june 2011, vol 4, no 4

For Payers, Purchasers, & Oncology P&T Committees

©2011 Green Hill Healthcare Communications, LLC

JUNE 2011 www.TheOncologyPharmacist.com VOL 4, NO 4

Complimentary Ce . . . . . . . . . . . 20Prevention and Treatment ofVenous Thromboembolism inCancer

ConferenCe news: Hopa . . . . 6Nutrition Support

Treatment of Challenging CancerPain

Radiation-Induced ToxicityTreatment Options

Minimizing Chemo Toxicities inMetastatic Colon Cancer

Identifying, Reporting, andManaging Medication Errors

Controversies in Care: BreastCancer, Bladder Cancer, andPediatric Ewing Sarcoma

supportive Care . . . . . . . . . . . . 12Treating Breakthrough Cancer Pain

Managing HypersensitivityReactions

pHarmaCy Careers . . . . . . . . 18The Pharmacy ReimbursementSpecialist

I N S I D E

Technician Melinda Tunnell shows pharmacist Chris Shattuck what drug she will inject into the infusion bag.

New Oncology PharmacyProvides “CleanestPossible Product”By Dawn Lagrosa

This past April, Mountain States Health Alliance’s Regional CancerCenter celebrated the 1-year anniversary of its new, state-of-the-art oncology pharmacy. Located in the Regional Cancer Center’s

dedicated medical oncology facility, the pharmacy provides USP<797>-compliant chemotherapy and supportive care agents as well asthe benefit of face-to-face collaboration between pharmacists and therest of the cancer care team.

CANCER CENTER PROFILE

Continued on page 24

SALT LAKE CITY—Identifying safetymeasures for patients receiving oralchemotherapy is of the upmost impor-tance, according to a presentation at theannual meeting of the Hematology/Oncology Pharmacy Association. Thisincludes monitoring the administrationof and adherence to the treatment as wellas ensuring the prevention of any med-ication errors.

“In my experience, patients do notthink it’s the doctor’s job to educatethem about their oral chemotherapy,thinking [the doctors] don’t have thetime or don’t want to do that,” said BethChen, PharmD, BCOP, oncology clinicalspecialist at Biologics, Inc, in Cary,North Carolina.

In addition, she noted that patients are

CONFERENCE NEWS

Oral Chemotherapy ShouldMirror the Current Standardsfor IV ChemotherapyPharmacists Should Monitor Patients ProactivelyBy Deborah Brauser

PHARMACOGENOMICS

KRAS Status, EGFR Inhibition,and Colorectal CancerBy Katharine A. Kinsman, PharmD, BCOPClinical Pharmacy Specialist in Medical Oncology, The Johns Hopkins Hospital,

Baltimore, Maryland

Rowena N. Schwartz, PharmD, BCOPDirector of Weinberg and Oncology Pharmacy, The Johns Hopkins Hospital,

Baltimore, Maryland

Continued on page 6

Pharmacogenomics is the study ofthe role of inherited and acquiredgenetic variation in drug response.1

A focus of research in recent years ongenome-wide association studies ultimate-

ly may help identify patient- and/or can-cer-specific biomarkers that will facilitateoptimization of drug therapy includingguiding drug selection, dose, and treat-

Continued on page 16

TOPPharmacist

You voted for theFind Out Who Won!

4

TOP_June_v6 2011_TOP 6/17/11 12:27 PM Page 1

Going to ASHP Summer Meeting? Stop by booth #608 to get your copy of this new groundbreaking study.

TOP_June_v6 2011_TOP 6/17/11 12:27 PM

June 2011 I VOL 4, nO 4 3www.TheOncologyPharmacist.com

Editorial Board

EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C.Gammon, BSPhOncologyPharmacist.net Warwick, RI

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase Cancer CenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDIndiana UniversityHospitalIndianapolis, IN

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud,PharmD, BCOP,FASHPThe University of TexasM. D. Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina College ofPharmacyColumbia, SC

Steve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

TOP_June_v6 2011_TOP 6/17/11 12:27 PM

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[email protected]

Editorial DirectorKristin Siyahian

[email protected]

Associate EditorDawn Lagrosa

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Quality Control DirectorBarbara Marino

Directors, Client ServicesJoe Chanley

[email protected]

Jack [email protected]

Production ManagerStephanie Laudien

Business ManagerBlanche Marchitto

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Editorial Contact:Telephone: 732-992-1891

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2011 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, 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.

EDITORIAL CORRESPONDENCE should beaddressed to EDITORIAL DIRECTOR, The OncologyPharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp,NJ 08831. E-mail: [email protected]. YEARLYSUBSCRIPTION RATES: United States and posses-sions: individuals, $105.00; institutions, $135.00; singleissues, $17.00. Orders will be billed at individual rate untilproof of status is confirmed. Prices are subject to changewithout notice. Correspondence regarding permission toreprint all or part of any article published in this journalshould be addressed to REPRINT PERMISSIONSDEPARTMENT, Green Hill Healthcare Commun i -cations, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist® do not necessarily reflect those of theEditorial Board, the Editorial Director, or the Publisher.Publication of an advertisement or other product mentionin The Oncology Pharmacist® should not be construed as anendorsement of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damage topersons or property arising out of or related to any use ofthe material contained in this periodical. The reader isadvised to check the appropriate medical literature and theproduct information currently provided by the manufac-turer of each drug to be administered to verify the dosage,the method and duration of administration, or contraindi-cations. It is the responsibility of the treating physician orother healthcare professional, relying on independent expe-rience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every efforthas been made to check generic and trade names, and toverify dosages. The ultimate responsibility, however, lieswith the prescribing physician. Please convey any errors tothe Editorial Director. BPA Worldwide membershipapplied for April 2011.

For Payers, Purchasers, & Oncology P&T Committees

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4 June 2011 I VOL 4, nO 4 www.TheOncologyPharmacist.com

With all the big news com-ing out at the annualmeeting of the Am -

erican Society of Clinical On -cology—vemurafenib and ipilimu -mab for melanoma, exemestane forbreast cancer prevention, bevacizu -mab for ovarian cancer—smallerstudies tend to be overlooked, at leastat first. But for pharmacists, theirresults are no less important. Thesestudies expand on our knowledge ofsupportive care treatments andpharmacy handling, as well as pro-

vide us with a point of view that is not pharmacist-specif-ic (see below).

Amidst all the big news, everyday practice continues, how-ever. With this issue of The Oncology Pharmacist, we finish ourcoverage of HOPA, highlighting some of the educationalseminars. I hope you will be able to incorporate some of thepractice strategies discussed. We also introduce a new column by Rowena Schwartz,

PharmD, BCOP, and her colleagues at The Johns HopkinsHospital. Over the next issues, they will discuss myriad impli-cations of pharmacogenomics to our practice. This informa-tion should be shared with your nonpharmacy team members.In addition, this issue announces the winner of the

inaugural T.O.P. Pharmacist award: Lindsay Kaster,PharmD, a clinical oncology pharmacist at Boise VeteransAffairs Medical Center in Idaho. Please join me in con-gratulating her for her hard work and dedication to oncol-ogy pharmacy and oncology patients. �

Patrick Medina,PharmD, BCOPEditor-in-Chief

From the Editor

NEUROPAIN-01: A Phase 2 Study of Oxycodoneand PregabalinIn a comparison of 2 strategies involving the combinationof oxycodone and pregabalin, researchers found that afixed dose of oxycodone with an increasing dose of prega-balin provided better neuropathic pain control than afixed dose of pregabalin with an increasing dose of oxy-codone. In addition, the “increasing pregabalin” groupexperienced less frequent side effects. Garassino MC, et al.Abstract 9028.

5HT3 Antagonist plus Dexamethasone with orwithout Aprepitant in Multiple-Day CisplatinRegimensAprepitant combined with a 5HT3 antagonist and dex-a methasone improved control of emesis in germ cell tumorpatients receiving a 5-day course of treatment containing cis-platin. This double-blind, placebo-controlled, crossoverphase 3 study randomized patients to aprepitant 125 mgon day 3 with 80 mg on days 4 to 7 or to placebo. Allpatients received a 5HT3 antagonist on days 1 to 5 anddexamethasone 20 mg on days 1 and 2. Patients crossedover for the second cycle of treatment. Blinded dexa -methasone 8 mg twice daily or 4 mg twice daily was addedin the placebo group, as was dexamethasone 4 mg twicedaily on day 8 in the aprepitant group. Brames MJ, et al.Abstract 9013.

LNH03-6B: Darbepoetin alfa Associated withProlonged PFSAlthough the US Food and Drug Administration has lim-ited the use of erythropoiesis-stimulating agents topatients receiving chemotherapy for noncurative intent,this randomized phase 3 trial found that prophylactic useof darbepoetin alfa was associated with improved progres-sion-free survival (PFS). In this second interim analysis of600 evaluable patients with diffuse large B-cell lymphoma,3-year PFS rates were 66% for patients in the darbepoetinalfa group compared with 58% in the standard treatmentgroup. Disease-free survival also improved; however, over-

all survival was not significantly longer in the darbepoe tinalfa group. Serious adverse events were similar in the 2 groups. Delarue R, et al. Abstract 9048.

Guarana for Cancer-Related FatigueGuarana (Paulinia cupana) taken orally as a dry extractduring chemotherapy or radiation therapy improved bothphysical and mental fatigue, as measured by the ChalderScale. In a set of 3 randomized, placebo-controlled trialswith crossover, guarana, a plant that has been used as astimulant since pre-Colombian times in the Amazonbasin, not only significantly improved fatigue scores, butalso did not produce any grade 3 or 4 toxicities. Del GiglioA, et al. Abstract e19706.

FACT: Fosbretabulin Tromethamine withCarboplatin and PaclitaxelAdding fosbretabulin tromethamine to carboplatin andpaclitaxel prolonged overall survival (OS) for patientswith anaplastic thyroid cancer. The final results of thisrandomized phase 2/3 trial also found that the rate ofpatients achieving OS tripled and a 35% reduction in therisk of death. Patients in the fosbretabulin tromethaminearm did, however, have more grade 1/2 hypertension andgrade 3/4 neutropenia. Sosa JA, et al. Abstract 5502.

Patient Perspectives on Maintenance TherapyPatients are amenable to maintenance therapy as long asthey experience no or mild side effects, according to thissemistructured survey during patients’ fourth or subsequentcycle of chemotherapy. Patients with low-grade Hodgkinlymphoma, lung cancer, or colorectal cancer were surveyedregarding their preferred route of administration and willing-ness to tolerate side effects for hypothetical maintenancetherapy. Patients identified oral therapy as their preferredroute of administration. Unexpectedly, researchers foundthat patients anticipated an unrealistic prolongation of over-all survival, prompting them to conclude that open and pre-cise information on benefits and side effects is essential. FrankS, et al. Abstract e1953. �

Abstracts of Interest

2011 Annual Meeting of the American Societyof Clinical Oncology

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

flooded with so much new informationduring an appointment that they oftenonly remember a small portion of whatthey are told. It is paramount, therefore,that these patients understand exactlywhat their treatment entails—includinghow to prepare, administer, and disposeof it safely and properly.“Having a dedicated appointment for

education is really the ideal situation,and we do this by phone,” said Chen,adding that these scheduled, periodicfollow-up calls should become routine.“It may not always be the pharmacistwho does this but consistency with spe-cific staff to develop a relationship withthe patient is good.”Other helpful recommendations for

patients may include a simple dosingcalendar, checklists of questions to askthe doctor at their next visit, and a jour-nal to keep track of any treatment-relat-ed adverse effects. “We’re really the oneswho need to be looking at drug interac-

tions, especially with TKIs [tyrosinekinase inhibitors]. Patients are often dis-missive, and physicians may not be thebest people to evaluate this,” said Chen.She noted that patients “very rarely”

stop taking their medication because itis something they just want to do.Instead, it is often because the drugmakes them feel worse, the cost may betoo much after their initial fill, or theyweren’t educated appropriately anddon’t realize the seriousness of their situ-ation. “Monitoring these situationsshould be proactive and not reactive.”A recent study examined the effects

of adherence to treatment with imatinibon molecular response in 87 patientswith chronic myelogenous leukemia(Marin D, et al. J Clin Oncol. 2010;28:2381-2387). For those who had anadherence rate higher than 90%, 93.7%had a major molecular response (MMR)and 43.8% had a complete molecularresponse (CMR). For those who had an

adherence rate of 90% or less, only13.9% had an MMR and none had aCMR. When the adherence was lessthan 80%, no patient achieved either anMMR or CMR.Although Chen said that no adher-

ence monitoring method is perfect, it’simportant to “select a couple that youcan use together.” Possible methods mayinclude:• Have patients bring in their med-ication, do a physical pill count,and report to the physician whenthere is a problem• Closely monitor refills to check forfinancial barriers• Use the microelectronic monitor-ing system to increase accessibilityto healthcare.Unfortunately, reports of medication

errors in regard to oral chemotherapy arecommon. According to a 2010 studyquoted by Chen that looked at 508 inci-dents, these errors occurred most fre-

quently during the ordering (47.2%)and dispensing (31.1%) phases, and themost common error involved the wrongdose (38.8%). In addition, “the wrongnumber of days supplied accounted for11% of errors but resulted in 39.3% ofthe adverse events reported.”She recommended that ways to

reduce ordering and dispensing errorsinclude not making any verbal orders(unless it’s to hold or discontinue treat-ment), implementing standardized dataentry and a standardized order program,using only a medication’s generic name,including orders for supportive care,implementing bar-code scanning, andsetting up a multiple-checkpoint system.“We should take what we are already

doing for IV chemotherapy and trans-late that to oral therapy,” said Chen.Overall, “the use of oral chemotherapyincreases the patient’s control but it alsoincreases the responsibility for their can-cer care.” �

Conference News

6 June 2011 I VOL 4, nO 4 www.TheOncologyPharmacist.com

Oral Chemotherapy Should Mirror... Continued from cover

SALT LAKE CITY—Early identifica-tion of nutrition status and treatment-related nutrition risk are important stepsin the continuum of care for cancerpatients, according to an oral presenta-tion at the annual meeting of theHematology/Oncology Pharmacy As -sociation.However, “provision of nutrition sup-

port…is extremely patient specific. Sothere are a lot of gray areas and a lot ofunknowns,” said Sharla Tajchman,PharmD, BCPS, BCNSP, critical care/nutrition support clinical pharmacy spe-cialist at The University of Texas M. D.Anderson Cancer Center in Houston,during her presentation.She noted that the American

Cancer Society has estimated thatalmost 25% of all deaths “in Westernsociety” result from cancer and up to20% of these are directly attributed tocachexia/malnutrition.A past study by Dewys and colleagues

found that at least 50% of all cancerpatients have significant weight loss,with the highest frequency foundamong patients with pancreas andmetastatic and nonmetastatic gastriccancer (Am J Med. 1980;69:491-497).These patients then often have a poor-er response to chemotherapy, worse per-formance status, and shorter survivalduration.Those who have inadequate oral

intake for an extended time or no oralintake for 7 days or more are especiallyat risk nutritionally, according to

