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HEMATOLOGYONCOLOGYPHARMACY™

JOURNAL OFVOL 1 I NO 4

DECEMBER 2011

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

©2011 Green Hill Healthcare Communications, LLCwww.JHOPonline.com

CLINICAL CONTROVERSIESBevacizumab in Metastatic Breast Cancer: Ready for Prime Time? CON: Katherine Mandock, PharmD, BCPS;

Scott A. Soefje, PharmD, BCOPPRO: Val R. Adams, PharmD, BCOP, FCCP

REVIEW ARTICLESCurrent Practice in the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in AdultsLisa K. Lohr, PharmD, BCOP, BCPS

The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous LeukemiaNatalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

From the LiteratureConcise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP

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3www.JHOPonline.com l Journal of Hematology Oncology Pharmacy Vol 1, No 4 l December 2011

EDITORIAL BOARD

CLINICAL CONTROVERSIESChristopher Fausel, PharmD, BCPS, BCOP Clinical DirectorOncology Pharmacy ServicesIndiana University Simon Cancer CenterIndianapolis, IN

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of PharmacyComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

ORIGINAL RESEARCH R. Donald Harvey, PharmD, FCCP, BCPS, BCOPAssistant Professor, Hematology/Medical Oncology Department of Hematology/Medical OncologyDirector, Phase 1 UnitWinship Cancer InstituteEmory University, Atlanta, GA

REVIEW ARTICLESScott Soefje, PharmD, BCOPAssociate Director, Oncology PharmacySmilow Cancer Hospital at Yale New HavenYale New Haven HospitalNew Haven, CT

FROM THE LITERATURERobert J. Ignoffo, PharmD, FASHP, FCSHPProfessor of Pharmacy, College of PharmacyTouro University–California Mare Island Vallejo, CA

Patrick J. Medina, PharmD, BCOPAssociate ProfessorDepartment of PharmacyUniversity of Oklahoma College of PharmacyOklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCPAssociate Professor, Pharmacy Program Director, PGY2 Specialty ResidencyHematology/OncologyUniversity of Kentucky College of PharmacyLexington, KY

SECTION EDITORS

CO-EDITORS-IN-CHIEF

Joseph Bubalo, PharmD, BCPS, BCOPAssistant Professor of MedicineOncology Clinical Specialist and Oncology LeadOHSU Hospital and ClinicsPortland, OR

Sandra Cueller, PharmD, BCOPDirectorOncology Specialty ResidencyUniversity of Illinois at Chicago Medical CenterChicago, IL

Sachin Shah, PharmD, BCOPAssociate ProfessorTexas Tech University Health Sciences CenterDallas, TX

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy PracticeSamford University McWhorter School of PharmacyBirmingham, AL

John M. Valgus, PharmD, BCOPHematology/Oncology Senior Clinical PharmacySpecialistUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Daisy Yang, PharmD, BCOP Clinical Pharmacy SpecialistUniversity of Texas M. D. Anderson Cancer CenterHouston, TX

EDITORS-AT-LARGE

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4 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com December 2011 l Vol 1, No 4

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PublisherJohn W. Hennessy

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Editorial DirectorDalia Buffery

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Associate EditorsBrett KaplanLara J. Lorton

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TABLE OF CONTENTS

DECEMBER 2011 VOLUME 1, NUMBER 4

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive,Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 by Green Hill Healthcare Communications LLC. All rights reserved. Journal ofHematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Com munications, LLC. No part of this publication may be reproduced or transmitted in any form or by anymeans now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher.Printed in the United States of America.

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CLINICAL CONTROVERSIES 6 Bevacizumab in Metastatic Breast Cancer: Ready for Prime Time?

CON: Katherine Mandock, PharmD, BCPS; Scott A. Soefje, PharmD, BCOPPRO: Val R. Adams, PharmD, BCOP, FCCP

REVIEW ARTICLES13 Current Practice in the Prevention and Treatment of Chemotherapy-Induced

Nausea and Vomiting in AdultsLisa K. Lohr, PharmD, BCOP, BCPS

25 The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous LeukemiaNatalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

FROM THE LITERATURE36 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Robert J. Ignoffo, PharmD, FASHP, FCSHP

PUBLISHING STAFF

MISSION STATEMENTThe Journal of Hematology Oncology Pharm -acy is an independent, peer-reviewed jour-nal founded in 2011 to provide hematologyand oncology pharmacy practitioners andother healthcare professionals with high-quality peer-reviewed information rele-vant to hematologic and oncologic condi-tions to help them optimize drug therapyfor patients.

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

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CLINICAL CONTROVERSIES


Controversy has developed over the label indica-tions for bevacizumab in metastatic breast cancer(MBC). The US Food and Drug Administration

(FDA) had granted accelerated approval for bevacizumabfor the treatment of MBC based on clinical trials thatdemonstrated a progression-free survival (PFS) advantage.This controversy begins when the postapproval trialsrequired with the FDA approval failed to demonstrate anoverall survival (OS) advantage in addition to the PFSadvantage. Subsequently, the Oncology Drug AdvisoryCommittee (ODAC) recommended, and ultimately theFDA issued its decision, to remove bevacizumab’s currentlabeled indication for MBC.1

In this debate we take the side that supports theFDA’s final decision to remove that indication. Our posi-tion is based on the arguments that reflect the regulato-ry, efficacy, safety, and economic perspectives. We willdemonstrate that this indication does not meet the stan-dard required for labeled indications, that the efficacy forthe indication does not show a clinical benefit, thatthere are serious safety concerns, and that the economicimpact is too great to justify the drug’s approval.

The FDA Modernization Act of 1997 permitted theFDA to approve the marketing of drugs “upon a deter-mination that the product has an effect on a clinicalendpoint or on a surrogate endpoint that is reasonablylikely to predict clinical benefit.”2 This is exactly whathas happened with bevacizumab.

However, the FDA’s Guidance for Industry also states,

“Where an accelerated approval is based upon a surro-gate endpoint or on an effect on a clinical endpointother than survival or irreversible morbidity, postmar-keting studies are ordinarily required ‘to verify anddescribe the drug’s clinical benefit and to resolve remain-ing uncertainty as to the relation of the surrogate end-point upon which approval was based to clinical benefit,or the observed clinical benefit to ultimate outcome (57FR 58942, December 11, 1992).’”3 This is the focus ofthe regulatory argument.

The FDA has not recognized PFS as an end point thatwill grant approval for first-line indications in oncology.PFS has not translated to OS in any clinical trial inMBC and is, therefore, not considered a surrogate forsurvival. The burden is then on the drug manufacturer todemonstrate a clinical benefit that meets the criteria forapproval, for example, OS, improved quality of life, oranother end point that the FDA has recognized.

One other such example in oncology is gefitinib,which was approved on a surrogate end point and wasthen pulled from the market when the primary end pointwas not met. Bevacizumab has not met the requirementsfor full approval for an MBC indication; therefore, theFDA’s decision was the correct one.

The results of the Eastern Cooperative OncologyGroup (ECOG) E2100 trial formed the basis for theFDA’s decision to grant bevacizumab conditional accel-erated approval for the first-line treatment of patientswith MBC. The ECOG E2100 study demonstrated analmost 2-fold increase in response rate and time to pro-gression, but it failed to show OS benefit when beva-cizumab was added to weekly paclitaxel therapy.4,5

Two additional phase 3 trials were designed to validatethe results from the E2100 study, while evaluating the useof bevacizumab in combination with other approvedchemotherapy in the first-line treatment of MBC.6,7

The AVADO (Avastin and Docetaxel) trial exam-ined the combination of docetaxel and bevacizumab

Dr Mandock is PGY-2 Oncology Resident, Smilow CancerHospital at Yale New Haven, and Dr Soefje is AssociateDirector, Oncology Pharmacy Services, Smilow CancerHospital at Yale New Haven, CT, and Section Editor ofJHOP; Dr Adams is Associate Professor, Pharmacy ProgramDirector, PGY2 Specialty Residency, Hematology Oncology,University of Kentucky College of Pharmacy, Lexington, andCo-Editor-in-Chief of JHOP.

Bevacizumab in Metastatic BreastCancer: Ready for Prime Time?CON: By Katherine Mandock, PharmD, BCPS; Scott A. Soefje, PharmD, BCOP

PRO: By Val R. Adams, PharmD, BCOP, FCCP

THE CASE AGAINST APPROVAL

The goal of this section is to feature current clinical controversies by presenting both sides of the problem. Readers are invited to submit articles that present the pro and

con of a relevant problem, as featured in the present article.

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Bevacizumab in Metastatic Breast Cancer

7www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 1, No 4 l December 2011

administered every 3 weeks6; RIBBON (Regimens inBevacizumab for Breast Oncology)-1 assessed cape -citabine, a taxane-based regimen (docetaxel or nab-paclitaxel) administered every 3 weeks, and an anthra-cycline-containing regimen administered alone or incombination with bevacizumab.7

As in the case of the E2100 trial, both AVADO andRIBBON-1 failed to demonstrate a significant differencein OS rates. Both trials did demonstrate statistically sig-nificant improvements in PFS and in the response rate;however, they failed to confirm the magnitude of thePFS benefit observed in the E2100 trial (Table).Statistical significance does not always correspond toclinical significance, and the clinical impact of addingbevacizumab to a regimen is unconvincing at best, inview of the incremental improvements in PFS observedin the confirmatory trials.6,7

The concern for the clinical benefit of bevacizumab asa first-line agent in MBC is multifactorial but hinges on 3major issues: (1) the disparity of benefit observed betweenthe E2100 trial and other phase 3 trials, (2) the suitabilityof PFS as a surrogate end point for OS, and (3) the lack ofa clearly defined patient population that is most likely tobenefit from the addition of bevacizumab to the treatmentregimen. The disparity in the magnitude of improvementin PFS between E2100 and other phase 3 studies is mostlikely reflective of the choice of chemotherapy.

