports the need for careful and ongoing assessment of CIPNs in patients receiving chemotherapy. Specifically, clinical practice procedures need to be developed that address the need for standardized assessContinued on page 22

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ments of CIPN, the frequency of CIPN evaluations while undergoing chemotherapy, and the length of assessments once treatment is completed. In addition, there is a need to determine the clinically significant amount of sensory and motor changes noted in either sensory or motor nerves that may warrant a dose reduction in the treatment drug and/or the need for a rehabilitation evaluation by a physical or occupational therapist. In the absence of evidence-based prevention or treatment modalities for CIPNs, clinicians must educate their patients about the functional changes they may expect to occur as a result of neurotoxic chemotherapy and assist patients in developing strategies to manage limitations resulting from CIPNs. ●

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2. Chemotherapy-induced peripheral neuropathies (CIPNs): a biobehavioral approach. In: Moore RJ, ed. Biobehavioral Approaches to Pain. New York, NY: Springer; 2008.

3. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376.

4. Kannarkat G, Lasher EE, Schiff D. Neurologic complications of chemotherapy agents. Curr Opin Neurol. 2007;20:719-725.

5. Paice JA. Peripheral neuropathy: experimental findings, clinical approaches. J Support Oncol. 2007;5:61-63.

6. Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep. 2006;10:279-287.

7. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Expert Opin Drug Saf. 2004;3:535-546.

8. Dunlap B, Paice JA. Chemotherapy-induced peripheral neuropathy: a need for standardization in measurement. J Support Oncol.

2006;4:398-399.

9. Paice JA. Chemotherapy-induced peripheral neuropathy: a dangerous but understudied syndrome. Pain Management SIG Newsletter.

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10. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy.

Semin Oncol. 2006;33:15-49.

11. Postma TJ, Heimans JJ. Grading of chemotherapy-induced peripheral neuropathy. Ann Oncol. 2000;11:509-513.

12. Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain. 2006;122:245-257.

13. Trask PC, Teno JM, Nash J. Transitions of care and changes in distressing pain. J Pain Symptom Manage. 2006;32:104-109.

14. Mantyh PW. Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci. 2006;7:797-809.

15. Cavaletti G, Bogliun G, Marzorati L, et al. Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy. Ann Oncol. 2004;15:1439-1442.

16. Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev. 2006;51:240-264.

17. Watkins LR, Hutchinson MR, Milligan ED, Maier SF. “Listening” and “talking” to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. Brain Res Rev. 2007;56:148-169.

18. Watkins LR, Hutchinson MR, Ledeboer A, et al. Norman Cousins Lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun.

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19. Wieseler-Frank J, Jekich BM, Mahoney JH, et al. A novel immuneto-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus. Brain Behav Immun.

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20. Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med. 2005;257:139-155.

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24. Verstappen CC, Postma TJ, Hoekman K, Heimans JJ. Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer. J Neurooncol.

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25. Dantzer R, O’Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46-56.

26. Visovsky C, Collins M, Abbott L, et al. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2007;11:901-913.

27. Joseph EK, Levine JD. Comparison of oxaliplatin- and cisplatininduced painful peripheral neuropathy in the rat. J Pain.

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28. Garrido N, Pérez-Martos A, Faro M, et al. Cisplatin-mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels. Biochem J. 2008;414:93-102.

29. Souid AK, Tacka KA, Galvan KA, Penefsky HS. Immediate effects of anticancer drugs on mitochondrial oxygen consumption. Biochem Pharmacol. 2003;66:977-987.

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31. Cavaletti G, Frigeni B, Lanzani F, et al; for the Italian NETox Group. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale. J Peripher Nerv Syst. 2007;12:210-215.

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52. von Delius S, Eckel F, Wagenpfeil S, et al. Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Invest New Drugs. 2007; 25:173-180.

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53. Stubblefield MD, Vahdat LT, Balmaceda CM, et al. Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clin Oncol (R Coll Radiol). 2005;17:271-276.

54. Vahdat L, Papadopoulos K, Lange D, et al. Reduction of paclitaxelinduced peripheral neuropathy with glutamine. Clin Cancer Res. 2001;7:1192-1197.

55. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. 2007;12:312-319.

56. Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Cancer Care.

2004;12:619-625.

57. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebocontrolled trial. J Clin Oncol. 2002;20:3478-3483.

58. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol. 1997;8:569-573.

59. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial.

J Clin Oncol. 1995;13:26-32.

60. Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep. 2006;10:279-287.

61. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361-1368.