Tajchman. She said it is also importantto predict what impact anticancertreatment will have on nutrition(Table). Tajchman noted that after a

patient’s nutritional risk is determined,it’s important to create a follow-upplan that defines the next move. “Aspharmacists, we know these side effectsand we mediate them. That’s our job.”This could involve counseling for the

patient by an oncology-trained nutritionsupport specialist (especially if they havedifficulty swallowing); nutrition-supporttherapy (NST); prophylactic pharma-cotherapy for treatment-related sideeffects, such as nausea, vomiting, andpain; and assessments for long-term com-plications. The latter may include elec-trolyte imbalances caused by nephrotox-ins from chemo therapy or adhesions andbowel obstruction from surgery.She urged caution, however, when it

comes to using appetite stimulants, asthe weight gain is usually seen in fatmass. “If our patients gain 5 lb of fat or5 lb of water, how does that impact

mortality? How does that impactchemotherapy? It lends a feeling ofcomfort by letting patients feel theyhave control so it’s not all bad. It’s justthat we don’t truly know their effecton outcomes.”In their guidelines for the care of adult

cancer patients, the American Societyof Parenteral and Enteral Nutrition(ASPEN) recommends that everypatient should receive a formal nutritionscreening on clinical presentation, aswell as a formal follow-up plan. Although the guidelines include that

nutrition support “should not be routine-ly used in patients undergoing activeanticancer treatment,” Tajchman saidthat the studies that were used to makethis assessment were limited and includ-ed “very heterogeneous” populations.The ASPEN guidelines note that

nutrition support is appropriate forpatients who are malnourished or pre-dicted to be unable to ingest adequatenutrients for 7 to 14 days. “This rec-ommendation is also for patientsundergoing hematopoietic stem cell

transplant,” said Tajchman. Past stud-ies on this, however, have shown con-flicting outcomes. “There’s not a goodanswer for these patients. I come acrossthis every day but unfortunately thereare no studies to lead us in the rightdirection.”Overall, “the guideline recommen-

dations are limited and should notreplace clinical judgment,” saidTajchman. “The guidelines give you astarting point.”She added that past research has

shown that nutritional markers such aspre-albumin can be improved withnutritional support, but no studieshave shown improved survival or mor-bidity. Still, “there are studies thatshow you can improve quality of life ifyou maintain performance status.”Tajchman recommended that pa -

tients who are moderately to severelymalnourished, have an anticipatedprolonged inability to meet nutritionalrequirements, have continued weightloss despite adequate oral intake,and/or have complications related tomalnutrition are the ones most likelyto need NST.However, “there are more ques-

tions than answers” when it comes tonutrition in cancer patients overall.“The mantra is: ‘It’s always better todo something than nothing.’ Butthat’s not always true with nutritionsupport and must be weighed verycarefully for every patient,” conclud-ed Tajchman. � —DB

Nutrition Support Needs to Be Patient SpecificThe Pharmacist’s Role in Nutrition Risk

Table Nutritional Considerations for Antitumor Therapies

Surgical procedures that include some removal of the stomach can lead to vitamin B12 deficiency.

Nutrition effects from radiation often subside within 2 months in those with acute/early illness, but strictures are common in head and neck cancersespecially during the chronic/late stage.

Placing a nasogastric tube in a patient before a cycle of chemotherapy may help with nutrition support, even if he or she has mucositis or stomatitis.

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

SALT LAKE CITY—Although radia-tion-induced toxicities are common inan outpatient setting, several treatmentoptions have proven very successful—aslong as the appropriate monitoringparameters are in place, according to apresentation at the annual meeting ofthe Hematology/Oncology PharmacyAssociation by Makala Pace, PharmD,BCOP, clinical pharmacy specialist atThe University of Texas M. D. AndersonCancer Center in Houston. She noted that the most widely used

radiation therapy is currently externalbeam radiation, which includes 3-dimensional conformal and intensity-modulated radiation therapies, stereo-tactic radiation therapy/surgery, andproton therapy. Internal radiation(including brachytherapy) and systemicradiation therapy (including radiophar-maceuticals) are also common. The development of radiation-relat-

ed toxicity is dependent on several fac-tors, including the area of body treated,the total dose given, the patient’s per-formance status, and concurrent thera-py. The levels of toxicity are categorizedinto acute (occurring during treat-

ment), subacute (developing between 2weeks and 3 months after therapy), andchronic (occurring more than 6 monthsafter treatment).

According to Pace, the most com-mon adverse effects include radiationdermatitis, mucositis and dysgeusia,esophagitis, parotitis, otitis, genitouri-nary conditions such as acute cystitis orobstructive urinary symptoms, diarrhea,and proctitis. For grade 1 radiation dermatitis, the

National Cancer Institute recommend-ed application 3 times daily of nonionic

moisturizers, such as Cetaphil, Aveeno,or Lubriderm; of hydrocortisone 1%cream; or of Biafine topical emulsion.For grade 2 and 3, they recommend nor-mal saline or modified Burow’s solutioncompresses, Polymyxin B/Neomycincream, or a hydrogel.For grade 4, other treatment options

include treating the infection, debride-ment of the tissue, application of vita-min E and pentoxifylline, and flexiblehydroactive hydrocolloid dressings. Thelatter helps the wound to “autolyticallydebride itself ” and is “best applied towounds that produce light to mediumexudate or transudate,” explained Pace.She cautioned that these dressingsshould not be applied over infectedwounds and can give off a foul odor 2 to 4 days after application.Regardless of grade, all patients with

radiation dermatitis should keep sunexposure from the affected area, shouldbe made aware that different affectedareas may require different treatmentapproaches, and should not applylotions or gels immediately beforeundergoing radiotherapy.Recommended treatments for muco -

sitis include an electrolyte solution,such as the supersaturated calciumphosphate rinse Caphosol that resem-bles human saliva, lidocaine/diphenhy-dramine/simethicone, antifungals, or aprotective barrier such as sucralfate orGelclair bioadherent oral gel. For dys-geusia, the recommendations includezinc sulfate, a weekly infusion of amifos-tine 500 mg, or time—as regenerationmay take up to 4 months.Other radiation-induced side effects

and recommended treatments include:• Dental caries/tooth decay: toothextraction or fluoride gels

• Esophagitis: lidocaine, nutritionalsupport, protective barriers, or acidsuppressants

• Inflammation of a parotid gland:aspirin or nonsteroidal anti-inflam-matory drugs

• Dry mouth: pilocarpine, artificialsaliva, amifostine, or cevimeline

• Otis externa: hydrocortisone/ neo -mycin/polymyxin B ear drops (withdecongestants or phenylephrine oticsolution for serious otitis)

• Acute cystitis: phenazopyridine oroxybutynin

• Obstructive urinary symptoms: oxy-butynin, tamsulosin, finasteride, orterazosin

• Diarrhea: low-residue diet, loper -amide, cholestyramine, oroctreotide. � —DB


Conference News

SALT LAKE CITY—Choosing ap -propriate treatment options and thenfollowing strict monitoring parame-ters are essential for patients withchallenging cancer pain, according toa presentation at the annual meetingof the Hematology/Oncology Pharm -acy Association.“Cancer patients with pain have risks

too. So risk stratification and risk mini-mization should be employed for allpatients,” said David S. Craig, PharmD,BCPS, from the H. Lee Moffitt CancerCenter and Research Institute inTampa, Florida.“Methadone pearls” from a recent

study recommend an electrocardiogramfor any high-risk patients (such as thoseat risk for heart rhythm disturbances)when concurrent QT prolonging drugsare used or there are significant drug–drug interactions, when treatment dosesare higher than 100 mg/day, if an intra-venous line is used, or if there are elec-trolyte abnormalities (Krantz M, et al.Ann Intern Med. 2009;150:387-395).Also, “if current QTc is greater than

450 msec but less than 500 msec, mon-itor more frequently. If it is greater than500 msec, watch out!” said Craig. He added that risk assessments can

be conducted with the 5-questionOpioid Risk Tool “to predict opioid-related aberrant behavior,” the 17-itempatient-assessed Current Opioid Mis -use Measure, and the 24-item Screenerand Opioid Assessment for Patientswith Pain–Revised. For patients deemed at high risk for

abuse, potential strategies can includefrequent office visits, random urinedrug screenings, and patient–provider

agreements. In addition, Craig recom-mended considering less abusable for-mulations, consultations with addic-tion specialists, and family memberin volvement.When patients use opioids, moni-

toring parameters should includewatching for constipation, sedation,or lethargy and keeping continuouswatch of alanine transaminase/aspar-tate transaminase (AST/ALT) andrenal function. For nonsteroidal anti-inflammatory drugs or corticosteroiduse, gastrointestinal bleeding andrenal and cardiovascular risks should

be monitored; AST/ALT and serumcreatinine should be watched whenantiepileptics are used; anticholiner-gic side effects, QT prolongation, andsuicide risk should be monitored fortricyclic antidepressants; and anti-cholinergic side effects, AST/ALT,and suicide risk should be watchedwith use of serotonin-norepinephrinereuptake inhibitors.Several resources offering guidance

are available to oncology pharmacists,including the upcoming “OpioidDrugs and Risk Evaluation andMitigation Strategies (REMS), Guide -lines for the Management of CancerPain in Adults and Children” by theAmerican Pain Society (www.ampainsoc.org), and recommendations by theNational Comp rehensive CancerNetwork (www.nccn.org) and theNational Cancer Institute (www.cancer.gov).In addition, the state of Washington

has released noncancer pain manage-ment guidelines, whereas Utah andOklahoma as well as the governmentof Canada have released guidelines onprescribing opioids.“Always remember adjuvants, other

alternatives, outcomes, and treatmentplans” for cancer pain, summarizedCraig. “And although opioids remainthe mainstay, think outside the boxwhen necessary.” � —DB

Treatment of Challenging Cancer PainRequires Close MonitoringPharmacists Should Assess Patients for Risks

When patients use opioids, monitoring parametersshould include watching for constipation, sedation, or lethargy and keeping continuous watch ofalanine transaminase/aspartate transaminase andrenal function.

Radiation-Induced Toxicity CommonTreatment Options for the Outpatient Setting

For dysgeusia, therecommendations includezinc sulfate, a weeklyinfusion of amifostine 500 mg, or time—asregeneration may take up to 4 months.

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

SALT LAKE CITY—Reliable tests aresorely needed to help determine thebest dose regimen before chemothera-py to minimize toxicities for patientswith metastatic colon cancer, accord-ing to a talk given at the annual meeting of the Hematology/OncologyPharm acy Association. Marlo Blazer, PharmD, BCOP, outpa-

tient oncology pharmacist at the ArthurG. James Cancer Hospital and RichardJ. Solove Research Institute at the OhioState University Medical Center inColumbus, explained that dihydropy-rimidine dehydrogenase deficiency(DPD) is responsible for the breakdownof the chemotherapy drug 5-fluorouracil(5FU). “The cytotoxic effects ofcapecitabine and 5FU can only occurafter conversion into the activenucleotides—and the amount of 5FUavailable for conversion is determinedby the extent of its breakdown.”

Unfortunately, 3% to 5% of thesepatients have a partial DPD and 0.2%have a complete loss. “The centralassumption to existing studies is thatthe degree of deficiency is proportional-ly related to severity of 5FU toxicity,”said Blazer. “For patients who are admit-ted for what we suspect is DPD, we seethe classic triad of toxicities: febrileneutropenia, mucositis, and diarrhea.And we often see dehydration becauseof the mucositis and diarrhea.”There are currently several ways to

test for DPD. However, a recent studyfrom France of 252 white colon cancerpatients found that these assays on theirown did not correlate with 5FU toxici-ty (Boisdron-Celle M, et al. Cancer Lett.2007;249:271-282). In fact, “no singletest had sufficient sensitivity and speci-ficity to detect true [DPD] deficiency.”Using a 2-step, 2-test approach (firsttesting for DPD single-nucleotide poly-morphism and plasma uracil, then con-ducting another test) did increase thevalues, and provided 83% sensitivityand 84% specificity. In other words,“98.8% of those with a grade 3 or 4 tox-

icity would have had their 5FU doseinitially reduced. But 8% of the patients

would have had an unnecessary dosereduction,” said Blazer.

In addition, past research has notlooked at the costs of these tests and fewstudies have assessed whether initial dosereductions were necessary—“only thatincidence of toxicity was reduced,”explained Blazer. “So should you test forDPD prior to beginning treatment? Andwhat if the test came back negative? To

Minimizing Chemo Toxicities for Patients with Metastatic Colon CancerReliable Tests Needed

www.TheOncologyPharmacist.com8 June 2011 I VOL 4, nO 4

Conference News

YERVOY™ (ipilimumab)

03/11 Printed in USA

Y

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rash (29%), and colitis (8%).

Now Approved

INDICATIONYERVOY is indicated for the treatment of unresectable or metastatic melanoma.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Important Safety Information

11:22 AM

“No single test hadsufficient sensitivity andspecificity to detect true[DPD] deficiency.”

—Marlo Blazer, PharmD,

BCOP

TOP_June_v6 2011_TOP 6/17/11 12:28 PM


Conference News

For additional information, please visit

www.YERVOY.com/hcp©2011 Bristol-Myers Squibb, Princeton, NJ 08543 731US11AB08002 03/11 Printed in USAYERVOY is a trademark of Bristol-Myers Squibb. All rights reserved.

Important Safety Information (continued)Recommended Dose Modifications:Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.Permanently discontinue YERVOY for any of the following:

corticosteroid dose to 7.5 mg prednisone or equivalent per day.

administration of first dose.

Immune-mediated Enterocolitis:

threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred

abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients.

intestinal perforation, 4 (0.8%) died as a result of complications, and

diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).

endoscopic evaluation for persistent or severe symptoms.

Immune-mediated Hepatitis:

threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and

>2.5X but ≤5X the ULN or total bilirubin elevation >1.5X but ≤3X the ULN; Grade 2).

patients for signs and symptoms of hepatotoxicity before each dose of YERVOY.

Immune-mediated Dermatitis:

life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients.

– 1 (0.2%) patient died as a result of toxic epidermal necrolysis.

dermatitis.

and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Immune-mediated Neuropathies:

Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

and additional cases of Guillain-Barré syndrome have been reported.

unilateral or bilateral weakness, sensory alterations, or paresthesia.

Immune-mediated Endocrinopathies:

to life-threatening immune-mediated endocrinopathies (requiring

of daily living; Grade 3-4) occurred in 9 (1.8%). – All 9 patients had hypopituitarism and some had additional

concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.

intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome.

endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.

– Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.

– Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms.

imaging studies through enlargement of the pituitary gland.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Pregnancy & Nursing:

and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

mother to the developing fetus.

many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY.

Common Adverse Reactions:The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Boxed WARNING regarding immune-mediated adverse reactions, on following pages.

1-2 4 11:22 AM

reduce risk of toxicity, we usually reduce75% to 80% upfront in these patientsand step them up slowly based on toler-ance. But there are no guidelines as far asdose reduction.”

A polymorphism of the UGT1A1gene also can lead to increased irinote-can-associated toxicity. A recent re -

view of 9 studies, however, had severallimitations, including that the tumortype was not restricted to just coloncancer and the doses and frequency ofthe medication varied widely.

Overall, the investigators found thatthe polymorphism did not put patientsat a significantly increased risk of

severe diarrhea. Patients with thehomozygous type of the polymorphism(UGT1A28*28), however, were 3.5times more likely to have a severe neu-tropenia event compared with thosewith the wild type (UGT1A1*1).

“At this point and time, this is theincidence that we see. Should we be

worried about giving the population atlarge irinotecan without testing firstfor the UGT1A1 polymorphism? Wejust don’t have a silver bullet for test-ing, where if we test them forUGT1A1 and they’re homozygousthen we can prevent neutropenia,”said Blazer. � —DB

TOP_June_v6 2011_TOP 6/17/11 12:28 PM


Conference News

YERVOY™ (ipilimumab) Injection, for intravenous infusion

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information]

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions]

INDICATIONS AND USAGE

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning]

Immune-mediated Enterocolitis

In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.

The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.

Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Hepatitis

In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Dermatitis

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information]

For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Immune-mediated Neuropathies

In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Endocrinopathies

In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

[see Warnings and Precautions].






