Document

© 2009 Green Hill Healthcare Communications, LLC

suPPortive care

Continued on page 12

Pharmacy Practice

Systems Approach CanImprove Cancer PainManagementBased on research by Barbara A. Murphy, MD

Challenges of OncologyPharmacy Practice in theCommunity Setting. Part 3

By Michele Woods, PharmD, BCOPIllinois Cancer Center, Peoria

The Leader

in News and

Meeting

Coverage

SAN DIEGO—A systems ap proachto pain and symptom managementcan boost the overall well-being ofpatients with cancer, according toBarbara A. Murphy, MD, a medicaloncologist who works with a multi-disciplinary healthcare team toimprove patients’ quality of life(QOL) and ensure coordinated care.

Speaking at the Scripps CancerCenter’s 29th annual conference onclinical hematology and oncology,she said it is “a moral imperative” toalleviate suffering in cancer patients.Murphy is director of the Pain andSymptom Management Program,Cancer Supportive Care Program;director of the Head and Neck

Research Program; associate profes-sor of medicine (hematology/oncolo-gy) and VICC member, Vanderbilt-Ingram Cancer Center, VanderbiltUniversity, Nashville, Tennessee.She told the audience it wouldrequire planning on their part to

Continued on page 6

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When you are ready to start designing youroncology clinic, you need to consider someof the “soft” requirements of clinic setup as

well as the equipment issues discussed in Part 2 of thisseries (September/October 2009). In this category, I


Pharmacy careers and education

Planning for a Great Residency Project

By Lisa Lohr, PharmD, BCOP, BCPSDepartment of Pharmacy Services, University of Minnesota

Medical Center, Fairview, Minneapolis

Conducting a practice-based major project canbe one of the most rewarding experiences for apharmacy resident. It provides opportunities to

learn real-world skills in project management, processimprovement, and practice-based practice-basedresearch. Working together to reach a common goal

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November/December 2009 • vol. 2, No. 7 www.theoncologypharmacist.com

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

DENVER—Bone loss is a growing concern amongbreast cancer survivors, because aromatase inhibitors areincreasingly being prescribed as adjunctive hormonaltherapy for estrogen receptor–positive breast cancer.Research shows significant decline in bone mineral den-sity (BMD) and increased risk of fracture among womenwho receive aromatase inhibitors.

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

Continued on page 8

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Teva is #1inOncology Products

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EDIT

OR

S’ L

ETTE

RAs this issue goes to press, heateddebate continues about healthcarereform and the possible implications

for oncology practice if the reforms are passed.But even without broader healthcare

reform, actions being taken by the US Foodand Drug Administration (FDA) could havean immediate impact on oncology practition-ers and their patients. The FDA hasannounced the Safe Use Initiative, intend-ed to reduce preventable adverse eventsdue to abuse or misuse of prescriptiondrugs. This initiative signals an expandingrole of the agency. “We’re moving beyondour traditional role of regulator of theindustry and reaching beyond to make surewe’re impacting use in the real world,” saidJanet Woodcock, MD, director of theFDA’s Center for Drug Evaluation andResearch at a news conference.

The FDA is also considering implementa-tion of one of its Risk Evaluation andMitigation Strategies (REMS) for opioids.These agents are mainstays of pain manage-ment in patients with cancer, and, although itis necessary to ensure that they are used safelyand appropriately, it is also important that anyrestrictions on their use are not prohibitive andthey remain available to patients who needthem. As discussed in the article on pain man-agement in this issue, however, good manage-ment of pain goes beyond drug therapy, and amultidisciplinary approach can improve symp-tom control and patients’ quality of life.Good bone health is also essential in

maintaining a patient’s mobility and qualityof life. New reports from the AmericanSociety for Bone and Mineral Researchdemonstrate the importance of preventingbone loss in patients with cancer and provide

reassurance that treatment with bisphos -phonates does not appear to promote devel-opment of cancer, which some earlier reportshad suggested.In addition to responsibilities to our

patients, many of us are involved in practicemanagement decisions and training of resi-dents. Lisa Lohr provides excellent sugges-tions for designing and implementing a resi-dency project. For pharmacists practicing incommunity cancer centers, Michele Woodscontinues her series providing suggestions onorganizational issues and hardware and soft-ware requirements for setting up a clinic inthis setting.We are planning for our third year of pub-

lication and look forward to hearing yourviews on healthcare reform and other issuesof importance to pharmacists and othermembers of the cancer care team. �

A Letter from the Editors

SUSAN GOODIN, PHARMD, FCCP, BCOP

PATRICK MEDINA, PHARMD, BCOP

News NotesNews Updates of Relevance to Everyday Oncology Practice

� Metastatic Lobular Breast Cancer TumorDNA SequencedCanadian researchers, in an attempt to precisely

characterize all somatic coding mutations that occurduring the development and progression of an indi-vidual cancer, have sequenced all 3 billion letters inthe DNA sequence of one estrogen receptor α–posi-tive metastatic lobular breast cancer tumor. With therecent advances in next-generation sequencing, there searc h ers were able to sequence the genome in justweeks. They found 32 somatic nonsynonymous cod-ing mutations in the metastatic tumor. On compari-son with the patient’s primary tumor from 9 yearsprior, five of those mutations were prevalent, six were

present at lower frequencies, 19 were not present,and two were undetermined. The five prevalentmutations were not previously known to researchersas being involved in cancer, thus identifying avenuesto pursue for the development of personalized medi-cines for patients (Nature. 2009;461:809-813).

� PV-10 Compassionate Use ProgramExtended to United StatesPV-10, an investigational agent being developed as

a therapeutic for a broad spectrum of cancers, is nowavailable to patients under the US Food and DrugAdministration’s compassionate use guidelines. Theagent will be available for indications that do not

involve visceral organs and are not subject to enroll-ment in ongoing clinical trials. Cancers that meetthese indications include certain breast cancers, basalcell carcinoma, squamous cell carcinoma, certainhead and neck cancers, and melanoma. The agent iscurrently available through St. Luke’s Hospital &Health Network, Bethlehem, Pennsylvania, and willbe extended to more sites in the upcoming months(Provectus Pharmaceuticals).

� UnitedHealthcare Offers Free Access toNCCN Drugs & Biologics CompendiumUnitedHealthcare 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 com-pendium as a mandated reference for oncology cov-erage policy. In January 2008, UnitedHealthcarebegan basing its benefit coverage for chemotherapydrugs used in outpatient settings on the compendi-um as well. The free access reflects the company’songoing commitment to ensuring physicians andpatients have access to evidenced-based care. Theaccess will also help save time by eliminating timespent on phone calls for coverage confirmation(UnitedHealthcare).

� 2010 Medicare Physician Fee ScheduleThe Centers for Medicare & Medicaid Services

(CMS) announced the final policies and paymentrates for services rendered during the 2010 calendaryear by practitioners who are paid under theMedicare Physician Fee Schedule (MPFS). In a suc-cess for radiation oncology, CMS will not implementits proposed 19% cut; instead radiation oncology pay-ments will be reduced by only 5% over the next 4years. CMS will also continue to use specialty sup-plemental survey data to determine practice expens-es for medical oncology. In a statement, AmericanSociety of Clinical Oncology CEO Allen S. Lichter,MD, expressed: “We are deeply concerned that thesecuts will continue to erode access to cancer care inthe United States. �

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, TheOncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: [email protected]. 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 con-firmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all orpart of any article published in this journal should be addressed to REPRINT PERMISSIONSDEPARTMENT, 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 necessarilyreflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertise-ment or other product mention in The Oncology Pharmacist® should not be construed as an endorsement ofthe product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with ques-tions about the features or limitations of the products mentioned. Neither the Editorial Board nor thePublisher assumes any responsibility for any injury and/or damage to persons or property arising out of orrelated to any use of the material contained in this periodical. The reader is advised to check the appropri-ate medical literature and the product information currently provided by the manufacturer of each drug tobe administered to verify the dosage, the method and duration of administration, or contraindications. It isthe responsibility of the treating physician or other healthcare professional, relying on independent expe-rience 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 respon-sibility, 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, 241Forsgate 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 OncologyPharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part ofthis 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 sys-tem, without written permission from the Publisher. Printed in the United States of America.

November/December 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 1

TOPNov_Dec09 11/17/09 10:14 AM Page 1

CON

TENTS

Vol. 2, No. 7 November/December 2009

Feature Articles9 Conference News

No link found between cancer and bisphosphonate use

14 Breast CancerCardiac toxicity and breast cancer: prevention, monitoring, and treatment

16 Continuing EducationChemotherapy-induced peripheral neuropathy: prevention and treatment

28 Cancer Center ProfileUniversity of Pittsburgh Medical Center Cancer Centersand Cancer Institute

28 Clinical Pharmacy Specialist SpotlightJames Natale, PharmD

Departments1 Editors’ Letter

1 News Notes

4 ViewpointHow the US Government rations health care

7 International Oncology News

23 Oncology Drug Codes

26 Recent FDA Approvals

32 In the Literature

33 Meetings

PUBLIsHING sTAFF

PublisherPhilip [email protected]

Editorial DirectorKaren [email protected]

Associate EditorDawn Lagrosa

Production ManagerLynn Hamilton

Director, Client servicesJohn W. [email protected]

Business ManagerBlanche [email protected]

Executive AdministratorAndrea Boylston

Circulation [email protected]

241 Forsgate Drive, Suite 205C

Monroe Twp, NJ 08831

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

™

John F. Aforismo, BsC Pharm, RPh, FAsCPRJ Health Systems International, LLC

Wethersfield, CT

David Baribeault, RPh, BCoPBoston Medical Center

Boston, MA

sylvia Bartel, RPh, MPHDana-Farber Cancer Institute

Boston, MA

Deborah Blamble, PharmD, BCoPThe University of Texas MD Anderson Cancer Center

Houston, TX

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove Research Institute

Columbus, OH

Betty M. Chan, PharmD, BCoPUSC/Norris Cancer Hospital

Los Angeles, CA

steven L. D’Amato, RPh, BCoPMaine Center for Cancer Medicine

Scarborough, ME

Bryna Delman Ewachiw, Bs, PharmDJohns Hopkins Bayview Medical Center

Baltimore, MD

Anjana Elefante, PharmD, Bsc, BscPhm, RPhRoswell Park Cancer Institute

Buffalo, NY

Beth Faiman, RN, MsN, APRN, BC, AoCN Cleveland Clinic Taussig Cancer Center

Cleveland, OH

Christopher Fausel, PharmDIndiana University Simon Cancer Center

Indianapolis, IN

Rebecca s. Finley, PharmD, MsJefferson School of Pharmacy

Philadelphia, PA

David C. Gammon, BsPharmUniversity of Massachusetts Memorial Hospital

Worcester, MA

Heidi D. Gunderson, PharmD, BCoPMayo Clinic Cancer Center

Rochester, MN

sandra Horowitz, PharmD, RPh The University of Texas MD Anderson Cancer Center

Houston, TX

Lew Iacovelli, Bs, PharmD, BCoP, CPP Moses H. Cone Health System

Greensboro, NC

Andrea A. Iannucci, PharmD, BCoPUniversity of California Davis Medical Center

Sacramento, CA

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

New York, NY

Dwight Kloth, PharmD, FCCP, BCoPFox Chase Cancer Center

Philadelphia, PA

Jim Koeller, MsUniversity of Texas at Austin

San Antonio, TX

Helen L. Leather, BPharmUniversity of Florida

Gainesville, FL

Christopher J. Lowe, PharmDNovant Health

Winston-Salem, NC

Helen McFarland, PharmD, BCoPUnion Memorial Hospital

Baltimore, MD

Emily Mackler, PharmD, BCoPUniversity of Michigan Health System & College of Pharmacy

Ann Arbor, MI

Laura Boehnke Michaud, PharmD, BCoP, FAsHPThe University of Texas MD Anderson Cancer Center

Houston, TX

Deborah Moradi, PharmDThe Angeles Clinic and Research Institute

Los Angeles, CA

LeAnn Best Norris, PharmD, BCPs, BCoPSouth Carolina College of Pharmacy

Columbia, SC

Debra L. Phillips, PharmDEast Carolina University

Greenville, NC

steve stricker, PharmD, MsSamford University McWhorter School of Pharmacy

Birmingham, AL

Timothy G. Tyler, PharmD, FCsHPDesert Regional Medical Center

Palm Springs, CA

John M. Valgus, PharmD, BCoPUniversity of North Carolina Hospitals and Clinics

Chapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCoPUniversity of Nebraska College of Pharmacy

Omaha, NE

EDITORIAL BOARD

Co-EDIToRs-IN-CHIEF

susan Goodin, PharmD,FCCP, BCoPCancer Institute of New Jersey

New Brunswick, NJ

Patrick Medina, PharmD,BCoPOklahoma University College of

Pharmacy

Tulsa, OK

2 GREEN HILL HEALTHCARE COMMUNICATIONS November/December 2009

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

www.BioOncology.com

A pioneer in cancer innovation —exploring new directions

At Genentech BioOncology, we’re leading the fi ght against cancer with innovative science and are working to transform cancer treatment.

A family of fi rsts — 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.



VIEWPO

INT

President Barack Obama deflectscriticism that his health-care planwill bring on government

rationing of medical care by arguingthat insurance companies ration care.Everyone knows private payers limitaccess to some health care. But govern-ment does it in far more byzantine andarbitrary ways.Consider the $450 billion Medicare

program. It provides a model for—indeed its bureaucracy could well endup running—the “public option” healthplan that Mr. Obama wants to offer allAmericans under the age of 65. Inrecent years, Medicare’s staff has beenaggressively restricting coverage forcostly treatments. Looking for ways tocontrol spending on medical products—and preserve the illusory “trust fund”that pays Medicare claims—is whatshapes the culture of the organizationand motivates the agency’s staff.This often means limiting access to

the costliest technologies. To do thisMedicare relies on its rationing andpricing systems. National coverage deci-sions (NCDs) are assessments issued byMedicare’s medical staff that define whois eligible for new but often expensivetreatments. Medicare then assigns med-ical products and procedures with

“codes” that determine which regulatedcategory they fall into. Finally, price“schedules” are developed by Medicare’sstaff each year to assign each uniquecode with its own updated paymentrate. The process for getting a favorablecode on a new product is a source ofintense lobbying. It can make or break atechnology.For a remote agency like Medicare,

far removed from clinical practice, it’seasier to try and manage the use of ahigh-cost but specialty treatment than amuch lower-cost but very widely usedproduct. Yet cheaper, more commonlyused products can still be mispriced andaccount for more total cost to theagency. For example, low-tech orthoticdevices and other “durable medicalequipment” are a known source ofwasteful spending. These medical prod-ucts often evade Medicare’s attention infavor of less used but more expensiveitems such as a biological cancer drug.Take the agency’s tortured decisions

concerning the use of implantabledefibrillators that jump-start stoppedhearts during cardiac arrest. Medicaresharply restricted their use in the1990s. Mounting research proved thatthe $30,000 devices could be savingmany more lives. So in 2003 Medicare

adopted a novel theory to expand cov-erage to some, but not everyone, whoneeded one. The agency said onlypatients with certain measures on theirelectrocardiograms (called “wideQRS”) seemed to benefit.It was an easily measurable but ulti-

mately imprecise way to allocate thedevices. After another major study firm-ly refuted the QRS theory, Medicareexpanded coverage again in 2005,potentially saving 2,500 additional livesaccording to a press release issued withthat decision.That experience wasn’t unique. From

1999 to 2007, Medicare denied access ina third of the treatments it evaluatedthrough its coverage process, taking anaverage of eight months to complete itsreviews. When coverage was granted, in85% of cases the treatments wererestricted, usually to patients with moreadvanced illnesses.Medicare is lately increasing its use of

the national coverage process and isbecoming more tightfisted. Since 2008,according to my review of Medicaredata, it conditioned access in 29% of itsreviews and denied new or expandedcoverage in fully 53% of cases.Medicare’s methods can also be arbi-

trary. Take the travails of the pharma-ceutical company Sepracor and its drugXopenex, an innovative respiratorymedicine that competes with the chem-ically distinct and much cheaper gener-ic albuterol. Both are inhaled aerosolsused to treat asthma and chronicobstructive pulmonary disease. Xopenexhas the same benefits as albuterol, butsome believe fewer of its cardiac sideeffects. Medicare didn’t agree.The agency tried to make a “national

coverage decision” on Xopenex butcouldn’t come up with a clinical justifi-cation to limit the drug’s usage. SoMedicare manipulated its paymentprocess, saying it would pay Xopenex aprice equivalent to the “least costlyalternative” form of generic albuterol,10 cents a treatment compared to about$2.50 for Xopenex. Then Medicare wassued by a patient, and a Federal courtrecently ruled the agency exceeded itsauthority.Medicare finally succeeded in reign-

ing in the use of Xopenex with its cod-ing system. By issuing Xopenex thesame classification as generic albuterol,it was able to pay both products thesame “blended” price—an average ofthe cost of each individual drug. That

lowered the price on Xopenex, but iron-ically increased what Medicare paid forthe generics.It’s not a stretch to say that Medicare

spent hundreds of cumulative man-hoursfocusing on Xopenex while other priori-ties languished. The question is why?There weren’t safety concerns. Xopenexmay have been used in lieu of a cheaperalternative, but at peak Medicare sales ofabout $300 million it represented far lessthan one one-thousandth of the agency’sbudget. Simply put, a few staffers insideMedicare were consumed with the drugand its higher price—revealing a processthat is capricious and often disconnectedfrom science.Worse still is how impenetrable these

programs have become. Drug anddevice companies spend millions of dol-lars trying to influence Medicare deci-sions. The hundreds of consultants theyhire 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 bythe Government Accountability Office(using 2001 data), with delays in “admin-istrative processing” due to “inefficien-cies and incompatibility” of data systemseating up 70% of the time spent process-ing appeals.There’s nothing inherently wrong

with a program like Medicare seekingvalue for taxpayers. But it shouldn’tmake up the rules as it goes. When pri-vate plans ration care, patients canappeal directly to an insurer’s medicalstaff. Only a small fraction of Medicare’sdenied claims—about 5%—are ever for-mally appealed because its process is soimpenetrable. People can also switchinsurers, and in many cases patientschose a policy because it matched theirpreferences in the first place. Theseoptions don’t exist in a governmenthealth program. �

—Scott Gottlieb

Dr. Gottlieb is a resident fellow at theAmerican Enterprise Institute and a formersenior official at the Centers for Medicare& Medicaid Services. He is partner to afirm that invests in healthcare companies,and he advises health plans.