62. Rao RD, Michalak JC, Sloan JA; for the North Central Cancer Treatment Group. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy. Cancer. 2007; 110:2110-2118.

63. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain. 2002;98:195-203.

64. Maestri A, De Pasquale Ceratti A, Cundari S, et al. A pilot study on the effect of acetyl-L-carnitine in paclitaxel and cisplatininduced peripheral neuropathy. Tumori. 2005;91:135-138.

65. Wong R, Sagar S. Acupuncture treatment for chemotherapyinduced peripheral neuropathy—a case series. Acupunct Med. 2006;24:87-91.

66. Lindeman E, Leffers P, Spaans F, et al. Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial. Arch Phys Med Rehabil.

1995;76:612-620.

67. Richardson JK, Sandman D, Vela S. A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Arch Phys Med Rehabil. 2001;82:205-209.

68. Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications. 2006;20:216-223.

69. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy. Diabetes Care. 2004;27:168-172.

70. Prendergast JJ, Miranda G, Sanchez M. Improvement of sensory impairment in patients with peripheral neuropathy. Endocr Pract.

2004;10:24-30.

71. Arnall DA, Nelson AG, Lopez L, et al. The restorative effects of pulsed infrared light therapy on significant loss of peripheral protective sensation in patients with long-term type 1 and type 2 diabetes mellitus. Acta Diabetol. 2006;43:26-33.

72. Forst T, Nguyen M, Forst S, et al. Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new salutaris device. Diabetes Nutr Metab.

2004;17:163-168.

73. Forst T, Pohlmann T, Kunt T, et al. The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy. Acta Diabetologica. 2002;39:1-6.

74. Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer. J Clin Oncol.

2003;21:1767-1774.

75. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol.

2007;25:4028-4029.

76. Hochster HS, Grothey A, Shpilsky A, Childs BH. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on response to FOLFOX+bevacizumab (BEV) in the CONcePT trial.

2008 ASCO Gastrointestinal Cancers Symposium. Abstract 280.

77. Nikcevich DA, Grothey A, Sloan JA, et al. Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N04C7.

J Clin Oncol. 2008;26(May 20 suppl):Abstract 4009.

78. Argyriou AA, Polychronopoulos P, Koustra A, et al. Is advanced age associated with increased incidence and severity of chemotherapyinduced peripheral neuropathy? Support Care Cancer. 2006; 14:223-229.

79. Pace A, Carpano S, Galie E, et al. Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity.

J Clin Oncol. 2007;25(18S):Abstract 9114.

November/December 2009

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ONCOLGY DRUG CODES

Oncology Drug Codes Medications Used for the Treatment of Leukemias The following sections include: • Associated ICD-9-CM codes used for the classification of leukemias • Drugs that have been FDA-approved in the treatment of leukemias. 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 leukemias. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) 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

Associated ICD-9-CM Codes Used for Leukemias 204

Lymphoid leukemia 204.00 Acute—without mention of having achieved remission 204.01 Acute—in remission 204.02 Acute—in relapse

205

204.10 Chronic—without mention of having achieved remission 204.11 Chronic—in remission 204.12 Chronic—in relapse Myeloid leukemia 205.00 Acute—without mention of having achieved remission 205.01 Acute—in remission 205.02 Acute—in relapse

206

205.10 Chronic—without mention of having achieved remission 205.11 Chronic—in remission 205.12 Chronic—in relapse Monocytic leukemia 206.00 Acute—without mention of having achieved remission 206.01 Acute—in remission 206.02 Acute—in relapse 206.10 Chronic—without mention of having achieved remission 206.11 Chronic—in remission 206.12 Chronic—in relapse

Generic (brand) name

HCPCS code: code description

alemtuzumab (Campath) arsenic trioxide (Trisenox) asparaginase (Elspar) azacitidine (Vidaza) bendamustine (Treanda) betamethasone (Celestone Soluspan)

J9010: injection, alemtuzumab, 10 mg J9017: injection, arsenic trioxide, 1 mg J9020: injection, asparaginase, 10,000 units J9025: injection, azacitidine, 1 mg J9033: injection, bendamustine HCl, 1 mg J0702: injection, betamethasone acetate, 3 mg and betamethasone sodium phosphate, 3 mg J8510: busulfan, oral, 2 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0172: chlorambucil, oral, 2 mg

busulfan (Myleran) chlorambucil (Leukeran) chlorambucil (Leukeran)