The E2100 trial evaluated bevacizumab in combina-tion with once-weekly paclitaxel therapy. Preclinicalevidence suggests an antiangiogenic activity that is asso-ciated with weekly paclitaxel therapy, which, whencombined with bevacizumab, may have acted synergisti-cally to result in the greater duration of PFS observed inE2100. Therefore, the robust benefit in PFS that wasseen with E2100 was most likely derived from fraction-ating the dose of paclitaxel weekly over 3 weeks ratherthan from the addition of bevacizumab to the regimen.8

In addition, all 3 studies used PFS as the primary effi-cacy end point.6-8 As noted earlier, PFS has not beendemonstrated as a good surrogate for OS in solid tumors,including MBC.9

Finally, the collective randomized controlled trialshave failed to identify a patient population that wouldderive the greatest potential benefit from the addition ofbevacizumab to chemotherapy. Heavily pretreatedpatients are not likely to experience significant benefitswith the addition of bevacizumab, as seen by the short-er PFS among the capecitabine-receiving cohort inRIBBON-1 versus patients who received taxane or an -thracycline chemotherapy.7

An earlier trial comparing the efficacy of capecitabinewith or without bevacizumab showed no differences inOS or PFS, confirming that bevacizumab is not likely to

have a significant survival impact in patients with MBCwho have received extensive treatment.10

In addition, data from RIBBON-2 suggest that insome chemotherapy cohorts, combinations with beva-cizumab may have a negative impact on PFS.11 In a sub-group analysis of second-line agents, the vinorelbinecohort demonstrated shorter PFS and OS comparedwith the placebo arm. These results must be interpretedwith caution, however, because they are based on a smallsample size that included a greater percentage of patientswith poor prognostic factors.11

In addition to questions regarding its clinical signifi-cance, the combination of bevacizumab and chemother-apy raises some serious safety concerns. After convergentsafety results from the phase 3 trials, the ATHENA(Avastin Therapy for Advanced Breast Cancer) trial wasconducted to further assess the safety of bevacizumabcombined with first-line chemotherapy.12 The most fre-quent grade 3 or more toxicities in ATHENA were neu-tropenia (5.4%), hypertension (4.4%), thromboem-bolism (3.2%), proteinuria (1.7%), and bleeding (1.4%),which confirmed the previously established adverseevents (AEs) associated with bevacizumab therapy.12

RIBBON-1 demonstrated that hypertension and pro-teinuria were consistently increased in the bevacizumabarms, regardless of the chemotherapy administered. Inaddition, the incidence of bleeding and febrile neutro -penia was >5% in patients receiving taxane-containingregimens.7 Disconcertingly, it appears that the more seri-ous AEs occur more frequently in the population ofpatients most likely to benefit from bevacizumab’s favor-able effects on PFS, namely, patients receiving weeklypaclitaxel therapy.7

With no evidence of improved survival in phase 3clinical trials, bevacizumab has failed to meet the con-ditions set under the current FDA regulatory standardsfor approval of first-line treatment for MBC, and it isassociated with potentially serious AEs. Until furtherstudies confirm an OS benefit or clinically and statisti-cally significant improvements in PFS in addition to anideal target population, bevacizumab should not beconsidered as a first-line agent in combination withchemotherapy for MBC.

With no evidence of improved survival inphase 3 clinical trials, bevacizumab has failedto meet the conditions set under the currentFDA regulatory standards for approval offirst-line treatment for MBC, and it isassociated with potentially serious AEs.




From an economics perspective, the use of beva-cizumab in MBC is not cost-effective. The estimatedcost for 1 year of life saved with a course of bevacizumabis $496,000.13 Compared with conventional valuesbetween $50,000 and $125,000 for other therapies, thisestimated cost of bevacizumab is several times higher.The cost of bevacizumab is approximately $62,000 in theclinical trials.13 The cost of the drug does not seem out ofline with the cost of current cancer therapies; however,the benefit—in this case, years of life saved—is so smallthat the cost-effective amount, which is cost divided byyears of life saved, becomes very large and outside the

range that is generally acceptable. In these times of medical economic scarcity, the con-

tinued approval of a drug that shows marginal benefit isnot in society’s best interest. If asked to pay out of pock-et, how many patients would accept bevacizumab, know-ing its high cost and the minimal additional life gained?We have demonstrated that bevacizumab has not

overcome the regulatory or efficacy hurdles required forapproval of a first-line agent for MBC. Combined withthe safety concerns and the tremendous associated cost,the FDA’s decision to pull the indication for the drug inthe treatment of MBC is acceptable.

Based on the scientific data and the regulatoryrequests, it is clear that the MBC indicationshould remain on the label of bevacizumab. The

rationale for continued approval is based on the argu-ments related to the 4 areas cited earlier: regulatory, effi-cacy, safety, and economic.

As noted before, the Modernization Act permits theFDA to approve a drug based on a surrogate end pointthat is reasonably likely to predict clinical benefit.2 Thisis the way the first-line indication for paclitaxel andbevacizumab for MBC was approved. The pivotal studyfor the accelerated approval for bevacizumab is the

Table Results of Randomized Controlled Trials of Chemotherapy with/without Bevacizumab in the Treatment of MetastaticBreast Cancer

Chemotherapy without bevacizumab

Chemotherapy withbevacizumab rate

Study/first- orsecond-line therapy

Chemotherapy ± bevacizumab

PFS HR (95% CI)

Median PFS, mo

Response rate, %

Median OS, mo

Median PFS, mo

Response rate, %

Median OS, mo

Difference in PFS, mo

ECOG E2100 (2007, 2009)first-linea

Paclitaxel weekly

0.60 (0.51-0.70) 5.9 21.2 25.2 11.8 36.9 26.7 5.9

AVADO (2010)first-lineb

Docetaxel 0.67 (0.54-0.83) 8.1 46.4 31.9 10.0 64.1 30.2 1.9

RIBBON-1(2011) first-linec

Capecitabine Taxane/anthracycline

0.69 (0.56-0.84)0.64 (0.52-0.80)

5.78.2/7.9

23.6 37.9

— 8.69.2/9.2

35.451.3

— 2.91.0/1.3

RIBBON-2 (2011) second-lined

Capecitabine Taxane Gemcitabine Vinorelbine

0.73 (0.49-1.08)0.64 (0.49-0.84)0.90 (0.61-1.32)1.42 (0.78-2.59)

4.15.85.57.0

35.848.732.926.1

16.4 6.98.06.05.7

15.438.315.052.6

18.0 2.82.20.5–1.3

aMedian PFS, P <.001; OS, P = .16.bStratified analysis; median PFS, P <.001; OS, P value not significant.cMedian PFS, capecitabine cohort, P <.001; median PFS, taxane/anthracycline cohort, P <.001; OS, capecitabine cohort, HR for OS, 0.85 (95% CI, 0.63-1.14), P = .27; OS, taxane/anthracycline cohort, HR for OS, 1.03 (95% CI, 0.77-1.38), P = .83.dDifferences in PFS benefit between the taxane, capecitabine, and gemcitabine cohorts were not statistically significant (P = .284); however, differences in PFS between the vinorelbine cohort and the other 3 cohorts were significant (P = .018); OS stratified HR, 0.90 (95% CI, 0.71-1.14); P = .374. AVADO indicates Avastin and Docetaxel; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RIBBON, Regimens in Bevacizumab for Breast Oncology.Sources: References 4-7, 10.

THE CASE FOR CONTINUED APPROVAL




ECOG E2100 trial.4 This trial randomized 722 patientsto paclitaxel alone or to paclitaxel plus bevacizumab.The trial was designed to measure PFS as the primaryend point; it required 546 events (in 685 patients) todetect a 2-month improvement, with a power of 85%.The improvement in PFS was impressive—5.8 monthswithout paclitaxel alone versus 11.3 months for pacli-taxel plus bevacizumab—and led to the FDA’s accelerat-ed approval. The secondary end points were also prom-ising, an improved response rate of 37% versus 21% (P <.001), and improved 1-year survival rate of 81% ver-sus 73% (P = .01), respectively.4 As is the case with allaccelerated approvals, the FDA requires ≥1 postmarket-ing studies to confirm or refute the perceived benefitthat had led to the accelerated approval.3Because of the business/financial risk involved with

performing large trials that may be rejected by the FDA,the process proceeds with planning meetings thatinclude the FDA, to ensure that the required end pointsand trial design are clearly defined and deemed accept-able. Accordingly, during a meeting between the manu-facturer (Genentech) and the FDA (a type B meeting)on February 2, 2009, the “FDA confirmed that the basisfor conversion to full approval will be demonstratedimprovement in progression-free survival and evidencethat survival is not impaired.”14 This is the key focus ofthe regulatory argument. With this confirmation, Genentech carried out the

RIBBON-1 and the AVADO trials, which were designedto demonstrate (1) a benefit in PFS, and (2) no detri-ment to OS. The postmarketing studies presented tothe FDA included the E2100 (N = 722), RIBBON-1(N = 1237), and AVADO (N = 736) trials, whichtotaled >2500 patients randomized and analyzed in thesetrials.4-7,10 The combined data with 24-month updateddata from AVADO showed median 1.9 months andmean 2.5 months of improvement in PFS, which werestatistically significant (hazard ratio, 0.67). This clearlymeets the first requirement of the FDA.14 The 1-year OSwas 77% and 82%, respectively, with a projected medi-an survival of 26.4 and 26.7 months, respectively, withchemotherapy alone or with bevacizumab. Although notsuperior, this clearly demonstrates that survival was notimpaired by treatment with bevacizumab.14 The primary concern of ODAC and of the FDA that

led to the removal of the approval stemmed from the sur-vival data (ie, evidence that patients lived longer) andthe quality-of-life data.15 This is unfortunate, becausethe trials were neither designed nor powered to answerthe survival question. With the first evaluation of theE2100 study, one can substitute the survival numbers forevent rate to see that the study is underpowered toanswer the OS question.4,5 The trial’s statistical design

stated the need for 546 PFS events in 685 patients toreach the 2-month threshold, with a power of 85%;however, only 483 deaths occurred among the 722patients, with a projected survival difference of 1.7months.4 This is close to the unwritten 2-month survivaladvantage that will reset the standard for diseases such aslung cancer.16,17 One of the reasons it is unfortunate that the E2100

trial was not designed or powered to answer the OS ques-tion is that the study was done before the drug’sapproval, which minimized the use of second-line beva-cizumab. The RIBBON-1 study was designed with 2cohorts: (1) a capecitabine ± bevacizumab cohort, and(2) a taxane/anthracycline ± bevacizumab cohort.7 Thecapecitabine cohort required 405 PFS events for 600patients to detect a 2-month survival difference; again,substituting deaths for PFS events makes it easy to seethat the study was underpowered; only 191 deaths

occurred among the 605 patients.7 The crossover factorfurther confounds the OS data: 85% of the placebo-receiving patients were given ≥1 subsequent chemo -therapy regimens, and >50% of those patients receivedchemotherapy plus bevacizumab.7 Therefore, comparingOS in this study would actually compare the timing (firstline vs second line) rather than the true impact of beva-cizumab versus no bevacizumab. In the end, it is clear that the postmarketing studies

conducted to facilitate the conversion of the initialaccelerated approval to the final regular FDA approvalwere not designed, powered, or intended to answer theimpact on OS. Instead, they were designed, carried out,and proved improved PFS, without deleterious effects onsurvival, which had been the FDA’s agreed upon endpoint for conversion to regular approval.14 From a regu-latory perspective, therefore, bevacizumab clearly shouldbe approved for breast cancer, which would require theFDA to honor its commitment and advice regardingrequired regulatory end points. The key question in this debate relates to efficacy—Is

a 2.5-month improvement in PFS and increased

It is clear that the postmarketing studiesconducted to facilitate the conversion of theinitial accelerated approval to the finalregular FDA approval were not designed,powered, or intended to answer the impacton OS. Instead, they were designed, carriedout, and proved improved PFS, withoutdeleterious effects on survival.




response rate sufficient for the agent to be used (offlabel) as first-line treatment for MBC? To answer thisquestion in a more objective fashion, we need to consid-er other precedence in MBC, such as the addition ofcapecitabine to docetaxel (compared with docetaxelalone). The pivotal study for approval of this combina-tion regimen came from a single study with a combined511 patients in the 2 arms (255/256).18

The results from this trial are very similar to the dataseen with bevacizumab plus chemotherapy: a 58-dayincrease in PFS, an increase from 22% to 32% inresponse rate, and a 90-day increased survival. Thechemotherapy plus bevacizumab improvements in PFSand response rate are numerically better than these data.Although we do not know the true effect on survival (asdiscussed above), if we estimate the impact to be approx-imately 2 months, this would seem to reach the usualsurvival threshold.