Reprinted with permission. © ScottGottlieb. Originally printed in OpinionJournal. The Wall Street Journal.September 30, 2009.

How the US Government Rations Health CareThe agency that would likely run the “public option” was

slow to pay for implantable cardiac defibrillators.

Viewpoint

HEMATOLOGYONCOLOGYPHARMACY

JOURNAL OF

��

��


IndicationALOXI® (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.

When patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their fi rst 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 specifi cally approved for prevention of both acute and delayed CINV associated with MEC6*

Can be used with multiple-day chemotherapy regimens6†

STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE

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

* 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.

www.ALOXI.com

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TOPNov_Dec09FINAL 11/17/09 12:50 PM Page 5

launch an assertive, proactive communi-cation program and to manage doserequirements of opioids.

Improving QOLThe holistic program used in her prac-

tice is committed to improving thepatients’ QOL by addressing not only

their physical cancer issues, but theiremotional and spiritual issues as well.“I’m not just talking about drugs,” shesaid. “Pain is a problem, and we havehad the tools to deal with that part ofthe problem.”

The purpose of Murphy’s oncologysupportive care program, she said, is to:

• Improve patients’ overall well-being and thus the QOL

• Enhance symptom control andfunctional outcome

• Modify health behaviors.The global construct, Murphy said,

includes patients’ perceptions of well-being, as influenced by their experiences,

points of view, expectations, and beliefs.1She reminded clinicians that health-related issues are only one factor whenconsidering QOL. Commonly assessedQOL domains include well-being on sev-eral fronts: physical, functional, social,emotional, spiritual, and financial.

Patients underreport psychological distress

Murphy said numerous studies useself-report questionnaires to concludethat cancer patients do not have alower QOL than healthy people.Murphy quoted the work of Breetveltand Van Dam2 who wrote about theso-called response shift: “Under theinfluence of a highly significant lifeevent, such as getting a life-threaten-ing disease…there will be a concur-rent change in the internalized stan-dard on which the patient bases theirperceptions.”

In other words, patients in thesestudies were underreporting their psy-chological distress; on their own, theyhad made the decision to move the bar.Breetvelt and Van Dam warned thatthe true nature of cancer and theresulting decrease in QOL could be“obscured totally.” They said these “I’mOK” studies were in contrast withother research that documented the derigueur experience of treating physi-cians, nurses, and other caretakers.They advised physicians not to put alot of stock in questionnaires.

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

Murphy said patient education canhelp overcome barriers to improvedQOL. “But patient education by itselfwill not improve their outcome,” shesaid. Barrier reduction can have moreof an effect on the outcome if it focus-es on such end points as knowledge,attitudes, practice patterns, and paincontrol, but, in studies, it has notbeen sufficient by itself.

“We hoped education would im -prove patient outcome, but you canchange knowledge and attitude andthat has not made a significant differ-ence in the outcome,” said Murphy. Astudy by Wells and associates foundthat a pain education program couldimprove knowledge and beliefs of thepatient and their primary caregiver, butthat continued access to pain-relatedinformation did not affect long-termpain outcomes.3

Moving beyond education“We need to move beyond educa-

tion—but where next?” asked Murphy.“More interventions are needed that canbe easily adopted by clinicians in varioussettings.” She suggested a “pain hotline”where patients could communicate their

SUPPORTIVE CA

RE ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI 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 coursesDOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and VomitingDosage 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. AdministrationALOXI 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.CONTRAINDICATIONSALOXI 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 PRECAUTIONSHypersensitivityHypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.ADVERSE REACTIONSBecause 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 refl ect 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 Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

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 fl atulence.

General: 1%: weakness, < 1%: fatigue, fever, hot fl ash, fl u-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 fl uctuations, 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 ExperienceThe following adverse reactions have been identifi ed 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 INTERACTIONSPalonosetron 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 signifi cant 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 signifi cantly 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 signifi cant 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 fi ve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Category BTeratology 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 DeliveryPalonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.Nursing MothersIt 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.

Pediatric UseSafety and effectiveness in patients below the age of 18 years have not been established.Geriatric UsePopulation 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 effi cacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI effi cacy in geriatric patients has not been adequately evaluated.Renal ImpairmentMild to moderate renal impairment does not signifi cantly 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 ImpairmentHepatic impairment does not signifi cantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.RaceIntravenous 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.OVERDOSAGEThere 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 fi xed 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 INFORMATIONSee FDA-Approved Patient Labeling (17.2) in full prescribing informationInstructions 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 OnlyMfd 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

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(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%)


Improving Cancer Pain ManagementContinued from cover


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pain to their providers. “This hadbeen used in a postoperative settingwhere it was found to be effective,but when studied in the oncology set-ting, it was not.”Murphy suggested that a model for

adequate pain control would includepatient reporting of pain levels, anassessment titration communication,and the physician’s cooperation.Patients, she suggested, could keep apain diary and a brief pain index. Shenoted her current investigation of anurse-managed narcotic-titration drug-order sheet,4 as a way to improve paincontrol. This phase 3 study is sponsoredby the National Cancer Institute.

Critical steps for adequate painoutcomeMurphy listed the critical steps that

should be considered for adequate painoutcome:1. Patient report of pain (and medicalstaff recognition of problem)

2. Assessment of pain by the provider3. Pain treatment plan4. Review of plan with patient5. Document assessment and plan

6. Patient follows treatment plan.To elucidate the critical steps in a spe-

cific plan, Murphy discussed a study byCleeland and colleagues, who examineda computerized telephone monitoringand alert system (with an interactivevoice-response system) that alerted clin-ic staff via e-mail when cancer patientpain levels exceeded a specified thresh-old.5 Telephone calls primarily rein-forced the patient’s use of prescribedmedication, provided information forthe management of symptoms, oraddressed the need for and arranged achange of medication. The researchersfound that this method reduced symp-tom severity and lowered symptom-related interference for the monitoredgroup compared with the control group.“The e-mail alert would go to a nurse,and she could react; we found thisphone call intervention worked reallywell,” said Murphy.

VHA studyAn earlier report by Cleeland and

associates described a joint collaborative(Veterans Health Administration [VHA]and Institute for Healthcare Im prove -

ment) that used a rapid-cycle improve-ment model to improve pain manage-ment within the VHA Health System.Each patient–healthcare pro vider dyadworked within a system to affect a bet-ter outcome.6The study’s goals were to improve

delivery of pain management to VHApatients and to compare team processand patient report data on key goalsfrom selected study units; 70 teamsfrom 22 Veterans Integrated ServiceNetworks participated.Findings were that the number of

patients experiencing moderate or severepain on study units dropped from 24% to17% while pain assessment increasedfrom 75% to 85%; pain-care plans forpatients with mild pain increased from58% to 78%; and the number of patientsprovided pain education increased from35% to 62%. “This study highlights thecritical issue of patients needing a plan ofcare,” said Murphy.

IT could address complex problemMurphy said that combining elec-

tronic medical records with a systemsapproach gives data at a glance. The twobasic components of a systems approach—elements and processes—can beapplied in the medical records setting.She explained it this way: In a car, the

dashboard gives the driver a glimpse of allthe information needed to make deci-sions while operating the vehicle.Dashboards in IT are essentially the

same. “You can look at the display andsay, ‘What am I doing well, or not well?’It allows you to search databases andidentify outcome issues at the patientlevel, the clinic level, and the providerlevel,” said Murphy, who pointed outthat, based on the patient’s report ofpain, the provider could match the levelof pain to the regimen prescribed. Shesaid that a lot of data could be organizedwith this system so that providers couldoffer adequate pain control for the manystakeholders. She added, “Pain controlis complex, but using information sys-tems and technology may hold the keyto this complex problem.” �

—Kristina Rebelo

References1. Murphy BA, Gilbert J, Cmelak A, Ridner SH.

Symptom control issues and supportive care ofpatients with head and neck cancers. Clin AdvHematol Oncol. 2007;5:807-822.

2. Breetvelt IS, Van Dam FS. Underreporting bycancer patients: the case of response-shift. SocSci Med. 1991;32:981-987.

3. Wells N, Hepworth JT, Murphy BA, et al.Improving cancer pain management throughpatient and family education. J Pain SymptomManage. 2003;25:344-356.

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

5. Cleeland CS, Vaporcian A, Shi Q, et al. Acomputerized telephone monitoring and alertsystem to reduce postoperative symptoms: a ran-domized trial. J Clin Oncol. 2008;26(15S):Abstract 9536.

6. Cleeland CS, Reyes-Gibby CC, Schall M, et al.Rapid improvement in pain management: theVeterans Health Administration and theInstitute for Healthcare Improvement collabo-rative. Clin J Pain. 2003;19:298-305.

Improving Cancer Pain Management

A model for adequate pain control wouldinclude patient reporting of pain levels, anassessment titration communication, andthe physician’s cooperation.

Intranasal Fentanyl Is Superiorto Oral Formulation forBreakthrough Cancer Pain

LISBON, PORTUGAL—Intranasalfen tan yl spray (INFS) confers meaning-ful relief of breakthrough cancer painfaster than transmucosal fentanyl citrate(OTFC) in most patients, according todata released at the 6th Congress of theEuropean Federation of Chapters of theInternational Association of the Studyof Pain. Sebastiano Mercadante, MD, director

of the Palliative Care Unit at LaMaddalena Hospital in Palermo, Italy,presented results in 139 patients who hadbeen randomized to treatment with INFSor OTFC titrated to doses of 50, 100, or200 µg and 200, 400, 600, 800, 1200, or1600 µg fentanyl, respectively.Trial participants were adult inpa-

tients or outpatients with cancer who

were experiencing at least threeepisodes of weekly breakthrough can-cer pain but no more than four dailyepisodes. All patients were using a sta-ble chronic opioid treatment for back-ground pain.Overall, 25% of episodes showed

meaningful pain relief at 5 minutesafter treatment with INFS versus 7%with OTFC. In addition, 51% ofINFS-treated patients had meaningfulpain relief at 10 minutes versus 24%with OTFC. The analysis also revealedthat patients found INFS easier toadminister. Overall, 90% of patientssaid that INFS was “easy” or “very easy”to use versus 40% for OTFC. “The pharmacodynamic profile of

INFS fits very closely with the tempo-ral characteristics of breakthrough can-cer pain,” Mercadante observed. The study also found that INFS was

well tolerated.

More than 90% of patients withcancer pain experience breakthroughpain, which is inadequately controlledin two thirds of cases, Mercadantepointed out.

Increased Public Awareness ofHead and Neck Cancer Needed

AMSTERDAM, THE NETHER-LANDS—New data demonstrate a lackof knowledge among Europeans aboutthe risk factors and symptoms of headand neck cancer.The findings were reported by

researchers who analyzed responses toonline questionnaires completed byabout 7500 people in France, Denmark,Italy, the Netherlands, Spain, Sweden,and the United Kingdom. The “About Face” survey revealed

that only 23% of participants wereaware of the term “head and neck can-

cer,” and less than half were able to cor-rectly identify symptoms of head andneck cancer. Sixty percent of respon-dents thought that brain tumors are atype of head and neck cancer.Most participants knew that there is a

link between head and neck cancer andsmoking or high alcohol intake, but fewpatients knew of the role of the humanpapilloma virus (HPV) infection orexcessive sun exposure in disease etiology. “Efforts need to address the gaps in

knowledge among the general public inhead and neck cancer,” according to C.Rene Leemans, MD, co-director of theVUMC Cancer Centre in Amsterdam,the Netherlands. This is particularlyimportant since knowledge gaps canlead to a delay in seeing a physician,which translates into a delay in diagno-sis, he added. �

—Jill Stein

Reports from International Meetings and ResearchersInternatIonal oncology news


min D deficiency, idiopathic hypercal-ciuria, primary hyperparathyroidism,hypocalciuria, and normocalcemichyperparathyroidism) are correctedand bisphosphonate therapy is usedappropriately.

Primary causes of osteoporosis aremenopause and aging. Secondary causesare diseases or conditions that exacer-bate bone loss.

“Doctors evaluating breast cancerpatients for possible bone loss shouldlook further than cancer drugs,” saidPauline Camacho, MD, an associate pro-fessor of medicine at Loyola UniversitySchool of Medicine, Chicago.

It is well documented that aromataseinhibitors can decrease BMD andincrease the risk of fractures in post-menopausal women. These medica-tions can decrease the body’s produc-tion of estrogen. Although estrogenfeeds cancer, the hormone also protectsagainst osteoporosis.

Camacho and colleagues reviewedcharts of 81 consecutive breast cancerpatients who were referred for treatmentor prevention of osteoporosis. Theresearchers found that 51 patients hadsecondary causes of bone loss, includingvitamin D deficiency (65%), excessivecalcium excretion in urine (16%), or anoveractive parathyroid gland (13%).Thirty patients did not have secondarycauses of bone loss.

All the patients received similar treat-ment with osteoporosis medications,such as alendronate and ibandronate.Women with secondary bone loss, how-ever, also received additional treatments.For example, vitamin D deficiency wastreated with prescription doses of vita-min D supplements, and excessive calci-um excretion was treated with a diuretic.

After 1 year, the breast cancerpatients with secondary causes of boneloss had stable BMD in their spines andnecks. BMD improved in the breastcancer patients who did not have sec-ondary causes of bone loss. BMD is theamount of calcium and other mineralspacked into a segment of bone and itpredicts osteoporosis.

Camacho said the study demonstratedthat bone loss “can be prevented inwomen undergoing hormonal therapy ifsecondary causes of bone loss are correct-ed and bisphosphonate osteoporosisdrugs are appropriately used.” She saidthe mean age of the women with second-ary causes of bone loss was 58 years, andthe mean age of the women without sec-ondary causes of bone loss was 63 years.

These study findings, which werepresented at the 31st annual meetingof the American Society for Bone andMin eral Research, suggest that health-care providers should discuss theimportance of treating secondary caus-es of bone loss with women undergoing

breast cancer therapy.“This study is good news for breast

cancer survivors, because they are wor-ried about their bones and so are theironcologists. We showed that with properworkup and appropriate treatment theydo quite well in terms of bone health. So

our findings are quite reassuring,” saidCamacho in an interview with TheOncology Pharmacist. “I think the mostimportant take-home point here is thataromatase inhibitors are being usedincreasingly in breast cancer patients andso these patients need to be thoroughly

evaluated and evaluated for secondarycauses of bone loss, such as calcium defi-ciency. We found vitamin D deficiencywas the most common problem. We sawit in 65% of the patients.”