November/December 2009

FDAapproved for leukemias

NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

$660.90

$570.22

96413, 96415

$43.58

$37.44

96413, 96415

$70.42

$58.01

96401, 96413

$5.74

$4.87

$21.60

$18.53

$6.85

$6.56

$4.46

$3.22

N/A

NDC level pricing $3.86

NDC level pricing S0172: not payable by Medicare

N/A

96401, 96409, 96413 96413 11900, 11901, 20600, 20605, 20610, 96372

N/A

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TOPNov_Dec09 11/17/09 10:16 AM Page 24

ONCOLGY DRUG CODES

Generic (brand) name

HCPCS code: code description

FDAapproved for leukemias

J9065: injection, cladribine, per 1 mg J9027: injection, clofarabine, 1 mg J8530: cyclophosphamide, oral, 25 mg J9090: cyclophosphamide, 500 mg J9091: cyclophosphamide, 1.0 gram J9092: cyclophosphamide, 2.0 grams J9100: injection, cytarabine, 100 mg J9110: injection, cytarabine, 500 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified daunorubicin J9150: injection, (Cerubidine) daunorubicin, 10 mg dexamethasone J1100: injection, (Decadron) dexamethasone sodium phosphate, 1 mg dexamethasone J8540: dexamethasone, (Decadron) oral, 0.25 mg doxorubicin HCl J9000: injection, doxorubicin (Adriamycin) hydrochloride, 10 mg fludarabine J9185: injection, (Fludara) fludarabine phosphate, 50 mg gemtuzumab J9300: injection, gemtuzumab ozogamicin (Mylotarg) ozogamicin, 5 mg hydrocortisone J1720: injection, (Solu-Cortef) hydrocortisone sodium succinate, up to 100 mg hydroxyurea J8999a: prescription drug, (Hydrea) oral, chemotherapeutic, not otherwise specified hydroxyurea S0176: hydroxyurea, (Hydrea) oral, 500 mg

cladribine (Leustatin) clofarabine (Clolar) cyclophosphamide oral (Cytoxan) Cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cytarabine (Cytosar-U) cytarabine (Cytosar-U) dasatinib (Sprycel)

idarubicin (Idamycin) imatinib (Gleevec) imatinib (Gleevec) interferon alfa-2b (Intron-A) mechlorethamine (Mustargen) mercaptopurine (Purinethol)

24

J9211: injection, idarubicin hydrochloride, 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0088: imatinib, 100 mg J9214: injection, interferon, alfa-2b, recombinant, 1 million units J9230: injection, mechlorethamine hydrochloride (nitrogen mustard), 10 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified

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NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

$58.20

$25.64

96413, 96415

$135.00

$116.40

96413, 96415

$2.09

$0.81

$30.34

$21.51

96409, 96413, 96415

$54.62

$43.03

96409, 96413, 96415

$98.30

$86.06

96409, 96413, 96415

$3.60

$1.72

$10.20

$3.92

NDC level pricing $25.20

NDC level pricing $15.24

$0.15

$0.08

$0.09

$0.38

11900, 11901,20600, 20605, 20610, 96372, 96374 N/A

$13.20

$3.69

96409

$330.32

$154.27

96413

$3,104.82

$2,622.30

96413, 96415

$2.46

$2.92

96365, 96366, 96372, 96374

NDC level pricing $1.28

NDC level pricing S0176: not payable by Medicare $98.56

$381.56 NDC level pricing $42.12

N/A

96409, 96413, 96415, 96450 96409, 96413, 96415, 96450 N/A

96409, 96413

N/A

N/A

96409

NDC level pricing S0088: not payable by Medicare $15.84

96372, 96401

$178.71

$147.34

96409

NDC level pricing

NDC level pricing

N/A

$21.90

N/A

N/A

November/December 2009

FDAapproved for leukemias

NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

Generic (brand) name

HCPCS code: code description

mercaptopurine (Purinethol)

S0108: mercaptopurine, oral, 50 mg

$4.09

methotrexate

J8610: methotrexate, oral, 2.5 mg J9250: methotrexate sodium, 5 mg J9260: methotrexate sodium, 50 mg J1030: injection, methylprednisolone acetate, 40 mg J1040: injection, methylprednisolone acetate, 80 mg J2920: injection, methylprednisolone sodium succinate, up to 40 mg J2930: injection, methylprednisolone sodium succinate, up to 125 mg J7509: methylprednisolone, oral, per 4 mg J9293: injection, mitoxantrone hydrochloride, per 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9266: injection, pegaspargase, per single dose vial J3490a: unclassified drugs