Consequently, I would propose that we could com-pare the efficacy of bevacizumab and chemotherapy tothe capecitabine plus docetaxel regimen. Because theutilization of capecitabine and docetaxel varies, thisperhaps could be used as a litmus test: if you use doc-etaxel and capecitabine, then you should considerusing bevacizumab plus chemotherapy; if you do notbelieve that adding capecitabine to docetaxel providesenough benefit to warrant using this combination, youwould likely not consider using bevacizumab pluschemotherapy.

In summary, I would argue that the threshold for effi-cacy has been determined by other regimens (primarilyby capecitabine added to docetaxel), and that beva-cizumab added to chemotherapy appears to provide verysimilar results and should therefore be available for use inthis setting.

The other side of efficacy is the toxicity level, or safe-ty, that is required to ensure a net benefit. It is clear thatefficacy trumps toxicity; this is most clearly demonstrat-ed with allogeneic hematopoietic stem-cell transplant(SCT) for acute myeloid leukemia (AML).19 However,when the efficacy is more marginal than the results withallogeneic SCT in AML, safety concerns become moreimportantly and appropriately scrutinized.

The pooled data presented to the FDA for beva-cizumab clearly show increased overall rates of grade 3and 4 toxicity with the addition of bevacizumab com-pared with chemotherapy alone (23% vs 36%, respec-tively).14 The toxicities in the combination group wereknown, expected, and consistent with adding beva-cizumab to chemotherapy in other settings. The mostcommon safety issues included increased rates of hyper-tension and proteinuria (approximately 11% increasedrate with bevacizumab), as well as an increase in arterial

thromboembolism and bleeding (approximately 1%higher rate for each).14

Again, it is important to compare this to previousacceptable evidence, such as in the capecitabine anddocetaxel regimen in MBC. The pivotal study forcapecitabine shows that the combination of these agentsled to at least 1 grade 3 toxicity in 76.5% of patientscompared with 57.6% of patients with docetaxel alone.18Although the toxicity level is different betweencapecitabine and bevacizumab, adding capecitabine todocetaxel increased the percentage of patients who hadat least 1 grade 3 AE more than the addition of beva-cizumab to chemotherapy (19% vs 13%, respectively).This is an appropriate comparison for toxicity, because asstated above, the efficacy is also similar.

In addition, it is important to note that regimens thatgenerate grade 3 and 4 AEs in the range of a 36% rateare common; this reminds us that preventing and man-aging these toxicities is crucial. Careful monitoring ofpatients’ blood pressure level and urine for protein, withappropriate intervention, can easily minimize thesebevacizumab-induced additional toxicities.14

In summary, the increased toxicity is real and quan-tifiable; however, it is easy to monitor and manage, andit certainly does not meet a threshold that would restrictthe drug from being used on or off label.

The last consideration is economics, which arguablyis the driving force behind this debate. By removing theapproval of bevacizumab for MBC, insurance companiesand the Centers for Medicare & Medicare Services havea reason to deny payment for this expensive therapy. Thecost of therapy, however, is not under the purview of theFDA’s authority and should not impact approval or dis-approval of a drug. In a real-world discussion regardingeconomics, not paying for bevacizumab for patients withbreast cancer because of its high cost would seem unrea-sonable at many levels.

An objective way to evaluate the drug’s cost shouldconsider other uses and benefits of bevacizumab, at sim-ilar doses. In the ECOG E3200 trial, patients with col-orectal cancer received FOLFOX4 (5-fluorouracil, leu-covorin, oxaliplatin) ± bevacizumab with a dose (10mg/kg every 2 weeks) used in the E2100 breast cancertrial.20 The results of this trial showed that adding beva-cizumab to this chemotherapy regimen increased PFS by2.6 months, response rates by 14%, and OS by 2.1months.20 Similarly, the ECOG 4599 trial evaluated car-boplatin and paclitaxel ± bevacizumab (15 mg/kg every3 weeks) in patients with advanced-stage non–small-celllung cancer (NSCLC). The results of this study showthat adding bevacizumab to this chemotherapy regimenincreased PFS by 1.7 months, increased response rate by20%, and OS by 2 months.17




These numbers look very similar to the cumulativeresults of adding bevacizumab (10 mg/kg every 2 weeks, or15 mg/kg every 3 weeks) to chemotherapy for breast can-cer: a PFS increase of 1.9 or 2.5 months (median andmean, respectively), increase in response rate of 11% to26%, and a projected survival from the E2100 study (asdiscussed above) of 1.7 months. If one views the abovedata as similar (as I do), then saying that it is cost-prohib-itive could be interpreted as saying that less money shouldbe spent for patients with breast cancer than for thosewith colorectal or lung cancer. Such a conclusion, Ibelieve, is ethically inappropriate.

In summary, although bevacizumab for MBC isexpensive, its efficacy, dosing, and, therefore, cost aresimilar to those seen with the use of this drug in col-orectal or lung cancer, which makes this argumentdefunct. Furthermore, the FDA does not consider costin its drug approval decisions.

Finally, Genentech followed the regulatory process andsought guidance from the FDA to design trials and reachend points required to convert a conditional, acceleratedapproval to a full, final FDA approval. The cumulativedata from these trials (with >2500 patients) demonstratethe achievement of PFS (median, 1.9 months; mean,2.5 months) and no detrimental effect on survival.Regretfully, the FDA does not have a PFS threshold thatthe agency would consider approvable. This appears to bea “bait and switch” maneuver; the FDA advised or agreedto a PFS end point, never stating how much was enough,but in the end only voiced concern that there was no evi-dence to demonstrate a survival advantage.

The FDA made a motion to maintain its acceleratedapproval, while allowing appropriate OS data to be col-lected; and yet, the FDA decided to remove its initialapproval. Based on the E2100 OS data (still inappro-priate, but the best we have), the compiled PFS, safetydata, and cost, bevacizumab should maintain its origi-nal approval, because the data look very similar toexisting precedence in MBC (capecitabine added todocetaxel), colorectal cancer (bevacizumab added toFOLFOX4), and NSCLC (bevacizumab added to car-boplatin plus paclitaxel). ■

Author Disclosure StatementDr Mandock and Dr Adams have reported no conflicts of

interest. Dr Soefje is on the advisory board of Topotarget.

References1. Pollack A. FDA revokes approval of Avastin for use as breast cancer drug. New YorkTimes. November 18, 2011. www.nytimes.com/2011/11/19/business/fda-revokes-approval-of-avastin-as-breast-cancer-drug.html?_r=1&ref=health. Accessed November20, 2011.2. US Food and Drug Administration Modernization Act of 1997, S 830, 105thCong, 1st Sess (1997). www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDAMA/FullTextofFDAMAlaw/UCM089145.pdf. Accessed November 20, 2011.3. US Food and Drug Administration. Guidance for industry: fast track drug devel-opment programs—designation, development, and application review. Proceduralrevision 2. January 2006. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079736.pdf. Accessed November 20, 2011. 4. Miller K, Wang M, Grawlow J, et al. Paclitaxel plus bevacizumab versus paclitaxelalone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.5. Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a phase IIItrial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breastcancer. J Clin Oncol. 2009;27:4966-4972. Epub 2009 Aug 31.6. Miles D, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel com-pared with placebo plus docetaxel for the first-line treatment of human epidermalgrowth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247. Epub 2010 May 24.7. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first linetreatment of human epidermal growth factor receptor 2-negative, locally recurrent ormetastatic breast cancer. J Clin Oncol. 2011;29:1252-1260. Epub 2011 Mar 7.8. Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weeklycompared with every-3-week paclitaxel for metastatic breast cancer, with trastuzumabfor all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2nonoverexpressors: final results of the Cancer and Leukemia Group B Protocol 9840. JClin Oncol. 2008;26:1642-1649.9. Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al. Evaluation of tumor response,disease control, progression-free survival, and time to progression as potential surrogateend points in metastatic breast cancer. J Clin Oncol. 2008;26:1987-1992. 10. Miller KD, Chap LL, Holmes FA, et al. Randomized phase III trial of capecitabinecompared with bevacizumab plus capecitabine in patients with previously treatedmetastatic breast cancer. J Clin Oncol. 2005;23:792-799. 11. Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind,placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab incombination with chemotherapy for second-line treatment of human epidermal growthfactor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29:4286-4293.Epub 2011 Oct 11.12. Smith IE, Pierga JY, Biganzoli L, et al, for the ATHENA Study Group. First-linebevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breastcancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol.2011;22:595-602. Epub 2010 Sep 5.13. Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits:are we making too much of too little or are we achieving too little by giving too much?Clin Cancer Res. 2010;16:5972-5980. 14. Horning S. Avastin combined with chemotherapy in HER2-negative first linemetastatic breast cancer (MBC). www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM219979.pdf. Accessed November 30, 2011. 15. National Cancer Institute. FDA approval for bevacizumab: metastatic HER2-neg-ative breast cancer. November 18, 2011. www.cancer.gov/cancertopics/druginfo/fda-bevacizumab. Accessed November 30, 2011.16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines inOncology (NCCN Guidelines®): non-small cell lung cancer v.2.2012. Updated 2011.www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed November 30, 2011.17. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with beva-cizumab for non–small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.18. Xeloda (capecitabine) package insert. Roche Pharmaceuticals; Nutley, NJ; 2011.19. Bishop MR, Pavletic SZ. Hematopoietic stem cell transplantation (Chapter 32).In: Abeloff MD, Armitage JO, Niederhuber JE, et al, eds. Abeloff’s Clinical Oncology. 4thed. Philadelphia, PA: Churchill Livingston; 2008:501-512.20. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination withoxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastaticcolorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.J Clin Oncol. 2007;25:1539-1544.