Selected Adverse Reactions in Study 1

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IP-B0001A-03-11 Issued: March 2011

3-4 4 11:22 AM

SALT LAKE CITY—Although it’simportant to strive for no chemotherapy-related medication errors, it’s just asimportant to have an organized system

in place to identify, report, and managethese errors when they occur, accord-ing to a presentation at the annual meet ing of the Hematology/Oncology

Pharmacy Association. “We’ve made progress in medication

errors both from understanding theirepidemiology in the past 15 years and

how we can mitigate them throughtechnology, workflow, and systemchanges,” said Sylvia Bartel, RPh,MHP, from the Dana-Farber Cancer

Identifying, Reporting, and Managing Medication ErrorsStrategies for Each Stage of the Process

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

Institute in Boston, Massachusetts.Still, errors occur for multiple reasons,

including understaffing, a lack of knowl-edge, or system failures—and mayinclude issues with order writing andcommunication, dose miscalculations,incorrect drug administration, or poordistribution.

“Our systems are really complicated,and sometimes we have mental lapses.We all work in very busy environments,and although we try to have a quiet spacefor pharmacists to process orders or forphysicians to write them, in reality thatis often not the case,” said Bartel. “Welearn from this by looking at how our sys-

tems fail and seeing where we haveredundancies and where we don’t haveredundancies but should.”

Because errors often start with theorder, it’s imperative that providers keepeverything clear, such as the drug, dose,and schedule. Dose miscalculations arealso common, often because of compli-

cated formulas for determining bodyweight, and drug shortages can lead tothe staff being unfamiliar with the sub-stitute medication.

“Chemo agents, by nature of whatthey are, can lend themselves to med-ication errors, particularly adverse drugreactions,” said Bartel. “We expectpatients to be sick, to have fatigue andnausea, but is that really an expectedadverse reaction or is it due to anerror?”

Although the person who discoversan error is supposed to call a specifiedphone number, put it into the comput-er system, or alert someone face toface, Bartel said that only 2% to 5% oferrors are discovered through “sponta-neous reporting.” Instead, she suggeststaking a hard look periodically at a par-ticular process and then gathering dataon it.

“Look at orders, go back to the cart,look at the workflow process. Whenerrors get reported, we really want tomake sure we look at how it happenedon multiple levels so that we get at theroot cause,” she said.

At Dana-Farber, they strive to makesure their error reporting system isanonymous, easy to use, and includes aseverity rating scale to assess potentialharm. The data then are used to devel-op process improvements. In addition,an oncology-specific self-assessmenttool from the Institute of SafeMedication Practices is expected to bereleased this fall.

When it comes to managing anerror, disclosing its occurrence to thepatient should be the first step, fol-lowed by giving support to staff mem-bers who might be upset and taking itpersonally. Bartel also suggested adopt-ing a “Just Culture” approach. “Man -agers need to help their staff look atsystem changes as opposed to having apunitive environment to catalog in aperformance review how many errorsthey were involved in. The individualis accountable for what is under theircontrol but it’s part of the broader con-text of the system.”

Overall, Bartel said that it’s impor-tant to create a work environment thatrewards error reporting, values safetyand continuous learning, and encour-ages managers and staff to have opendiscussions about potential risks andhow best to avoid them. “It’s just a newway of thinking.” � —DB


Conference News

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

Table 1: Selected Adverse Reactions in Study 1

Percentage (%) of Patientsa

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100

n=380

gp100 n=132

System Organ Class/ Preferred Term

Any Grade

Grade3–5

Any Grade

Grade3–5

Any Grade

Grade 3–5

Gastrointestinal Disorders Diarrhea ColitisSkin and Subcutaneous Tissue Disorders Pruritus RashGeneral Disorders and Administration Site Conditions Fatigue

328

3129

41

55

02

7

375

2125

34

43

<12

5

202

118

31

10

00

3

a Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1

Percentage (%) of Patients

YERVOY3 mg/kgn=131

YERVOY3 mg/kg+gp100

n=380

Any Immune-mediated Adverse ReactionEnterocolitisa,b

Hepatotoxicitya

Dermatitisa

Neuropathya

Endocrinopathy Hypopituitarism Adrenal insufficiencyOther Pneumonitis Meningitis Nephritis Eosinophiliac

Pericarditisa,c

157121440

00110

12723

<1111

<1<100

<1

a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established.

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Immunogenicity

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Immunogenicity assay results are 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 incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information]

In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Nursing Mothers

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Pediatric Use

Safety and effectiveness of YERVOY have not been established in pediatric patients.

Geriatric Use

Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment

No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

Hepatic Impairment

No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

OVERDOSAGE

There is no information on overdosage with YERVOY.

PATIENT COUNSELING INFORMATION

See MEDICATION GUIDE in Full Prescribing Information.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1281558A2 IP-B0001A-03-11 Issued: March 2011

When it comes tomanaging an error,disclosing its occurrenceto the patient should bethe first step.

TOP_June_v6 2011_TOP 6/17/11 12:28 PM


Conference News

Controversies in Care: New Treatment Considerations forBreast, Bladder Cancer and Pediatric Ewing SarcomaBisphosphonates, Neoadjuvant Therapy, and Dose-Dense Therapy Remain Debatable

ANAHEIM—Effective managementof breakthrough cancer pain requiresoptimizing background therapy forchronic pain and accurately assessingthe type of breakthrough pain, said pre-senters at the 45th American Societyof Health-System Pharmacists MidyearClinical Meeting & Exposition.“Knowing the type of breakthrough

cancer pain can help match the rightdrug with the right goal,” said Mary LynnMcPherson, PharmD, BCPS, CDE, whois professor and vice chair, Department

of Pharmacy Practice and Science,University of Maryland School ofPharmacy in Baltimore. Newer rapid-onset opioids are becoming the standardof management but opioids are oftensuboptimal when used alone.The prevalence of breakthrough

cancer pain varies, with estimatesranging from 30% to 90%, said StevenD. Passik, PhD. The pathophysiologyis complex, with simultaneous noci-ceptive and neuropathic pain processesoccurring, he said.

Older cancer patients may need to beprobed for cancer pain because theyoften underreport their pain or will indi-cate that it’s controlled when it may notbe, said Passik, who is associate attendingpsychologist, Department of Psychiatryand Behavioral Sciences, MemorialSloan-Kettering Cancer Center in NewYork City.Breakthrough cancer pain has been

described as spikes of pain that occuron top of baseline well-controlled pain.Breakthrough pain typically has an

onset of less than 3 minutes, occurs 1 to4 times daily, and has an average dura-tion of 30 minutes. A combination of symptom assess-

ment tools, patient history, and a phys-ical examination to assess pain shouldbe used to devise the treatment plan,said Passik. “Cancer pain patients aremorphing into chronic pain patients,”he said. “You have to plan their opioidtherapy in the same way as noncancerchronic pain patients.”Unfortunately, no tools specific for

SUPPORTIVE CARE

Treating Breakthrough Cancer Pain Requires Recognition,Matching Drug to GoalPharmacists Should Parallel Pharmacokinetics with Pain

By Wayne Kuznar

SALT LAKE CITY—Bisphosphonatesmay have a role as an adjuvant breastcancer treatment, cisplatin-based neo -adjuvant chemotherapy should be con-sidered for treating bladder cancer, anddose-dense chemotherapy may add ben-efit for patients with pediatric Ewingsarcoma, according to 3 presentations atthe “Controversies in Care” session atthe annual meeting of the Hematology/Oncology Pharmacy Association.

Bisphosphonates in Breast Cancer“We use bisphosphonates commonly inour practice but there are classificationsbased on whether they contain nitro-gen,” said Jared M. Freml, PharmD,BCOP, clinical pharmacy specialist–oncology at Kaiser Permanente inDenver, Colorado, in his discussion onthe early and delayed use of bisphos-phonates in breast cancer patients.He explained that clodronate and

etidronate are non-nitrogen treatmentsthat bind to the bone surface. As theyaccumulate there, osteoclasts breakdown, resulting in the accumulation ofcytotoxic levels. Nitrogen-containingbisphosphonates include pamidronate,ibandronate, risedronate, alendronate,and zoledronic acid (ZA). These treat-ments also bind to the bone and “aretaken up by osteoclast,” resulting incytotoxic levels. They also inhibit themevalonate pathway. “I think it’s smart that we’ve looked at

bisphosphonates as possible antitumoragents, as they have demonstratedantiproliferative and proapoptotic activ-ity in cell and animal cultures,” said

Freml. In addition, bisphosphonates thatcontain nitrogen inhibit the migrationand invasion of tumor cells.“Sequencing might be an important

thing to consider as we’re giving thesedrugs,” he added. Doxorubicin and pacli-taxel followed by ZA has shown syner-gistic antitumor effects, and pamidronateand ZA have been shown to inhibitangiogenesis in mouse models. Studies that have looked specifically

at clinical outcomes for treatment withadjuvant bisphosphonates for patientswith estrogen receptor– or progesteronereceptor–positive breast cancer, howev-er, have shown mixed results. Whereasin the randomized Austrian Breast andColorectal Cancer Study Group Trial,12 of 1803 patients (randomized to 4treatment arms) showed a significantincrease in disease-free survival forthose receiving treatments containingZA compared with hormonal treatmentonly, the 3360-patient Neo-AdjuvantZoledronic Acid to Reduce Recurrence(AZURE) trial did not. Neither trialshowed a statistically significant in -crease in overall survival.In these 2 trials, plus 2 others cited by

Freml, there was a significant benefit inbone mineral density at 36 and 60months for those who received ZA. “Ithink it’s important that [we] didn’t seeany adverse reactions except as expected:flulike symptoms, pyrexia, bone pain,and headache.” The one exception was ahigher incidence of osteonecrosis of thejaw in the AZURE trial. Freml said that although the role of

bisphosphonate adjuvant therapy for

breast cancer “is evolving,” the optimaladministration has yet to be defined, andit is unclear which patient group is mostlikely to benefit from this treatment.“There are some interesting theories

being generated from early studies, butit is difficult to conclude that these arepractice changing at this time,” hesummarized.

Neoadjuvant Therapy in BladderCancerSurgery is currently considered the stan-dard-of-care treatment for bladder can-cer. However, “we’re hoping neoadju-vant therapy will reduce tumor volumeand lead to less invasive surgery andbladder preservation, and also give usgood prognostic information when weassess response to chemotherapy,” saidJessica Poirier Duda, PharmD, BCOP,specialty practice pharmacist at theArthur G. James Cancer Hospital andRichard J. Solove Research Institute atthe Ohio State University MedicalCenter in Columbus.She noted that there is a high risk of

recurrence in these patients and lowoverall survival rates. “So there may be alot of micrometastatic disease that wedon’t know when tumor burden is low.And patients may be able to toleratechemo better when we don’t have com-plications from surgery or radiation.“Although radical cystectomy is the

gold standard for the treatment of local-ized muscle-invasive bladder cancer, cis-platin-based neoadjuvant combinationchemotherapy should be consideredbased on performance status,” said Duda.

She noted, however, that large, random-ized, multicenter trials assessing neoadju-vant chemotherapy are sorely lacking.

Dose-Dense Therapy in PediatricEwing SarcomaSurgery, if possible, is the current stan-dard of care for local therapy, accord-ing to David Henry, MS, BCOP,FASHP, associate professor and inter-im chair–pharmacy practice at theUni versity of Kansas School of Pharm -acy, in his discussion of the potentialbenefits and risks of dose-dense thera-py for pediatric Ewing sarcoma.Radiation is used commonly if surgeryis not possible or for further controlafter surgery, but treatment can varyaccording to circumstances.The question of whether dose densi-

ty can play a role in this setting hasbeen raised in past studies. One foundthat increasing doses of doxorubicinwas associated with better outcomes,although it compared less intense ther-apies than are used at present. Anotherfound an increase in 5-year overall sur-vival, from 61% to 72%, after addingifosfamide and etoposide for half the cycles of vincristine/doxorubicin/cyclophosamide/dactinomycin. Therewas no improvement found, however,for patients with metastatic disease,which is becoming common in severalother studies too.“There are no data for metastatic

disease for dose-dense therapy,” saidHenry. “Overall, is there a role for doseintensity? Right now it’s a fairly debat-able question.” � —DB

See also page 26.

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Supportive Care

breakthrough cancer pain are validatedfully for routine clinical use. Pain is butone item among many contained ingeneral cancer symptom scales, butscales such as The M. D. AndersonSymptom Inventory, the EdmontonSymptom Assessment Scale, and theMemorial Symptom Assessment Scalecan help put pain into the context ofother symptoms.Key elements of the history include

illnesses relevant to opioid therapy (ie,respiratory, hepatic, renal disease),medical illnesses suggestive of sub-stance abuse (ie, hepatitis, HIV/AIDS,sexually transmitted diseases, liver dis-ease, tuberculosis), and a history ofsubstance abuse including alcohol,tobacco, and prescription drugs.“Cancer doesn’t protect a patient fromhaving an addiction,” and patientswith a history of addiction are not can-didates for rapid-onset opioids, he said.Smokers have a higher rate of opioidabuse than nonsmokers, he added.The Mental Health Inventory-5 can

be used as part of the psychiatric histo-ry, and a score of less than 52 should

trigger a formal evaluation.Urine screens to monitor compli-

ance and possible diversion of opioidsare useful even in cancer pain manage-ment, he said. The Current OpioidMisuse Measure is a 17-item tool toaddress ongoing medication misuse butbecause this tool “overidentifies” mis-use and abuse, it should only be used toidentify potential cases for follow-up.In the treatment of breakthrough

cancer pain, controlling baseline per-sistent pain is paramount before mov-ing forward, said McPherson.“The patients are in the driver’s seat,

and we need to control their pain totheir satisfaction,” she said. For somepatients, this may mean that achievinga numerical rating scale pain score of 3or 4 (on a 0 to 10 scale) is satisfactoryto allow them to interact with theirfamilies, whereas in others it may beinadequate.One challenge in selecting the right

drug is that the preferred option maynot be possible because of cost andreimbursement barriers, problems withtolerability, and certain disease- or

cancer therapy–related barriers, suchas dysphagia, mucositis, and nausea.The preferred pharmacologic agent

to treat breakthrough pain will havepharmacokinetics that match the char-acteristics of the pain, she said. Forpain brought on by predictable inci-dents, short-acting opioids with sloweronset than fentanyl products can beused. Volitional pain, such as withwound care, should be premedicated.For idiopathic or spontaneous pain

with intense and/or fast onset, such asunpredictable pain upon awakening,rapid-onset opioids are a good option.For end-of-dose pain, background

therapy should first be optimized.Instead of more frequent administra-tion of the dose, “stick with the dosageinterval that’s approved and increasethe dose,” advised McPherson.She recommends using the Alberta

Breakthrough Pain Assessment Tool, aresearch tool, to educate patients aboutbreakthrough cancer pain. After under-standing the difference between paintypes, patients should be encouraged todistinguish chronic pain from break-

through cancer pain in pain diaries.Alternatively, 3 questions should be

incorporated into the assessment:• Do you have pain flare-ups?• Are they predictable? If so, whatare the causes?