$3.56

S0108: not payable by Medicare $0.12

$0.27

$0.21

$2.68

$2.12

$5.84

$3.79

$11.46

$7.27

$2.36

$2.56

$4.15

$3.45

$0.54

$0.06

$116.50

$66.77

NDC level pricing $3,280.00

NDC level pricing $2,747.51

methotrexate sodium methotrexate sodium methylprednisolone (Depo-Medrol) methylprednisolone (Depo-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Medrol) mitoxantrone (Novantrone) nilotinib (Tasigna) pegaspargase (Oncaspar) peginterferon alfa-2a (Pegasys) peginterferon alfa-2a (Pegasys) peginterferon alfa-2b (Peg-Intron)

S0145: injection, pegylated interferon alfa-2a, 180 mcg per mL J3490a: unclassified drugs

peginterferon alfa-2b (Peg-Intron)

S0146: injection, pegylated interferon alfa-2b, 10 mcg per 0.5 mL pentostatin J9268: injection, (Nipent) pentostatin, per 10 mg prednisolone (Millipred, J7510: prednisolone, Orapred, Veripred) oral, per 5 mg prednisone J7506: prednisone, oral, per 5 mg rituximab J9310: injection, (Rituxan) rituximab, 100 mg teniposide Q2017: injection, (Vumon) teniposide, 50 mg thioguanine J8999a: prescription drug, (Tabloid) oral, chemotherapeutic, not otherwise specified tretinoin J8999a: prescription drug, (Vesanoid) oral, chemotherapeutic, not otherwise specified

November/December 2009

NDC level pricing $589.12

NDC level pricing $106.42

$2,182.80

NDC level pricing S0145: not payable by Medicare NDC level pricing S0146: not payable by Medicare $1,426.47

ONCOLGY DRUG CODES

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CPT administration codes N/A

N/A 96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 11900, 11901, 20600, 20605, 20610, 96372 11900, 11901, 20600, 20605, 20610, 96372 96365, 96366, 96372, 96374 96365, 96366, 96372, 96374 N/A 96409, 96413 N/A

96401, 96413, 96415 96372

96372

96372

96372

96409, 96413

$0.56

$0.02

N/A

$0.05

$0.05

N/A

$664.32

$563.33

96413, 96415

$376.55

$325.57

96413, 96415

NDC level pricing NDC level pricing

NDC level pricing NDC level pricing

N/A

N/A

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ONCOLGY DRUG CODES

Generic (brand) name

HCPCS code: code description

vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS)

J9370: vincristine sulfate, 1 mg J9375: vincristine sulfate, 2 mg J9380: vincristine sulfate, 5 mg

FDAapproved for leukemias

NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

$8.12

$5.72

96409

$16.24

$11.44

96409

$40.60

$28.59

96409

When billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for Tasigna) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement.

References • HCPCS Level II Expert 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 4; RJ Health Systems International LLC; 4th Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN Drugs & Biologics Compendium; 2009; www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 4th Quarter 2009 (effective dates 10/1/09-12/31/09).

a

Prices listed herein are effective as of November 1, 2009.

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.

This information was supplied by:

MORE ONCOLOGY DRUG CODES ONLINE Lymphomas Brain Cancers Head and Neck Cancers PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

www.theoncologypharmacist.com

Recent FDA Approvals Folotyn for Relapsed or Refractory Peripheral T-cell Lymphoma The first single-agent therapy for relapsed or refractory peripheral T-cell lymphoma, pralatrexate injection (Folotyn, Allos Therapeutics), has been approved by the US Food and Drug Administration (FDA).

The approval for this indication was based on overall response rate. At current, improvement in progression-free survival and overall survival has not been demonstrated. Additional clinical studies are ongoing to verify and describe the agent’s clinical benefits.

Cervarix Cervical Cancer Vaccine The FDA has approved a new human papillomavirus (HPV) bivalent (types 16 and 18) vaccine, recombinant (Cervarix, GlaxoSmithKline) for the prevention of cervical precancers and cervical cancer associated with oncogenic HPV types 16 and 18 for use in girls and young

26

women aged 10 to 15 years. The approval was based on a study that showed the vaccine to be 93% efficacious in the prevention of cervical precancers associated with HPV 16 and 18 in women without evidence of current infection or prior exposure to these types of HPV at time of vaccination.

Votrient for Advanced Renal Cell Carcinoma The FDA has approved the oral agent pazopanib (Votrient, GlaxoSmithKline) for treatment of advanced renal cell carcinoma. The agent, which interferes with angiogenesis, was approved based on a 435-patient study that examined progression-free survival (PFS). PFS averaged 9.2 months for patients who received the drug compared with 4.2 months for those who did not.