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REVIEW ARTICLE


The impact of chemotherapy-induced nausea andvomiting (CINV) for the patient with cancercannot be overemphasized. Uncontrolled CINV

has been cited as one of the greatest fears among peopleundergoing cancer treatments.1,2 Advances in antiemetictherapy in the past 20 years have improved patient expe-riences and outcomes. Despite this, the majority ofpatients with cancer will experience CINV during theirchemotherapy treatments.1,3-6 In particular, nausea is lesswell controlled than vomiting. Uncontrolled CINVsymptoms lead to reduced quality of life, decreased abili-ty for self-care, and low patient morale, as well as toincreased healthcare costs.4-7 Preventing and controllingCINV is a vital part of the pharmaceutical care of the

patient with cancer. This article reviews the current ther-apies available for the prevention and treatment of CINV.

NeurophysiologyCINV represents a wide range of symptoms, from

mild, queasy nausea to repetitive vomiting and retch-ing. Acute symptoms can begin within minutes of theadministration of chemotherapy, but delayed symptomscan also last for many days afterward. AnticipatoryCINV can also occur before chemotherapy administra-tion, as a result of a conditioned response to poor emet-ic control in previous cycles of chemotherapy. AcuteCINV is described as symptoms occurring within thefirst 24 hours after chemotherapy. Delayed CINV isexperienced by patients after the acute phase; thesenausea and vomiting symptoms usually peak at about 2to 3 days after chemotherapy but may last for severaldays longer.

Dr Lohr is Oncology Pharmacy Specialist, Oncology MedicationTherapy Management, Masonic Cancer Center, University ofMinnesota Physicians/Fairview, Minneapolis, MN.

Current Practice in the Prevention andTreatment of Chemotherapy-InducedNausea and Vomiting in AdultsLisa K. Lohr, PharmD, BCOP, BCPS

Background: Chemotherapy-induced nausea and vomiting (CINV) is a significant complicationfor patients with cancer. Patients have different risk factors for CINV, and chemotherapy agentsdiffer in their emetogenicity. Despite therapeutic advances, the majority of patients with cancer willexperience CINV during their chemotherapy treatment.Objective: To review the current therapies available for the prevention and treatment of CINVin patients with cancer. Discussion: Several important neurotransmitters are involved in the emetic process, and theseserve as targets for pharmacologic antiemetics. The serotonin (5-hydroxytryptamine) type-3 (5-HT3) receptor antagonists form the cornerstone of antiemetic regimens for moderately or high-ly emetogenic chemotherapy, and they have few adverse effects. The four 5-HT3 antagonists cur-rently available for the prevention and treatment of CINV are ondansetron, granisetron, dolasetron,and palonosetron. Dexamethasone is used in conjunction with 5-HT3 antagonists for moderatelyto highly emetogenic regimens. It has some adverse effects associated with short-term use,although this is seen less than with long-term use. Neurokinin-1 antagonists have a differentantiemetic mechanism and are useful when used in combination with a 5-HT3 antagonist anddexamethasone. Other antiemetics—such as dopamine antagonists, olanzapine, or cannabi-noids—are useful in some circumstances. Choosing an appropriate antiemetic regimen requiresassessment of the emetogenicity of the chemotherapy agents and a consideration of patient-related risk factors. Conclusion: The care for patients with cancer can be improved by the development of standardantiemetic regimens based on the emetogenicity of particular antineoplastic agents and proto-cols. Standard regimens should be adjusted based on an individual patient’s response to the par-ticular drug regimen.

J Hematol Oncol Pharm.2011;1(4):13-21.www.JHOPonline.comDisclosures are at end oftext

5-Lohr_Cover 12/19/11 11:22 AM

REVIEW ARTICLE


In addition to chemotherapy, many other medicalconditions can lead to nausea and vomiting in patientswith cancer. These include hypercalcemia, gastropare-sis, gastrointestinal reflux, brain metastases, infections,and many others. Many medications used by patientswith cancer can lead to nausea and vomiting, includinganti biotics, antifungals, opiate analgesics, and others. Itis important to consider these other causes and treatthem appropriately, even though they may coincidewith CINV.

The symptoms of CINV result from activation of partsof the central nervous system (CNS) and the peripheralnervous system. In the classically described pathway, thetoxin exposure is detected by the chemoreceptor triggerzone in the CNS, as well as via the enterochromaffin cellsin the gastrointestinal tract. In addition, signals from thecerebral cortex, the limbic system, and the vestibular sys-tems can trigger or accentuate the emetic response. Inreaction to these signals, the vomiting center of the CNSactivates the emetic response, which includes salivation,contraction of the abdominal muscles, relaxation of theesophageal sphincter, and contraction of the stomachmuscles, as well as tachycardia, dizziness, and sweating.

The transmission of the vomiting signals seen withCINV involves multiple neurotransmitters and recep-tors. The predominant receptors are the serotonin (5-hydroxytryptamine) type-3 (5-HT3) receptor antago-nists, neurokinin-1 (NK1) antagonists, and dopaminereceptors. Additional neurotransmitters involvedinclude corticosteroid, endogenous cannabinoids,GABA, acetylcholine, and histamine. The activation orinhibition of these neurotransmitters forms the basis ofpharmacologic therapy for CINV. Because multiple neu-rotransmitters are involved in this process, multipleantiemetic medications are necessary for the maximalprevention and treatment of CINV.

Risk FactorsThe risk for CINV varies among patients who receive

chemotherapy. Patient-related risk factors as sociatedwith higher rates of CINV include female sex, younger age, poor emetic control in previouschemotherapy cycles, a history of motion sickness ornausea during pregnancy, anxiety and/or depression, andno history of alcohol abuse.

The primary determinant of the prevalence of CINV

is the inherent emetogenicity of the chemotherapyagents administered. The emetogenicity of chemothera-py agents has been classified into 4 categories.7,8 Highlyemetogenic agents are those causing CINV in <90% ofpatients. The largest group is the moderately emetogenicagents, leading to CINV in 30% to 90% of patients. Lowemetogenic level chemotherapy results in CINV symp-toms in 10% to 30% of patients. Finally, agents withminimal emetogenicity cause CINV symptoms in fewerthan 10% of patients.7,8

Table 1 lists the emetogenicity of various chemo -therapy agents given by injection. The characteristicsof CINV seen with oral chemotherapy agents are dif-ferent with regard to onset, duration, and severity.8Most oral chemotherapy agents have minimal to lowemetogenicity, but some have moderate to high emeto-genicity. Table 2 lists the emetogenic level seen withoral chemotherapy agents.

In addition to the emetogenicity, other chemother-apy-related risk factors include high doses, fast infu-sions, and multiday chemotherapy administration.Multiday chemotherapy regimens are particularly chal-lenging, because the delayed CINV symptoms are over-laid on the latter day’s acute CINV. Because mostchemotherapy regimens use more than 1 antineoplasticagent given on a single day, it is difficult to predict theemetogenicity of these combination regimens. It is rec-ommended that the antiemetic regimen be designed tobe consistent with the highest emetogenicity associat-ed with the chemotherapy agents given on each day.

The 5-HT3 AntagonistsThe 5-HT3 receptor antagonists are effective anti -

emetic agents associated with minimal adverse effects.These agents block serotonin release from the gastroin-testinal tract in addition to blocking serotonin recep-tors in the CNS. When initially approved in the early1990s, the 5-HT3 antagonists became the first highlyactive antiemetics that did not have substantialadverse effects. The 4 agents in this class—dolasetron,granisetron, ondansetron, and the most recentlyapproved palonosetron—are available in a variety ofdosage forms in adults (Table 3).

The 5-HT3 antagonists are more potent as antiemet-ic agents than antinausea medications. These agentsdemonstrate a plateau effect: once enough medicationhas been given to block the receptors, more medicationis not more effective. For patients who can take oralmedications, oral therapy is as effective as intravenous(IV) dosing.1,7,9,10 Except for palonosetron, the 5-HT3antagonists are not more effective than other agents(ie, prochlorperazine, aprepitant, or dexamethasone)for the prevention of delayed CINV.1,9-13

Because most chemotherapy regimens usemore than 1 antineoplastic agent given on a single day, it is difficult to predict theemetogenicity of these combination regimens.

5-Lohr_Cover 12/19/11 11:22 AM

Current Practice in the Prevention and Treatment of CINV


Table 1 Emetogenic Level Associated with Injectable Chemotherapy Agents

Chemotherapy agent Emetogenic level

Aldesleukin (Proleukin) Low: ≤12 million U/m2

Moderate: >12 million-15 millionU/m2

Alemtuzumab (Campath) Minimal

Arsenic Trioxide (Trisenox) Moderate

Asparaginase (Elspar) Minimal

Azacitadine (Vidaza) Moderate

Bendamustine (Treanda) ModerateBevacizumab (Avastin) Minimal

Bleomycin (Blenoxane) Minimal

Bortezomib (Velcade) Low

Busulfan (Bulsulfex) Moderate

Cabazetaxel (Jevtana) Low

Carboplatin (Paraplatin) Moderate, with high risk fordelayed CINV

Carmustine (BiCNU) Moderate: ≤250 mg/m2

High: >250 mg/m2

Cetuximab (Erbitux) Minimal

Cisplatin (Platinol) Moderate: <50 mg/m2

High: ≥50 mg/m2, with high riskfor delayed CINV

Cladribine (Leustatin) Minimal

Clofarabine (Clolar) Moderate

Cyclophosphamide(Cytoxan)

Moderate: ≤1500 mg/m2, withhigh risk for delayed CINVHigh: >1500 mg/m2, with high risk for delayed CINV

Cytarabine (Ara-C, Cytosar-U)

Minimal: <100 mg/m2

Low: 100-200 mg/m2

Moderate: >200 mg/m2

Dacarbazine (DTIC) High

Dactinomycin (Cosmegen) Moderate

Daunorubicin (Cerubidine) Moderate

Decitabine (Dacogen) Minimal

Docetaxel (Taxotere) Low

Doxorubicin (Adriamycin) Moderate, with high risk fordelayed CINV

Doxorubicin Liposomal(Doxil)