• How often do you have them?Addressing the cause of pain can be

as simple as prescribing antitussivemedication for cough that triggers painand avoiding invasive procedureswhen they won’t change patient man-agement.After selecting a therapy, counsel

patients to preempt pain when theyrecognize a prodrome. In selecting the dose for a short-act-

ing opioid for breakthrough, 10% to15% of the daily background medica-tion dose is a standard rule. Whenusing rapid-onset opioids, always startat the lowest dose, even if switchingfrom one fentanyl to another. Ensurethat patients are opioid-tolerantbefore starting a rapid-onset agent:“You cannot start a transdermal fen-tanyl patch unless someone is opioid-tolerant,” she said. �

ANAHEIM—Hypersensitivity or infu-sion reactions to chemotherapy agents ormonoclonal antibodies can be life-threatening but often can be managedwith premedications or titration of infu-sion rates, said Catherine Christen,PharmD, at the 45th American Societyof Health-System Pharmacists MidyearClinical Meeting & Exposition.Medications associated with infu-

sion reactions are platinum agents, tax-anes, liposomal doxorubicin, etopo-side, and monoclonal antibodies.Hypersensitivity reactions can beeither allergic (IgE-mediated) or non-allergic (anaphylactoid). Type I hypersensitivity reactions are

usually IgE reactions. They occur aftermultiple infusions and within minutes ofexposure, although delayed reactions(hours later) can occur. “Positive skintests are a helpful diagnostic tool [fortype I hypersensitivity reactions],” be -cause they have a very high negative pre-dictive value, she said. Anaphylactoid reactions do not

have an IgE basis, and may instead becaused by complement activation, saidChristen, clinical assistant professor ofpharmacy, College of Pharmacy, andclinical pharmacist, gynecology oncolo-gy, University of Michigan HealthSystems, Ann Arbor. Anaphylactoidreactions occur with initial drug expo-sure; they usually respond to pretreat-ment with antihistamines and epineph-rine. Cremophor-containing paclitaxelhas been associated with hypersensitivity

reactions, including anaphylaxis.For infusion reactions, start at a slow

rate and titrate up the rate of infusion astolerated, she said.

CarboplatinHypersensitivity reactions to carboplatinare more common than with otherchemotherapeutic agents, she said. In one series of ovarian cancer

patients with hypersensitivity reactionsto carboplatin, successful desensitizationwas possible in 37 of 38 patients (105 of106 successful desensitizations). Skintesting was performed before each desen-sitization; 5 of 7 patients with a remotehistory of hypersensitivity reactionsbecame skin test–positive, and theauthors concluded that such patientswere at risk of developing more severehypersensitivity reactions (HesterbergPE, et al. J Allergy Clin Immunol. 2009;123:1262-1267).Carboplatin desensitization proto-

cols in which suboptimal doses aregiven incrementally to render mastcells and basophils unresponsive toantigens “require a 1:1 RN-to-patientratio,” she said. Eight to 12 dilutionsteps are usually required.Castells and colleagues described a

standardized 12-step rapid desensitiza-tion protocol for platinum-basedchemotherapy (and paclitaxel, doxoru-bicin, and rituximab), in which therate of infusion is increased every 15minutes until the final dose is given (JAllergy Clin Immunol. 2008;122:574-

580). “The protocol takes 6 hours ormore,” said Christen. Of 413 desensiti-zations performed, 94% elicited eithermild or no reactions, and all patientswere able to receive the full target dose.Desensitization protocols must be car-

ried out each time drug therapy is givenon an intermittent basis, as withchemotherapy. “You need to desensitizewith every dose,” she said.

TaxanesPaclitaxel hypersensitivity may be ananaphylactoid or IgE-mediated reaction,which tends to occur early, during thefirst or second infusion, said Christen.When encountering a reaction to

paclitaxel, interrupt the infusion andadminister protocol medicines—corti-costeroids, diphenhydramine, andalbuterol, she said. If the symptomsresolve, the infusion can then be restart-ed at a lower rate and titrated up.To avoid hypersensitivity reactions

to future paclitaxel infusions, sheadvises premedicating with additionalantihistamines and corticosteroids,and a slow infusion rate that is titratedup as tolerated. Substitution of anoth-er taxane or a desensitization protocolsimilar to the one described for carbo-platin may be tried. Hypersensitivityoccurs less frequently with docetaxelthan with paclitaxel, and reactions todocetaxel can be managed similarly tothose with paclitaxel.

Etoposide/Teniposide

Hypersensitivity reactions to etoposidecan occur with the first treatment ormultiple courses, and can be anaphylac-toid or IgE-mediated. Etoposide does notcontain Cremophor; if infusion reactionsoccur, options are switching to tenipo-side or trying an etoposide desensitiza-tion protocol.

Liposomal DoxorubicinAcute infusion-related reactions, possi-bly caused by activation of complement,have been documented in up to 10% ofpatients treated with a first infusion ofliposomal doxorubicin. To minimize therisk of infusion reactions, Christen rec-ommended an initial infusion rate of 1 mg/min. Reactions resolve over thecourse of several hours to 1 day after theinfusion is stopped.

Monoclonal AntibodiesInfusion reactions to monoclonal anti-bodies can be IgE-mediated allergic reac-tions to foreign proteins or nonallergicreactions to cytokine release. Reactionsto monoclonal antibodies occur primari-ly with chimeric products.To manage monoclonal antibody–

induced infusion reactions, Christenadvised pretreating with acetaminophenand an antihistamine and slowly titratingthe infusion to the full rate. “Interruptthe infusion as needed and treat reac-tions,” she said. “You can usually restartthe infusion at a 50% lower rate thantitrate up to completion.”Risk factors for fatal outcomes in

recipients of rituximab are chronic lym-phocytic leukemia, mantle cell lym-phoma, high circulating lymphocytecounts (>50 mm3), bulky disease, and

Managing Hypersensitivity Reactions Premedication and Titration Useful Strategies

TOP_June_v6 2011_TOP 6/17/11 12:28 PM


The Oncology Pharmacist congratulates LindsayKaster, PharmD, for being chosen by more than750 of her peers as this year’s T.O.P.

Pharmacist award winner. “The best part of the job,”says Kaster, a clinical oncology pharmacist at the BoiseVeterans Affairs (VA) Medical Center in Idaho, “isthat it just brings that team dynamic together.”Kaster has won accolades from colleagues like

Brenda S. Dunn, PharmD, MBA, a pharmacy execu-tive with Veterans Integrated Service Network 20, forher commitment to cost-cutting. “Lindsay’s proactiveapproach includes cost-avoidance measures for theveterans as well as the pharmacy, a dose-roundingprogram to reduce drug wasting, a comprehensiveerror-prevention process, a thorough review ofadverse drug reactions with education to providers onhow to eliminate or decrease future occurrences,development of a stability chart for pharmacy andnursing use, appropriate premedication practices, andstrategies to effectively work with medication back- orders and national shortages.”Kaster says that because she does not depend on

reimbursements for her paycheck, she can focus all ofher attention on cost and quality. With the increasingcriticism of the fee-for-service reimbursement modeldominating most of the healthcare industry, she isproud to say that she saves the government moremoney than she makes.“I’ll say, ‘we can do this instead, because it will save

$1000 and it has the same efficacy data,’” she tells TheOncology Pharmacist. “Instead of pounding out orders, Ispend my days trying to optimize the medications mypatients are taking. A big part of my job is decreasingcosts to taxpayers.”But Kaster’s attention to the bottom line does not

come at the expense of patient care. Replacing costlymedications with cheaper ones can save money with-out compromising value. And better yet, reducing thenumber of drugs a patient takes can improve his orher well-being. “I love the patients because they’re so resilient,”

she says. “I deal only with cancer patients. Some peo-ple think that’s depressing, but they’re so strong andcourageous.”Kaster sits in on physician clinics and consults with

oncologists regularly on prescription decisions. ManyVA patients take up to 10 medications, so Kastermust play a part in helping them with chronic careneeds, such as hypertension and hyperlipidemia.

The PastAn Idaho native, Kaster grew up in Bruneau, whichshe calls “God’s country.” Her family was veryinvolved with rodeos, and Kaster spent her childhood

Idaho’s Lindsay Kaster Named T.O.P. Pharmacist By Daniel Denvir

I love the patients because they’re soresilient,” she says. “I deal only with cancer patients. Some people think that’s

depressing, but they’re so strong and courageous.”

—Lindsay Kaster, PharmD“

TOP Pharmacist

TOP_June_v6 2011_TOP 6/17/11 12:28 PM


riding horses—and tractors. She went to CarrollCollege in Helena, Montana, and did research atSeattle’s Fred Hutchinson Cancer Research Center.She has lived in Spain and traveled throughoutEurope. Then, she returned home to get her Doctor ofPharmacy degree at Idaho State University. “I kind of stumbled into pharmacy,” Kaster says. “I

wanted to go to medical school, and I shadowed abunch of physicians and didn’t really like it too much.I was graduating from college with a degree in biolo-gy and didn’t really know what to do. My mom, whois a nurse, said she loved the pharmacists she workedwith. So I applied.”

The PresentIt is Kaster’s ability to work with people throughoutthe cancer center that stands out the most. “Lindsayis the most enthusiastic and motivated young phar-macist I have worked with,” says Amber K. Fisher,PharmD, BCPS, director of Boise VA MedicalCenter’s PGY2 Ambulatory Residency Program.“She is extremely talented at working with theoncology clinic staff, staff pharmacists, technicians,and patients.”She needs to be motivated. The national back orders

for a number of important chemotherapy drugs haveforced Kaster to think up creative solutions, fromgetting a delivery just moments before a patientarrives to sharing drugs with VA facilities in otherparts of the country. “The whole pharmacy team has been really

stretched thin because there have been so many short-ages on drugs that we use on a daily basis. It can be real-ly stressful not knowing one day to the next if we willbe able to give a patient his life-saving medication.”This is especially important at the Boise clinic,

where they have no physicians on staff. Doctors oncontract come through once a week. But most of thetime, she and the nurses run the show.“I believe that an oncology pharmacist is invaluable

in the care of heme/onc patients, and this role will onlycontinue to expand in the future,” Kaster tells TheOncology Pharmacist. “Ninety-eight percent of support-ive care decisions in our clinic are made by a team of apharmacist, nurse practitioner, and primary nurse.”

Tim Santos, acting chief of pharmacy at the BoiseVA, commends Kaster for her work implementing newinspection regulations from the VA’s Office of theInspector General and The Joint Commission. Santosand Kaster worked together to get the facility compli-ant with new procedures governing the safe handlingof hazardous drugs and chemotherapy transportation.“She applied her considerable talent for the tena-

cious pursuit of a goal by completing the developmentof the necessary forms, educating staff, and participat-ing in the evaluation of appropriateness of the compe-tencies chosen by staff members.”The Boise VA also serves a very particular popula-

tion: Their patients are veterans, and most live in ruralareas. Most have to travel 1 hour or more to visit thecenter. “We have to do things a little different herethan you would do things at a bigger facility,” she says. She says that the teamwork drew her to oncology,

and that makes it “really different from any otherhealthcare field.”

The FutureKaster is young, and she has impressed colleagues withher energy and commitment. And she has a lot moreplanned for the future. For one, this is the first year sheis eligible to become board certified. Now that she hascompleted the required years of residency and practice,

she wants to make it happen. She also wants to teach,and perhaps one day, after she has more experience onthe job, write a textbook. Kaster is already a preceptor and mentor for PGY1

residents, and she visits pharmacy students at IdahoState University each year to make a pitch for oncolo-gy, where she employs a creative touch by grabbing stu-dents’ attention with a David Letterman–style Top Tenlist. “I think a lot of people overlook oncology becausethey think it’s depressing, so my goal is to get studentsinterested,” she says.And her goals don’t stop there. She would like to do

more research that will benefit Idahoans. “There’s a lotof research to get done, especially on the rural popula-tions we have here.”Dunn says that someone like Kaster, both kind and

shrewd, is the perfect person for the VA. “The BoiseVA Medical Center is proud to have Dr Kaster as partof our clinical team, and we are extremely fortunateto have someone as kind-hearted and clinically mind-ed as Lindsay to serve our veterans.” �

“Despite the challenges ofaddressing cancer disease

state management, Lindsay has continually built and maintained positive professional relationshipswith both staff and patients.”

—Brenda S. Dunn, PharmD, MBA, in her nomination of Kaster

“

Her dedication to continuous improve-

ment of work processes andprocedures has led toenhanced service delivery to our veterans.”

—Tim Santos, in his nominationof Kaster

A Commitment to HelpingThose with Cancer

As the T.O.P. Pharmacist award winner,Lindsay Kaster, PharmD, chose the Leukemia

& Lymphoma Society to receive a donation.

The Leukemia & Lymphoma Society Lindsay chose the Leukemia & LymphomaSociety because it works to cure leukemia, lym-phoma, Hodgkin disease, and myeloma and toimprove the quality of life of patients and theirfamilies. As the world’s largest voluntary healthagency dedicated to hematologic malignancies,the organization develops specific goals each year.This year’s vision includes a focus on fundingresearch projects that offer the best chance ofaccelerating development of new, promising thera-pies, creating better access to clinical trials, andproviding all people traversing the cancer contin-uum access to the information and services theyneed to fight and manage their disease.

The Leukemia & Lymphoma Society also hasdeveloped long-term goals, which it terms theNorth Star 2015 Vision. This vision aims to createa better future for patients with hematologicmalignancies. This includes achieving a high curerate for most patients, helping those patients whocontinue to need treatment to manage their ill-ness with good quality of life, and helping patientsand their families and caregivers navigate thehealthcare system.

If you wish to join Lindsay in helping theLeukemia & Lymphoma Society, you can donateonline at www.LLS.org or through the mail:

The Leukemia & Lymphoma Society Donor ServicesP.O. Box 4072Pittsfield, MA 01202

“

TOP Pharmacist

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Pharmacogenomics

ment duration.2 The identification of therole of KRASmutations in select patientswith colorectal cancer (CRC) who arecandidates for epidermal growth factorreceptor (EGFR) in hibitors is one exam-ple of the clinical application of theadvances in pharmacogenomics.

Targeting EGFRThe current management of a patientwith metastatic CRC may include sur-gery, local therapy with radiofrequencyablation, or transarterial chemoem-bolization, but the primary treatmentremains pharmacotherapy with chemo -therapy. Chemotherapy has been shownto improve disease-related symptomsand overall quality of life in patientswith metastatic disease, downsizelesions in patients with potentiallyresectable disease, and ultimately pro-long survival.3 The number of activechemotherapy agents is few, however,with treatment consisting of the combi-nation of or single-agent therapy withfluorouracil, capecitabine, oxaliplatin,and/or irinotecan. One of the most sig-nificant advances in drug therapy formetastatic CRC in the past decade hasbeen the addition of targeted therapy tochemo therapy. Cetuximab and panitu-mumab target EGFR, whereas beva-cizumab targets angiogenesis. Theseagents have been shown to play a role intreatment of metastatic CRC but,unfortunately, not all patients benefitequally from them.Inhibition of the EGFR is one strate-

gy for management of select malignan-cies. Cetuximab, a chimeric monoclon-al antibody, and panitumumab, a fullyhumanized monoclonal antibody, targetthe external binding sites of theEGFR.4,5 Although the EGFR isexpressed on many nonmalignanthuman cells, higher levels are expressedin certain cancers, such as CRC. Thebinding of the EGFR to the extracellu-lar binding site of EGFR activates sev-eral signal transduction pathways, caus-ing downstream changes in geneexpression and ultimately cell growthand proliferation.Randomized trials with cetuximab

and panitumumab, alone and com-bined with chemotherapy, have shownthese drugs to benefit individuals withmetastatic CRC, as measured by pro-longed progression-free survival andincreased time to disease progression.6-8Single-agent cetuximab has beenshown to improve overall survival inpatients with metastatic CRC whencompared with best supportive care.6,9Despite the benefits seen with theseagents, they are not without chal-lenges. The cost of therapy is signifi-cant and may be prohibitive for somepatients. In addition, these drugs have

side effects, such as rash, and potential-ly serious infusion-related reactions.6-10As with any drug therapy, there isinterest in reserving these agents forthose patients likely to benefit fromtreatment and avoiding the costs andrisks in those unlikely to benefit fromtreatment.