—John Schieszer


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ERBITUX® (cetuximab): FOR PATIENTS WITH HEAD AND NECK CANCER*

1. E

Important Safety Information Including Boxed WARNINGSInfusion Reactions� 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

� 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 patientswho require treatment for infusion reactions

Cardiopulmonary Arrest� 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� 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� 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� 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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ERBITUX + RT: 26% reduction in

Risk of Death from SCCHN1,2

Bone Loss in Breast Cancer PatientsContinued from cover



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© 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.

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.

I

Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients

—

Electrolyte Depletion� 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� 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� 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� 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� The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes),

headache, diarrhea, and infection� 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%). Themost common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), andweight loss (11%)

For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

Please see brief summary of Full Prescribing Information includingBoxed WARNINGS regarding infusion reactions and

cardiopulmonary arrest on adjacent page.

ERBITUX + RT (%) RT Alone (%)(n = 208) (n = 212)

Grades Grade Grades Grade1-4 3/4 1-4 3/4

Mucositis/stomatitis 93 56 94 52

Dysphagia 65 26 63 30

Xerostomia 72 5 71 3

Radiation dermatitis 86 23 90 18

*INDICATIONS� 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�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 failedSCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

† 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

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No. (%) of Patients

ERBITUX + RT RT Alone(n = 211) (n = 213)

Delivery of planned RT dose

Adequate delivery per protocol 184 (87.2) 187 (87.8)

Inadequate delivery per protocol 27 (12.8) 26 (12.2)

DENVER—There appears to be norelationship between the use of bisphos -phonates and the development of can-cer, according to researchers at Colum -bia University College of Physiciansand Surgeons.

A letter to the editor in the January1, 2009, issue of the New EnglandJournal of Medicine cited reports ofesophageal cancer following treatmentwith alendronate as well as alen-dronate combined with other oral bis-

phosphonates. Since then, controversyhas surrounded this issue.

“We need to rectify this issue. There isno relationship between the use of bis-phosphonates and esophageal cancer,”said John Bilezikian, MD, professor of

medicine at Columbia UniversityCollege of Physicians and Surgeons,New York.

In a study presented at the 31stannual meeting of the American


No Link Found between Cancer andBisphosphonate Use


Society for Bone and Mineral Research,Bilezikian and his colleagues examinedclinical and postmarketing data regard-ing risedronate. This agent has beenstudied in placebo-controlled phase 3trials for up to 3 years and in more than19,000 patients. Risedronate has also

been studied in active-controlled stud-ies with 4000 additional patients.

Patients in the placebo-controlledstudies were randomized to receiverisedronate 2.5 mg daily (N = 4998),risedronate 5 mg daily (N = 5395), orplacebo daily (N = 5363). The inci-

dence of esophageal cancer in thesecombined risedronate studies was0.04% (two patients) in the 2.5-mggroup, 0.02% (one patient) in the 5-mg group, and 0.04% (two patients) inthe placebo group.

Overall, the researchers found that

the incidence rate for esophageal can-cer was 19 per 100,000 patient-years ofobservation in placebo patients, 22 per100,000 in the 2.5-mg, daily patients,and 9 per 100,000 in the 5-mg-dailypatients. In the active-control studies,no cases of esophageal cancer were

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

INDICATIONS AND USAGESquamous Cell Carcinoma of the Head and Neck (SCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressingmetastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a singleagent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who areintolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warningsand Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith 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 treatmentbenefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is notrecommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) andClinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux,included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred 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 withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warningand Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, 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 andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (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 patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of Erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious 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 pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and Electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary.

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADVERSE REACTIONSThe 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 reac-tions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologictoxicity 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 ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor 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 3and 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 in1–4% 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 Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (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 LocoregionallyAdvanced SCCHN

Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

Body System Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of PatientsBody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4Skin/AppendagesAcneform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 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”.

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

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

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

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), 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 toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARRESTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]

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Cancer and Bisphosphonate UseContinued from page 9


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

In postapproval surveillance fromMay 1998 to January 9, 2009, with morethan 18 million patient-years of expo-sure, reported esophageal cancer coinci-

dent with risedronate use was very rareor less than 0.1 per 100,000 patient-years of exposure.

“Many clinicians and their patientsare confused about this issue,” saidBilezikian in an interview with TheOncology Pharmacist. “After the New

England Journal report, patients startedcalling their physicians and saying ‘Iam not going to take that medicine,’but it wasn’t true and they were misled.We are now trying to make the pointby using data to argue that the reportwas not well founded.”

He said healthcareproviders should re as-sure their patients thatthere is no link be -tween bisphosphonateuse and esophageal can-cer. According to theNational Cancer In -stitute Surveillance, Ep -idemiology and End Re -sults (SEER) database, the incidence ofesophageal cancer in American men andwomen 65 years of age is 23.3 per100,000 per year. In Caucasian women65 years of age, the incidence is 11.2 per100,000 per year. Bilezikian said theincidence of esophageal cancer eventsobserved among risedronate or placebo-treated patients was consistent with thebackground rates in the population.

David Prelutsky, MD, associate clini-cal professor of medicine at WashingtonUniversity School of Medicine, St.Louis, Missouri, said these finding arevery important because they help clarifythis area of controversy.

“This study is clinically relevant, as itreassures primary care physicians, whoprescribe the bulk of bisphosphonates,that they are doing no harm. No physi-cian wants to prevent one problem andthen possibly cause another with a treat-ment. These data are reassuring,” saidPrelutsky in an interview with TheOncology Pharmacist. �

—John Schieszer

TrimSize: 7.875”x10.875”

Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended 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 AdvancedColorectal Carcinoma1 Treated with Erbitux Monotherapy

Erbitux plus BSC BSC alone(n=288) (n=274)

Body System Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0Body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <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 infusion-related.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneformrash (14%). ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable 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 beinfluenced 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 antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

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

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly 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 ofcetuximab (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 fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue 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 UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics ofcetuximab have not been studied in pediatric populations. Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OVERDOSAGEThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly 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 controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared 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 weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATIONAdvise 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 08876Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

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

1236886A5ER-B0001A-07-09 Rev July 2009

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John Bilezikian,MD

NCCN Updates BreastCancer Guidelines

New breast cancer guidelines from theNational Comprehensive Cancer Network(NCCN) include three notable updates.First, despite the increasing number ofwomen with cancer in one breast whochoose to have the other breast removed,the updated guidelines discourage pro-phylactic mastectomy except for womenwho are at high risk. If prophylactic mas-tectomy is being considered, according tothe NCCN guidelines, its benefits must bebalanced with the risk of disease recur-rence, the social and psychologicalissues associated with bilateral mastec-tomy, and the overall risks of contralater-al mastectomy. Another change is thatthe guidelines now recommend sentinelnode mapping and excision rather thanfull axillary lymph node dissection forwomen with clinically negative lymphnodes, provided that they are being treat-ed by clinicians with experience in sen-tinel node biopsy. The guidelines alsoinclude a new regimen (fluorouracil/epirubicin/cyclophosphamide followed byweekly paclitaxel) as an option for adju-vant therapy for invasive breast cancer.

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would include computer/phone needs,references, the formulary, and yourPharmacy and Therapeutics (P&T)committee.

Computer/phone needsData and phone lines often need to

be requested early in the planningprocess, so you need todecide what your computerneeds are as early as possi-ble. Will you work from adesktop or laptop computer?What are the data require-ments of your automateddispensing system? Doesyour refrigerator monitoringsystem require a dedicatedphone line? You may needto request these things (andkeep requesting them) atthe beginning.

ReferencesReferences are another important

part of the pharmacy that are often leftto chance. While the clinic is beingplanned, start a list of preferred refer-ences and check for updated versions.Determine whether you will use print oronline versions. This decision might bemade based on personal preference oroverall cost. Ease of use might beanother factor, if multiple personnelwill be using the reference or if the ref-

erence will be needed at multiple sites.Mobility is also a factor. Consider aPDA/smartphone with loaded refer-ences if you will be very mobile.

The formularyThere are many good reasons to have

a written formulary in an outpatientclinic. You will use it everytime you develop or updatesystems in the clinic. Thiswould include when switch-ing wholesalers, implement-ing automated dispensingsystems, adopting electronicmedical records, and design-ing preprinted chemotherapyorder sheets, just to name afew. A written formulary alsocomes in handy when devel-oping guidelines for dose

rounding, high/low limits, and compati-bility/stability charts. In our clinic, Ihave also posted the written formularyon our intranet as a means of communi-cation with our clinical and financialstaff. The formulary answers many fre-quently asked questions, includingthose about brand/generic names, man-ufacturers, single-dose versus multiple-dose vials, and vial size availability. Italso makes staff aware of what we keepin stock and what requires notice forordering (Table).

Regarding treatment drugs, we make

few formulary decisions in the classicsense. Mainly, we choose whether tokeep a drug in stock or order whenneeded based on utilization. Keepinginventory of low-volume drugs to aminimum reduces waste. Making vialsize information readily available tostaff facilitates dose rounding. The sup-portive care aspect of treatment offersmore opportunities for traditional for-mulary management. More agents in aclass, for example, antiemetics, allowsfor selection between clinical equiva-lents based on cost. Posting your for-mulary can keep everyone informed ofthe current choices.

The P&T committeeDepending on the size of your

practice, you may benefit from start-ing a P&T committee. Even smallerpractices may be able to standardizetheir clinical services using a clinicalcommittee of some kind. Either way,pharmacists should take an activerole in obtaining physician agree-ment for standardization and guide-

line development. For the sake ofsimplicity, I will refer to this processas the P&T committee.

Ideally, the clinical pharmacistshould coordinate the P&T commit-tee. To get started, choose a physi-cian champion who is the most likely to be both sympathetic to stan-d ardization and (if possible) inspirebuy-in from other physicians. Thephysician champion can help deter-mine how to choose other physicianmembers and how they will rotatethrough the committee. Next, inter-ested nonphysician members shouldbe invited. These members will varydepending on the practice, but mayinclude midlevel practitioners, aclinical nurse specialist or nurse edu-cator, and financial counselors/busi-ness office staff (voting or nonvot-ing). It is also important to decidehow decisions will be implementedand enforced.

The next step is the preparation ofthe agenda. The pharmacist/coordinatorprepares each meeting’s agenda by solic-

iting topics from committeemembers and other physicians.Topics may also be suggested byother members of the clinicalstaff. I often present new druginformation at this time, makeformulary reviews, or clarifyconfusing drug policies. If I havestudents, they present drug uti-lization reviews or interestingdrug information questions thatmay change practice. Agendasshould be sent out about 3 to 4days before each meeting, andshould include a standard for-mat of objective, summary,and references, so that com-mittee members can preparefor meetings.

ConclusionSetting up or remodeling an

oncology clinic in the commu-nity practice setting presentsmany challenges. The articles inthis series have discussed selec-tion of equipment, softwareneeds, and organizational issuesto be considered. Careful plan-ning and coordination withother members of the health-care team are essential to main-taining a safe, efficient oncologyclinic and providing high-quali-ty care for patients. �

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Challenges of Oncology Pharmacy Practice Continued from cover

Table. Sample Posted Formulary

Michele Woods, PharmD,BCOP

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

Generic Brand 24* Type Vial sizes Manufacturer Representative Contact

Paclitaxel Abraxane SDV 100 mg Abraxis John Doe XXX-XXX-protein-bound XXXXparticles (albumin-bound)

Alemtuzumab Campath • SDV 30 mg Genzyme/Bayer John Doe XXX-XXX-XXXX

Amifostine Ethyol • SDV 500 mg MedImmune John Doe XXX-XXX-XXXX

Anastrozole Aridimex PO PO AstraZeneca Jim Smith XXX-XXX-XXXX

Arsenic trioxide Trisenox • SDV 10 mg Cephalon Jim Smith XXX-XXX-XXXX

Azacitidine Vidaza SDV 100 mg Celgene Betty Jones XXX-XXX-XXXX

Bevacizumab Avastin SDV 400 mg, Genentech Ann Taylor XXX-XXX-100 mg XXXX

Bleomycin SDV 30 U, 15 U Generic Ann Taylor XXX-XXX-XXXX

Bortezomib Velcade SDV 3.5 mg Millennium Tim Anderson XXX-XXX-XXXX

Capecitabine Xeloda PO PO Roche Sally Jennings XXX-XXX-XXXX

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


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Planning for a Great Residency ProjectContinued from cover

can provide many learning opportuni-ties for the resident and preceptor.Using a structured plan for conductinga residency project will enhance theeducational experiences as well asallow for project completion during theresidency year.

Generating an idea for the projectGenerating the idea for the project

will require a lot of input from the pre-ceptor. Because work on the projectshould start as soon as possible in theyear, many residency programs generateproject concepts before the residenteven begins the program. Some of thebest residency projects arise out of prac-tice-based problems, after looking back-ward to find the root of the problem.Project ideas can also be developed outof departmental strategic goals andquality improvement initiatives, as wellas national benchmarks, such as JointCommission requirements and theNational Patient Safety Goals. The best projects are concise, interest-

ing to both the resident and preceptor,and relevant to pharmacy practice.Projects with a focus that is too broad orthat contains too many objectives canbe very problematic. The scope of theproject must remain contained to pro-vide a quality learning opportunity andto make sure that the project can becompleted during the residency year.Handing projects from one resident tothe next does not allow the residents toparticipate during all phases of the proj-ect. “Project drift” can occur when theproject’s goals shift because of newobstacles or when newcomers to theproject propose a new focus to the proj-ect. This should be avoided. In projectsbased on implementation of a processchange, thought should be given todesigning the intervention at this stage.The intervention should be accomplish-able given the resources available duringthe project year and afterward, so thatthe project will yield useful outcomes,and should rely as little as possible onthe availability of outside resources (eg,information technology [IT] support,physician time). The purpose of thestudy and primary and secondary out-comes of the study should be set, and theresident should be able to state them inone or two simple sentences.

Designing the studyThe next step in a successful residen-

cy project is the creation of a compre-hensive timeline. Essentially, this out-lines the steps involved in projectcompletion and the estimated timeneeded. Time spent in this phase willpay off later in increased efficiency. Itallows for identification of whenresources (eg, resident project time, IT

support) will be needed. Responsibilitiesand roles of the project team membersshould also be assigned. Regular meet-ings should be scheduled to trackprogress as well as identify and solveroadblocks so that the project can con-tinue successfully. Delays will be en -countered in every residency project,and setting an aggressive timeline canallow for unexpected delays and ensurethat the project is completed.After setting a timeline, the next step

is designing the actual study. Residencystudy projects can take many forms.Although it is possible to have residen-cy projects that do not involve data col-lection, more complex projects that sys-tematically investigate asituation or confirm accom-plishment of a goal are pre-ferred. Published studiesgenerally are grouped intodescriptive reports, observa-tional studies, and experi-mental studies. Descriptivereports include case reportsand case series that investi-gate a particular clinicalproblem. These offer a greatintroduction into publish-ing, providing the resident experiencein formal case presentation and manu-script preparation. Observational stud-ies in clude cohort studies, case-control,and cross-sectional studies. These stud-ies do not involve an intervention, butexamine the association between a riskor exposure and the development of anoutcome. To gain useful information,these studies are usually large, requiringsubstantial time and re sources, and areusually not appropriate for 1-year resi-dency projects. A randomized clinicaltrial will provide the most scientificproof of the research question. In thesestudies, the investigator actively inter-venes and measures the effect of thatintervention. Although it is the goldstandard of research, a randomized clini-cal trial is very time-consuming andexpensive, making it, most likely, a betterfit for a research fellowship.Quasi-experimental study designs are

appropriate for many residency projects.Although scientifically limited in estab-lishing causality, they are able to mea - sure the effect of an intervention. Theposttest-only analysis simply measuresthe outcome after an intervention andis the weakest of the group. This analy-sis type may be used if no data were col-lected before the intervention. Theposttest with control comparison analy-sis uses an outcome measurement in theexperimental group as well as the con-trol group, but does not show that theoutcome improved after the interven-tion. The pretest and posttest design isprobably the most commonly used. Itmeasures the outcome before and after

an intervention, but is prone to tempo-ral bias. Temporal bias occurs whensomething else that could influence theoutcome (eg, new lab test methodology,new physician staff) happens concur-rently with the intervention. Thepretest and posttest with control design

is stronger than the posttestwith control design becauseit measures the outcomebefore and after the inter-vention, both in the experi-mental group and in a con-trol group that did not havethe intervention. This con-trols for some confoundersbut doubles the resourcesneeded for data collection.Other considerations in

designing the study are thedefinition of the outcome measures, theinclusion and exclusion criteria, samplesize, setting, and data sources. Types ofoutcome measures include economic(direct costs), clinical (clinical effects,physiologic measures, length of stay), orhumanistic variables (quality of life,patient satisfaction). The outcomemeasure should be as precise and as rel-evant as possible given the availableresources. For example, mea suringvenous thromboembolisms (VTEs) byvenography after hospitalization is moreclinically relevant, but it may only bepossible to mea sure the surrogatemeasure of the provision of appropriateVTE prophylaxis during hospitaliza-tion. Inclusion and exclusion criteriashould be chosen to best represent thepopulation of interest. A more homo-geneous sample, chosen with a lot ofexclusion criteria, is less variable but itless likely the data can be extrapolatedto the general population. A heteroge-neous sample, chosen with few exclu-sion criteria, would be more variableand less likely to yield a specific result,but more representative of the whole.Comparator groups should be as similarto the study population as possible andmay include patients at a differentlocation, those offered “usual care,” orhistorical controls.Planning for data collection should

include the source of the data, such asmedical records or billing records. Acommon problem in residency projectsis the collection of too much data, just incase it is needed. This is time-consumingand can discourage the resident. If you

guard against “project drift” and collectonly the data to match the outcomemeasures, this phase will go smootherand faster. The resident should thinkahead at this point to how the data willbe analyzed and presented. This will helphim or her focus on the outcomes ofinterest. For example, if the proportion ofpatients with creatinine clearance <30mL/min is needed, collect that data as ayes/no field, instead of recording all thelaboratory values on admission. Samplesize in a randomized controlled trial isdefined by statistical calculations, but inquasi-experimental designs, the samplesize is usually estimated based on the per-sonal experience of the preceptor andavailable time and resources. The data-collection tool should be prepared at thispoint, including only the relevant infor-mation needed. The data-collection toolshould be tested on a few patients beforefine-tuning it. A plan for removingpatient-specific data should be made, toprotect the patients’ privacy. Data-col-lection tools can range from simple one-page paper forms to complicated data-base-driven electronic tools, based onthe needs of the project.