Moderate

Eribulin (Halaven) LowEpirubicin (Ellence) Moderate, with high risk for

delayed CINV

Etoposide (VePeSid) Low

Fludarabine (Fludara) Minimal

Fluorouracil (Adrucil) Low


Gemcitabine (Gemzar) Low

Idarubicin (Idamycin) Moderate with high risk ofdelayed CINV

Ifosfamide (Ifex) Moderate

Interferon alpha-2b (Intron A) Low: <10 million U/m2

Moderate: ≥10 million U/m2

Ipilimumab (Yervoy) Minimal

Irinotecan (Camptosar) Moderate, with some risk fordelayed CINV

Ixabepilone (Ixempra) Low

Mechlorethamine (Mustargen) High

Melphalan (Alkeran) Moderate

Methotrexate (Trexall) Minimal: <50 mg/m2

Low: 50-249 mg/m2

Moderate: ≥250 mg/m2, with some risk for delayed CINV

Mitomycin (Mutamycin) Low

Mitoxantrone (Novantrone) Low

Nelarabine (Arranon) Minimal

Ofatumumab (Arzerra) Minimal

Oxaliplatin (Eloxatin) Moderate

Paclitaxel (Taxol) Low

Paclitaxel Protein Bound(Abraxane)

Low

Panitumumab (Vectibix) MinimalPegasparaginase (Oncaspar) Minimal

Peginterferon alfa-2b (Sylatron) Minimal

Pemetrexed (Alimta) Low

Pentostatin (Nipent) Low

Pralatrexate (Folotyn) Moderate

Rituximab (Rituxan) Minimal

Romidepsin (Istodax) Low

Streptozocin (Zanosar) High

Temozolamide (Temodar) Moderate

Temsirolimus (Torisel) Minimal

Teniposide (Vumon) Low

Thiotepa (Thiotepa) Low

Topotecan (Hycamptin) Moderate

Trastuzumab (Herceptin) Minimal

Vinblastine (Velban) Minimal

Vincristine (Oncovin) Minimal

Vinorelbine (Navelbine) Minimal

CINV indicates chemotherapy-induced nausea and vomiting.Sources: References 7-9, 15.

5-Lohr_Cover 12/19/11 11:22 AM

REVIEW ARTICLE


The 5-HT3 antagonists are well tolerated and havefew adverse effects. The most often reported side effectsinclude headache, constipation, and diarrhea. In addi-tion, prolonged corrected QT (QTc) interval and othercardiac dysrhythmias have been reported, with an inci-dence of up to approximately 5% (based on Lexicompand Micromedex information). It is unclear what thetrue incidence of adverse events is for the different 5-HT3 antagonists, because these are likely underreported. The US Food and Drug Administration (FDA) has

now warned that IV dolasetron should not be used forthe prevention of CINV, because the drug increases therisk for torsades de pointes. The FDA has added warn-ings to the label of ondansetron against the use of thedrug by patients with a long QT syndrome and is rec-ommending electrocardiographic monitoring forpatients at high risk for this event—those with elec-trolyte abnormalities, congestive heart failure, or brad-yarrhythmias, and patients using concomitant medica-tions that can increase the QTc interval. For patientswithout underlying cardiac rhythm disorders or concur-rent treatment with other medications that prolong theQTc interval, it is not clear how clinically significantthis potential adverse effect is. It is generally accepted that there are no substantial

differences in antiemetic efficacy among the 5-HT3antagonists, except for palonosetron.7,9,10,14,15 With itslonger half-life, palonosetron was shown in the originalclinical trials to have equivalent or superior effectivenessin the acute and the delayed phases of CINV.7,10,15 Theseoriginal trials were hampered by including comparatorgroups that did not reflect the standard of care for high-ly or moderately emetogenic chemotherapy. Since then, several studies have provided information

that further delineates the effects of palonosetron.16-20When taken in total, current evidence suggests thatpalonosetron has a small, but real, increase in antiemet-ic efficacy, especially in the delayed phase.7,16-20 In lightof this new evidence, the National ComprehensiveCancer Network (NCCN) guidelines now listpalonosetron as the preferred 5-HT3 antagonist for high-ly and moderately emetogenic chemotherapy.7The antiemetic guidelines from the Multinational

Association of Supportive Care in Cancer (MASCC), aswell as the guideline from the American Society ofClinical Oncology (ASCO), identify palonosetron asthe preferred 5-HT3 antagonist for moderately emeto-genic chemotherapy that is not based on anthracycline-cyclophosphamide regimens.9,15 Palonosetron, however,is substantially more expensive than the alternativeagents, and cost-effectiveness should be taken into con-sideration when choosing among the available 5-HT3receptor antagonists.

Table 2 Emetogenic Level Associated with OralChemotherapy Agents


Altretamine (Hexalen) High

Bexarotene (Targretin) Low

Busulfan (Myleran) Minimal: <4 mg Moderate: ≥4 mg

Capecitabine (Xeloda) Low

Chlorambucil (Leukeran) Minimal

Cyclophosphamide (Cytoxan) Low: <100 mg/m2/day Moderate: ≥100 mg/m2/day

Dasatinib (Sprycel) Minimal

Erlotinib (Tarceva) Minimal

Etoposide (VePeSid) Moderate

Everolimus (Afinitor) Minimal

Fludarabine (Fludara) Low

Gefitinib (Iressa) Minimal

Hydroxyurea (Hydrea) Minimal

Imatinib (Gleevec) Moderate

Lapatinib (Tykerb) Low

Lenalidomide (Revlimid) Minimal

Lomustine (CeeNU) Moderate

Melphalan (Alkeran) Minimal

Mercaptopurine (Purinethol) Minimal

Methotrexate (Trexall) Minimal

Nilotinib (Tasigna) Low

Pazopanib (Votrient) Low

Procarbazine (Matulane) High

Sorafenib (Nexavar) Minimal

Sunitinib (Sutent) Minimal

Temozolamide (Temodar) Low: ≤75 mg/m2/day Moderate: >75 mg/m2/day

Thalidomide (Thalomid) Minimal

Thioguanine (Tabloid) Minimal

Topotecan (Hycamptin) Low

Tretinoin (Vesanoid) Low

Vandetanib (Zactima) Minimal to low

Vorinostat (Zolinza) Low

Sources: References 7-9, 15.

5-Lohr_Cover 12/19/11 11:22 AM



CorticosteroidsCorticosteroids, and dexamethasone in particular,

have long been used for the prevention and treatment ofCINV. Despite the widespread use of corticosteroids,their precise antiemetic mechanism of action is stillunclear. The potential mechanisms may include activa-tion of glucocorticoid receptors in the CNS, decreasedrelease of serotonin, inhibition of prostaglandin synthe-sis in the cerebral cortex, and alteration of cortical inputinto the emetic center in the CNS.21Although dexamethasone can be used alone for a

chemotherapy regimen with low emetogenicity, it ismore often used in conjunction with a 5-HT3 antago-nist, with or without an NK1 receptor antagonist, formoderately to highly emetogenic regimens. In these sit-uations, dexamethasone adds about 15% to 20%21 tothe complete antiemetic response rate. Dexamethasoneis active in the acute and the delayed phases of CINV. The short-term use of dexamethasone in doses used

in CINV is usually well tolerated, although the drug issometimes underutilized, because of concern for itsassociated adverse effects.21 The most frequentlyreported adverse effects include insomnia, anxiety,mood changes, increased appetite, mild fluid reten-tion, stomach discomfort, hyperglycemia, and a burn-ing in the rectal/vaginal area when IV doses areinfused too rapidly. Hyperglycemia is often seen in patients with preex-

isting or undiagnosed diabetes. In some patients, thehyperglycemic effect is significant enough to warrantadditional glucose monitoring or alterations of antidia-betic medications.The appropriate dexamethasone dose depends on the

emetogenicity of the chemotherapy and on whether anNK1 antagonist is coadministered. One group ofresearchers explored the dose–response relationship ofdexamethasone in the context of highly emetogenicchemotherapy, showing that the 12-mg and 20-mg doses

of the drug were associated with a higher completeresponse rate than the 4-mg and 8-mg doses.22 Theinvestigators also studied different doses and regimens ofdexamethasone in moderately emetogenic chemothera-py and found that higher doses were not more effectivethan a single 8-mg dose.23These studies have helped shape the current dosing

recommendations found in the various guidelines. Thedose and schedule of dexamethasone should be modifiedif a patient will also receive an NK1 antagonist.Aprepitant and fosaprepitant inhibit the cytochrome(CY) P450 3A4–based metabolism of dexamethasoneand result in an approximately 2-fold increase in the areaunder the curve (AUC) of dexamethasone. Overall,dexamethasone doses are reduced by half if used concur-rently with aprepitant. Available CINV guidelines differ slightly in their rec-

ommendations for dexamethasone dose.7,9,15 Most guide-lines recommend 12 mg to 20 mg of dexamethasone forthe acute phase of highly emetogenic chemotherapy and8 mg to 12 mg for moderately emetogenic chemotherapy.For regimens with a high risk of delayed CINV, oral dex-amethasone 8 mg daily or twice daily for 2 to 3 days isrecommended, depending on whether an NK1 antago-nist is also given.7,9,15 Newer research has explored the question of whether,

when administered with palonosetron, a single dose ofdexamethasone offers the same efficacy as the typical 3-day dexamethasone regimen.24,25 Two noninferioritystudies enrolled patients receiving moderately emeto-genic chemotherapy. All 632 patients in the 2 studiescombined received IV palonosetron 0.25 mg and IV dex-amethasone 8 mg before chemotherapy administration.The patients in the control arms of both studies alsoreceived oral dexamethasone on days 2 and 3 (8 mg dailyin one study and 4 mg twice daily in the other study).24,25 Both trials showed that the 1-day dexamethasone reg-

imen was noninferior to the 3-day regimen for patients

Table 3 Dosing of Serotonin Type 3 Antagonists in Adults

AgentDose for acute CINV (on any day of highly/moderately emetogenic chemotherapy) Dose for delayed CINV

Dolasetron (Anzemet) Oral: 100 mg Oral: 100 mg/day

Granisetron (Kytril, oral)

Granisetron (Sancuso, patch)

Oral: 2 mg once or 1 mg twice dailyIV: 1 mg Topical: 3.1 mg/24 hr (1 patch/7days)

Oral: 1-2 mg/day or 1 mg twice dailyTopical: Continuation of patch up to 7 days

Ondansetron (Zofran) Oral: 16-24 mgIV: 8-24 mg

Oral: 8 mg twice daily or 16 mg/day

Palonosetron (Aloxi) IV: 0.25 mg once None

IV indicates intravenous.