Elitek for Management of Plasma Uric Acid Levels The FDA has approved rasburicase

G REEN H ILL H EALTHCARE C OMMUNICATIONS

(Elitek, sanofi-aventis US) for use in the initial management of plasma uric acid (PUA) levels in adults with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis syndrome and subsequent elevations of PUA. Approval was based on a phase 3 trial that demonstrated that rasburicase significantly reduced PUA levels compared with oral allopurinol (the current standard therapy).

Arzerra for Chronic Lymphocytic Leukemia The FDA has granted accelerated approval of ofatumumab (Arzerra, GlaxoSmithKline/Genmab) for use in patients with chronic lymphocytic leukemia (CLL) that is refractory to fludarabine and alemtuzumab. Approval was based on a study in which 42% of patients with treatment-refractory CLL responded to treatment with ofatumumab, a monoclonal antibody drug

targeting the CD20 protein on B cells.

These patients had a median duration of response of 6.5 months. Common adverse events included neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.

Istodax for Cutaneous T-cell Lymphoma The FDA has approved romidepsin (Istodax, Gloucester Pharmaceuticals) for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Approval of the histone deacetylase inhibitor was based on efficacy data from two studies totaling 167 patients. The overall response rates, defined as the proportion of patients with confirmed complete response or partial response, were 34% and 35%.

The complete response rate was 6% in both studies. ● November/December 2009

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NHL Mantle Cell Trial Now Recruiting Investigators and Enrolling Study Participants Celgene CC-5013-MCL-001

A Phase 2 Study for Patients With Relapsed/Refractory Mantle Cell Non-Hodgkin’s Lymphoma Primary Investigator André Goy, MD Primary Objective To determine the tumor response and duration of response of lenalidomide monotherapy in subjects with mantle cell lymphoma (MCL) who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib Key Eligibility Criteria* • Individuals with MCL previously treated with all of the following (alone or in combination): – Bortezomib† – An anthracycline or mitoxantrone – Rituximab – Cyclophosphamide • Individuals must have documented relapse after bortezomib treatment or be refractory to bortezomib • Excluding individuals who are candidates for high-dose chemotherapy/allogeneic stem cell transplant *Additional criteria apply. †Note: When the agent bortezomib is mentioned this also includes ANY BORTEZOMIB-CONTAINING REGIMEN.

Study Design

Pretreatment Phase (4 Weeks)

N=133

• MCL diagnosis confirmed by local pathological review

Treatment Phasea (until disease progression)

• Lenalidomide starting dose 25 mg po once dailyb

Lenalidomide will be dosed po once daily on days 1-21 of each 28-day cycle.

Subjects with creatinine clearance ≥30 mL/min but <60 mL/min will receive a lower starting dose of lenalidomide 10 mg po once daily.

Dose may be escalated to 15 mg po once daily if no dose-limiting toxicities occur during the first 2 cycles.

a

b

Investigational use of lenalidomide.

For more information contact Deborah Ingenito, Celgene Study Manager dingenito@celgene.com (908) 673-9581 www.clinicaltrials.gov (NCT00737529)

EMERGETM is a trademark of Celgene Corporation. ©2008 Celgene Corporation 10/08 CELGO8010T

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CANCER CENTER PROFILE

Cancer Center Profile University of Pittsburgh Medical Center Cancer Centers and Cancer Institute

T

he University of Pittsburgh Medical Center (UPMC) Cancer Centers work in tandem with the University of Pittsburgh Cancer Institute (UPCI) to offer advances in cancer prevention, early detection, diagnosis, and treatment throughout a three-state region (western Pennsylvania, Ohio, West Virginia). UPCI has been designated as a Comprehensive Cancer Center by the National Cancer Institute (NCI).

UPCI ranked 11th in funding from the NCI in 2007, and 12th among U.S. News & World Report’s “Best of the Best” cancer programs in the nation.

UPMC’s network of 2300 physicians, scientists, staff, and other healthcare professionals provides clinical care to 30,000 patients annually at its facilities while engaging in cutting-edge cancer research. Medical, radiation, and surgical oncologists and disease-specific specialists collaborate closely in a model of multidisciplinary care. Ancillary service providers in behavioral medicine, rehabilitation, social work, palliative care, nutrition, and genetic counseling are incorporated into the multidisciplinary

team to ensure that all aspects of care are addressed.

The hub and satellite network of UPMC Cancer Centers consists of more than 45 community-based locations in western Pennsylvania and two centers in Ireland.