Getting approvalThe next step in the process is writing

the protocol and the institutionalreview board (IRB) submission. If allthe aspects discussed have been consid-ered, writing the proposal should be fair-ly simple. A usual proposal outlineincludes an introduction/justification,purpose/outcomes, methods, plan foranalysis, data-handling plan, and refer-ences. Obtaining IRB approval ensuresthat the project is ethical and protectsthe human subjects and their privacy. Itis required for projects that generatedata that will be published or presentedoutside of the institution. Most IRBsclassify projects according to the riskthey pose to the patients. Many residen-cy projects will qualify for the less inten-sive “exempt” or “expedited” reviews,because they pose minimal to no risk tothe patient.

Implementing the projectAfter approval by the IRB and resi-

dency advisory council, the project canproceed. If the project is using a quasi-experimental design, data collection isusually the next step. It is important for

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


Lisa Lohr, PharmD,BCOP, BCPS


ORLANDO—Cardiac toxicity relat-ed to chemotherapy is not a new topicbut it is an increasingly important one inlight of emerging data showing adverseeffects from many molecularly targetedagents as well as the older anthracyclines.Especially for patients with breast cancer,there is keen interest in better under-standing the true level of risk and thebest means of preventing, monitoring,and treating cardiac toxicity.Concerns have been raised about

trastuzumab, especially when it is givenin conjunction with an anthracycline,which is a common practice. But at the2009 annual meeting of the AmericanSociety of Clinical Oncology (ASCO),an international group of investigatorsfrom the phase 3 Herceptin Adjuvant(HERA) trial reported that the inci-dence of cardiac end points remains loweven with longer-term follow-up.Investigators assessed the cardiac

safety of trastuzumab after 3.6 years’median follow-up among 1682 patientswho received adjuvant trastuzumab for1 year and 1719 patients in the obser-vation arm. Several cardiac end pointswere evaluated:• Significant drop in left ventricularejection fraction (LVEF), defined asan absolute decline of ≥10% to<50%

• Confirmed significant LVEF drop,defined as an asymptomatic (NewYork Heart Association [NYHA]class I) or mildly symptomatic(NYHA class II) significant LVEFdrop, unless the next LVEF assess-ment indicated a return to levelsthat did not meet the definition ofsignificant LVEF drop, or as identi-fied by the treatment-unblinded car-diac advisory board

• Severe congestive heart failure(CHF, NYHA class III or IV and sig-nificant LVEF drop).

“The cumulative incidence of any typeof cardiac end point among patients ran-domized to 1 year of tras tuzumabincreased during the scheduled treat-ment period, but remained relativelyconstant thereafter,” reported MarionProcter, MSci, of Frontier ScienceScotland, Ltd, Kincraig, Kingussie,

United Kingdom (a nonprofit researchfoundation).Cardiac dysfunction in the trastu -

zumab group after 1 year was 0.6% forsevere CHF and 3.0% for confirmedsignificant LVEF drop. After 3.6 years,the incidence of cardiac dysfunctionafter trastuzumab remained low: 0.8%for severe CHF and 3.6% for confirmedsignificant LVEF drop. In the observationarm, there were no cases of severe CHF,but 0.6% had confirmed significant LVEFdeclines, and one patient suffered a car-diac 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 car-diac disease in six of 1682 patients, butthe remaining affected patients had afavorable outcome, Procter said.All occurrences of severe CHF and

85% of the confirmed significant LVEF

drops occurred during the scheduledtreatment period. In contrast, anthra-cycline-associated cardiotoxicity canoccur years after treatment, the authorspointed out. “Cardiac dysfunction in the trastu -

zumab group is consistent with preclin-ical findings that in trastuzu mab-associated cardiac dysfunction, nosignificant rate of myocardial cell deathis observed,” he said. “This is differentfrom the mechanism of anthracycline-associated cardiotoxicity.”These findings are consistent with

those of a study reported at theCanadian Cardiovascular Congress2009, which showed that trastuzumab-related cardiac toxicity is “largelyreversible.” In a study by MichaelMcDonald, MD, of the Heart FunctionClinic at Toronto Gen eral Hospitaland associates, 14 of 18 patients withbreast cancer who were treated withtrastuzumab had decreases in LVEF of≥10% and showed signs of heart fail-ure. Trastuzumab therapy was stoppedin 13 of these patients, and at 3months’ follow-up, all had near-normalization of LVEF and improve-ment in symptoms. Patients were ableto resume trastuzumab therapy andcompleted the course of treatment.

Heart disease and breast irradiationIn another study presented at the

ASCO annual meeting, Harvard investi-gators examined the cardiac effects ofleft-sided chest irradiation in breast can-cer patients in the Nurses’ Health Studyand found risk to be associated with base-line Framingham risk score.The study population included 3849

women with nonmetastatic breast cancerwho were treated with radiotherapy.They were categorized according to low(n = 1764), intermediate (n = 1495), andhigh (n = 601) Framingham score, andrisk of coronary heart disease (CHD) wasdetermined after adjusting for age andCHD risk factors.The investigators found that left-sided

breast radiotherapy raised the risk of hav-ing a CHD event by 80% in women withlow baseline cardiac risk, but did notincrease risk in the other two cohorts,reported Ronald C. Chen, MD, of theHarvard Radiation Oncology Program,Boston. “With modern radiotherapytechniques,” he suggested, “this differ-ence may be smaller.”The findings could have implica-

tions for treatment decision-making.“A simple office-based Framinghamscore can be calculated to assess base-line cardiac risk. Women with early-stage left-sided breast cancer and lowbaseline cardiac risk should weigh thepotential benefits of breast conserva-tion against a small absolute increasein risk of CHD after radiotherapy,” hesuggested.

Patients often not referred forcareCertainly, one means of managing

chemotherapy-related toxicity is to diag-nose and treat it early and appropriately;however, Stanford University investiga-tors have shown that cancer patientswho “silently” develop left ventriculardysfunction may not be referred to cardi-ologists. The study was presented at theAmerican College of Cardiology (ACC)annual scientific session in April.In the retrospective analysis led by

Geoffrey Yoon, MD, based on 88patients receiving anthracyclines ortrastuzumab between 2005 and 2007,mean LVEF (60% at baseline) droppedbelow normal during or after chemo -therapy in 41% of patients, of which25% had no overt symptoms of heartfailure. Among the asymptomaticgroup, only 37% were referred to a car-diologist, 33% received an angiotensin-converting enzyme inhibitor or angio -

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

Optimal monitoring ofchemotherapy patientsAlso at the ACC session, Daniel J.

Lenihan, MD, professor of cardiologyat The University of Texas M. D.Anderson Cancer Center, Houston, dis-cussed how best to monitor for cardiaceffects. Guidelines recommend measur-ing LVEF periodically, but this is insuf-ficient because more than one third ofpatients with heart failure have normalejection fractions, he pointed out.Furthermore, as the “mainstay” of diag-nosis, symptomatology is insufficient aswell, he added, and biomarker testingis not yet recommended, although tro-ponin and brain natriuretic peptidelevels have been found useful.Lenihan’s observations were echoed

in a recent article in The LancetOncology (2009;10:391-399), whichemphasized that LVEF is commonlyused for screening for toxic effects butunderestimates cardiac damage. Altenaand colleagues further maintained thatevidence to support current guidelinesfor monitoring is not robust.The authors reviewed the current

data for the various approaches andconcluded:• Echocardiography assesses systolicand diastolic cardiac function.Especially when it involves contem-porary techniques, such as tissuevelocity imaging of the early dias-tole, strain, and strain rate, echocar-diography might permit earlierdetection of subclinical signs of car-diac dysfunction.

• Multigated acquisition (MUGA)scintigraphy is a reliable method forassessing LVEF but is somewhatinsensitive for detecting subtlechanges in cardiac function.MUGA scintigraphy, therefore, haslimited value in the early detectionof cardiotoxicity.

• Serum cardiac biomarkers arepromising as a screening strategyfor early cardiovascular damage.

• Cardiac magnetic resonance imag-ing, combined with gadolinium en -hancement, is a promising screeningstrategy for the detection of subclin-ical damage. Persistent increases introponin I or N-terminal pro-brain(B-type) natriuretic peptide con-centrations seem to identify patientsat risk for cardiotoxicity. �

—Caroline Helwick

Breast CancerCardiac Toxicity and Breast Cancer: Prevention,

Monitoring, and Treatment

BR

EAST CA

NCER


Guidelines recommend measuring LVEFperiodically, but this is insufficient becausemore than one third of patients with heartfailure have normal ejection fractions.



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Program #CIK10278 • RELEASE DATE: December 15, 2009 • EXPIRATION DATE: December 14, 2010

Continuing EduCation

at www.thEonCologypharmaCist.Com

Chemotherapy-induced PeripheralNeuropathy: Prevention and Treatment

HOW TO RECEIVE CREDITTo 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 educationcertificate can be printed by following the directions online after successful com-pletion of the post-test.

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

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

LEARNING OBJECTIVESAfter 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 AUDIENCERegistered pharmacists and other interested healthcare professionals, especiallythose caring for cancer patients

COSTThis program is complimentary for all learners.

EDITORIAL BOARDTimothy R. McGuire, PharmD, FCCP,BCOPCollege of PharmacyUniversity of Nebraska Medical Center986000 Nebraska Medical CenterOmaha, NE 68198

Rhonda J. Moore, PhDScientific Review OfficerSpecial Review and LogisticsBranchDivision of Extramural ActivitiesNational Cancer InstituteNational Institutes of Health6166 Executive BoulevardRockville, MD 20852

Virginia Sun, RN, PhD(c)Senior Research SpecialistDepartment of Population SciencesDivision of Nursing Research andEducationCity of Hope1500 East Duarte RoadDuarte, CA 91010

Constance Visovsky, PhD, RN,ACNP-BCAssociate ProfessorUniversity of Nebraska MedicalCenterCollege of Nursing985330 Nebraska Medical CenterOmaha, NE 68198-5330

PLANNING COMMITTEELois ColburnExecutive DirectorCenter for Continuing EducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

Brenda Ram, CMPCoordinator Center for Continuing EducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

Dawn LagrosaAssociate EditorGreen Hill Healthcare Communications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Karen RosenbergEditorial DirectorGreen Hill Healthcare Communications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

FACULTY/PLANNER DISCLOSURESIt is the policy of the University of Nebraska Medical Center,Center for Continuing Education that all planners and facultyparticipating in continuing education activities provided bythe University of Nebraska Medical Center, Center forContinuing Education are to disclose to the audience any realor apparent conflicts of interest with providers of commercialproducts and/or devices relating to the topics of this educa-tional activity and also disclose discussion of labeled/unap-proved uses of drugs or devices discussed in their presenta-tion. The planners and faculty have been advised that thisactivity must be free from commercial bias and based uponall the available scientifically rigorous data from research thatconforms to accepted standards of experimental design, datacollection, and analysis.

The authors, reviewers, and planning committee members list-ed below have stated they have no significant or substantialrelationship with providers of commercial products and/ordevices discussed in this activity and/or with any commercialsupporter 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-BCThe following author has stated that he has the

following financial relationships:

• Timothy McGuire, PharmD, FCCP, BCOP, has received re -search support from AstraZeneca.

ACCREDITATION AND CONTACT HOURS STATEMENTThe University of Nebraska Medical Center, Centerfor Continuing Education is accredited by the Ac -creditation Council for Pharmacy Education as aprovider of continuing pharmacy education. TheACPE provider number is 0447-0000-09-085-

H04-P. To receive the 1 contact hour of continuing education cred-it, pharmacists should complete the activity requirements andevaluation at the conclusion of the activity. Approval is valid fromthe initial release date of December 15, 2009. The expiration dateis December 14, 2010. A statement of credit will be available forprinting online upon completion of the post-test with a score of70% or better and the evaluation instrument.

BY CONSTANCE VISOVSKY, PhD, RN, ACNP-BC1; RHONDA J. MOORE, PhD21University of Nebraska Medical Center, College of Nursing, Omaha, Nebraska; 2National Cancer Institute, National Institutes of Health, Rockville, Maryland

Chemotherapy-induced peripheral neuropathies (CIPNs) pre -sent an increasingly common neuropathic and pain syndromein cancer survivors.1,2 Peripheral neuropathy is the end result

of peripheral, motor, sensory, and autonomic neuron damage sec-ondary to neurotoxic chemotherapy agents that inactivate the com-ponents required to maintain the metabolic needs of the axon. Thedamage caused by chemotherapeutic agents can cause subsequentand long-term functional abnormalities of structural lesions in theperipheral and central nervous systems (CNS).3-5 CIPN is sensory,dose-related, and cumulative. It is usually delayed and may appearweeks to months after the initiation of therapy. The chemothera-peutic agents most often associated with CIPNs are the platinum-based compounds, taxanes, vinca alkaloids, thalidomide, and borte-zomib.3-10 Although the incidence of peripheral neuropathy resultingfrom a single agent can be significant, the administration of two neu-rotoxic agents is not uncommon and results in higher grades of over-all neurotoxicity.11 At this time, no standard or evidenced-basedtherapies exist to prevent or treat CIPNs. This article aims to providean understanding of CIPNs and to review the evidence for both itsprevention and treatment.

Case studyA 56-year-old right-handed woman, a 2-year survivor of a stage

IIIB adenocarcinoma of the left lung (Pancoast tumor) previouslytreated with cisplatin-gemcitabine-paclitaxel, presented to theclinic with left shoulder pain radiating into the left arm and hand,grade 3 CIPN, weight loss, hand weakness, poor appetite, andcough. She was clinically diagnosed with stage IV adenocarcino-ma. During her previous treatment, she had developed grade 3CIPN. She articulated the dominance of CIPN and pain on herquality of life (QOL):

I no longer remember what it is like to not be in pain. I can’t thinkof anything else but the pain and I can’t concentrate at all. It hasbeen like this for over 5 months. I have pain all over, under thecuff of my left arm, the doctor calls it subclavicle pain, and on myarm. I have lost time because of pain. I have pain that increaseswhen I have chemotherapy, and I have pain that increases when Idon’t have chemotherapy. I am damned. I am so tired, I hurt, andI can’t walk without the pain. I can’t feel my feet anymore or myfingers. I can’t drive, and I have lost my independence.

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


ated with a Pancoast tumor can extend along an ulnarnerve distribution of the arm to the elbow and is fre-quently relentless and unremitting. Although a rela-tively unique scenario, this case illustrates the poten-tial for severe complications from cancer and CIPN.