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receiving moderately emetogenic chemotherapy. How -ever, in one study, the benefit was most apparent inpatients receiving chemotherapy other than anthracy-cline-cyclophosphamide regimens, and in the otherstudy there was a trend toward better nausea control onday 3 with the 3-day dexamethasone regimen.24,25

Neurokinin-1 AntagonistsThe NK1 antagonists block the action of substance P

on the emetic pathways. Aprepitant is the NK1 antagonistadministered orally. Fosaprepitant is a prodrug of aprepi-tant, administered intravenously. Early trials of aprepitantshowed that aprepitant administration significantlyincreased the complete antiemetic response by 12% to20%, depending on the trial.26 In these trials, aprepitantwas administered orally (125 mg before chemotherapyand 80 mg on days 2 and 3), along with a 5-HT3 antago-nist and dexamethasone, in patients receiving moderatelyand highly emetogenic chemotherapy.26

Aprepitant and fosaprepitant were very well toleratedin these trials, and adverse effects did not differ betweenthe 2 treatment arms.26 Venous irritation has been notedwith IV administration, which may require dilution in alarger volume of IV solution. Aprepitant/fosaprepitant isrecommended for patients receiving highly emetogenicchemotherapy, as well as those receiving moderatelyemetogenic chemotherapy associated with a high risk fordelayed nausea and vomiting.

Aprepitant is metabolized primarily via theCYP3A4 pathway and to a lesser degree via CYP1A2and CYP2C19 pathways. The activity of aprepitantmay be altered when administered with medicationsthat are CYP3A4 inhibitors or inducers. Aprepitantitself is a moderate inhibitor of CYP3A4 and may affectthe concentrations of other agents metabolized by thispathway.26,27

The results of clinical trials and clinical observationdo not reveal any clinically relevant drug interactionswith chemotherapy agents metabolized via the CYP3A4pathway. One important drug interaction, however, isseen with corticosteroids. Dexamethasone is metabolizedvia the CYP3A4 pathway, and roughly a 2-fold increase

in AUC is seen when dexamethasone is administeredwith aprepitant, although this effect is greater with oraldexamethasone than with IV doses of the drug.26, 27

In addition, aprepitant is an inducer of the CYP2C9pathway, and it has effects on the elimination of the S-isomer of warfarin, which is metabolized by theCYP2C9 pathway.26, 27 Approximately 5 days after com-pletion of aprepitant therapy a reduction is seen in theS-isomer concentration, with a concurrent decrease inthe international normalized ratio (INR). Becauseaprepitant is used intermittently, the INR value shouldbe monitored closely for 2 weeks after each dose or cycleof aprepitant or fosaprepitant.

To enable IV administration of the first dose of anNK1 antagonist before chemotherapy, fosaprepitant wasdeveloped as an IV prodrug of aprepitant. A pharmaco-kinetic analysis showed that a 115-mg IV dose of fos-aprepitant is equivalent to that of a 125-mg oral dose ofaprepitant.28

Increasing evidence shows that the initial dose of anNK1 antagonist provides most of the antiemetic activity ofaprepitant or of fosaprepitant. A recent trial demonstrat-ed the effectiveness of a single 150-mg dose of fosaprepi-tant in the prevention of CINV.29 In this large study of2247 patients receiving highly emetogenic chemotherapy,one group received fosaprepitant IV 150 mg beforechemotherapy and the other group received the typicalaprepitant oral regimen of 125 mg, 80 mg, and 80 mg over3 days. All patients received ondansetron and dexa -methasone, although patients in the fosaprepitant armreceived more dexamethasone on days 3 and 4, because ofthe expectation that the drug interaction would have dis-sipated. The complete emetic response in the fosaprepi-tant arm was found to be noninferior to that seen in theaprepitant arm (71.9% vs 72.3%, respectively).29

Other AntiemeticsThe group consisting of the 5-HT3 antagonists, dex-

amethasone, and the NK1 antagonists define the mostactive antiemetic medications, but there is still a needfor alternative antiemetics. In general, it is best to con-sider agents with a different pharmacologic mechanismof action. Dopamine antagonists, such as prochlorper-azine or promethazine, are often used for breakthroughCINV symptoms. The butyrophenones (eg, haloperidol,droperidol) are highly active antiemetics but can causesignificant sedation and have the potential to prolongthe QTc interval.

The benzodiazepine lorazepam is frequently used forthe treatment of breakthrough nausea and vomiting.Exactly how lorazepam acts as an antiemetic is unclear,but it likely affects the limbic or cortical input into thevomiting center. Its additional activity in reducing anx-

The group consisting of the 5-HT3

antagonists, dexamethasone, and the NK1

antagonists define the most activeantiemetic medications, but there is still aneed for alternative antiemetics. In general,it is best to consider agents with a differentpharmacologic mechanism of action.

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Table 4 Prevention and Treatment of CINV Based on NCCN Guidelines

ANTIEMETIC OPTIONS

Emetic risk associatedwith IV/oral chemotherapy

Acute phase 5-HT3 antagonist

Acute phase NK1antagonist

Acute phase steroid Delayed phase Adjunct therapies

IV chemotherapy

High emetic risk Dolasetron PO or Granisetron PO, IV, or transdermalor Ondansetron PO or IV orPalonosetron IV(preferred)

Aprepitant PO 125 mg orFosaprepitant IV115 mg on day 1

Dexamethasone POor IV 12 mg on day 1

Aprepitant PO 80 mg on days 2-3plus dexametha-sone PO 8 mg ondays 2-4

Consider addition of lorazepam and/orH2 blocker or PPI

Fosaprepitant IV150 mg on day 1

DexamethasonePO or IV 12 mg on day 1

DexamethasonePO 8 mg on day 2,then 8 mg twicedaily on days 3-4

Consider addition of lorazepam and/orH2 blocker or PPI

Moderate emetic risk Dolasetron PO or Granisetron PO, IV,or topical orOndansetron PO orIV or PalonosetronIV (preferred)

± Aprepitant POa

125 mg orFosaprepitant IVa

115 mg on day 1

Dexamethasone POor IV 12 mg on day 1

5-HT3 antagonist(dolasetron,granisetron, orondansetron) ondays 2-3 orDexamethasonePO 8 mg on days 2-3 or AprepitantPO 80 mg on days2-3 (if NK1 antago-nist used on day 1)

Consider additionof lorazepam and/orH2 blocker or PPI

Low emetic risk Dexamethasone PO or IV 12 mg/day or MetoclopramidePO or IV 10-40 mg/day (then every 4-5 hrs PRN) orProchlorperazine PO or IV 10 mg/day (then every 4-5 hrs PRN)

None Consider addition oflorazepam and/or H2blocker or PPI

Minimal emetic risk No routine prophylaxis No routine prophylaxis

None

Oral chemotherapy

High-to-moderate emetic risk

Granisetron POdaily orOndansetron POdaily

None None None Consider additionof lorazepam and/orH2 blocker or PPI

Low-to-minimal emetic risk

Only if patient experiences CINV: Metoclopramide PO 10-40 mg/day (then every 4-6 hrs PRN) or Prochlorperazine PO 10 mg/day (then every 4-6 hrs PRN) or Haloperidol PO 1-2 mg every 4-6 hrs PRN

None Consider additionof lorazepam and/orH2 blocker or PPI

Treatment of breakthrough CINV

Dexamethsone PO or IV 12 mg/day or Dolasetron PO 100 mg/day or Dronabinol PO 5-10 mg every3-6 hrs or Granisetron PO 1-2 mg/day or 1 mg twice daily, or IV 1 mg/day or Haloperidol PO or IV 0.5-2.0 mg every 4-6 hrs or Lorazepam PO or IV 0.5-2 mg every 4-6 hrs or Metoclopramide PO or IV 10-40 mg every 4-6 hrs or Olanzapine PO 2.5-5.0 mg twice daily or Ondansetron PO or IV 16 mg/day or Prochlorperazine PR 25 mg every 12 hrs, or PO or IV 10 mg every 4-6 hrs or Promethazine PO or IV12.5-25.0 mg every 4 hrs or Scopolamine patch every 72 hrs

NCCN, National Comprehensive Cancer Network; PO, oral; PPI, proton pump inhibitor.aAprepitant should be added for select patients receiving certain chemotherapies of moderate emetic risk (eg, carboplatin, cisplatin, doxorubicin,epirubicin, ifosfamide, irinotecan, or methotrexate).

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Antiemesis V.1.2012. © 2011National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ and illustrations herein may not be reproduced inany form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCNGuidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and allother NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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REVIEW ARTICLE


iety is an added benefit. When low-to-moderate doses(ie, 0.5-1.0 mg) are used, excessive sedation is not usual-ly a problem. Cannabinoids can be useful adjunctive treatments for

CINV in selected patients. Dronabinol, and morerecently nabilone, are orally available cannabinoidagents. These medications have substantial adverseeffects, such as sedation, dysphoria or euphoria, and drymouth, as well as other CNS adverse effects. Theseagents are usually reserved for patients who have aninadequate response to other antiemetics and who cantolerate the associated adverse effects.

Olanzapine was originally developed as an atypicalantipsychotic medication but was found to haveantiemetic activity thought to be caused by its inhibito-ry activity at various serotonin and dopamine receptors.After early experience with olanzapine in the treatmentof nausea and vomiting in hospice patients, noncon-trolled studies of olanzapine have shown the drug’s activ-ity in conjunction with 5-HT3 antagonists and dexa -methasone in CINV. A recent comparison study showed that a group of

patients receiving olanzapine (along with a 5-HT3antagonist and dexamethasone) had a substantiallyimproved complete emetic response rate compared withpatients who did not receive olanzapine.30 The most fre-quently reported adverse effects with olanzapine includedrowsiness, dry mouth, and dizziness. Olanzapine is alsohighly active in relieving breakthrough CINV symptomsin patients with highly refractory symptoms and is per-haps most often used in this situation.31,32 Gabapentin also has been studied in the prevention

of nausea and vomiting. Early research with this agentbegan after the drug’s antiemetic action was noticed inpatients with breast cancer who were receiving the drugto help relieve hot flashes. After showing activity in the prevention of CINV in

noncontrolled trials, gabapentin was studied in a ran-domized, double-blind fashion in 8 patients.33 Thegabapentin dose in the experimental arm was titratedupward 5 days before chemotherapy began and contin-ued until 5 days after chemotherapy. Patients in botharms received standard therapy with ondansetron anddexamethasone. Significantly more patients had com-plete antiemetic response in the treatment arm than in

the control arm, and the gabapentin therapy was welltolerated.33 More research will help to define the role ofgabapentin in the prevention of CINV.