The hub-and-spoke model ensures extensive distribution of radiation therapy and medical oncology facilities throughout the tri-state region, said Barry Lembersky, MD, a medical oncologist. “Our pathways of standard of care are uniform throughout this area, and the full array of clinical trials is available to patients at all satellite facilities,” he said.

Thirteen areas of expertise The range of knowledge covers virtually all types of adult cancer, with 13 areas of expertise being recognized, including a world-renowned melanoma program. Other programs are devoted to brain cancers, breast cancer, colon and gastrointestinal cancers, head and neck cancers, leukemias and lymphomas, liver cancer, lung cancer, gynecologic cancers, prostate and urologic cancers, and stemcell transplantation.

The Melanoma and Skin Cancer Program consists of both basic and clinical research and has patients coming from all over the world to participate in clinical trials for melanoma under the direction of John Kirkwood, MD. Major areas of research range from the development of a melanoma vaccine to the search for biomarkers to aid in the devel-

opment of personalized treatments.

UPMC was one of the first centers to use a digital mole mapping system to assess high-risk patients for skin cancer.

In addition, UPMC has “a well-organized pancreatic cancer program whereby patients with all forms of pancreatic cancer and all stages are seen in a multidisciplinary clinic with innovative clinical trials in the preoperative setting and the adjuvant and metastatic setting,” Lembersky said.

For instance, a preoperative clinical trial of gemcitabine with radiation therapy and bevacizumab is in progress, with the goal of evaluating the downstaging and histologic changes that occur with such treatment. “That’s a pretty novel approach that holds promise not only for better outcome but for the paradigm of evaluating new drugs and new drug combinations; give the drugs prior to pancreatic resection to look for surrogate markers of response (ie, tumor necrosis), and correlate it with long-term outcome,” he said. “The treatment has been very well tolerated and resection rates are high. In most patients, there is evidence of significant necrosis and chemotherapy or radiation effect, and what that means for survivorship is uncertain at this time.”

Other research involves the testing of a vaccine for colon cancer prevention in persons at high risk for developing the disease. In a novel approach, the vaccine is directed against an abnormal variant of the gene MUC1, which is altered and produced in excess in advanced adeno-

Clinical Pharmacy Specialist Spotlight: James Natale, PharmD

T

he dramatic changes these advances and relishthat have occurred in es the learning environoncology pharmacy over ment as well as the opporthe past decade have presented tunity to be involved in James Natale, PharmD, with a total patient care. continuous series of challenges, “What we did just a each of which he has found few years ago, we’re not rewarding. doing today,” he said.

Natale, who did his under“The interesting thing graduate work at Duquesne about tumors is that University, was an oncology resthere will probably never ident at the University of James Natale, PharmD be a ‘silver bullet’ for Pittsburgh Medical Center oncology. Each tumor (UPMC) Cancer Centers in 1998 and has such various mechanisms; not just 1999, before the advent of targeted ther- different tumors types like lung cancer apies and the use of genomics in selecting versus breast cancer, but even within pharmacotherapy. As a clinical pharma- the breast tumor itself is a heterogecy specialist at UPMC Cancer Centers neous mix of clonal populations of since 2000, he now takes advantage of cells. We’re constantly looking at new 28

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markers of these cells and ways to combine agents that attack these new markers.”

With three colleagues, he rotates through three major services: hematology, oncology, and bone marrow transplant. This set-up affords him an opportunity to stay current in each service. “You see everything, so you don’t lose touch,” he said. “It’s advantageous professionally and personally because it lessens the chance of burning out while always presenting a new challenge. As you come back to a service that you did months ago, there’s always some new drug you might be working with.” ● —WK

mas and cancer. Stimulating an immune response against the protein encoded by MUC1 in precancerous growths may not only trigger the immune system to destroy the abnormal cells to prevent progression to cancer but may also prevent polyp recurrence. MUC1 vaccines have been tested for safety and immunogenicity in patients with late-stage colon cancer and pancreatic cancer.

Integrated drug discovery program allows for range of studies A vertically integrated drug development program at UPCI, called Molecular Therapeutics Drug Discovery, employs 69 members with interests in one of four areas: chemical diversity, molecular targets, pharmacokinetics/ pharmacodynamics, and phase 1 clinical trials. “The goal is to have seamless movement from chemistry into patients, and if we make observations in patients, to be able to take them back and look at them on a mechanistic/molecular level,” said Merrill Egorin, MD, professor of medicine at UPCI. “We are one of the six NCI animal pharmacology contractors, so that puts us in the pipeline of any drug that the NCI is considering putting into patients,” he said. “We’ve got an early signal on what’s coming through the NCI. If we have inplace methods to measure the drug— we’ve defined its metabolism, we know its molecular targets, and we have assays to measure those molecular targets in animal models of tumors—it’s a huge strength when we put in a request to do a first-in-human study or phase 2 study,” Egorin said.