KRAS Status and EGFR InhibitionMutations in KRAS have been identi-fied, and select mutations appear toimpact the activity of EGFR inhibitorsin patients with malignancies such asCRC.11 Although these mutationshave been evaluated in several tumors,the largest body of evidence for theimplications of KRAS mutations, aswell as the most significant effect onthe treatment continuum, has oc -curred with metastatic CRC. Ap -proximately 35% to 45% of patientswith metastatic CRC will have muta-tions in the pathways downstreamfrom the EGFR, which effectively pro-vide an escape mechanism that allowsthe tumors to overcome the pharmaco-logic blockade induced by anti-EGFRmolecules.11 This promotes a perma-nently active state where cells canevade apoptosis. KRAS is a protoonco-gene that is the most commonlymutated gene in this pathway. Thereare only a few mutations in the KRASgene, and more than 90% involve 3codons: 12, 13, and 61.11 If KRASremains unmutated, it is referred to asKRAS wild type (WT). Because thenumber of mutations is low and testingfor the mutations is relatively easy,tumor DNA testing has become anarea of interest in predicting responseto therapy and prognosis.12There is a growing body of evidence

addressing the relationship betweenKRAS mutation and response to anti-EGFR monoclonal antibodies. Initialstudies for cetuximab and panitumu -mab did not evaluate KRAS mutationstatus, but retrospective analyses havebeen completed since, and both single-arm and randomized trials provide com-parisons of efficacy between KRAS

WT and KRAS-mutated patients. In -dividually, these trials are difficult tocompare, but a recent meta-analysis andretrospective consortium analysis sum-marize the data clearly.13,14 Individualswho are KRAS WT who have receivedanti-EGFR monoclonal antibody thera-py have significantly improved overallsurvival compared with KRAS-mutatedpatients. In addition, KRASWT patientshad significantly longer progression-freesurvival and time to progression withanti-EGFR monoclonal therapy. Further,KRAS-mutated patients had significant-ly higher treatment failure rates withanti-EGFR monoclonal therapy.13-15

Anti-EGFR Therapy and CRC The unequivocal benefit seen in KRASWT patients when compared withKRAS-mutant patients with metastaticCRC has led to additional studiesattempting to replicate the findings inother solid tumors. Cetuximab is usedin both non-small cell lung cancer andhead and neck cancer, and it will beimportant to determine the role ofKRAS mutation on the efficacy ofcetuximab in these cancers. Thus far,trials comparing cetuximab pluschemotherapy with chemotherapyalone in non-small cell lung cancerhave not shown differences in out-comes for patients with KRAS muta-tions. Further study is warranted. Other areas for continued research

include further investigating compo-nents downstream of KRAS, identify-ing whether mutations in codon 12 or13 are more predictive of response, andintegrating additional molecular bio-markers, such as BRAF, PTEN, orPIK3CA aberrations. Finally, there aremixed results in the prognostic value ofKRAS mutations, and further study isnecessary before this information canbe of use.Overall, the evidence to date illus-

trates that patients with CRC andKRASmutations are virtually insensitiveto anti-EGFR therapy. The data are socompelling that the prescribing infor-mation for both cetuximab and pani-

tumumab have been modified to indi-cate that these agents are only to beused in KRAS WT patients. Further,the National Comprehensive CancerNetwork has issued guidelines thatstrongly recommend KRAS genotyp-ing of tumor tissue (either primarytumor or metastatic disease) in allpatients at the time of diagnosis ofmetastatic CRC.16 Although patientswith mutations at codon 12 or 13should not receive cetuximab or pan-itumumab, patients without muta-tions who receive these agents aloneor in combination with other anti-cancer agents may derive significantbenefit, including improved responserate, progression-free survival, andoverall survival with the administra-tion of cetuximab or panitumumab.With further study, we will continue,hopefully, to better identify subgroupsof patients who will most benefitfrom targeted therapy and improveclinical outcomes for patients withmetastatic CRC. �

References1. Weinshilboum RM, Wang L. Pharmacogenetics andpharmacogenomics: development, science, and transla-tion. Ann Rev Genomics Hum Genet. 2006;7:223-245.2.Wang L, McLeod HL, Weinshilboum RM. Genomicsand drug response. N Engl J Med. 2011;364:1144-1153. 3.Cunningham D, Atkin W, Lenze HJ, et al. Colorectalcancer. Lancet. 2010;375:1030-1047.4. Vectabix (panitumumab) [package insert]. ThousandOaks, CA: Amgen Inc; 2011.5. Erbitux (cetuximab) [package insert]. Branchburg,NJ: ImClone Systems Inc; 2011. 6. Cunningham D, Humblet Y, Siena S, et al.Cetuximab monotherapy and cetuximab plus irinotecanin irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345.7. Van Cutsem E, Peeters M, Siena S, et al. Open-labelphase III trial of panitumumab plus best supportive carecompared with best supportive care alone in patientswith chemotherapy-refractory metastatic colorectalcancer. J Clin Oncol. 2007;25:1658-1664.8. Bokemeyer C, Bondarenko I, Makhson A, et al.Fluorouracil, leucovorin, and oxaliplatin with and with-out cetuximab in the first-line treatment of metastaticcolorectal cancer. J Clin Oncol. 2009;27:663-671.9. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al.Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048.10. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC:phase III trial of cetuximab plus irinotecan after fluo-ropyrimidine and oxaliplatin failure in patients withmetastatic colorectal cancer. J Clin Oncol. 2008;26:2311-2319.11. Rizzo S, Bronte F, Fanale D, et al. Prognostic vs pre-dictive molecular biomarkers in colorectal cancer: isKRAS and BRAF wild type status required for anti-EGFR therapy? Cancer Treat Rev. 2010;36S3:S56-S61.12. Malumbres M, Barbacid M. RAS oncogenes: thefirst 30 years. Nat Review Cancer. 2003;3:459-465.13. Dahabreh IJ, Terasawa T, Castaldi PJ, TrikalinosTA. Systematic review: anti-epidermal growth factorreceptor treatment effect modification by KRAS muta-tions in advanced colorectal cancer. Ann Intern Med.2011;154:37-49.14. DeRoock W, Claes B, Bernasconi D, et al. Effects ofKRAS, BRAF, NRAS, and PIK3CA mutations on theefficacy of cetuximab plus chemotherapy in chemothera-py-refractory metastatic colorectal cancer: a retrospectiveconsortium analysis. Lancet Oncol. 2010;11:753-762.15. Allegra CJ, Jessup JM, Somerfield MR, et al.American Society of Clinical Oncology provisional clin-ical opinion: testing forKRAS gene mutations in patientswith metastatic colorectal carcinoma to predict responseto anti-epidermal growth factor receptor monoclonalantibody therapy. J Clin Oncol. 2009;27:2091-2096.16. National Comprehensive Cancer Network. ClinicalPractice Guidelines in Oncology: Colon Cancer. V.3.2011.www.nccn.org/professionals/physician_gls/pdf/colon.pdf.Accessed June 1, 2011.

KRAS Status, EGFR Inhibition... Continued from cover

Katharine A. Kinsman, PharmD, BCOP Rowena N. Schwartz, PharmD, BCOP

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Pharmacy Careers

With the ever-increasing costof oncology drugs as well aspatient copays, a new role

was created to help patients managetheir financial needs at the SouthwestCancer Center, in cooperation with theCentral Pharmacy, University MedicalCenter, Lubbock, Texas, the county’sand Texas Tech University’s primaryteaching hospital. The pharmacy re -imbursement specialist works withunfunded/self-pay patients, locallyfunded patients, Medicare with Part Dpatients, insured patients offered somechemotherapy by their insurance butdenied the best new therapies fortheir cancer, and insured patientswhose insurance will pay for the ther-apy they need but who cannot them-selves handle the expense of thecopay ($10,000 per month for someoral chemotherapy agents).

This specialist, Michelle PrietoFlores, spends upward of 80% of hertime on the telephone, talking withdrug manufacturers, dealing with spe-cialty pharmacies, and systematicallyfollowing the required procedures forenrollment in patient-assistance pro-grams. Typically, the process of securingneeded medications is initiated when aphysician orders chemotherapy or sup-portive treatments, then the pathwaybecomes more complex, branching offbased on the specific cancer and theninto intravenous or oral agents. Fromthere, the pathway diverges again,dependent on into which paymentgroup the patient falls. Over time, theestablishment of points of contact withmanufacturers and pharmacies will helpmove the process along.

Most manufacturers offer patient-assistance programs, and the reimburse-ment specialist is familiar with them all.Many not-for-profit organizations offerthese programs as well. In addition, cer-tain specialty pharmacies can be help-ful, often finding a patient-assistanceprogram or foundation for a patient.This work creates a network of “care”for oncology patients that transcends

geographic location to try to ensure thateach patient receives the treatment heor she needs.

Finding the right program for thepatient, however, is only the beginning.The reimbursement specialist’s nextstep is providing medical forms. Often,this leads to completing the formswith/for the patient. For patients con-fronted by anxiety about their condi-tion and what lies ahead, sometimeswith added difficulties due to lack ofeducation, low socioeconomic status, orlanguage difficulties, the burden of med-ical paperwork can be overwhelming.By removing this burden, the reim-bursement specialist can make the dif-ference between a patient seekingappropriate treatment or giving up.

The pharmacy reimbursement spe-

cialist is a key member of the interdisci-plinary teams that are required to meetcurrent standards of care in oncology,particularly with patients who endurediseases that require expensive and/or

extensive medications. Delivering thefinest and most comprehensive care isultimately best practice on a healthcarelevel, a business level, an ethical level,and a human level. �

The Pharmacy Reimbursement SpecialistBy Susan S. Hendrick, PhDTexas Tech University and Southwest Cancer Center, Lubbock, Texas

Michelle Prieto Floresof Lubbock, Texas,had no idea that

what seemed like just onetemporary phase of her worklife would become a passion-ate professional commitment.During her late teens, PrietoFlores worked with grouphomes for mentally chal-lenged persons, eventuallybecoming the manager of oneof the homes. She was famil-iar with medications, having

helped family with medication administration for severalyears. In addition, as a home manager, she frequentlyneeded to pick up medications for residents under her careat the local pharmacy, where she became acquainted witha pharmacist.

Deciding to change jobs, she applied for a position as apharmacy clerk. She didn’t get the clerk position, but shegot a phone call from the pharmacist she knew—a phonecall that changed her career path forever. The pharmacistinvited Prieto Flores to work for her as a pharmacy techni-cian (which she did), subsequently helping Prieto Floresobtain her pharmacy technician license. When the phar-macist moved to the Central Pharmacy at UniversityMedical Center, Prieto Flores moved with her. Working inthe inpatient pharmacy, she learned virtually all aspects ofthe pharmacy.

The pharmacy director saw Prieto Flores’s potential andasked her to take a new position, that of a PharmacyReimbursement Specialist. Her new role was to work withboth unfunded/self-pay and county-funded oncologypatients to try to secure needed medications. AlthoughPrieto Flores still had her office in Central Pharmacy, muchof her work moved to the Southwest Cancer Center (SCC).The position grew as the hematology/oncology patient basegrew. As the SCC added clinics, physicians, and services,

Prieto Flores was in demand. Within a couple of years, shewas asked to work directly in the SCC a few days per week,and finally a full-time position was created for her.Administrators, physicians, extenders, and nurses appreci-ated the value in having this position staffed full time. Onceagain, Prieto Flores grew her position, both because of theincreasing complexity of her job and because she was goodat answering the requests of the physicians and meeting theneeds of the patients, always with warmth and her charac-teristic smile. As she is quick to say, “At the end of the day,it’s for the patient.”

When Michelle comes into a clinic room, there is animmediate sense that she is there to help. She doesn’t prom-ise miracles, but rather she says, “The only promise I makeis that I’ll give it all I’ve got,” which is quite a lot. Her ded-ication is important, because the world of medications andthe patients who she serves have grown steadily since shebegan. The advent of oral chemotherapies changed the ter-rain, as did the development of Medicare Part D.

So what does her job look like now? She now works witha diverse group of patients who have a diverse set of needs,and her aim is to “treat everyone as if he or she was a mem-ber of my family.”

What keeps someone doing a tough job, day after day,hassle after hassle, form after form? The answer Prieto Floresgave was “I love what I do.” She also gave another answer,without necessarily even knowing it may be the primarymotivation for her. She said that she goes home from workwith gratitude for being allowed to spend just “one moreday” with her loved ones. Some people don’t get thatchance. The opportunity to have “just one more day” maybe what causes patients to struggle with difficult chemother-apy regimens and sometimes debilitating radiation treat-ments. Outsiders and even insiders to the oncology worldsometimes wonder why patients hang on to hope and treat-ment, even when the treatment is not working. Perhaps theanswer is “just one more day with my loved ones.” AndPrieto Flores does as much as she can to help as manypatients as she can get “just one more day.”

“One More Day”Why One Woman Became an Oncology Pharmacy Reimbursement Specialist

Most manufacturers offerpatient-assistanceprograms, and thereimbursement specialistis familiar with them all.Many not-for-profitorganizations offer theseprograms as well.

Michelle Prieto Flores

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The risk of venous thromboem-bolism (VTE) in the generalpopulation is substantial, with

an approximate incidence of 1 VTEcase per 1000 individuals. This trans-lates to more than 200,000 new casesannually in the United States.1 Moreimportant, almost 30% of patients withVTE will die within 30 days of the ini-tial diagnosis.1 Although not all thosedeaths are directly related to VTE or itssequelae, approximately 20% of thosedying within this 30-day period will becaused by pulmonary embolism (PE).1Despite significant advances in the

diagnosis and management of VTE, itsincidence has not substantially changedsince the 1980s.1 The risk of havingVTE is elevated by a number of factors,including1:• Central venous catheter/transve-nous pacemaker

• Hospital or nursing home confine-ment

• Hormone replacement therapy • Increasing age• Male sex• Malignancy

• Neurologic disease with extremityparesis

• Oral contraceptives• Pregnancy• Previous superficial vein thrombosis• Surgery• Trauma• Varicose veins.

Venous Thromboembolism andMalignancyVTE may be a presenting sign of anoccult malignancy. Of all new cases ofVTE, approximately 20% are associatedwith active malignancy.2 It is remark-able to note that patients with cancerhave a 4- to 6-fold higher risk for VTEcompared with patients without can-cer.3 Therefore, otherwise healthyadults presenting with VTE without anobvious cause may warrant additionaltesting to rule out occult malignancies.VTE is also a major concern for

patients with cancer, and it must beconsidered a serious complication of analready diagnosed cancer. For patientswith cancer, the incidence of VTEapproaches 1 in 200 patients.4 Ap -

proximately 20% of VTE cases occurin patients with cancer,2 which meansthat cancer-related cases of VTEaccount for more than 40,000 of the200,000 cases seen annually in theUnited States. Fifteen percent ofpatients with cancer will have sympto-matic, diagnosed VTE, and, astound-ingly, almost 50% of patients with cancer are found to have VTE at post-mortem examination.5 The risk ofVTE in patients with cancer is com-pounded by the fact that many pa tientsin this population are older people,aged >55 years.VTE is the second leading cause of

death in hospitalized patients withcancer, and the risk of death from VTEin patients with cancer is 3- to 8-fold

higher than in comparable patientswithout cancer.6 Furthermore, patientswith cancer and symptomatic deep-veinthrombosis (DVT) exhibit a high riskfor recurrent DVT/PE that persists formany years after the initial episode.7

Other Risk FactorsOther factors that increase the risk forVTE in patients with cancer includethe type of malignancy. In men, tumorsof the prostate, colon, lung, and brainare among the cancer types with thehighest risk for VTE. In women, breast,ovarian, and lung cancers are associat-ed with increased VTE risk.4,8 Hem -atologic malignancies, such as lym-phoma and multiple myeloma,especially when the latter disease is

In men, tumors of the prostate, colon, lung, and brainare among the cancer types with the highest risk forVTE. In women, breast, ovarian, and lung cancers areassociated with increased VTE risk.