Pathophysiology and EpidemiologyIt has been hypothesized that neurotoxic chemicals

directly damage nerve fibers by inactivation of com-ponents required to maintain the metabolic needs ofthe axon. The longer and larger distal axons are affect-ed first and this may result in interruptions of axonaltransport and degeneration of myelinated nerve fibersand unmyelinated axons.8-10 In a recent animal-modelstudy of paclitaxel-induced CIPN, abnormalities inthe axonal mitochondria of sensory nerves were foundto contribute to paclitaxel-induced neuropathicpain.12 Under normal circumstances, large sensoryneurons do not conduct noxious stimuli. These largemyelinated sensory fibers are preferentially injured byneurotoxic chemotherapeutic agents. Injury or dam-age to large sensory fibers by chemotherapeutic treat-ments can also result in the paresthesias, dysesthesias,and decreased proprioceptive abilities. These stimulican be detected by nerves within the body as well asby the semicircular canals of the inner ear. Thus,CIPNs induce a type of neuropathic pain and repre-sent a serious yet understudied consequence of cancertreatment. The sensory and motor symptoms and signsof CIPNs are potentially disabling and can have a sig-nificant impact on QOL for patients with cancer.13,14Moreover, even when CIPN is not a dose-limiting sideeffect, its onset may severely affect QOL and causechronic discomfort and pain.6-11

Prevalence and incidenceThe prevalence of CIPNs is not known because of

a lack of adequate standardized assessment, measure-ment, and reporting mechanisms.3,9,11 Toxicity-grad-ing scales used to detect CIPN vary widely, and spe-cific guidelines for these instruments are lacking.The incidence of CIPN varies depending on thedrugs, dosage, and treatment schedules used.3-11 Theincidence of severe CIPN has been estimated atabout 3% to 7% in individuals treated with singleagents and upward of 38% in those treated with mul-tiple chemotherapeutic agents.3-11

Risk factorsRisk factors associated with worsening CIPN symp-

toms include prior use of chemotherapies (particularlyplatinum-based therapies), older age, and female gen-der. Comorbid conditions that appear to place patientsat greater risk for CIPN include diabetes, humanimmuno deficiency virus infection, alcoholism, preexist-ing neuropathies (diabetic neuropathy, small fiber neu-ropathies), and vitamin B deficiencies.3,6,11,13-15 Thesymptoms associated with CIPNs also vary widely(Table 1), and little is known about other risk factors.Moreover, even when neurophysiologic methods areused to diagnose CIPNs, there is still wide variation inthe resultant symptoms, which enhances the difficultyin predicting and modeling which patients are poten-tially at the greatest risk.4-11

MechanismsThe sensory and motor symptoms and signs of

CIPNs are potentially disabling and can have a signif-icant impact on QOL.1-11 Yet, the mechanisms and riskfactors associated with the development of CIPNshave not been fully elucidated. Several interestingmechanisms have been proposed. For instance, inpatients with cancer, the immune response to tumorcells contributes to an already adverse proinflammato-ry state. One potential consequence is that tumoralinvasion at central or peripheral sites can lead tomechanical damage, proteolysis, and the release ofinflammatory pain mediators, including proinflamma-tory cytokines (ie, interleukin-1, interleukin-6, andtumor necrosis factor-a). These may result in damageto surrounding tissues and may also play a prominentrole in the initiation, development, and maintenanceof chronic pain states, including neuropathic pain.16-26Other research has examined the impact of plat-

inum-based cancer chemotherapies on mitochondri-al function.27 Alterations in mitochondrial functionhas been noted in cancer cell resistance tochemotherapeutic agents. Cisplatin’s toxic sideeffects appear to be associated with mitochondrialinjury in vivo and in vitro, highlighting the plausiblerole of mitochondria, including the role of produc-tion of mitochondrial electron transport chain reac-tive oxygen species in models of other forms ofpainful peripheral neuropathy.27-30

Variation in symptoms: presentation, progression, and resolutionThe primary effects of CIPN are sensory, occurring

in a stocking-and-glove distribution in the toes andfingers. The lack of gold-standard measures for CIPNand the wide variation in symptoms contribute to lim-itations in symptom management in patients. CIPNcan vary in its onset, severity, and length, and its res-olution cannot be predicted, as the symptomology canlast from a few days to a lifetime.3-11 The symptoms aredescribed briefly below.• The majority of patients report a gradual onset ofneuropathic symptoms, although some developsymptoms more rapidly.3-11

• The primary effects are sensory, occurring in astocking-and-glove distribution in the toes andfingers.3-11

• Terms such as “burning,” “tingling,” “electric shocksensation,” and “painful numbness” have all beenused to describe the sensations.4,8

• Patients may also report increased pain during walk-ing, with descriptions of sensations such as “walkingon shards of glass” or “stepping on razorblades.”4,8

• Physical examination may reveal tactile allodynia,cold allodynia, hypersensitivity, and loss of deep ten-don reflexes.4,8

• Motor symptoms such as declines in muscle strengthcan lead to muscle weakness and atrophy, precipitat-ing functional impairment.

• Patients may also experience a loss of propriocep-tion, the unconscious perception of movement andspatial orientation within the body.

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

at a great risk for falls because they also tend to lose allsense of the position of their feet. This raises concernsabout their ability to drive safely, particularly whenthey are unable to feel the brakes or lack the strengthto press a pedal adequately.7,9,15Heterogeneity in CIPN-related symptoms can range

from an almost exclusively sensory to a sensory-motorneuropathy, with or without clinical evidence of auto-nomic impairment.3,11,13-15,24-26 Recent insight fromanimal and human studies suggests that the great het-erogeneity in the underlying mechanism(s) of nerveinjury caused by individual agents may partly explainthe wide variation in the resultant symptoms.3,11,24,26,31-34Chemo therapeutic toxicity is also influenced by mul-tiple genetic factors and nongenetic factors, includingage, gender, and drug-drug interactions.26,31-38 Themanifestations of adverse drug reactions also differbetween men and women. Women tend to ex periencegreater toxicity from chemo therapeutic drugs thanmen.34 Recent studies suggest that the mechanismsunderlying the various forms of peripheral neuropathymay actually be different, and therapies have to be tai-lored in light of these different neurotoxic effects.27These issues further contribute to the difficulties in



Complimentary




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.



Complimentary




Table 2. Pharmacologic Prevention and Treatment of CIPN

Continued from page 17

CIPN indicates chemotherapy-induced peripheral neuropathy.

AgentAcetyl L-carnitine

Amifostine

Calcium/magnesium infusions

Carbamazepine

Gabapentin

Glutamine

Glutathione

Nortriptyline

Vitamin E

StudiesBianchi G, et al. 200535

Maestri A, et al. 200564

Hilpert F, et al. 200542

Leong SS, et al. 200374

Moore D, et al. 200343

Openshaw H, et al. 200444

Gamelin L, et al. 200448

Hochster HS, et al. 200775

Hochster HS, et al. 200876

Nikcevich DA, et al. 200877

Eckel F, et al. 200251

von Delius S, et al. 200752

Rao RD, et al. 200762

Stubblefield MD, et al. 200553

Vahdat L, et al. 200154

Wang WS, et al. 200755

Cascinu S, et al. 199559

Cascinu S, et al. 200257

Smyth JF, et al. 199758

Hammack JE, et al. 200263

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

Conclusions• Tested for the treatment of preexisting paclitaxel-or cisplatin-induced peripheral neuropathy

• Nonrandomized design and small sample sizes arelimitations

• Randomized clinical trials are necessary before recommendation as a potential treatment for CIPN

• Due to negligible toxicity, low cost, and lack ofinterference with chemotherapy, may be a viablepreventive treatment for oxaliplatin-based therapy

• Because of negligible toxicity, low cost, and lackof interference with chemotherapy, may be aviable preventive treatment for patients receivingoxaliplatin-based therapy

• No grade 2 to 4 neuropathy in patients treatedwith carbamazepine vs 30% in historical controls

• In patients with colorectal cancer, no differencesin neurotoxicity with carbamazepine

• Randomized, placebo-controlled trials are necessary to determine use for prevention ortreatment of CIPN

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

• Patients developed less grade 1 to 2 CIPN ascompared with controls

• Larger, randomized, placebo-controlled trials arenecessary to assess efficacy for the prevention ofCIPN

• Significantly less CIPN experienced by patients

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

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

• Reduced the incidence and severity of cisplatin-related CIPN

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




Complimentary

Continuing eduCation

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Chemotherapy-induced Peripheral Neuropathy: Prevention andTreatment: A Pharmacist’s PerspectiveBY TIMOTHY R. MCGUIRE, PHARMD, FCCP, BCOPUniversity of Nebraska College of Pharmacy, Omaha

Commentary

Chemotherapy-induced peripheral neuropathy(CIPN) is a relatively common and poorlytreated 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 particularlyimportant. The ability of any given agent to pre-vent CIPN needs to be weighed against any real ortheoretical concern of diminished antitumoreffect. Because the mechanisms of CIPN arethought to be at least in part an extension of thedrug’s mechanism of antitumor effect (eg, tubulininhibition, DNA adduct formation), the proposedprotective agents (amifostine, calcium/magne-sium, vitamin E, glutamine, N-acetylcysteine, glu-tathione, acetyl L-carnitine, and erythropoietin)need to be used thoughtfully. This is particularlytrue given that there is no strong evidence thatmany of these agents lower rates of CIPN. One method of reducing the rates of CIPN is

related to advances in drug development and for-mulation of anticancer drugs. For example, carbo-platin was developed by the addition of a morecomplex and bulky-leaving group to the cisplatinmolecule, leading to the production of less reac-tive platinum species and lower rates of several ofthe toxicities associated with cisplatin, includingCIPN. Oxaliplatin is much more like cisplatindespite its more complex chemical structure, andsubstantial reduction in CIPN compared with cis-platin has not been realized. Cisplatin may be

more likely to produce permanent neurologicdamage, consistent with the science showingthree times more platinum-DNA adduct forma-tion in the dorsal root ganglia with cisplatin com-pared with oxaliplatin.1 The CIPN associatedwith docetaxel is less severe than that with pacli-taxel. Variation is also seen among the vinca alka-loids, vinblastine and vinorelbine, which are asso-ciated with lower rates of CIPN compared withvincristine. The differences between these antim-itotic drugs are based on differences in their affin-ity for axonal microtubules. In addition to drug selection that can minimize

CIPN, a number of new formulations of neurotoxicchemotherapy may improve tolerability. Forinstance, although nanoparticle albumin-boundpaclitaxel is not less likely to produce CIPN thansolvent-based paclitaxel, the CIPN that developsmay be more reversible.2The inhibitors of tumor progression commonly

used to treat multiple myeloma (thalidomide,lenalidomide, and bortezomib) have differing liabil-ity for CIPN. Thalidomide is a common cause ofCIPN, which is only slowly or incompletelyreversible and related to cumulative dose. In com-parison, CIPN is uncommon with lenalidomideand, when present, is usually mild. Bortezomib isassociated with neuropathy in approximately onethird of patients.3 Bortezomib-induced CIPN, how-ever, is generally more rapidly reversible than thatwith thalidomide, and resolves in most patientsafter dose reduction or discontinuation.3,4 Un -fortunately, determining the clinical nature of the

CIPN associated with these agents is difficult giventhat patients with multiple myeloma may have ahistory of receiving neurotoxic therapy, and theunderlying disease itself may be associated withneurologic deficit.4 It is not always possible to switch between drugs

of the same class because of either nonequiva-lence in a given tumor or lack of data demonstrat-ing clinical equipose. In addition, lower rates ofCIPN are often at the cost of higher rates ofmyelosuppression or other toxicities that may cre-ate equal or greater clinical issues.In conclusion, although prevention of CIPN is

preferred given the lack of agents to effectivelytreat CIPN and the potential irreversibility of thedamage, there are limited data on the value of pre-ventive agents. In addition, antagonism of antitu-mor activity with preventive therapies is not a set-tled issue. The appropriate selection of bothanalog and formulation may be an effectivemethod of minimizing this important complica-tion of chemotherapy. �

References1. McWhinney SR, Goldberg RM, McLeod HL. Platinum neuro-toxicity pharmacogenetics. Mol Cancer Ther. 2009;8:10-16.

2. Schiff D, Wen PY, van den Bent M. Neurological adverse effectscaused 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 duringtreatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120.

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

predicting which patients from which populations willexhibit long-term damage from chemotherapeutictreatments.39-41Some chemotherapeutic ag ents are known to

induce neurotoxicity that extends beyond the discon-tinuation of therapy, a phenomenon known as coast-ing.3 It is still quite difficult to predict whether other-wise neurologically normal patients will exhibitsusceptibility to the neurotoxic effects of chemo thera-py.3-11 The diagnosis, assessment, and management ofCIPNs are also complicated by the lack of a reliableand standardized means to diagnose and monitorpatients at risk of or who become symptomatic fromthis complication of treatment.26,31,32 Finally, no well-established guidelines exist for dose reduction.8-11 Thiswide variation in symptoms remains a significant bar-

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

Prevention of CIPNChemoprotectantsChemoprotectants such as amifostine have been

tested as a means of detoxifying chemotherapy andfacilitating DNA repair while not interfering with theefficacy of chemotherapy (Table 2). In the studies test-ing the effect of amifostine on peripheral neuropathyassociated with taxane-based chemotherapy regimens,no differences were found in sensory or motor neuro-toxic symptoms in patients treated with amifostine.Amifostine was also found to be ineffective in pre-venting or reducing the neurotoxic effects of high-dose paclitaxel.42-44

Vitamin EVitamin E has been thought to protect against cellular

oxidative damage and side effects, such as numbness, tin-gling, burning, and/or pain in peripheral extremities pro-duced by cisplatin and other cytotoxic drugs. Three stud-ies examined the cytoprotective effect of vitamin Esupplementation on the development of CIPN followingthe administration of cisplatin, paclitaxel, or a combina-tion regimen.45-47 The findings, based on subjective, clin-ical, and electrophysiologic assessments, showed that theincidence of neurotoxicity was lower in the group thatreceived 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 andtreatment of CIPN.



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Chemotherapy-induced Peripheral Neuropathy: Prevention andTreatment: A Nurse’s Perspective BY VIRGINIA SUN, RN, PhD(c)City of Hope, Duarte, California

Knowledge of current treatment and supportivecare strategies for common cancer-related tox-icities is critical to the provision of quality

nursing care. Visovsky and Moore provide a compre-hensive overview of the epidemiology, prevalence,characteristics, and management of chemotherapy-induced peripheral neuropathy (CIPN). The articlewill not only serve as an excellent resource for clini-cal oncology nurses, but also allow them to providecomprehensive education for cancer patients aboutwhat to expect with CIPN. The assessment and management of CIPN contin-

ues to be a clinical challenge for healthcare profes-sionals for several reasons that are addressed by theauthors and others. First, there is great variability inthe characteristics of symptoms related to CIPN.This may, in part, be related to the specific class ofchemotherapeutic agents that causes CIPN, but cur-rently there is no conclusive evidence that explainsthis variability. The variability in symptom charac-teristics also poses a clinical challenge for developingeffective assessment and follow-up protocols forCIPN. Second, although research is ongoing, CIPNis still overall a poorly understood phenomenon.Current evidence related to the underlying neurobi-ology, actual prevalence rates, and a lack of definitiveanimal models are factors that affect our overallunderstanding of CIPN.1 Finally, despite the growingnumber of clinical trials testing various therapeuticoptions for CIPN, currently there is no standard, evi-dence-based treatment for the prevention or treat-ment of CIPN.2 Understanding the relationship between CIPN

and quality of life (QOL) is important not only forpatients but also for nurses caring for individuals withcancer. To thoroughly understand how CIPN affectsthe QOL of our patients, there is a need to capturethe overall experience of living with CIPN from thepatient’s perspective. Few qualitative studies con-ducted in recent years have attempted to understand

CIPN from the subjective perspective. Bakitas con-ducted an excellent qualitative study that describedthe CIPN symptom experience and the effect ofsymptoms on everyday life.3 Patients described CIPNas “background noise” that can be overshadowed byother treatment- and disease-related issues, butCIPN’s unpleasantness can interfere with daily activ-ities and socialization. The awareness of CIPN wasoften inaccurate and its occurrence surprisingbecause most patients did not recall being educatedor advised to anticipate the symptoms. When moni-toring CIPN, clinicians primarily focused on how thesymptoms affected motor functionality (dexterity,gait) but rarely asked about CIPN’s effect on dailyliving. CIPN caused disruptions with daily living,leisure, work, and family roles. Patients who reporteda pain component to their CIPN often experiencedfunctional difficulties, fatigue, sleep disturbance, andmood disturbances. Patients also described the use ofmultiple processes in learning to live with CIPN. Similar results have been described in another

qualitative study conducted by Closs and colleagues4as well as in our work at the City of Hope. Ourdescriptive, mixed methods study explored theimpact of peripheral neuropathy on QOL in 53patients with colorectal cancer. Our qualitative datasuggest that although patients did not find the dyses-thesias and cold-related allodynia distressing, theacute sensations were surprising when first experi-enced, and patients made adjustments in life (eatingand drinking habits related to cold foods and bever-ages) to cope with these neuropathic symptoms.5There are several ways that nurses can contribute

clinically and scientifically to the sparse evidence inCIPN prevention and management. By keepingabreast with the most current information on CIPNmanagement, nurses are better equipped to providequality care and support to cancer patients livingwith CIPN. The prompt assessment of symptomsrelated to CIPN is essential for determining appro-

priate and effective management strategies. Theassessment of CIPN should continue throughouttreatment and beyond, because chronic CIPN canoccur months and even years beyond treatment.6Most important, nurses must be vigilant in educat-ing patients on what to expect with CIPN. It is evi-dent from some of the current evidence that clini-cians are not doing an optimal job of providingpatients with timely information on CIPN. Beyondpharmacologic treatments, it may also be helpful fornurses to discuss nonpharmacologic supportive carestrategies to cope with CIPN, such as personal safe-ty measures to prevent burns, falls, or other prob-lems that may be related to sensory motor deficits.7Finally, for nurses who are committed to advancingthe science of CIPN management, there is a needfor more studies and evidence that focuses on out-comes beyond the efficacy of therapeutic agents.8Studies that characterize the time of onset, dura-tion, and resolution or persistence of CIPN areneeded to develop a more comprehensive and sub-jective understanding of CIPN.1 �

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

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

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

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

5. Sun V, Otis-Green S, Shibata S, et al. Symptom concerns andQOL in oxaliplatin-induced peripheral neuropathy. 2008ASCO 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: areview and implications for oncology nursing practice. Clin JOncol Nurs. 2007;11:361-376.