Treatment Regimen RecommendationsConsensus and evidence-based guidelines and recom-

mendations have been published from 3 major profes-sional oncology groups. The guideline from ASCO wasupdated in 2011.9 Recommendations from the MASCCand the European Society of Medical Oncology wereupdated and published in 2011.15 The guidelines fromthe NCCN are revised and electronically published fre-quently, often multiple times annually, as new informa-tion becomes available.7 Although there are some differences between the

guidelines, they largely agree on the basic framework ofrecommended antiemetic treatment of CINV.7,9,15 Theprevention of acute CINV in patients receiving highlyemetogenic chemotherapy should include a 5-HT3antagonist and dexamethasone, along with an NK1antagonist. For the prevention of delayed CINV in thosereceiving highly emetogenic chemotherapy, dexametha-sone and an NK1 antagonist (if the IV 150-mg fos-aprepitant dose is not used) is recommended.7,9,15 For cases with moderately emetogenic chemotherapy,

patients should receive a 5-HT3 antagonist and dexam-ethasone, with or without an NK1 antagonist, in theacute phase. Options for the delayed phase include pro-phylaxis with a 5-HT3 antagonist, dexamethasone, or anNK1 antagonist plus dexamethasone.7,9,15Patients receiving low emetogenic chemotherapy can

be given a single dose of dexamethasone, a dopamineantagonist, or a 5-HT3 antagonist. Patients who arereceiving minimally emetogenic chemotherapy general-ly do not require any preventive antiemetic. Patients receiving oral chemotherapy associated with

a high or moderate emetic potential should be given anantiemetic medication before each dose of the oralchemotherapy.7,9,15 Those receiving oral chemotherapywith a low to minimal emetic potential, as-neededantiemetics should be sufficient. Recommendationsfrom the more frequently updated NCCN guidelines areshown in Table 4. Many patients have breakthrough CINV symptoms.

Patients receiving moderately to highly emetogenicchemotherapy should be sent home with 1 to 2 medica-tions to use for breakthrough symptoms, if they occur.The best choice of antiemetic medications wouldinclude agents from a different class with a differentmechanism of action than those of the antiemetics givenfor prophylaxis. Patients should be encouraged to take their as-need-

ed antiemetics at the beginning of a nausea episode,

The prevention of acute CINV in patientsreceiving highly emetogenic chemotherapyshould include a 5-HT3 antagonist anddexamethasone, along with an NK1antagonist is recommended.

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before the symptoms get worse. Patients should be madeaware that many medications used for breakthroughCINV can cause more sedation than other agents. Ifrefractory CINV symptoms continue, the additionalagents should be administered on a scheduled basis, andthe patient should be evaluated for the need for IVhydration or for electrolyte supplementation. In addition, the antiemetic effectiveness should be

evaluated before the next cycle of chemotherapy, andpotential modifications should be considered. Thesemay include scheduling active as-needed medications,upgrading the antiemetic regimen to a regimen withgreater emetogenic level, or adding olanzapine or acannabinoid medication. Patients who develop anticipatory nausea and vomit-

ing may receive lorazepam the night before and the morn-ing of the chemotherapy regimen, before they arrive at thetreatment center. They may also be offered behavioralinterventions, such as relaxation techniques or hypnosis.

ConclusionBecause of the multiple neurotransmitters and organs

involved in the emetic response, multiple antiemetics,with different mechanisms of action are needed to pre-vent and treat CINV. By matching the antiemetic regi-men to the emetogenic level of the chemotherapy regi-men, patients can be offered the optimal preventiveregimens. Pharmacists are uniquely positioned to ensurethat patients receive the appropriate CINV preventionand treatment, to manage adverse effects, and toimprove patient outcomes. ■

Author Disclosure StatementDr Lohr has reported no conflicts of interest.

References1. Panesar K. Strategies for managing chemotherapy-induced nausea and vomiting.US Pharmacist. 2011;36(oncology suppl):12-15.2. Trigg ME, Higa GM. Chemotherapy-induced nausea and vomiting: antiemetic tri-als that impacted clinical practice. J Oncol Pharm Practice. 2010;16:233-244. Epub2010 Jan 19.3. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuingneed for novel therapies. Ann Oncol. 2011;22:30-38. Epub 2010 Oct 14.4. Kris MG. Why do we need another antiemetic? Just ask. J Clin Oncol.2003;21:4077-4080. Epub 2003 Oct 14.5. Roscoe JA, Morrow GR, Hickok JT, et al. Nausea and vomiting remain a signifi-cant clinical problem: trends over time in controlling chemotherapy-induced nauseaand vomiting in 1413 patients treated in community clinical practices. J PainSymptom Manage. 2000;20:113-121.6. Haiderali A, Menditto L, Good M, et al. Impact on daily functioning and indi-rect/direct costs associated with chemotherapy-induced nausea and vomiting (CINV)in a US population. Support Care Cancer. 2011;19:843-851. Epub 2010 Jun 9.7. National Comprehensive Care Network. NCCN clinical practice guidelines inoncology. Antiemesis. V1.2012. July 20, 2011. www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed November 14, 2011.8. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents anddefinition of antineoplastic agent emetogenicity—state of the art. Support CareCancer. 2011;19(suppl 1):S43-S47. Epub 2010 Oct 24.9. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society ofClinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198. Epub 2011 Sep 26.

10. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med.2008;358:2482-2494.11. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists beadministered beyond 24 hours after chemotherapy to prevent delayed emesis?Systemic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol.2005;23:1289-1294.12.Huang JQ, Zheng GF, Deuson R, et al. Do 5-hydroxytryptamine3 receptor antag-onists (5-HT3) improve the antiemetic effect of dexamethasone for preventingdelayed chemotherapy-induced nausea and vomiting (CINV)? A meta-analysis ofrandomized controlled trials. J Clin Oncol. 2004;22(14 suppl):Abstract 6037.13. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine receptor antag-onists versus prochlorperazine for control for delayed nausea caused by doxorubicin:a URCC CCOP randomized controlled trial. Lancet Oncol. 2005;6:765-772.14. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly eme-togenic chemotherapy in adults. Cochrane Database of Systemic Reviews 2010. Issue 1.Article No: CD006272. Published online January 20, 2010. http://summaries.cochrane.org/CD006272/serotonin-receptor-antagonists-to-prevent-nausea-and-vomiting-after-chemotherapy. Accessed November 14, 2011.15. Multinational Association of Supportive Care in Cancer. MASCC/ESMOantiemetic guideline 2011. April 2011. http://data.memberclicks.com/site/mascc/MASCC_Guidelines_English_2011.pdf. Accessed November 14, 2011.16. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versusgranisetron plus dexamethasone for the prevention of nausea and vomiting duringchemotherapy: a double-blind, double-dummy, randomized, comparative phase IIItrial. Lancet Oncol. 2009;10:115-124. Epub 2009 Jan 8.17. Botrel TE, Clark OAC, Clark L, et al. Efficacy of palonosetron (PAL) comparedto other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nauseaand vomiting (CINV) in patients receiving moderately or highly emetogenic(MoHE) treatment: systemic review and meta-analysis. Support Care Cancer.2011;19:823-832. Epub 2010 May 22.18. Mattiuzzi GN, Cortes JE, Blamble DA, et al. Daily palonosetron is superior toondansetron in the prevention of delayed chemotherapy-induced nausea and vomit-ing in patients with acute myelogenous leukemia. Cancer. 2010;116:5659-5666.19. Yu Z, Liu W, Wang L, et al. The efficacy and safety of palonosetron compared withgranisetron in preventing highly emetogenic chemotherapy-induced vomiting in theChinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel,comparative clinical trial. Support Care Cancer. 2009;17:99-102. Epub 2008 Sep 30.20. Likun Z, Xiang J, Yi B, et al. A systematic review and meta-analysis of intra-venous palonosetron in the prevention of chemotherapy-induced nausea and vomit-ing in adults. Oncologist. 2011;16:207-216. Epub 2011 Jan 31.21. Grunberg SM. Antiemetic activity of corticosteroids in patients receiving can-cer chemotherapy: dosing, efficacy and tolerability analysis. Ann Oncol. 2007;18:233-240. Epub 2006 Nov 15.22. The Italian Group for Antiemetic Research. Double-blind, dose-finding study offour intravenous doses of dexamethasone in the prevention of cisplatin-inducedacute emesis. J Clin Oncol. 1998;16:2937-2942.23. The Italian Group for Antiemetic Research. Randomized, double-blind, dose-finding study of dexamethasone in preventing acute emesis induced by anthracy-clines, carboplatin, or cyclophosphamide. J Clin Oncol. 2004;22:725-729.24. Celio L, Frustaci S, Denaro A, et al. Palonosetron in combination with 1-dayversus 3-day dexamethasone for prevention of nausea and vomiting following mod-erately emetogenic chemotherapy: a randomized, multicenter, phase III trial. SupportCare Cancer. 2011;19:1217-1225. Epub 2010 Jun 25.25. Aapro M, Fabi A, Nolè F, et al. Double-blind, randomized, controlled study ofthe efficacy and tolerability of palonosetron plus dexamethasone for 1 day with orwithout dexamethasone on days 2 and 3 in the prevention of nausea and vomitinginduced by moderately emetogenic chemotherapy. Ann Oncol. 2010;21:1083-1088.26. Curran MP, Robinson DM. Aprepitant: a review of its use in the prevention ofnausea and vomiting. Drugs. 2009;69:1853-1878.27. Aapro MS, Walko CM. Aprepitant: drug-drug interactions in perspective. AnnOncol. 2010;21:2316-2323. Epub 2010 May 20.28. Lasseter KC, Gambale J, Jin B, et al. Tolerability of fosaprepitant and bioequiva-lency to aprepitant in healthy subjects. J Clin Pharmacol. 2007;47:834-840. Epub2007 May 24.29.Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the preventionof chemotherapy-induced nausea and vomiting associated with cisplatin therapy:randomized, double-blind study protocol—EASE. J Clin Oncol. 2011;29:1495-1501.Epub 2011 Mar 7.30. Tan L, Liu J, Liu X, et al. Clinical research of olanzapine for prevention ofchemotherapy induced nausea and vomiting. J Exper Clin Can Res. 2009;28:131-137.31. Jackson WC, Taverneir L. Olanzapine for intractable nausea in palliative carepatients. J Palliat Med. 2003;6:251-255.32. Srivastava M, Brito-Dellan N, Davis MP, et al. Olanzapine as an antiemetic inrefractory nausea and vomiting in advanced cancer. J Pain Symptom Manage.2003;25:578-582.33. Cruz FM, Cubero DIG, Taranto P, et al. Gabapentin for the prevention ofchemotherapy-induced nausea and vomiting: a pilot study. Support Care Cancer.Epub 2011 April 5.