CONTINUING EDUCATION

Improving the Prevention and Treatment of VenousThromboembolism in Cancer: The Strategic Role of the Health-System Pharmacist

PROGRAM P10068 • RELEASE DATE: APRIL 22, 2011 • EXPIRATION DATE: APRIL 22, 2012

ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

TARGET AUDIENCE

This activity was developed for health-systempharmacists and oncology pharmacists.

LEARNING OBJECTIVES

After completing this activity, the reader should beable to:• Explain the epidemiology and risk factors ofvenous thromboembolism (VTE) in cancer

• Summarize current evidence-based guidelinesfor prevention and treatment of VTE in cancer,with special attention to the differences and sim-ilarities across guidelines

• Discuss key data from randomized clinical trialsof low-molecular-weight heparins in preventionof recurrent VTE in cancer

• Describe emerging strategies in VTE prophylaxisand treatment

SPONSOR

This activity is sponsored by Medical LearningInstitute, Inc., a nonprofit medical accreditationcompany, and Center of Excellence Media, LLC.

INSTRUCTIONS fOR CREDIT

1. Read the article in its entirety2. Log on to www.TheOncologyPharmacist.com3. Select “Continuing Education”4. Click on this article’s title from the listshown

5. Select “Click here to complete the posttestand obtain a CE certificate online”

6. Complete and submit the CE posttest and CEActivity Evaluation

7. Print your Statement of Completion

PhARmACIST DESIGNATION

Medical Learning Institute, Inc., is ac credit-ed by the Accreditation Council for Phar m -

acy Education (ACPE) as a pro vider of continuingpharmacy education. Com pletion of this activityprovides for 1.0 contact hour (0.1 CEU) of continu-ing education credit. The universal activity numberfor this activity is 0468-9999-10-059-H01-P.

This activity is provided free of charge to partici-pants. Upon completion of the evaluation and scor-

ing 70% or better on the posttest, you will imme-diately receive your certificate online. If you do notachieve a score of 70% or better on the posttest,you will be asked to take it again. Please retain acopy of the certificate for your records.

fACULTy DISCLOSURES

Before the activity, all faculty will disclose theexistence of any financial interest and/or rela-tionship(s) they might have with the manufac-turer(s) of any commercial product(s) to be dis-cussed during their presentation(s): honoraria,expenses, grants, consulting roles, speaker’sbureau membership, stock ownership, or otherspecial relationships. Presenters will inform par-ticipants of any off-label discussions.

Paul Dobesh, PharmD, FCCP, BCPS, is a consultantto Ortho-McNeil and sanofi-aventis.

Gary M. Owens, MD, is a consultant to Auxilium,Biosense Webster, Centocor Ortho Biotech, Eli Lilly,Genentech, and Novartis.

Gary C. Yee, PharmD, FCCP, BCOP, is on the advi-sory board for Amgen.

Nancy Nesser, JD, PharmD, a reviewer for MLI,has nothing to disclose.

The associates of Medical Learning Institute,Inc., the accredited provider for this activity, andCenter of Excellence Media, LLC, do not haveany financial relationships or relationships toproducts or devices with any commercial inter-est related to the content of this CE activity forany amount during the past 12 months.

DISCLAImER

The information provided in this CE activity isfor continuing education purposes only and isnot meant to substitute for the independentmedical judgment of a healthcare provider rel-ative to diagnostic and treatment options of aspecific patient’s medical condition. Tradenames used in this supplement are for thelearner’s reference only. No promotion of orbias toward any product should be inferred.

COmmERCIAL SUPPORT

ACkNOwLEDGmENT

This activity is supported by an educationalgrant from sanofi-aventis.

Venous Thromboembolism a Major Concern in Patients with CancerBy Gary M. Owens, MDPresident, Gary Owens Associates, Philadelphia, Pennsylvania

TOP_June_v6 2011_TOP 6/17/11 12:28 PM

treated with immunomodulators, havea very high risk for VTE events.4Finally, VTE increases the risk for

cancer-related death in hospitalizedpatients.9 The Figure illustrates that thepercentage of patients who suffer in-hos-

pital death is higher with either metasta-tic or nonmetasta tic disease when VTEis a comorbid condition.9The risk for VTE is certainly in creased

in patients diagnosed with a malignancy.That risk can further be compounded by

such factors as the treatment of thedisease by selected chemothera-peutic agents, the placement of acentrally dwelling catheter, oreven by surgical procedures target-ed at removing the lesion. It is therefore essential that oncolo-

gists and other providers caring forpatients with cancer are aware of theserisks and take steps to prevent and toaggressively manage cancer-related VTE.At a minimum, physicians must activelyintervene to prevent VTE in patientswith cancer who are undergoing surgeryor who are hospitalized. In addition,strong consideration should be given toconsider preventive therapies for high-risk ambulatory patients with cancer (eg, patients with myeloma receivingimmunomodulatory therapy) and toengage in long-term treatment (>6months) for patients with cancer whohave VTE to prevent VTE recurrence. �

References1. Heit JA. Venous thromboembolism epidemiology:implications for prevention and management. SeminThromb Hemost. 2002;28(suppl 2):3-13.2.Heit JA, O’Fallon WM, Petterson TM, et al. Relative

impact of risk factors for deep vein thrombosis and pul-monary embolism: a population-based study. Arch InternMed. 2002;162:1245-1248.3. Heit JA, Silverstein MD, Mohr DN, et al. Risk factorsfor deep vein thrombosis and pulmonary embolism: a pop-ulation-based case-control study. Arch Intern Med.2000;160:809-815.4. Lee AY, Levine MN. Venous thromboembolism andcancer: risks and outcomes. Circulation. 2003;107(23 suppl1):I-17-I-21.5. El-Shami K, Griffiths E, Streiff M. Nonbacterial throm-botic endocarditis in cancer patients: path ogenesis, diag-nosis, and treatment. Oncologist. 2007;12:518-523.6. Heit JA, Silverstein MD, Mohr DN, et al. Predictors ofsurvival after deep vein thrombosis and pulmonaryembolism: a population-based case-control study. ArchIntern Med. 1999;159:445-453.7. Prandoni P, Lensing AW, Cogo A, et al. The long-termclinical course of acute deep vein thrombosis. Ann InternMed. 1996;125:1-7.8. Heit JA. Cancer and venous thromboembolism: scopeof the problem. Cancer Control. 2005;12(suppl 1):5-10.9. Khorana AA, Francis CW, Culakova E, et al. Throm -boembolism in hospitalized neutropenic cancer patients.J Clin Oncol. 2006;24:484-490.

June 2011 I vol 4, no 4 21www.Theoncologypharmacist.com

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

18

16

14

12

10

8

6

4

2

0All

(N = 66,016)Nonmetastatic(N = 20,591)

No VTE VTE

Hospital Deaths

Mortality, %

Metastatic(N = 17,360)

Several international organizationshave developed clinical practiceguidelines for the prevention and

treatment of venous thromboembolism(VTE) in patients with cancer.1 In theUnited States, 3 organizations havedeveloped guidelines for VTE—theAmerican College of Chest Physicians(ACCP), the American Society ofClinical Oncology (ASCO), and theNational Com pre hensive Cancer Net -work (NCCN).2-4 The guidelines differin their scope and methods used todevelop the guideline. The ACCP andASCO guidelines are based on a sys-tematic review and formal evaluation ofstudy quality. The first set of NCCNguidelines was based on a systematicreview, but annual revisions are basedon review of recently published researchand responses to questions asked by cli-nicians at member institutions.1 TheASCO and NCCN guidelines are limit-ed to the prevention and treatment ofVTE in patients with cancer.

Prevention of VenousThromboembolismThe ACCP, ASCO, and NCCN guide-lines agree that all hospitalized patients

with cancer, including those undergo-ing surgery, should receive prophylac-tic anticoagulation (in the absence ofcontraindications).2-4 Re c ommendedagents include low-dose unfractionatedheparin, low-molecular-weight heparin(LMWH), or fondaparinux. Patientsundergoing major abdominal or pelvicsurgery should receive prolonged pro-phylaxis (ie, up to 4 weeks).For ambulatory cancer patients, the

ACCP, ASCO, and NCCN guidelinesagree that routine VTE prophylaxis isnot recommended. The ASCO andNCCN guidelines list certain high-riskpatient groups that are exceptions tothe recommendation (Table). Although the ASCO and NCCN

guidelines consider those who arereceiving thalidomide or lenalidomidewith chemotherapy or dexamethasoneas high-risk patients, the NCCN guide-line adds specific information on dex-amethasone dose and incorporates a riskassessment model and recommenda-tions developed by an internationalgroup of experts.5 In contrast to otherVTE risk assessment models, that riskassessment model was developed specif-ically for patients with multiple myelo-

ma who are treated with thalidomide orlenalidomide. The recommended agents for VTE in

high-risk patients vary depending onthe guideline and risk category. The

ASCO guideline does not list aspirin asa recommended prophylactic agent,probably because its literature searchonly included randomized controlled tri-als published through the end of 2006.3

Guidelines for the Prevention and Treatment of VenousThromboembolism in CancerBy Gary C. Yee, PharmD, FCCP, BCOPProfessor of Pharmacy Practice and Associate Dean for Academic Affairs, College of Pharmacy,

University of Nebraska Medical Center, Omaha, and a member of the utilization management committee

and national pharmacy & therapeutics committee for a large pharmacy benefits manager

Table Comparison of Guidelines for the Prevention of VTE in Ambulatory Patients with Cancer

ASCO NCCN

Definition of high-risk patients

Patients receivingthalidomide orlenalidomide withchemotherapy ordexamethasone

Select patients receiving highly thrombotic antiangiogenic therapy (ie, multiple myeloma patients receiv-ing thalidomide/lenalidomide and high-dose dexamethasone [≥480mg/month]), doxorubicin, or multiagent chemotherapy)

Myeloma patients with ≥2 individualor myeloma risk factors

Recommendedagent(s)

LMWH or warfarin(INR ~1.5)

LMWH (eg, enoxaparin 40 mg sub -cutaneous every 24 hr) or warfarin (INR 2-3)

Low-risk myeloma outpatients: aspirin (81-325 mg/day)

ASCO indicates American Society of Clinical Oncology; INR, international normalized ratio;LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolism.

Figure. VTE and Inpatient Mortality.VTE indicates venous thromboembolism.Adapted with permission from Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

TOP_June_v6 2011_TOP 6/17/11 12:28 PM



The NCCN guidelines recommendLMWH or full-dose warfarin for mostpatients, but lists aspirin as an option forselected patients (eg, low-risk myelomaoutpatients).4

This variability in the guideline rec-ommendations reflects the lack of rig-orous evidence on the prevention ofVTE in patients with multiple myelo-ma. Guideline recommendations arelikely to change as the results of ran-domized controlled trials are published.For example, Palumbo and colleaguesrecently reported the results of a ran-domized controlled comparison ofaspirin (100 mg/day), fixed low-dosewarfarin (1.25 mg/day), or LMWH(enoxaparin 40 mg/day) as VTE pro-phylaxis in 667 patients with multiplemyeloma treated with thalidomide-based regimens.6 Of 659 analyzed

patients, 43 (6.5%) developed anevent, a composite end point thatincluded serious thromboembolicevents, acute cardiovascular events, orsudden deaths during the first 6months of treatment. The event ratefor the different thromboprophylaxisarms was not significantly different.Vali dated risk assessment models arealso needed to predict the risk of VTEin patients with multiple myeloma.

Treatment of VenousThromboembolismThe ACCP, ASCO, and NCCN guide-lines agree that all patients with cancerand established VTE should be treatedwith anticoagulation.2-4 Re c ommendedagents include unfractionated heparin,LMWH, or fondaparinux, and the rec-ommended duration of initial therapy

is a minimum of 5 days. Long-termtherapy with LMWH is recommendedfor up to 6 months.

Each of the guidelines recommendsthat anticoagulation be continued forlonger than 6 months in selectedpatients with cancer. The ACCPguideline recommends “subsequentanti coagulation with LMWH or war-farin indefinitely or until the cancer isresolved” (grade 1C recommenda-tion).2 The ASCO guidelines statethat “indefinite anticoagulationshould be considered for selectedpatients with active cancer, such asthose with metastatic disease andthose receiving chemotherapy” (panelconsensus).3 The NCCN guidelinesrecommend indefinite anticoagula-tion if the pa tient has active cancer orpersistent risk factors. �

References1. Khorana AA, Streiff MB, Farge D, et al. Venousthromboembolism prophylaxis and treatment in cancer:a consensus statement of major guideline panels and callto action. J Clin Oncol. 2009;27:4919-4926.2. Kearon C, Kahn SR, Agnelli G, et al. Anti -thrombotic therapy for venous thromboembolic disease:American College of Chest Physicians Evidence-BasedClinical Practice Guidelines (8th Edition). Chest.2008;133(6 suppl):454S-545S.3. Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology guideline: rec-ommendations for venous thromboembolism prophy-laxis and treatment in patients with cancer. J ClinOncol. 2007;25:5490-5505.4. National Comprehensive Cancer Network. Venousthromboembolic disease. Version 1. 2011. www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Ac ces sedApril 14, 2011. 5. Palumbo A, Rajkumar SV, Dimopoulos MA, et al.Prevention of thalidomide- and lenalidomide-associatedthrombosis in myeloma. Leukemia. 2008;22:414-423.6. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, war-farin, or enoxaparin thromboprophylaxis in patientswith multiple myeloma treated with thalidomide: aphase III, open-label, randomized trial. J Clin Oncol.2011;29:986-993.

Case Scenarios in the Prevention and Treatment of VTEin Patients with CancerBy Paul Dobesh, PharmD, FCCP, BCPSProfessor of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha

Patients with cancer undergoingsurgical procedures are at higherrisk for the development of

venous thromboembolism (VTE) com-pared with patients without cancerundergoing similar surgical proce-dures.1,2 Patients with cancer undergo-ing surgery are considered to be one ofthe highest risk groups for the develop-ment of VTE, with event rates similarto those in patients undergoing ortho-pedic surgery.3,4 This high risk for VTE isbecause patients undergoing cancer sur-gery end up with all 3 parts of Virchow’striad: venous stasis, vascular damage,and a hypercoagulable state. Therefore,VTE prophylaxis in these patients isvery recommended.3,4 The decision onwhat to use for prophylaxis has alsobeen extensively studied.

In the Enoxaparin in Cancer(ENOXACAN) study, 631 patientsundergoing elective abdominal orpelvic surgery for cancer were random-

ized to enoxaparin 40 mg subcutaneous-ly once daily or to unfractionatedheparin (UFH) 5000 units subcuta-neously 3 times daily.5 The first dose ofanticoagulant was given 2 hours beforesurgery and continued for 10 days. Theprimary end point of the ENOXACANstudy was the incidence of total VTEdetermined by venography. Althoughthe primary end point was reduced byalmost 20% at 10 days with the use ofenoxaparin compared with UFH, thisdifference was not significant (14.7% vs18.2%). There was also no significantdifference in the incidence of totalbleeding or major bleeding (4.1% vs2.9%) between the groups.