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

Calcium and magnesiumInfusions of calcium and magnesium have been used

as a means of preventing oxaliplatin-associated CIPN.Oxalate, an oxaliplatin metabolite, seeks out and bindsto calcium and magnesium.48 In one study, 140 patientswere randomly assigned to receive calcium gluconateand magnesium sulfate or placebo before and afteroxaliplatin to reduce neurotoxicity. Improvements inthe clinical manifestations of acute neurotoxicity were

reported after infusion of calcium and magnesium, andat the end of oxaliplatin therapy, 65% of the patients inthe calcium/magnesium infusion group had no symp-toms of neuropathy compared with only 37% in thecontrol group.48 There was concern that tumor responserates may be lower in patients who received calciumand magnesium infusions. A subsequent review of com-puted tomography scans from the trial, however,showed that the antitumor response rates were actually

numerically higher in the group that received the calci-um and magnesium infusions compared with those whoreceived placebo. Thus, calcium and magnesium infu-sions appear to offer a safe, cost-effective means of pre-venting oxaliplatin-related peripheral neuropathy.49,50

CarbamazepineCarbamazepine, an anticonvulsant drug, appears to

protect against oxaliplatin-induced neurotoxicity by




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slowing the rate of recovery of voltage-activated sodiumchannels. Carbamazepine was tested in the prevention ofCIPN in a single nonrandomized pilot study consisting of10 previously treated patients with advanced colorectalcancer receiving oxaliplatin, leucovorin, and 5-fluo-rouracil. Results indicated the absence of World HealthOrganization grade 2 to 4 neuropathy development inthe patients treated with carbamazepine compared with30% who experienced grade 2 to 4 neuropathy in a his-torical control group.51 In a randomized controlled trial,von Delius and colleagues tested the efficacy and safetyof carbamazepine for the prevention of oxaliplatin-asso-ciated neuropathy in 36 patients with advanced colorec-tal cancer.52 No differences were found between thegroups on assessments of neurotoxicity. Further random-ized, placebo-controlled trials are necessary to determineif carbamazepine can be used to prevent or treat CIPN.

GlutamineGlutamine, a neutral gluconeogenic nonessential

amino acid, is thought to have neuroprotective effects forpatients receiving paclitaxel.53 In one study, 12 womenwith advanced breast cancer were given glutamine 10 gdaily for 4 days starting 24 hours after completion ofpaclitaxel and 33 women did not receive glutamine.Only 8% of women treated reported dysesthesias inthe fingers and toes compared with 40% of the womenwho did not receive glutamine.54 In another study,Stubblefield and colleagues examined the neuropro-tective effect of glutamine on 46 patients scheduled toreceive high-dose paclitaxel before stem cell transplant.53Seventeen patients received glutamine, and 29 patientsmade up the control group. Responses to questions aboutneurologic symptoms and results of electrodiagnostictesting indicate that those who received glutaminedeveloped less weakness, loss of vibratory sensation, andtoe numbness compared with those in the control group.In a nonrandomized pilot study, Wang and colleaguestested the efficacy of glutamine for reducing the inci-dence and severity of peripheral neuropathy in patientsreceiving oxaliplatin in 86 patients with colorectal can-cer.55 Glutamine supplementation significantly reducedthe incidence and severity of oxaliplatin-induced neu-ropathy. The percentage of grade 3 to 4 sensory neuropa-thy was lower in the glutamine group after four cycles oftreatment and remained that way for six cycles. Theresults suggest that glutamine is a potential neuroprotec-tive agent but must be studied in larger populations in arandomized, placebo-controlled trial. Concerns still existabout glutamine supplements protecting tumor cells fromthe cytotoxic effects of chemotherapy.55

GlutathioneSome evidence shows that glutathione, a naturally

occurring thiol tripeptide, may also prevent neurotoxici-ty induced by platinum compounds by preventing theinitial accumulation of platinum adducts in the dorsalroot ganglia.56 Three studies testing the potential neuro-protective effects of glutathione have been published.57-59 Following all cycles of chemotherapy, the incidence ofneuropathy was greater in the placebo-treated arms com-pared with those who received glutathione. Further ran-domized clinical trials are needed to test the effectivenessof this agent in CIPN.

Treatment of CIPNHistorically, treatments for CIPNs have been support-

ive.60 Neuropathic pain management is aimed at thereduction of symptoms, generally by suppressing neu-ronal activity, not glial cell activation, which has alsorecently been associated with the development andmaintenance of chronic pain states.13,61 At this time, nomedications exist that can fully relieve the sensory andmotor loss associated with advanced CIPNs. The needsof patients with CIPNs are largely unmet because of theabsence of adequate assessment and evidence-basedtreatments that could be widely applied across clinicalCIPN patient populations and could potentially preventor mitigate this increasingly common clinical problem.11

GabapentinGabapentin is an antiepileptic medication that has

demonstrated efficacy for the treatment of neuropathicpain, possibly in patients with CIPNs. Gabapentin wasinitially synthesized to mimic the chemical structure ofthe neurotransmitter gamma-aminobutyric acid, but it isnot believed to act on the same brain receptors.Although the exact mechanism of action is unknown,the therapeutic action of gabapentin on neuropathicpain is thought to involve voltage-gated calcium chan-nels. In a phase 3, randomized, double-blind, placebo-controlled, crossover trial, 115 patients with sympto-matic CIPN were randomized to receive eithergabapentin or placebo over the course of two 6-weekphases separated by a 2-week “washout” period. No sig-nificant differences were reported between the groups onscores of symptom distress or mood states. The only sig-nificant difference between the groups was in the McGillPain Rating Index, which showed lower pain in thegabapentin group at the end of the first 6-week treatmentperiod. The study failed to demonstrate the benefit ofgabapentin to treat CIPN symptoms.62

NortriptylineNortriptyline, a tricyclic antidepressant, works by

blocking the reuptake of serotonin and norepinephrinein the pain-modulating system within the CNS.63 In arandomized, double-blind, placebo-controlled, cross overstudy, 51 patients treated with cisplatin received escalat-ing doses of nortriptyline up to 100 mg/day over a 4-weekperiod. Responses to questionnaires concerning pain,sleep, QOL, and neuropathic symptoms also indicate arelatively modest benefit in cisplatin-induced paresthesiaover the placebo group. Objective mea sures of neuropa-thy were not used in this small pilot study, and thus theeffectiveness of nortriptyline in reducing paresthesiasrelated to CIPN cannot be established.

Acetyl L-carnitineAcetyl L-carnitine is an acetylated form of L-carnitine

that has shown neuroprotective effects and may be usefulin treating peripheral nerve injury. Two small studiesexamined the use of acetyl L-carnitine in the treatmentof preexisting paclitaxel- or cisplatin-induced peripheralneuropathy.64 Patients who received acetyl L-carnitineshowed improvement in neuropathy symptoms and inobjective measures of sensory and motor neuropathy;however, small sample sizes and nonrandomized one-group designs limit these studies. Further randomized

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

Alternative treatmentsAcupunctureIn one case series study testing the use of acupuncture

in five patients with CIPN, this modality was found toimprove sensation and gait, resulting in decreased anal-gesic use. Control of symptoms persisted for 6 monthsfor four of the five patients treated.65

Physical activity/exerciseThree relatively small studies examined progressive

resistance exercise, aerobic exercise, and stretchingexercises in the treatment of diabetic peripheral neu-ropathy and myotonic dystrophy. All three studiesfound significant improvement in stance, functionalreach, and peroneal and sural motor nerve conductionvelocity. The findings of these studies should be inter-preted with caution, as they have not been replicated inpatients who have or are at risk for CIPN.66-68

Pulsed infrared light therapy (PILT)PILT, also called anodyne therapy, consists of deliver-

ing infrared light to the feet of patients with diabetes, butit has not been tested as a treatment for CIPN. Followinga series of treatments, significant improvement in sensa-tion, neuropathic symptoms, and pain was evident inmost patients.69 Prendergast and colleagues found ano-dyne therapy improved sensory impairments as measuredby peroneal nerve function and current perceptionthresholds in 26 participants after 10 treatments deliv-ered over 2 weeks, each lasting 40 minutes.70 In anotherstudy, significant improvements in sensation were foundwhen PILT treatments were given for 30 minutes threetimes a week over an 8-week period.71

Transcutaneous electrical nerve stimulation(TENS)TENS has been tested in patients with diabetic neu-

ropathy, but not in patient populations with cancer. Ina randomized clinical trial of 19 patients with diabeticneuropathy, Forst and colleagues compared TENS withpseudostimulation by an electrically inactive device.72Significant subjective improvements in neuropathysymptoms, including numbness, pain, and allodynia,were demonstrated in 70% of treatment group partici-pants compared with 29% in the control group.

Capsaicin ointmentCapsaicin has been studied for the treatment of

peripheral neuropathy in the diabetic population, withinconclusive results that prevent recommendation at thistime. Although 10 patients who received capsaicin com-pleted a study with a significant decrease in hypoesthesia,two patients discontinued treatment due to erythema orgeneralized allergic skin reaction at the application site.73

ConclusionsEvidence supports the need for careful and ongoing

assessment of CIPNs in patients receiving chemothera-py. Specifically, clinical practice procedures need to bedeveloped that address the need for standardized assess-





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ments of CIPN, the frequency of CIPN evaluationswhile undergoing chemotherapy, and the length ofassessments once treatment is completed. In addition,there is a need to determine the clinically significantamount of sensory and motor changes noted in eithersensory or motor nerves that may warrant a dose reduc-tion in the treatment drug and/or the need for a reha-bilitation evaluation by a physical or occupational ther-apist. In the absence of evidence-based prevention ortreatment modalities for CIPNs, clinicians must edu-cate their patients about the functional changes theymay expect to occur as a result of neurotoxicchemotherapy and assist patients in developing strate-gies to manage limitations resulting from CIPNs. �

References1. Shaiova L. Difficult pain syndromes: bone pain, visceral pain, and

neuropathic pain. Cancer J. 2006;12:330-340.2. Chemotherapy-induced peripheral neuropathies (CIPNs): a biobe-

havioral approach. In: Moore RJ, ed. Biobehavioral Approaches toPain. New York, NY: Springer; 2008.

3. Wickham R. Chemotherapy-induced peripheral neuropathy: areview and implications for oncology nursing practice. Clin J OncolNurs. 2007;11:361-376.

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

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

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

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

8. Dunlap B, Paice JA. Chemotherapy-induced peripheral neuropa-thy: a need for standardization in measurement. J Support Oncol.2006;4:398-399.

9. Paice JA. Chemotherapy-induced peripheral neuropathy: a danger-ous but understudied syndrome. Pain Management SIG Newsletter.2007;17(1). http://onsopcontent.ons.org/Publications/SigNewsletters/pm/pm17.1.html. Accessed January 1, 2008.

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 periph-eral neuropathy. Ann Oncol. 2000;11:509-513.

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

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

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

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

16. Moalem G, Tracey DJ. Immune and inflammatory mechanisms inneuropathic 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 forpain control and increasing the efficacy of opioids. Brain Res Rev.2007;56:148-169.

18. Watkins LR, Hutchinson MR, Ledeboer A, et al. Norman CousinsLecture. Glia as the “bad guys”: implications for improving clinicalpain control and the clinical utility of opioids. Brain Behav Immun.2007;21:131-146.

19. Wieseler-Frank J, Jekich BM, Mahoney JH, et al. A novel immune-to-CNS communication pathway: cells of the meninges surround-ing the spinal cord CSF space produce proinflammatory cytokinesin response to an inflammatory stimulus. Brain Behav Immun.2007;21:711-718.

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

21. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances inneuropathic pain: diagnosis, mechanisms, and treatment recom-mendations. Arch Neurol. 2003;60:1524-1534.

22. White FA, Jung H, Miller RJ. Chemokines and the pathophysiolo-gy of neuropathic pain. Proc Natl Acad Sci U S A. 2007;104:20151-20158.

23. Seruga B, Zhang H, Bernstein L, Tannock IF. Cytokines and theirrelationship to the symptoms and outcome of cancer. Nat RevCancer. 2008;8:887-899.

24. Verstappen CC, Postma TJ, Hoekman K, Heimans JJ. Peripheralneuropathy due to therapy with paclitaxel, gemcitabine, and cis-platin in patients with advanced ovarian cancer. J Neurooncol.2003;63:201-205.

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

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

27. Joseph EK, Levine JD. Comparison of oxaliplatin- and cisplatin-induced painful peripheral neuropathy in the rat. J Pain.2009;10:534-541.

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

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

30. Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin.Mutat Res. 2001;478:23-43.

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

32. Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemother-apy-induced peripheral neurotoxicity using the Total NeuropathyScale. Neurology. 2003;61:1297-1300.

33. Cavaletti G, Zanna C. Current status and future prospects for thetreatment of chemotherapy-induced peripheral neurotoxicity. Eur JCancer. 2002;38:1832-1837.

34. Armstrong T, Almadrones L, Gilbert MR. Chemotherapy inducedperipheral neuropathy. Oncol Nurs Forum. 2005;32:305-311.

35. Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neuro-physiological responses of paclitaxel- or cisplatin-induced neuropa-thy to oral acetyl-L-carnitine. Eur J Cancer. 2005;41:1746-1750.

36. Bove L, Picardo M, Maresca V, et al. A pilot study on the relationbetween cisplatin neuropathy and vitamin E. J Exper Clin CancerRes. 2001;20:277-280.

37. Ueno H, Kiyosawa K, Kaniwa N. Pharmacogenomics of gem citabine:can genetic studies lead to tailor-made therapy? Br J Cancer.2007;97:145-151.

38. Postma TJ, Vermorken JB, Liefting AJ, et al. Paclitaxel-inducedneuropathy. Ann Oncol. 1995;6:489-494.

39. Cavaletti G, Bogliun G, Marzorati L, et al. Early predictors ofperipheral neurotoxicity in cisplatin and paclitaxel combinationchemotherapy. Ann Oncol. 2004;15:1439-1442.

40. England JD, Asbury AK. Peripheral neuropathy. Lancet.2004;363:2151-2161.

41. Postma TJ, Heimans JJ, Luykx SA, et al. A phase II study of pacli-taxel in chemonaïve patients with recurrent high-grade glioma.Ann Oncol. 2000;11:409-413.