Researchers at UPCI are also involved in a number of ongoing studies with the target poly (ADP-ribose) polymerase (PARP), an enzyme involved in the recognition of DNA damage and repair. By inhibiting PARP, the hope is that the activity of anticancer drugs can be potentiated, presumably by decreasing the resistance or increasing the sensitivity of tumor cells to standard chemotherapy.

BRCA1- and BRCA2-mutated tumors should be specifically sensitive to inhibition of PARP, according to Egorin. This synthetic lethal approach has already been validated in vitro and in preclinical models. “There has already been a clinical study with a different PARP inhibitor that has demonstrated the case that BRCA tumors will respond to this, and the toxicities are essentially none,” he said. ● —Wayne Kuznar November/December 2009

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PHARMACY CAREERS AND EDUCATION

Planning for a Great Residency Project Continued from page 13 the preceptor to monitor the resident closely during this phase. Many residency programs allow for special project time to be assigned, outside of rotational responsibilities. This is one of the phases where the timeline can go haywire, so planning for delays and close preceptor monitoring is necessary for a successful project. Gearing up for the collection of data in the post-phase may require some motivational skills on the part of the preceptor.

Implementation of the intervention can be very rewarding for the resident.

It may include committee decision making, presentations to administrators, designing therapy protocols, conducting process analysis, assisting in developing IT solutions, teaching pharmacists, physicians and patients, or re-engineering a problematic process. As much of this step as possible should be delegated to the resident. These career skills can contribute to the residentâ&#x20AC;&#x2122;s future plans.

Presentation of the project After analysis of the data and formulation of conclusions, the next step in a successful residency project is the preparation of the material for verbal and written presentation. Condensing the study method, data, and conclusions into a 10- to 20-minute presentation can be challenging. Many aspects can be summarized, given the likely audience of the presentation. Most data are best presented in graphic form. Comp-

CONTINUING EDUCATION CREDITS

licated tables and replication of the data-collection form or treatment protocol onto a single slide should be avoided. Adequate time should be devoted to a discussion of the conclusions, implications of the data, and the plan for future work. After initial slide review by the preceptor, the resident should be given opportunities to practice the presentation in front of an audience at least twice before the regional residency conference. In addition, the resident should take every opportunity to present the project internally to appropriate committees, departments, or task forces. Even if there is not time or opportunity for publication, the resident should write a manuscript based on the study, using a format appropriate for publication, to gain the experience of formal, scientific writing.

A successful residency project can provide many important real-world learning experiences for the resident and foster the mentoring relationship between the resident and the preceptor. Advance planning can turn the residency project into a meaningful experience for both the resident and preceptor. â&#x2014;?

Suggested Readings

Current activities at www.COEXM.com include:

â&#x20AC;˘ ASHP Foundation. Residency Research Tips. www.ashpfoun dation.org/MainMenuCategories /ResearchResourceCenter/Foster ingYoungInvestigators/Residency ResearchTips_1.aspx. â&#x20AC;˘ Barletta JF. Conducting a successful residency research project. Am J Pharm Educ.

2008;72:92. â&#x20AC;˘ Hartung DM, Touchette D. Overview of clinical research design. Am J Health Syst Pharm. 2009;66:398-408. â&#x20AC;˘ Lipowski EE. Developing great research questions. Am J Health Syst Pharm. 2008; 65:1667-1670. â&#x20AC;˘ Planas LG. Intervention design, implementation and evaluation.

Am J Health Syst Pharm. 2008; 65:1854-1863.

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

â&#x20AC;˘ Weber RJ, Cobaugh DJ. Developing and executing an effective research plan. Am J Health Syst Pharm. 2009; 65:2058-2065.

November/December 2009

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In the Literature IN THE LITERATURE

Concise Reviews of Studies Relevant to Cancer Care ■ Improved Event-free Survival in Children and Adolescents with Ph+ ALL Background: Imatinib monotherapy has been shown to produce high response rates in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), but with recurrence in months. It has been used in combination with intensive hyperfractionated

cyclophosphamide, vincristine, doxorubicin, and dexamethasone therapy followed by blood and marrow transplantation (BMT) in adults with Ph+ ALL. Efficacy and tolerability with multiagent chemotherapy in children is not known.