In the Canadian Colorectal DVTProphylaxis Trial, 1349 patients under-going colorectal surgery were random-ized to the same regimens of enoxaparinand UFH6 as in the ENOXACANstudy. In this Canadian study, 35% ofthe patients (n = 475) were undergoingcolorectal surgery for cancer. In thissubgroup, the incidence of VTE was13.9% in the enoxaparin group com-pared with 16.9% in the UFH group.6

The efficacy and safety betweenusing a low-molecular-weight hepa rin(LMWH) or UFH for in-hospital VTEprophylaxis in patients undergoing sur-gery for cancer has been evaluated in ameta-analysis.7 This meta-analysis in -cluded 14 randomized trials that com-pared these regimens in surgical cancerpatients. Although patients receivingLMWH did not demonstrate any reduc-tion in mortality (relative risk [RR],

0.89; 95% confidence interval [CI],0.61-1.28), there was a significantreduction in deep-vein thrombosis(DVT) with the use of LMWH (RR,0.72; 95% CI, 0.55-0.94). Most of thisoverall benefit to the use of LMWH wasin the comparison to patients receivingUFH twice daily (RR, 0.66; 95% CI,0.44-0.99), with less difference demon-strated in comparison to UFH 3 timesdaily (RR, 0.78; 95% CI, 0.53-1.15).There was also no significant differencebetween the 2 regimens with regard tominor or major bleeding.7

Another important question thatarises with the use of VTE prophylaxisin patients having cancer surgery is theappropriate duration of prophylaxis.Although VTE prophylaxis for mostindications is usually given for the dura-tion of hospitalization or until thepatient is mobile, data suggest that alonger duration is indicated in patientsundergoing surgery for cancer.

The ENOXACAN II study evaluatedpatients undergoing gastrointestinaltract, genitourinary tract, or femalereproductive organ cancer surgery.8 All

patients received enoxaparin 40 mgsubcutaneously once daily for 6 to 10days. Patients (n = 332) were then ran-domized in a double-blind fashion tocontinue taking enoxaparin at the samedose or placebo for an additional 21days. The primary end point was theincidence of venographic VTE at 1month, which was significantly reducedby 60% with the use of enoxaparincompared with placebo (4.8% vs 12%;P = .02), as well as a 60% reduction inproximal DVT (0.6% vs 1.8%). Thissignificant 60% reduction in the pri-mary end point was still evident at the3-month follow-up (5.5% vs 13.8%; P = .01). The use of extended prophy-laxis with enoxaparin did not produce asignificant increase in any bleedingevent (5.1% vs 3.6%) or major bleeding(0% vs 0.4%) compared with placebo.8

These results have been confirmed by2 additional studies.9,10 The Cancer,Bemiparin, and Surgery Evaluation(CANBESURE) study randomized 703patients undergoing abdominal or pelvicsurgery for cancer to bemiparin 3500 IUsubcutaneously once daily or placeboafter completing 6 to 10 days of bemi-parin (same dose).9 At 3-month follow-up, major VTE was reduced by morethan 80% with the use of extendedbemiparin compared with placebo (0.8%vs 4.6%; P = .010). Major bleeding wasnot significantly different between thegroups (0.6% vs 0.3%; P = .572).9

The Fragmin After Major AbdominalSurgery (FAME) trial was slightly differ-ent in that it enrolled all patients under-

Case Scenario 1J. B. is a 54-year-old obese manrecently diagnosed with stage IIIcolon cancer. He is admitted todayfor surgical resection of theinvolved bowel segment and willsubsequently receive FOLFOX (5FU, leucovorin, and oxaliplatin)as adjuvant chemotherapy. He hasno history of cancer or thromb o -embolic events. Is thromboem-bolism a concern in this patient?

Another importantquestion that arises withthe use of VTE prophylaxisin patients having cancersurgery is the appropriateduration of prophylaxis.

TOP_June_v6 2011_TOP 6/17/11 12:29 PM

going abdominal surgery and had anopen-label design.10 Patients were ran-domized to dalteparin 5000 IU subcuta-neously once daily for 7 days or 28 days.Overall, VTE events were significantlyreduced with extended-duration dal-teparin prophylaxis at the 1-month fol-low-up (7.3% vs 16.3%; P = .012).Although 58% of the patients in theFAME trial had abdominal surgery forcancer, the results for the subgroup ofpatients with cancer are not provided.Minor and major bleeding were not sig-nificantly increased with the extendedduration of VTE prophylaxis. Based onthe results of these studies, extendedVTE prophylaxis is recommended forpatients undergoing abdominal or pelvicsurgery for cancer.3,4

The treatment of VTE in patientswith cancer requires a differentapproach compared with that for

the patient without cancer. The typicalpatient without cancer who has VTEreceives an injectable anticoagulant andwarfarin together for a minimum of 4days and until the international normal-ized ratio (INR) becomes therapeutic inthe range of 2 to 3. At that time, theinjectable anticoagulant (UFH, LMWH,or fondaparinux) is then discontinuedand the patient continues taking war-farin for at least 3 to 6 months, depend-ing on the etiology of the VTE.4 Inpatients with cancer, the managementshould be an LMWH for 3 to 6 months,without the typical initiation of war-farin. This different management strate-gy is srongly recommended in clinicalguidelines and supported by well-con-ducted randomized clinical trials. Al -though dalteparin is currently the onlyLMWH to be approved by the US Foodand Drug Administration for treatmentof VTE in patients with cancer, all 3LMWHs available in the United Stateshave clinical evidence to support theiruse for VTE therapy.Tinzaparin was compared with a stan-

dard vitamin K antagonist in the treat-ment of VTE in the Trial of the Effect ofLow-Molecular-Weight Hep arin VersusWarfarin on Mortality in the Long-TermTreatment of Proximal Deep Vein

Thrombosis (LITE).11 In the LITE trial,200 patients with cancer with acutesymptomatic proximal vein thrombosiswere randomized in an open-label fash-ion to tinzaparin 175 IU/kg subcuta-neously once daily for 3 months or toUFH intravenous bolus and infusionoverlapped with warfarin until day 6 andthe INR was therapeutic (2-3), withwarfarin continued for 3 months. At 3months, the incidence of recurrent VTEwas reduced by 40% in the tinzaparingroup compared with the usual-caregroup, but this did not achieve signifi-cance (6% vs 10%). Pa tients receivingtinzaparin did have a significant 56%reduction in recurrent VTE at the end of12 months (7% vs 16%; P = .04). Theincidence of minor bleeding, majorbleeding, and death were similarbetween the groups.11In another study, enoxaparin 1.5

mg/kg subcutaneously once daily for 3months was compared with the samedose of enoxaparin overlapped with war-farin for at least 4 days, with warfarincontinued at an INR of 2 to 3 for 3months.12 The 146 patients with cancerin this trial were diagnosed with pul-monary embolism (PE) and/or DVT andthen randomized to 1 of the 2 treatmentgroups in an open-label fashion. Theprimary outcome of recurrent VTE andmajor bleeding at 3 months occurred in10.5% of enoxaparin patients and21.1% of warfarin patients (P = .09).While mortality was cut by more than50% with the use of enoxaparin com-pared with warfarin (11.3% vs 22.7%; P= .07), this trial was not large enough tofind a significant difference in mortality.Fatal bleeding was significantly reducedwith the use of enoxaparin comparedwith warfarin (0% vs 8%; P = .03),whereas other major bleeding did notachieve statistical significance (9% vs17%; P = .07).12Dalteparin was compared with war-

farin therapy for treatment of PE and/orDVT in patients with cancer in theComparison of Low-Molecular-WeightHeparin versus Oral Anti coagulantTherapy for Long-Term Anti coagulationin Cancer Patients with VenousThromboembolism (CLOT) trial.13Patients in the CLOT trial (n = 676)were randomized in an open-label fash-ion for 6 months of anticoagulant thera-py. Patients randomized to dalteparinreceived 200 IU/kg (maximum dose of18,000 IU) subcutaneously once dailyfor 1 month, and then approximately150 IU/kg subcutaneously once daily forthe remaining 5 months. The usual-carepatients received dalteparin 200 IU/kg(maximum dose of 18,000 IU) subcuta-neously once daily overlapped with avitamin K antagonist for at least 5 days,and the INR was therapeutic (2-3), withthe vitamin K antagonist continued forthe remaining 6 months. At 6 months,

the primary end point of recur-rent VTE was significantly re -duced by 50% with the use of dal-teparin compared with usual care(8% vs 16%; P = .002). Mortalitywas not reduced at 6 months with theuse of dalteparin compared with usualcare (39% vs 41%; P = .53), and majorbleeding was also not different betweenthe groups (6% vs 4%; P = .27).13 In a 12-month follow-up of the CLOT

trial, mortality was 59% in both groups (P= .62). In this trial, in 75% of the patientswith metastases, the mortality rate withdalteparin was similar to that of usualcare (72% vs 69%; P = .46).14 In the 25%of patients without metastases, there wasa 45% significant reduction in mortalitywith the use of dalteparin compared withusual care (20% vs 36%; P = .03).14Although these data are from a post hocanalysis of the data, it clearly requires fur-ther study in a larger patient sample.One of the major questions that

remains unanswered from clinical trialsis what to do after the initial 6-monthtreatment with LMWH? There are atleast 4 options: 1. Give no further anticoagulationtherapy

2. Continue anticoagulation withwarfarin (INR 2-3)

3. Continue anticoagulation withtreatment doses of LMWH

4. Continue anticoagulation withprophylaxis doses of LMWH.

Future research will need to focus onanswering the best approach for contin-ued therapy, if it is needed at all.

Current guidelines do not supportthe use of primary VTE prophy-laxis in patients with cancer.

Despite the current lack of a recom-mendation, clinical trials have begunto demonstrate a benefit in primaryprophylaxis in certain patients at highrisk for cancer. A number of trials have evaluated the

ability of LMWH to prevent mortalityin patients without a current VTEevent.15-19 One study evaluated theLMWH nadroparin for 6 weeks inpatients with metastasized or locallyadvanced solid tumors.15 Patients wererandomized to placebo or to therapeuticweight-adjusted nadroparin subcuta-neously twice daily for the first 2 weeks

and then once daily for another 4 weeks.Median survival was 8.0 months forpatients receiving nadro parin comparedwith 6.6 months for patients receivingplacebo (P = .021). Major bleeding wasnot significantly increased with the useof nadroparin (3% vs 1%; P = .021).15Although these results with nadro -

parin seem impressive, other trials ofLMWH for improvement in survival inpatients with cancer have not repeatedthese same findings. The Improvingwith Nadroparin the Prognosis inAdvanced Cancer Treatment (INPACT)trial evaluated 503 patients with hor-mone-refractory prostate cancer within 6months of diagnosis (41%), locallyadvanced pancreatic cancer within 3months of diagnosis (26%), or non-smallcell lung carcinoma (stage IIIB) within 3months of diagnosis (33%).16 Patients inthe INPACT trial were randomized toobservation or subcutaneous nadroparin.The nadro parin regimen consisted of full-dose treatment for 2 weeks, followed byhalf-dose treatment for 4 weeks.Nadroparin was then given in up to 6cycles of no nadroparin for 4 weeks fol-lowed by full dose for 2 weeks. All-causemortality was not different between thenadroparin and observation patients(57% vs 61%). These results were con-sistent across all types of cancer includ-ed in the trial. One limitation to thetrial is the use of open-label nadroparinfor the treatment of VTE in 30% of theobservation patients.16In the FAMOUS trial, subcutaneous

dalteparin 5000 IU once daily or place-bo was given for 1 year to 385 patientswith advanced malignancy.17 Mortalityat 1, 2, and 3 years was not differentbetween the groups (P = .19).17Trials evaluating LMWH for the pri-

mary prevention of VTE have recentlybeen more consistent than the trialsevaluating mortality. In the Pro -phylaxis of Thromboembolism DuringChemotherapy (PROTECHT) trial,1150 patients with metastatic or local-ly advanced solid organ cancer wererandomized in a double-blind fashion2:1 to a prophylaxis dose of nadroparin(3800 IU) subcutaneously once daily orplacebo for the duration of chemother-apy (maximum of 4 months).18 The pri-mary end point of venous or arterialthromboembolic events was reduced byalmost 50% with the use of nadroparincompared with placebo (2% vs 3.9%; P = .02). The benefit was provided with-

June 2011 I vol 4, no 4 23www.Theoncologypharmacist.com

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

Case Scenario 2A. K. is a 42-year-old woman diag-nosed with stage IIB breast cancer.She had a lumpectomy with surgi-cal axillary staging and has sincebeen receiving radiation andchemotherapy. Two months intotherapy, she presents to the hos pitalwith right lower-leg pain, swelling,and tenderness. A du plex ultra-sound is positive for proximal DVT.What should be the approach totreatment in this patient?

Case Scenario 3M. S. is a 65-year-old man withnewly diagnosed pancreatic cancer.The oncology team has decided to initiate treatment with gem -citabine and radiation. He has nohistory of thrombophilia or VTE,but the team wishes to discuss thepossible risks and benefits of pri-mary prevention in this patient.

TOP_June_v6 2011_TOP 6/17/11 12:29 PM



out a significant increase in major (0.7%vs 0%; P = .18) or minor (7.4% vs 7.9%)bleeding.18

In the CONKO-004 trial 312 chemo -therapy-naïve patients with advancedpancreatic cancer were randomized toobservation or enoxaparin 1 mg/kg sub-cutaneously once daily for 12 weeks fol-lowed by enoxaparin 40 mg subcuta-neously once daily.19 At the end of theinitial 12 weeks of therapy, the primaryend point of symptomatic VTE wasreduced by 87% with the use of enoxa-parin (1.3% vs 9.9%; P <.01). This pro-vides a number needed to treat of only 12patients to prevent one symptomaticVTE with the use of enoxaparin in thispatient population. The incidence ofbleeding was not significantly increasedduring this 12-week period with the useof enoxaparin (3.8% vs 2.6%; P = .6).After the median follow-up period of30 weeks, the lower dose of enoxaparinstill provided a significant reduction insymptomatic VTE (5% vs 14.5%; P<.05). The incidence in bleeding wasincreased in both groups comparedwith the 12-week assessment, but thedifference was still not statistically sig-nificant (6.3% vs 9.9%).19

Results of the Evaluation of AVE5026

in the Prevention of Venous Throm -boembolism in Cancer Patients Un -dergoing Chemotherapy (SAVE-ONCO) trial should be available bymid-2011. This is the largest trial to eval-uate the primary VTE prophylaxis inpatients with cancer. The SAVE-ONCOtrial is set to randomize 3200 patients tosemuloparin 20 mg subcutaneously oncedaily or placebo for 3 to 7 months.