42. Hilpert F, Stahle A, Tome O, et al. Neuroprotection with amifos-tine in the first-line treatment of advanced ovarian cancer with car-boplatin/paclitaxel-based chemotherapy. A double blind, placebo-controlled, randomized phase II study from the Arbeitsgeme inschaftGynakologische Onkologie (AGO) Ovarian Cancer Study Group.Support Care Cancer. 2005;13:797-805.

43. Moore D, Donnelly J, McGuire WP, et al. Limited access trial usingamifostine for protection against cisplatin and three hour paclitax-el induced neurotoxicity: a phase II study of the GynecologicOncology Group. J Clin Oncol. 2003;21:4207-4213.

44. Openshaw H, Beamon K, Synod TW, et al. Neurophysiolgical studyof peripheral neuropathy after high-dose paclitaxel: lack of neuro-protective effect of amifostine. Clin Cancer Res. 2004;10:461-467.

45. Bove L, Picardo M, Maresca V, et al. A pilot study on the relationbetween cisplatin neuropathy and vitamin E. J Exper Clin CancerRes. 2001;20:277-280.

46. Pace A, Savarese A, Picardo M, et al. Neuroprotective effect ofvitamin E supplementation in patients treated with cisplatinchemotherapy. J Clin Oncol. 2003;21:927-931.

47. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for prophylax-is against chemotherapy-induced neuropathy: a randomized con-trolled trial. Neurology. 2005;64:26-31.

48. Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxali-platin-related neurotoxicity by calcium and magnesium infusions: aretrospective study of 161 patients receiving oxaliplatin combinedwith 5-fluorouracil and leucovorin for advanced colorectal cancer.Clin Cancer Res. 2004;10(12 pt 1):4055-4061.

49. Grothey A. Oxaliplatin—safety profile: neurotoxicity. Semin Oncol.2003;30(4 suppl 15):5-13.

50. Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatin-relatedneurotoxicity: interest of calcium magnesium infusion and noimpact on its efficacy. J Clin Oncol. 2007;26:1188-1189.

51. Eckel F, Schmelz R, Adelsberger H, et al. Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study [in German].Dtsch Med Wochenschr. 2002;127:78-82.

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

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

54. Vahdat L, Papadopoulos K, Lange D, et al. Reduction of paclitaxel-induced 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 pre-venting oxaliplatin-induced neuropathy in colorectal cancerpatients. Oncologist. 2007;12:312-319.

56. Ocean AJ, Vahdat LT. Chemotherapy-induced peripheral neuropa-thy: pathogenesis and emerging therapies. Support Cancer Care.2004;12:619-625.

57. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect ofreduced glutathione on oxaliplatin-based chemotherapy inadvanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002;20:3478-3483.

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

59. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect ofreduced glutathione on cisplatin-based chemotherapy in advancedgastric cancer: a randomized double-blind placebo-controlled trial.J Clin Oncol. 1995;13:26-32.

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

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

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

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

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

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

66. Lindeman E, Leffers P, Spaans F, et al. Strength training in patientswith myotonic dystrophy and hereditary motor and sensory neu-ropathy: a randomized clinical trial. Arch Phys Med Rehabil.1995;76:612-620.

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

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

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

70. Prendergast JJ, Miranda G, Sanchez M. Improvement of sensoryimpairment in patients with peripheral neuropathy. Endocr Pract.2004;10:24-30.

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

72. Forst T, Nguyen M, Forst S, et al. Impact of low frequency transcu-taneous electrical nerve stimulation on symptomatic diabetic neu-ropathy 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 capsaicintreatment on small nerve fibre function and neurovascular control insymptomatic diabetic neuropathy. Acta Diabetologica. 2002;39:1-6.

74. Leong SS, Tan EH, Fong KW, et al. Randomized double-blind trialof combined modality treatment with or without amifostine inunresectable 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 magne-sium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol.2007;25:4028-4029.

76. Hochster HS, Grothey A, Shpilsky A, Childs BH. Effect of intra-venous (IV) calcium and magnesium (Ca/Mg) versus placebo onresponse 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 intravenouscalcium and magnesium (IV CaMg) on oxaliplatin-induced senso-ry neurotoxicity (sNT) in adjuvant colon cancer: results of thephase 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 advancedage associated with increased incidence and severity of chemotherapy-induced peripheral neuropathy? Support Care Cancer. 2006;14:223-229.

79. Pace A, Carpano S, Galie E, et al. Vitamin E in the neuroprotec-tion of cisplatin induced peripheral neurotoxicity and ototoxicity. J Clin Oncol. 2007;25(18S):Abstract 9114.




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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 col-umn 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

Medications Used for the Treatment of Leukemias

Oncology Drug Codes

Associated ICD-9-CM Codes Used for Leukemias

204 Lymphoid leukemia204.00 Acute—without mention of having achieved remission204.01 Acute—in remission204.02 Acute—in relapse

204.10 Chronic—without mention of having achieved remission204.11 Chronic—in remission204.12 Chronic—in relapse

205 Myeloid leukemia205.00 Acute—without mention of having achieved remission205.01 Acute—in remission205.02 Acute—in relapse


206 Monocytic leukemia206.00 Acute—without mention of having achieved remission206.01 Acute—in remission206.02 Acute—in relapse


NCCN Drugs Current MedicareFDA- & Biologics code price allowableapproved Compendium (AWP-based (ASP + 6%), CPT

Generic (brand) HCPCS code: for off-label use for pricing), effective effective administrationname code description leukemias leukemias 11/1/09 10/1/09-12/31/09 codes

alemtuzumab J9010: injection, � $660.90 $570.22 96413, 96415(Campath) alemtuzumab, 10 mgarsenic trioxide J9017: injection, � $43.58 $37.44 96413, 96415(Trisenox) arsenic trioxide, 1 mgasparaginase J9020: injection, � $70.42 $58.01 96401, 96413(Elspar) asparaginase, 10,000 unitsazacitidine J9025: injection, � $5.74 $4.87 96401, 96409, 96413(Vidaza) azacitidine, 1 mgbendamustine J9033: injection, � $21.60 $18.53 96413(Treanda) bendamustine HCl, 1 mgbetamethasone J0702: injection, � $6.85 $6.56 11900, 11901, 20600,(Celestone Soluspan) betamethasone acetate, 20605, 20610, 96372

3 mg and betamethasone sodium phosphate, 3 mg

busulfan J8510: busulfan, � $4.46 $3.22 N/A(Myleran) oral, 2 mgchlorambucil J8999a: prescription drug, � NDC NDC N/A(Leukeran) oral, chemotherapeutic, level level

not otherwise specified pricing pricingchlorambucil S0172: chlorambucil, � $3.86 S0172: not N/A(Leukeran) oral, 2 mg payable by

Medicare


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cladribine J9065: injection, � $58.20 $25.64 96413, 96415(Leustatin) cladribine, per 1 mgclofarabine J9027: injection, � $135.00 $116.40 96413, 96415(Clolar) clofarabine, 1 mgcyclophosphamide J8530: cyclophosphamide, � $2.09 $0.81 N/Aoral (Cytoxan) oral, 25 mgCyclophosphamide J9090: cyclophosphamide, � $30.34 $21.51 96409, 96413, 96415injection (Cytoxan) 500 mgcyclophosphamide J9091: cyclophosphamide, � $54.62 $43.03 96409, 96413, 96415injection (Cytoxan) 1.0 gramcyclophosphamide J9092: cyclophosphamide, � $98.30 $86.06 96409, 96413, 96415injection (Cytoxan) 2.0 gramscytarabine J9100: injection, � $3.60 $1.72 96409, 96413, (Cytosar-U) cytarabine, 100 mg 96415, 96450cytarabine J9110: injection, � $10.20 $3.92 96409, 96413,(Cytosar-U) cytarabine, 500 mg 96415, 96450dasatinib J8999a: prescription drug, � NDC NDC N/A(Sprycel) oral, chemotherapeutic, level level

not otherwise specified pricing pricingdaunorubicin J9150: injection, � $25.20 $15.24 96409, 96413(Cerubidine) daunorubicin, 10 mgdexamethasone J1100: injection, � $0.15 $0.08 11900, 11901,20600, (Decadron) dexamethasone 20605, 20610, 96372,

sodium phosphate, 1 mg 96374dexamethasone J8540: dexamethasone, � $0.09 $0.38 N/A(Decadron) oral, 0.25 mgdoxorubicin HCl J9000: injection, doxorubicin � $13.20 $3.69 96409(Adriamycin) hydrochloride, 10 mgfludarabine J9185: injection, � $330.32 $154.27 96413(Fludara) fludarabine phosphate, 50 mggemtuzumab J9300: injection, gemtuzumab � $3,104.82 $2,622.30 96413, 96415ozogamicin (Mylotarg) ozogamicin, 5 mghydrocortisone J1720: injection, � $2.46 $2.92 96365, 96366, (Solu-Cortef) hydrocortisone sodium 96372, 96374

succinate, up to 100 mghydroxyurea J8999a: prescription drug, � NDC NDC N/A(Hydrea) oral, chemotherapeutic, level level

not otherwise specified pricing pricinghydroxyurea S0176: hydroxyurea, � $1.28 S0176: not N/A(Hydrea) oral, 500 mg payable by

Medicareidarubicin J9211: injection, idarubicin � $381.56 $98.56 96409(Idamycin) hydrochloride, 5 mgimatinib J8999a: prescription drug, � NDC NDC N/A(Gleevec) oral, chemotherapeutic, level level

not otherwise specified pricing pricingimatinib S0088: imatinib, � $42.12 S0088: not N/A(Gleevec) 100 mg payable by

Medicareinterferon alfa-2b J9214: injection, interferon, � $21.90 $15.84 96372, 96401(Intron-A) alfa-2b, recombinant,

1 million unitsmechlorethamine J9230: injection, � $178.71 $147.34 96409(Mustargen) mechlorethamine hydrochloride

(nitrogen mustard), 10 mgmercaptopurine J8999a: prescription drug, � NDC NDC N/A(Purinethol) oral, chemotherapeutic, level level

not otherwise specified pricing pricing



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mercaptopurine S0108: mercaptopurine, � $4.09 S0108: not N/A(Purinethol) oral, 50 mg payable by

Medicaremethotrexate J8610: methotrexate, � $3.56 $0.12 N/A

oral, 2.5 mgmethotrexate J9250: methotrexate � $0.27 $0.21 96372, 96374, 96401,sodium sodium, 5 mg 96409, 96450methotrexate J9260: methotrexate � $2.68 $2.12 96372, 96374, 96401,sodium sodium, 50 mg 96409, 96450methylprednisolone J1030: injection, � $5.84 $3.79 11900, 11901, 20600,(Depo-Medrol) methylprednisolone acetate, 40 mg 20605, 20610, 96372methylprednisolone J1040: injection, � $11.46 $7.27 11900, 11901, 20600,(Depo-Medrol) methylprednisolone acetate, 80 mg 20605, 20610, 96372methylprednisolone J2920: injection, � $2.36 $2.56 96365, 96366,(Solu-Medrol) methylprednisolone sodium 96372, 96374

succinate, up to 40 mgmethylprednisolone J2930: injection, � $4.15 $3.45 96365, 96366,(Solu-Medrol) methylprednisolone sodium 96372, 96374

succinate, up to 125 mgmethylprednisolone J7509: methylprednisolone, � $0.54 $0.06 N/A(Medrol) oral, per 4 mgmitoxantrone J9293: injection, mitoxantrone � $116.50 $66.77 96409, 96413(Novantrone) hydrochloride, per 5 mgnilotinib J8999a: prescription drug, � NDC NDC N/A(Tasigna) oral, chemotherapeutic, level level

not otherwise specified pricing pricingpegaspargase J9266: injection, pegaspargase, � $3,280.00 $2,747.51 96401, 96413, 96415(Oncaspar) per single dose vialpeginterferon J3490a: unclassified drugs � NDC NDC 96372alfa-2a (Pegasys) level level

pricing pricingpeginterferon S0145: injection, � $589.12 S0145: not 96372alfa-2a (Pegasys) pegylated interferon alfa-2a, payable by

180 mcg per mL Medicarepeginterferon J3490a: unclassified drugs � NDC NDC 96372alfa-2b (Peg-Intron) level level

pricing pricingpeginterferon S0146: injection, � $106.42 S0146: not 96372alfa-2b (Peg-Intron) pegylated interferon alfa-2b, payable by

10 mcg per 0.5 mL Medicarepentostatin J9268: injection, � $2,182.80 $1,426.47 96409, 96413(Nipent) pentostatin, per 10 mgprednisolone (Millipred, J7510: prednisolone, � $0.56 $0.02 N/AOrapred, Veripred) oral, per 5 mgprednisone J7506: prednisone, � $0.05 $0.05 N/A

oral, per 5 mgrituximab J9310: injection, � $664.32 $563.33 96413, 96415(Rituxan) rituximab, 100 mgteniposide Q2017: injection, � $376.55 $325.57 96413, 96415(Vumon) teniposide, 50 mgthioguanine J8999a: prescription drug, � NDC NDC N/A(Tabloid) oral, chemotherapeutic, level level

not otherwise specified pricing pricingtretinoin J8999a: prescription drug, � NDC NDC N/A(Vesanoid) oral, chemotherapeutic, level level

not otherwise specified pricing pricing



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vinCRIStine J9370: vincristine sulfate, � $8.12 $5.72 96409(Vincasar PFS) 1 mgvinCRIStine J9375: vincristine sulfate, � $16.24 $11.44 96409(Vincasar PFS) 2 mgvinCRIStine J9380: vincristine sulfate, � $40.60 $28.59 96409(Vincasar PFS) 5 mg

aWhen 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 inorder 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).

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 CommonProcedure Coding System; NCCN, National Comprehensive Cancer Network.

This information was supplied by:

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

MORE ONCOLOGY DRUG CODES ONLINE

LymphomasBrain Cancers

Head and Neck Cancers

www.theoncologypharmacist.com

Recent FDA ApprovalsFolotyn for Relapsed orRefractory Peripheral T-cellLymphomaThe first single-agent therapy for relapsedor refractory peripheral T-cell lymphoma,pralatrexate injection (Folotyn, AllosTherapeutics), has been approved by theUS Food and Drug Administration (FDA).The approval for this indication was basedon overall response rate. At current, im -provement in progression-free survivaland overall survival has not been demon-strated. Additional clinical studies areongoing to verify and describe the agent’sclinical benefits.

Cervarix Cervical CancerVaccineThe FDA has approved a new humanpapillomavirus (HPV) bivalent (types 16and 18) vaccine, recombinant (Cervarix,GlaxoSmithKline) for the prevention ofcervical precancers and cervical cancerassociated with oncogenic HPV types16 and 18 for use in girls and young

women aged 10 to 15 years. Theapproval was based on a study thatshowed the vaccine to be 93% effica-cious in the prevention of cervical pre-cancers associated with HPV 16 and 18in women without evidence of currentinfection or prior exposure to thesetypes of HPV at time of vaccination.

Votrient for Advanced RenalCell CarcinomaThe FDA has approved the oral agentpazopanib (Votrient, GlaxoSmithKline)for treatment of advanced renal cell car-cinoma. The agent, which interfereswith angiogenesis, was approved basedon a 435-patient study that examinedprogression-free survival (PFS). PFSaveraged 9.2 months for patients whoreceived the drug compared with 4.2months for those who did not.

Elitek for Management ofPlasma Uric Acid LevelsThe FDA has approved rasburicase

(Elitek, sanofi-aventis US) for use in theinitial management of plasma uric acid(PUA) levels in adults with leukemia,lymphoma, and solid tumor malignan-cies who are receiving anticancer ther-apy expected to result in tumor lysissyndrome and subsequent elevations ofPUA. Approval was based on a phase 3trial that demonstrated that rasburicasesignificantly reduced PUA levels com-pared with oral allopurinol (the currentstandard therapy).

Arzerra for ChronicLymphocytic LeukemiaThe FDA has granted acceleratedapproval of ofatumumab (Arzerra,GlaxoSmithKline/Genmab) for use inpatients with chronic lymphocyticleukemia (CLL) that is refractory to flu-darabine and alemtuzumab. Approvalwas based on a study in which 42% ofpatients with treatment-refractory CLLresponded to treatment with ofatu-mumab, a monoclonal antibody drug

targeting the CD20 protein on B cells.These patients had a median duration ofresponse of 6.5 months. Commonadverse events included neutropenia,pneumonia, pyrexia, cough, diarrhea,anemia, fatigue, dyspnea, rash, nausea,bronchitis, and upper respiratory tractinfections.