Design: Patients with Ph+ ALL aged 1 to 21 years (N = 92) received imatinib 340 mg/m2/day introduced stepwise into their chemotherapy regi-

men. Exposure to imatinib was increased progressively in five patient cohorts that received the agent from 42 to 280 days before maintenance therapy. Ph- ALL patients (N = 65) who received the same chemotherapy without imatinib were used as comparators. Patients with compatible sibling donors underwent BMT with imatinib given for 6 months following.

Presents The Second Annual 2009 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 with this series of newsletters focusing on the challenges in 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

CLINICAL TOPICS: • Retreatment Settings

• Stem Cell Mobilization

• Maintenance Therapy

• Cytogenic Testing

• Do CRs Correlate with Clinical Benefit?

• To Transplant or Not to Transplant…That is the Question

• Perspectives on Relevant End Points of Clinical Trials

• Sequencing Strategies

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

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G REEN H ILL H EALTHCARE C OMMUNICATIONS

Summary: Continuous imatinib exposure improved outcome in patients in the fifth cohort with a 3-year eventfree survival (EFS) of 80% ± 11% (95% CI, 64%-90%). Three-year EFS was similar for patients in the fifth cohort treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66%96%) or sibling-donor BMT (57% ± 22%; 95% CI, 30.4%-76.1%). No appreciable increase in toxicities was associated with adding imatinib to intensive chemotherapy.

Takeaway: Imatinib added to intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL. Outcomes were not superior when imatinib plus chemotherapy was added to BMT. Schultz KR, et al; for the Children’s Oncology Group. J Clin Oncol. 2009 Oct 5. Epub ahead of print.

■ Hormonal Therapy for Prostate Cancer and Comorbid Conditions Background: Hormonal therapy (HT), when combined with external beam radiation therapy (RT), improves cancer-specific and overall survival versus RT alone. A recent postrandomization hypothesis-generating analysis suggested that men with moderate to severe comorbidity did not receive this survival benefit. Which condition(s) eliminates this benefit was not determined.

Design: Risk of all-cause mortality was measured by Cox regression in 5077 men (median age, 69.5 years) with localized or locally advanced prostate cancer. The patients were treated with or without a median of 4 months of neoadjuvant HT followed by RT. Summary: Neoadjuvant HT use was not associated with an increased risk of all-cause mortality in men with no comorbidity (9.6% vs 6.7%, adjusted HR, 0.97; 95% CI, 0.72-1.32; P = .86) or a single coronary artery disease (CAD) risk factor (10.7% vs 7.0%, adjusted HR, 1.04; 95% CI, 0.75-1.43; P = .82) after median follow-ups of 5.0 and 4.4 years, respectively. However, for men with CAD-induced congestive heart failure (CHF) or myocardial infarction (MI), after a median follow-up of 5.1 years, neoadjuvant HT use was significantly associated with an increased risk of all-cause mortality (26.3% vs 11.2%, adjusted HR, 1.96; 95% CI, 1.04-3.71; P = .04).

Takeaway: Neoadjuvant HT use is significantly associated with all-cause mortality among men with a history of CAD-induced CHF or MI. No association was found among men with no comorbidity or a single CAD risk factor.

Nanda A, et al. JAMA. 2009;302: 866-873. ●

November/December 2009

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Meetings JANUARY 2010

3-6

©iStockphoto.com/Kendra Wolford

MIAMI, FL 27th Annual Miami Breast Cancer Conference www.cancerlearning.com

22-24 ORLANDO, FL

©iStockphoto.com/Mike Coddington

2010 Gastrointestinal Cancers Symposium www.asco.org

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MINNEAPOLIS, MN 7th Annual Mayo Clinic Hematology Review www.mayo.edu

©iStockphoto.com/Stas Volik

FEBRUARY 2010

13-16 SAN DIEGO, CA

©iStockphoto.com/Craig Cozart

Scripps Cancer Center’s 30th Annual Conference: Clinical Hematology and Oncology www.scripps.org

25 CHANDLER, AZ Multidisciplinary Head and Neck Cancer Symposium www.headandnecksymposium.org November/December 2009

4-6

BETHESDA, MD 8th International Symposium on Targeted Anticancer Therapies (TAT 2010) www.nddo.org

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 Body as a Whole 86 10 Increased Cough 13 1 combination with chemotherapy or as part of a hematopoietic stem cell transplant. The Fever 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 Flushing 5 0 LDH Increase 7 0 PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Heme 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

MEETINGS

MARCH 2010

5-7

SAN FRANCISCO, CA Genitourinary Cancers Symposium www.asco.org

(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

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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