Semuloparin is an ultra-LMWH withan anti-Xa to anti-IIa ratio of more than30:1 compared with most LMWHs thathave a ratio of 3:1 or 4:1.20 Semuloparinhas a half-life of 16 to 20 hours, whichallows for once-daily administration.Semuloparin has already demonstratedefficacy and safety in patients undergo-ing orthopedic and abdominal surgery.20

If the results of the SAVE-ONCO trialdemonstrate a significant benefit of pri-mary VTE prophylaxis, as seen in thePROTECHT and CONKO-004 trials, achange in the guidelines supporting pri-mary VTE prophylaxis in appropriatepatients with cancer may be warranted. �

References1. Gallus AS. Prevention of post-operative deep leg veinthrombosis in patients with cancer. Thromb Haemost.1997;78:126-132.2. Rahr HB, Sørensen JV. Venous thromboembolism

and cancer. Blood Coagul Fibrinolysis. 1992;3:451-460.3. Nicolaides A, Arcelus J, Belcaro G, et al. Pre ventionof venous thromboembolism. European ConsensusStatement, 1-5 November 1991, developed at OakleyCourt Hotel, Windsor, UK. Int Angiol. 1992;11:151-159.4. Geerts WH, Bergqvist D, Pineo GF, et al. Preventionof venous thromboembolism American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines(8th Edition). Chest. 2008;133(6 suppl):381S-453S.5. Efficacy and safety of enoxaparin versus unfractionat-ed heparin for prevention of deep vein thrombosis inelective cancer surgery: a double-blind randomized mul-ticenter trial with venographic assessment. ENOXA-CAN Study Group. Br J Surg. 1997;84:1099-1103.6. McLeod RS, Geerts WH, Sniderman KW, et al, forthe Canadian Colorectal Surgery DVT ProphylaxisTrial. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients under-going colorectal surgery. Results of the CanadianColorectal DVT Prophylaxis Trial: a randomized, dou-ble-blind trial. Ann Surg. 2001;233:438-444.7. Akl EA, Terrenato I, Barba M, et al. Low-molecular-weight heparin vs unfractionated heparin for periopera-tive thromboprophylaxis in patients with cancer: a sys-tematic review and meta-analysis. Arch Intern Med.2008;168:1261-1269.8. Bergqvist D, Agnelli G, Cohen AT, et al. Duration ofprophylaxis against venous thromboembolism withenoxaparin after surgery for cancer. N Engl J Med.2002;346:975-980.9. Kakkar VV, Balibrea JL, Martínez-González J, et al, forthe CANBESURE Study Group. Extended prophylaxiswith bemiparin for the prevention of venous throm-boembolism after abdominal or pelvic surgery for cancer:the CANBESURE randomized study. J Thromb Haemost.2010;8:1223-1229.10. Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, etal, for the FAME Investigators. Prolonged prophylaxiswith dalteparin to prevent late thromboembolic compli-cations in patients undergoing major abdominal surgery:a multicenter randomized open-label study. J ThrombHaemost. 2006;4:2384-2390.

11. Hull RD, Pineo GF, Brant RF, et al, for the LITETrial Investigators. Long-term low-molecular-weightheparin versus usual care in proximal-vein thrombosispatients with cancer. Am J Med. 2006;119:1062-1072.12. Meyer G, Marjanovic Z, Valcke J, et al. Comparisonof low-molecular-weight heparin and warfarin for thesecondary prevention of venous thromboembolism inpatients with cancer: a randomized controlled study.Arch Intern Med. 2002;162:1729-1735.13. Lee AYY, Levine MN, Baker RI, et al, for the CLOTInvestigators. Low-molecular-weight heparin versus acoumarin for the prevention of recurrent venous throm-boembolism in patients with cancer. N Engl J Med.2003;349:146-153.14. Lee AYY, Rickles FR, Julian JA, et al. Randomizedcomparison of low-molecular-weight heparin andcoumarin derivatives on the survival of patients withcancer and venous thromboembolism. J Clin Oncol.2005;23:2123-2129.15. Klerk CPW, Smorenburg SM, Otten H-M, et al. Theeffect of low-molecular-weight heparin on survival inpatients with advanced malignancy. J Clin Oncol.2005;23:2130-2135.16. Buller HR, Prins MH. The effect of the low-molec-ular-weight heparin nadroparin on the survival inpatients with cancer: a randomized trial (for theINPACT Investigators). J Thromb Haemost. 2009;7(suppl 2):1203. Abstract LB-MO-004.17. Kakkar AK, Levine MN, Kadziola Z, et al. Low-mol-ecular-weight heparin, therapy with dalteparin, and sur-vival in advanced cancer: the Fragmin AdvancedMalignancy Outcome Study (FAMOUS). J Clin Oncol.2004;22:1944-1948.18. Agnelli G, Gussoni G, Bianchini C, et al, for thePROTECHT Investigators. Nadroparin for the preven-tion of thromboembolic events in ambulatory patientswith metastatic or locally advanced solid cancer receiv-ing chemotherapy: a randomised, placebo-controlled,double-blind study. Lancet Oncol. 2009;10:943-949.19. Riess HB, Pelzer U, Opitz B, et al. A prospective,randomized trial of chemotherapy with and without thelow molecular weight heparin (LMWH) enoxaparin inadvanced pancreatic cancer patients. J Thromb Haemost.2009;7(suppl 2):1203. Abstract LB-MO-003.20. Eikelboom JW, Weitz JI. New anticoagulants.Circulation. 2010;121:1523-1532.

And although they might not know it,the patients benefit too. “Those of us inoncology sleep a whole lot better at nightknowing that whatever is infused in thepatient is the cleanest possible productthat we can give,” Vanessa Bramble,director of oncology services, tells TheOncology Pharmacist.

Karen Meyer, a pharmacist at thefacility, seconds that opinion: “Knowingthat we have aseptic technique and asterile area in which to work makes ahuge difference. Like Vanessa said, weknow that we produce the best productthat we can.”

Each day, Monday through Friday, thepharmacy staffs 2 pharmacists and 2technicians who, each week, preparebetween 80 and 100 doses of chemo ther-apy for outpatients and an additional 15doses for inpatients at the Johnson CityMedical Center, across the street fromthe Regional Cancer Center inNortheast Ten nessee. The facility has 2chemotherapy hoods in its negative-pressure room and 1 laminar horizontalflow hood for non chemo therapy medica-tion preparation in its buffer room,according to Bramble.

Setting Up the FacilityWhen building the new cancer centerparent organization Mountain States

Health Alliance showed its commitmentto patient-centered care and nationalquality standards by making a largefinancial investment in the new pharma-cy, says Bramble. “We knew right at theinception of the project—building thededicated outpatient center—that wewanted to be USP <797>-compliant,”says Bramble, noting that pharmacy staffwere involved in the design. In addition,

an outside consultant who specializes inpharmacy design was engaged to doarchitectural drawings for the facility.

Using the footprint of the space, theconsultant worked with onsite pharmacystaff to ensure that the finished facilitywould be optimized for workflow process-es while meeting all safe-handling crite-ria. In addition, separate air handlers andback-up generators were installed.

Enhancing CareThe hospital’s electronic medical re -cord system made the trip to the newfacility with the cancer care team,smoothing the transition. And with theteam “working much closer together, wehave an opportunity to work on review-ing order sets, protocols, and the like,”says Bramble. “We’re so blessed to havethe medical oncologists, nurses, phar-macists, and the entire team to conferwith one another; communication hasbeen enhanced.”

In addition, the new space allows for aclassroom area within the pharmacy toaccommodate residents from Bill GattonCollege of Pharmacy, part of EastTennessee State University. “It has really added to our program. Althoughthe students are solely dedicated to theGatton School of Pharmacy, they addthat other layer to our physicians and ournurses and everybody—another personto call and discuss cases with amongother things,” says Bramble.

The new center not only allows for arange of multidisciplinary services in onelocation, but also has led to commenda-tion from the American College ofSurgeons’ Commission on Cancer,which noted in the accreditation processthe facility’s range of state-of-the-artservices and equipment. �

New Oncology Pharmacy Provides... Continued from cover

The technician shows the pharmacist that it is the right drug in the rightamount.

Cancer Center Profile

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THANK YOU FORMAKING US#1Source: © Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)

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Supportive Care

HOLLYWOOD, FL—Patients receivingchemotherapy are at risk for reactivation ofthe hepatitis B virus (HBV), and this canhave a significant negative impact on out-comes, including death from liver failure.According to Emmy Ludwig, MD, ofMemorial Sloan-Kettering Cancer Center(MSKCC), New York, one-third of theworld has been exposed to HBV, “makingit an enormous problem.”

Fortunately, HBV reactivation can beprevented with the prophylactic use ofeffective antiviral agents, for which recom-mendations were presented by Ludwig atthe 2011 National Comp rehensive CancerNetwork (NCCN) annual meeting.

Although reactivation can occurspontaneously, it typically occurs as aresult of immunosuppressive therapies incancer, autoimmune disease, and organtransplantation. The risk does not endwhen chemotherapy is completed, butpersists for at least 6 months, possiblylonger in stem cell transplant patientsand in those receiving rituximab. Therisk of liver failure from HBV reactiva-

tion has been linked to the use of ritux-imab—precipitating a black-box warningfor these patients.

Recommendations for Screeningand ProphylaxisAntiviral prophylaxis can preventchemotherapy-related HBV reactivation.A systematic review of 14 studies (LoombaR, et al. Ann Intern Med. 2008;148:519-528) evaluated the use of lamivudine inpatients with chemotherapy who testedpositive for the hepatitis B surface antigen(HBsAg). Of 108 patients who receivedlamivudine prophylactically, none devel-oped HBV reactivation or HBV-relatedliver failure. Other studies made similarfindings among patients with cancer.

Although lamivudine is effective, mostpatients will become resistant to lamivu-dine at 5 years, Ludwig noted. “We do notrecommend lamivudine because of thehigh resistance rate,” she said.

Newer agents such as entecavir areextremely effective, have less propensityfor resistance, and are less likely to inter-

act with other medications. Entecavir,therefore, is the preferred antiviral atMSKCC, she said.

In March 2009, MSKCC initiatedHBV screening of all new patients receiv-ing immunosuppressive therapy. Among4065 patients screened, almost 10% test-ed positive for either the HBsAg or thehepatitis B core antibody (HBcAb). Allof these patients were treated with antivi-ral prophylaxis, and none experiencedHBV reactivation.

The potential benefits have led manygroups to endorse HBV screening for pa -tients receiving immunosuppressive thera-py, including the Am erican, Euro pean, andAsian-Pacific Associations for the Study ofLiver Diseases; the Infectious DiseasesSociety of America; the American Gastro -enterology Association; the Am ericanCollege of Rheumatology; and the Centersfor Disease Control and Pre vention.

The NCCN suggests that antiviraltherapy “be strongly considered in patientswith acute HBV infection undergoinghematopoietic stem cell transplant or

other intensive immunosuppression,”although this is based on limited data, thegroup acknowledged. Also in its ClinicalPractice Guidelines for Non-Hodgkin’sLymphomas (V.2.2011), the NCCN rec-ommends HBsAg and HBcAb screeningfor all patients receiving rituximab.

But such recommendations are notuniversal. Routine screening is not rec-ommended by the American Society ofClinical Oncology, which deems the evi-dence to be “insufficient to determine thenet benefits and harms of routine screen-ing for chronic HBV infection in individ-uals with cancer who are about to receivecytotoxic or immunosuppressive therapyor who are already receiving therapy”(Artz AS, et al. J Clin Oncol. 2010;28:3199-3202).

Ludwig said that despite those reserva-tions, she personally recommends universalscreening. “The data, honestly, are imper-fect, and there are no large, randomized tri-als. However, if I had hepatitis B and weregetting chemotherapy, I would put myselfon an antiviral,” she commented. �

Hepatitis B Screening and ChemotherapyProphylactic Use of Antivirals Can Prevent HBV ReactivationBy Audrey Andrews

HOLLYWOOD, FL—The evidencebacking the use of myeloid growth fac-tors in patients at high risk for febrileneutropenia is solid, according to JeffreyCrawford, MD, of Duke Cancer In -stitute, Durham, North Carolina.

Myeloid growth factors are the pri-mary means of preventing chemothera-py-induced neutropenia. This often leadsto febrile neutropenia, which can befatal in 10% of patients, according to adatabase of more than 40,000 individu-als. Concerns recently have been raised,however, that their use is associated withmyelodysplastic syndrome (MDS) andacute myeloid leukemia (AML).

As chairman of the National Com - p rehensive Cancer Network (NCCN)’sMyeloid Growth Factors Panel, Crawfordreassured clinicians that benefits substan-tially outweigh any risks associated withthe granulocyte colony-stimulating factors(G-CSFs) filgrastim and pegfilgrastim.Including a discussion of MDS/AML asso-ciated with the use of G-CSFs was the onlymajor change to the guidelines in 2011, henoted during a presentation at the 2011NCCN annual meeting.

Timing of Growth Factor UseIn a 2008 study conducted by Crawford’sgroup, febrile neutropenia developedduring the first 3 cycles in 11% ofpatients. Because most febrile neutrope-

nia events occur during the first cycle ofchemotherapy, clinicians should initiategrowth factors from the beginning oftreatment, and continue them in subse-quent treatments, in any patient with a20% or higher risk.

“Our window for starting prophylaxis isnot big. We should start 24 to 72 hoursafter chemotherapy is completed,” henoted. When administration is delayed,the duration of grade 4 neutropenia may belonger and the risk of febrile neutropeniagreater, Crawford pointed out. “The datasuggest that what we do in the very firstcycle of treatment makes a big difference.”

Some clinicians also try to lowerfebrile neutropenia risk by reducing thedose of chemotherapy, but this is notadvised because it diminishes the sur-vival benefit obtained from full-dosechemotherapy, he explained.

Similarly, prophylactic antibiotics canadd to the protective benefit of G-CSFs inselected settings but should not be usedinstead of growth factors. “The routine

application of prophylactic antibioticsshould be limited to high-risk inpatientswith hematologic malignancies and stemcell transplantation,” he said.

Is Pegfilgrastim Better thanFilgrastim?Is the newer, and costlier, G-CSF peg fil grastim superior to filgrastim?Pegfilgrastim has a unique neutrophil-regulated clearance and, because of highsustained serum levels, is a longer-lastingdrug, although clinical efficacy appearsto be similar.

Although the clinical outcomes forthe single dose of pegfilgrastim and thedaily dose of filgrastim were compara-ble in a 2007 meta-analysis (KudererNM, et al. J Clin Oncol. 2007;25:3158-3167), the impact of pegfilgrastim onoverall survival and disease-free sur-vival has been apparent in all majorprognostic subgroups studied to date,Crawford said.

Sargramostim is an alternative agentthat is associated with more toxicity andhas therefore received only a category 2Brecommendation in the NCCN ClinicalPractice Guidelines for Myeloid GrowthFactors (V.1.2011).

MDS/AML Risk Not a MajorConcernIt does appear that use of a G-CSF is

associated with an increased risk ofMDS/AML, Crawford acknowledged.The risk was elevated in a recent meta-analysis, regardless of tumor type ortreatment regimen (Lyman GH, et al. JClin Oncol. 2010;28:2914-2924); howev-er, all-cause mortality was significantlylower among patients who receivedgrowth factor support.

“There was an increase in MDS andleukemia, but the all-cause mortalityanalysis showed a significant reductionin risk. Leukemia risk was 0.005%, butthe survival benefit was 5%. Thisamounts to an almost 10-fold differencein probabilities,” he said. “There clearlyis an overall net benefit of G-CSF.”

Who Should Receive Prophylaxis?Primary G-CSF prophylaxis should bedetermined by the chemotherapy regimen,the NCCN guidelines, and treatmentintent (curative vs palliative). Clinic iansshould then determine whether thepatient’s risk is high (>20%), intermediate(10%-20%), or low (<10%).

High-risk patients, whose risk is ele-vated 5-fold over low-risk patients,should receive growth factors, regardlessof treatment intent; low-risk patientsshould not receive them; and intermedi-ate-risk patients should be considered for treatment based on risk factors,Crawford said. � —AA

Myeloid Growth Factors for Prevention of NeutropeniaNCCN Helps Guide Optimal Use

See also page 12.

Primary G-CSF prophylaxisshould be determined by the chemotherapyregimen.

TOP_June_v6 2011_TOP 6/17/11 12:29 PM

�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

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Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

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Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

This activity is jointly sponsored by Global Education Groupand Medical Learning Institute, Inc.

Coordination for this activity provided by Center of Excellence Media, LLC.

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This activity is supported by educational grant from Cephalon Oncology,Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

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At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community.

A commitment to patients — We created Genentech BioOncology™

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june 2011, vol 4, no 4

Documents

oncology clinicalspecialist

pm page

cancer care team

bladder cancer

drug response

cancer center profilecontinued

supportive care agents

johns hopkins hospital