Istodax for Cutaneous T-cellLymphomaThe FDA has approved romidepsin(Istodax, Gloucester Pharmaceuticals)for the treatment of cutaneous T-celllymphoma in patients who havereceived at least one prior systemictherapy. Approval of the histonedeacetylase inhibitor was based on effi-cacy data from two studies totaling 167patients. The overall response rates,defined as the proportion of patientswith confirmed complete response orpartial response, were 34% and 35%.The complete response rate was 6% inboth studies. �


• Lenalidomide starting dose 25 mg po once dailyb

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

Pretreatment Phase (4 Weeks)

• MCL diagnosis confirmed by local pathological review

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

A Phase 2 Study for Patients With Relapsed/Refractory Mantle Cell Non-Hodgkin’s Lymphoma

Primary Investigator André Goy, MD

Primary ObjectiveTo 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

Treatment Phasea (until disease progression)

Investigational use of lenalidomide.

For more information contact Deborah Ingenito, Celgene Study Manager [email protected] (908) 673-9581www.clinicaltrials.gov (NCT00737529)

N=133

NHL Mantle Cell TrialNow Recruiting Investigators and Enrolling Study ParticipantsCelgene CC-5013-MCL-001



CAN

CER CEN

TER PR

OFILE

The University of PittsburghMedical Center (UPMC) CancerCenters work in tandem with the

University of Pittsburgh Cancer Institute(UPCI) to offer advances in cancer pre-vention, early detection, diagnosis, andtreatment throughout a three-stateregion (western Pennsylvania, Ohio,West Virginia). UPCI has been designat-ed as a Comprehensive Cancer Centerby 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 pro-fessionals provides clinical care to 30,000patients annually at its facilities whileengaging in cutting-edge cancer re -search. Medical, radiation, and surgicaloncologists and disease-specific special-ists collaborate closely in a model of mul-tidisciplinary care. Ancillary serviceproviders in behavioral medicine, reha-bilitation, social work, palliative care,nutrition, and genetic counseling areincorporated into the multidisciplinary

team to ensure that all aspects of care areaddressed.The hub and satellite network of

UPMC Cancer Centers consists of morethan 45 community-based locations inwestern Pennsylvania and two centers inIreland. The hub-and-spoke model ensures

extensive distribution of radiation thera-py and medical oncology facilitiesthroughout the tri-state region, saidBarry Lembersky, MD, a medical oncolo-gist. “Our pathways of standard of careare uniform throughout this area, and thefull array of clinical trials is available topatients at all satellite facilities,” he said.

Thirteen areas of expertiseThe range of knowledge covers virtu-

ally all types of adult cancer, with 13areas of expertise being recognized,including a world-renowned melanomaprogram. Other programs are devoted tobrain cancers, breast cancer, colon andgastrointestinal cancers, head and neckcancers, leukemias and lymphomas, livercancer, lung cancer, gynecologic cancers,prostate and urologic cancers, and stem-cell transplantation.The Melanoma and Skin Cancer

Program consists of both basic and clini-cal research and has patients comingfrom all over the world to participate inclinical trials for melanoma under thedirection of John Kirkwood, MD. Majorareas of research range from the develop-ment of a melanoma vaccine to thesearch for biomarkers to aid in the devel-

opment of personalized treatments.UPMC was one of the first centers to usea digital mole mapping system to assesshigh-risk patients for skin cancer.In addition, UPMC has “a well-orga-

nized pancreatic cancer program where-by patients with all forms of pancreaticcancer and all stages are seen in a multi-disciplinary clinic with innovative clini-cal trials in the preoperative setting andthe adjuvant and metastatic setting,”Lembersky said.For instance, a preoperative clinical

trial of gemcitabine with radiation thera-py and bevacizumab is in progress, withthe goal of evaluating the downstagingand histologic changes that occur withsuch treatment. “That’s a pretty novelapproach that holds promise not only forbetter outcome but for the paradigm ofevaluating new drugs and new drug com-binations; give the drugs prior to pancre-atic resection to look for surrogate mark-ers of response (ie, tumor necrosis), andcorrelate it with long-term outcome,” hesaid. “The treatment has been very welltolerated and resection rates are high. Inmost patients, there is evidence of signif-icant necrosis and chemotherapy or radi-ation effect, and what that means for sur-vivorship is uncertain at this time.”Other research involves the testing of

a vaccine for colon cancer prevention inpersons at high risk for developing thedisease. In a novel approach, the vaccineis directed against an abnormal variant ofthe gene MUC1, which is altered andproduced in excess in advanced adeno-

mas and cancer. Stimulating an immuneresponse against the protein encoded byMUC1 in precancerous growths may notonly trigger the immune system todestroy the abnormal cells to preventprogression to cancer but may also pre-vent polyp recurrence. MUC1 vaccineshave been tested for safety and immuno-genicity in patients with late-stage coloncancer and pancreatic cancer.

Integrated drug discovery pro-gram allows for range of studiesA vertically integrated drug develop-

ment program at UPCI, called Mol -ecular Therapeutics Drug Discovery,employs 69 members with interests inone of four areas: chemical diversity,molecular targets, pharmacokinetics/pharmacodynamics, and phase 1 clinicaltrials. “The goal is to have seamlessmovement from chemistry into patients,and if we make observations in patients,to be able to take them back and look atthem on a mechanistic/molecular level,”said Merr ill Egorin, MD, professor ofmedicine at UPCI.“We are one of the six NCI animal

pharmacology contractors, so that puts usin the pipeline of any drug that the NCIis considering putting into patients,” hesaid. “We’ve got an early signal on what’scoming through the NCI. If we have in-place methods to measure the drug—we’ve defined its metabolism, we knowits molecular targets, and we have assaysto measure those molecular targets inanimal models of tumors—it’s a hugestrength when we put in a request to doa first-in-human study or phase 2 study,”Egorin said.Researchers at UPCI are also

involved in a number of ongoing studieswith the target poly (ADP-ribose) poly-merase (PARP), an enzyme involved inthe recognition of DNA damage andrepair. By inhibiting PARP, the hope isthat the activity of anticancer drugs canbe potentiated, presumably by decreas-ing the resistance or increasing the sen-sitivity of tumor cells to standardchemotherapy.

BRCA1- and BRCA2-mutated tu -mors should be specifically sensitive toinhibition of PARP, according toEgorin. This synthetic lethal approachhas already been validated in vitro andin preclinical models. “There hasalready been a clinical study with a dif-ferent PARP inhibitor that has demon-strated the case that BRCA tumors willrespond to this, and the toxicities areessentially none,” he said. �

—Wayne Kuznar

University of Pittsburgh Medical Center Cancer Centers and Cancer Institute

Cancer Center Profile

Clinical Pharmacy Specialist Spotlight: James Natale, PharmD

The dramatic changesthat have occurred inoncology pharmacy over

the past decade have presentedJames Natale, PharmD, with acontinuous series of challenges,each of which he has foundrewarding.Natale, who did his un der-

graduate work at DuquesneUniversity, was an oncology res-ident at the University ofPittsburgh Medical Center(UPMC) Cancer Centers in 1998 and1999, before the advent of targeted ther-apies and the use of genomics in selectingpharmacotherapy. As a clinical pharma-cy specialist at UPMC Cancer Centerssince 2000, he now takes advantage of

these advances and relish-es the learning environ-ment as well as the oppor-tunity to be involved intotal patient care.“What we did just a

few years ago, we’re notdoing today,” he said.“The interesting thingabout tumors is thatthere will probably neverbe a ‘silver bullet’ foroncology. Each tumor

has such various mechanisms; not justdifferent tumors types like lung cancerversus breast cancer, but even withinthe breast tumor itself is a heteroge-neous mix of clonal populations ofcells. We’re constantly looking at new

markers of these cells and ways tocombine agents that attack thesenew markers.”With three colleagues, he rotates

through three major services: hematol-ogy, oncology, and bone marrow trans-plant. This set-up affords him anopportunity to stay current in eachservice. “You see everything, so youdon’t lose touch,” he said. “It’s advan-tageous professionally and personallybecause it lessens the chance of burn-ing out while always presenting a newchallenge. As you come back to a serv-ice that you did months ago, there’salways some new drug you might beworking with.” �

—WK

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Planning for a Great Residency ProjectContinued from page 13

the preceptor to monitor the residentclosely during this phase. Many resi-dency programs allow for special proj-ect time to be assigned, outside of rota-tional responsibilities. This is one ofthe phases where the timeline can gohaywire, so planning for delays andclose preceptor monitoring is necessaryfor a successful project. Gearing up forthe collection of data in the post-phasemay require some motivational skillson the part of the preceptor.

Implementation of the interventioncan be very rewarding for the resident.It may include committee decisionmaking, presentations to administrators,designing therapy protocols, conductingprocess analysis, assisting in developingIT solutions, teaching pharmacists,physicians and patients, or re-engineer-ing a problematic process. As much ofthis step as possible should be delegatedto the resident. These career skills cancontribute to the resident’s future plans.

Presentation of the projectAfter analysis of the data and formu-

lation of conclusions, the next step in asuccessful residency project is the prepa-ration of the material for verbal andwritten presentation. Condensing thestudy method, data, and conclusionsinto a 10- to 20-minute presentationcan be challenging. Many aspects canbe summarized, given the likely audi-ence of the presentation. Most data arebest presented in graphic form. Comp -

licated tables and replication of thedata-collection form or treatment pro-tocol onto a single slide should beavoided. Adequate time should bedevoted to a discussion of the conclu-sions, implications of the data, and theplan for future work. After initial slidereview by the preceptor, the residentshould be given opportunities to prac-tice the presentation in front of anaudience at least twice before theregional residency conference. In addi-tion, the resident should take everyopportunity to present the projectinternally to appropriate committees,departments, or task forces. Even ifthere is not time or opportunity forpublication, the resident should write amanuscript based on the study, using aformat appropriate for publication, togain the experience of formal, scientif-ic writing.

A successful residency project canprovide many important real-worldlearning experiences for the residentand foster the mentoring relationshipbetween the resident and the precep-tor. Advance planning can turn theresidency project into a meaningfulexperience for both the resident andpreceptor. �

Current activities at www.COEXM.com include:

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Suggested Readings

• ASHP Foundation. ResidencyRe search Tips. www.ashpfoundation.org/MainMenuCategories/ResearchResourceCenter/Foster ingYoungInvestigators/ResidencyResearchTips_1.aspx.

• Barletta JF. Conducting a successful residency research project. Am J Pharm Educ.2008;72:92.

• Hartung DM, Touchette D.Overview of clinical researchdesign. Am J Health SystPharm. 2009;66:398-408.

• Lipowski EE. Developing greatresearch questions. Am JHealth Syst Pharm. 2008;65:1667-1670.

• Planas LG. Intervention design,implementation and evaluation.Am J Health Syst Pharm. 2008;65:1854-1863.

• Weber RJ, Cobaugh DJ.Developing and executing aneffective research plan. Am JHealth Syst Pharm. 2009;65:2058-2065.


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� Improved Event-free Survivalin Children and Adolescentswith Ph+ ALLBackground: Imatinib monotherapy

has been shown to produce highresponse rates in Philadelphia chromo-some–positive (Ph+) acute lymphoblas-tic leukemia (ALL), but with recurrencein months. It has been used in combina-tion with intensive hyperfractionated

cyclophosphamide, vincristine, doxoru-bicin, and dexamethasone therapy fol-lowed by blood and marrow transplanta-tion (BMT) in adults with Ph+ ALL.Efficacy and tolerability with multiagentchemotherapy in children is not known.

Design: Patients with Ph+ ALLaged 1 to 21 years (N = 92) receivedimatinib 340 mg/m2/day introducedstepwise into their chemotherapy regi-

men. Exposure to imatinib wasincreased progressively in five patientcohorts that received the agent from42 to 280 days before maintenancetherapy. Ph- ALL patients (N = 65)who received the same chemotherapywithout imatinib were used as com-parators. Patients with compatible sib-ling donors underwent BMT with ima-tinib given for 6 months following.

Summary: Continuous imatinib ex -posure improved outcome in patients inthe fifth cohort with a 3-year event-free survival (EFS) of 80% ± 11%(95% CI, 64%-90%). Three-year EFSwas similar for patients in the fifthcohort treated with chemotherapy plusimatinib (88% ± 11%; 95% CI, 66%-96%) or sibling-donor BMT (57% ±22%; 95% CI, 30.4%-76.1%). Noappreciable increase in toxicities wasassociated with adding imatinib tointensive chemotherapy.

Takeaway: Imatinib added to inten-sive chemotherapy improved 3-yearEFS in children and adolescents withPh+ ALL. Outcomes were not superiorwhen imatinib plus chemotherapy wasadded to BMT.

Schultz KR, et al; for the Children’sOncology Group. J Clin Oncol. 2009Oct 5. Epub ahead of print.

� Hormonal Therapy forProstate Cancer andComorbid ConditionsBackground: Hormonal therapy

(HT), when combined with externalbeam radiation therapy (RT), improvescancer-specific and overall survival ver-sus RT alone. A recent postrandomiza-tion hypothesis-generating analysis sug-gested that men with moderate to severecomorbidity did not receive this survivalbenefit. Which condition(s) eliminatesthis benefit was not determined.

Design:Risk of all-cause mortality wasmeasured by Cox regression in 5077 men(median age, 69.5 years) with localizedor locally advanced prostate cancer. Thepatients were treated with or without amedian of 4 months of neoadjuvant HTfollowed by RT.

Summary: Neoadjuvant HT usewas not associated with an increasedrisk of all-cause mortality in men withno comorbidity (9.6% vs 6.7%, adjust-ed 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 5.0and 4.4 years, respectively. However,for men with CAD-induced conges-tive heart failure (CHF) or myocardialinfarction (MI), after a median fol-low-up of 5.1 years, neoadjuvant HTuse was significantly associated withan increased risk of all-cause mortali-ty (26.3% vs 11.2%, adjusted HR,1.96; 95% CI, 1.04-3.71; P = .04).

Takeaway: Neoadjuvant HT use issignificantly associated with all-causemortality among men with a history ofCAD-induced CHF or MI. No associa-tion was found among men with nocomorbidity or a single CAD risk factor.

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

In the LiteratureConcise Reviews of Studies Relevant to Cancer Care


IN TH

E LITERATUR

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A Newsletter Series for Cancer Care Professionals

Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, are pleased tooffer your multidisciplinary cancer team with this series ofnewsletters focusing on the challenges in treating patientswith multiple myeloma.

SAGAR LONIAL, MDAssociate Professor of

Hematology and Oncology Emory University School of Medicine

� Earn Continuing Education Credits �

Each newsletter will feature:

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

• Retreatment Settings

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• Do CRs Correlate withClinical Benefit?

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• Stem Cell Mobilization

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(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 single-agent 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 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2009 Biogen Idec Inc. and Genentech, Inc. 7140918 November 2009

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

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non–progressing (including stable disease), low-grade, 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. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Infections Rituxan is not recommended for treatment of patients with severe active infections. The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In

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

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 institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.Table 1Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by

NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy Adverse reactions information below is based on 1250 patients who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Whole 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendages 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory System 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and Nutritional Disorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

22-24 ORLANDO, FL2010 Gastrointestinal CancersSymposiumwww.asco.org

30 MINNEAPOLIS, MN7th Annual Mayo Clinic HematologyReviewwww.mayo.edu

13-16 SAN DIEGO, CAScripps Cancer Center’s 30th AnnualConference: Clinical Hematologyand Oncologywww.scripps.org

25 CHANDLER, AZMultidisciplinary Head and NeckCancer Symposiumwww.headandnecksymposium.org

JANUARY 2010

FEBRUARY 2010

3-6 MIAMI, FL27th Annual Miami Breast CancerConferencewww.cancerlearning.com

4-6 BETHESDA, MD8th International Symposium onTargeted Anticancer Therapies (TAT 2010)www.nddo.org

5-7 SAN FRANCISCO, CAGenitourinary Cancers Symposiumwww.asco.org

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Across approved NHL indications

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 InformationThe most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse

reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.

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 GELA trial1‡

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

In the E1496 trial1

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)

In the Marcus trial1

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)

IndicationsRITUXAN® (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

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

DRIVING BETTEROUTCOMES IN NHL

PROVEN OUTCOMES ACROSS MULTIPLE ENDPOINTS1-3

* 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.

TOPNov_Dec09FINAL 11/17/09 12:58 PM Page C4

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