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New Data: 5-Year Median Follow-up

W

P

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In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies▼ Of the 69% of MP patients who received subsequent therapies,

50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

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5-Lohr_Cover 12/19/11 11:23 AM

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IMPORTANT SAFETY INFORMATIONVELCADE Warnings and Precautions ▼ Women should avoid becoming pregnant while being treated

with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

▼ Peripheral neuropathy, including severe cases, may occur—manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

▼ Patients with risk factors for, or existing heart disease, should be closely monitored

▼ Acute diffuse infiltrative pulmonary disease has been reported

▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement

▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Adverse Reactions Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page.

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5-Lohr_Cover 12/19/11 11:24 AM

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

V-11-0264 12/11

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5-Lohr_Cover 12/19/11 11:24 AM

REVIEW ARTICLE

25www.JHOPonline.com l Journal of Hematology Oncology Pharmacy lVol 1, No 4 l December 2011

Chronic myelogenous leukemia (CML) is ahematologic malignancy initiated by a translo-cation event that results in the fusion of the

breakpoint cluster region (BCR) of chromosome 22with the Abelson leukemia oncogene (ABL) tyrosinekinase on chromosome 9 in bone marrow stem cells.This chromosomal abnormality is known as thePhiladelphia (Ph) chromosome.1,2

The dysregulation of ABL kinase activity transformsthe stem cell, resulting in the production of undifferen-tiated blasts as opposed to normally differentiatedwhite blood cells. Left untreated, CML progresses

through an indolent chronic phase to a lethal phase ofblast crisis within 3 to 5 years.1

Before the advent of tyrosine kinase inhibitor (TKI)therapy, median survival for patients who had pro-gressed to advanced disease—the accelerated phase—ranged from 6 to 39 months.3,4 For patients in blast cri-sis, survival was from 2 to 8 months.5,6

Historically, conventional cytotoxic agents such asbusulfan and hydroxyurea were used to control periph-eral blood counts but did not prevent the progression ofdisease.1,7 Therapy would become less effective after 3to 5 years of treatment, after which the disease wouldtransform to accelerated phase or blast crisis. Interferon(IFN)-alpha was the first therapy that was demonstrat-ed to increase overall survival (OS) in CML, and sur-vival was marginally increased with the addition oflow-dose cytarabine.8

Dr Greisl is Oncology Clinical Pharmacist, Department ofPharmacy, and Dr Fausel is Clinical Director, OncologyPharmacy Services, Indiana University Simon CancerCenter, Indianapolis.

The Evolution of Tyrosine KinaseInhibitor Therapy: Improving Outcomesin Patients with Newly DiagnosedChronic Myelogenous LeukemiaNatalie J. Greisl, PharmD; Christopher A. Fausel, PharmD, BCPS, BCOP

Background: Before 2001, therapy for chronic myelogenous leukemia (CML) was mainlylimited to hydroxyurea, interferon (IFN)-alpha, and allogeneic stem-cell transplant (SCT).Additional therapies, including busulfan, hydroxyurea, cytarabine, and splenic radiation,were used; however, they had limited efficacy in CML. Objective: To review the advances in the pharmacotherapy of chronic-phase CML (CML-CP)and highlight the clinical data regarding the use of dasatinib and nilotinib in patients with newlydiagnosed CML-CP. Discussion: Only allogeneic SCT provides the potential for long-term, disease-free survival inCML-CP, but suitable donors are lacking for many patients, and the associated toxicity is formi-dable. Imatinib mesylate was initially shown to have superior activity in achieving hematologic andcytogenetic responses relative to IFN-based therapy in patients with IFN-alpha–refractory diseaseand, later, in newly diagnosed patients with CML-CP. In recently published phase 3 randomizedtrials that compared nilotinib and dasatinib with imatinib in patients with newly diagnosed CML-CP, significantly improved rates of molecular response and cytogenetic remission were seen at18 months of follow-up with dasatinib and 24 months of follow-up with nilotinib. On the basis ofthese trials, dasatinib and nilotinib received US Food and Drug Administration approval in 2010for the treatment of newly diagnosed adults with Philadelphia chromosome–positive CML-CP.Conclusion: The post-imatinib era for first-line treatment of CML is emerging, but long-term dataare needed to confirm the optimal therapy for newly diagnosed disease. Because of the relative-ly immature data in first-line therapy with second-generation tyrosine kinase inhibitors, it remainsto be seen whether an increase in response rates will translate into longer progression-free sur-vival, and whether the toxicities associated with nilotinib and dasatinib will decrease over time.

J Hematol Oncol Pharm.2011;1(4):25-32.www.JHOPonline.comDisclosures are at end of text

6-Greisl_Cover 12/19/11 11:26 AM

REVIEW ARTICLE


A transformative discovery in cancer therapeuticswas the characterization of the adenosine triphosphate(ATP) binding site on the BCR-ABL tyrosine kinase,and its role in imatinib-mediated inhibition of thatkinase.9 Imatinib, a BCR-ABL TKI, became standardfirst-line therapy when it was shown to be superior toIFN-alpha plus cytarabine therapy.10 However, muta-tions in the BCR-ABL tyrosine kinase binding siteinduce imatinib resistance in some patients, necessitat-ing active second-line therapy, which led to the devel-opment and the US Food and Drug Administration(FDA) approval of 2 second-generation TKIs—dasa-tinib and nilotinib. As discussed below, these 2 agentshave been shown to achieve cytogenetic remissionsand molecular responses in patients with CML who areintolerant of or whose disease is refractory to imatinib.

This review discusses the advances in the pharma-cotherapy of chronic-phase CML (CML-CP) and high-lights the clinical data regarding the use of dasatiniband nilotinib in patients with newly diagnosed disease.

The Pre-Imatinib EraBusulfan was a frontline treatment for CML when in

1963 a clinical trial demonstrated its superiority over 6-mercaptopurine therapy during an era when the goal oftherapy for patients with CML was limited to normal-ization of the white blood cell count.11 Hydroxyurea,originally synthesized almost a century earlier, wasfound to have antileukemic effects in mice and wassubsequently investigated as a therapy for CML.12

Metabolic experiments in that study suggested thathydroxyurea inhibited DNA synthesis, thereby block-ing the proliferation of transformed blasts. Additionalclinical studies demonstrated that hydroxyureaimproved survival in patients with CML by extendingthe length of the chronic phase.13,14 As recently as1993, the median survival for a patient with CML-CPtaking hydroxyurea as a frontline medication wasapproximately 5 years.14 Busulfan and hydroxyureahave minimal potential to induce cytogenetic responseand do not alter the disease course of CML.13,14

In the 1980s, IFN-alpha, a nonspecific, immune-mod-ulating agent, advanced into clinical trials for the treat-

ment of patients with CML. In randomized clinical trials,IFN-alpha demonstrated efficacy by its ability to induce atleast partial hematologic responses in 55% to 86% ofpatients, at least minor cytogenetic responses of 10% to52%,8,15-18 a 12% to 20% absolute improvement in the 5-year survival rate, and an increase in median OS of 1 to 2years over previous therapies.19

IFN-alpha has a considerable toxicity profile thatincludes flulike symptoms along with arthralgia andmyalgia and depression.8,20

A study comparing therapy with IFN-alpha mono -therapy and IFN-alpha plus cytarabine in patients withrecently (≤6 months) diagnosed CML-CP showed thatthe 3-year OS increased from 79.1% among patientsreceiving IFN-alpha alone to 85.7% among thosereceiving IFN-alpha plus cytarabine.8 In addition, com-bination therapy increased the percentage of patientswho achieved a major cytogenetic response (MCyR)from 24% to 41%.8

Allogeneic stem-cell transplant (SCT) is the onlyproved option for achieving cure in CML. After a 3- to5-year follow-up, disease-free survival of patients withgood prognostic factors undergoing transplant fromhuman leukocyte antigen (HLA)-matched relateddonors can be as high as 78%; it ranges from 46% inpatients aged >40 years to 61% in patients aged <30years, for HLA-matched unrelated donors.21,22

Because of age limitations, the limited availability ofappropriately matched donors, and the toxicities asso-ciated with treatment, only 30% of patients with CMLmeet the eligibility criteria for allogeneic SCT, pre-cluding its widespread use.23-26 Furthermore, in additionto long-term complications, such as infections and sec-ondary malignancies, late relapses have been seen aslong as 14 years or more after transplant.27-29

The Imatinib EraThe introduction of imatinib, a multikinase

inhibitor with high specificity for the inhibition ofBCR-ABL activity, revolutionized the treatment ofCML.30 Imatinib was developed from a small-moleculelibrary in a screening for inhibitors of protein tyrosinekinases.31 Imatinib competes with ATP for binding tothe BCR-ABL tyrosine kinase in a region known as thephosphate-binding loop (P-loop).9 The interaction ofimatinib with the BCR-ABL tyrosine kinase is confor-mationally sensitive; only the closed conformation ofthe P-loop serves as a binding site. Cell-culture studiesconfirmed that imatinib inhibited the growth of CMLblasts in vitro.31

Imatinib was studied in a phase 1 dose-escalationtrial that examined 83 patients with CML-CP in whomIFN-alpha therapy had failed.32 Patients were succes-

Because of age limitations, the limitedavailability of appropriately matcheddonors, and the toxicities associated withtreatment, only 30% of patients with CMLmeet the eligibility criteria for allogeneicSCT, precluding its widespread use.


sively assigned to dosing groups ranging from 25 mg to1000 mg daily. All doses were well tolerated, and themost common adverse events (AEs) reported were nau-sea, myalgia, edema, and diarrhea.32 Of the 54 patientswho received a dose of 300 mg or more, 98% achievedcomplete hematologic response, 54% achieved cyto-genic response, and 13% achieved complete cytogenicresponse (CCyR).32 In a second analysis of this study, patients with CML

who had progressed to blast crisis also responded toimatinib, but to a lesser extent.33 A total of 38 patientswith CML were in myeloid blast crisis and 20 patientseither had Ph-positive (Ph+) acute lymphoblasticleukemia (ALL) or were in lymphoid blast crisis.Although 21 of the 38 patients (55%) in myeloid blastcrisis responded with a decrease in blasts in the marrow,only 4 (19%) of them achieved complete hematologicresponse. Although 70% of the patients with ALL/lym-phoid blast crisis responded to imatinib, the diseasesubsequently relapsed in virtually all the responders.33In a phase 2 study, 454 patients with CML-CP in

whom IFN-alpha therapy had failed were treated withoral imatinib 400 mg once daily.34 Complete hemato-logic response was achieved by 95% of the patients andMCyR was achieved by 60% of patients. After a meanfollow-up of 18 months, 89% of the patients remainedin chronic phase and 95% were still alive. IntolerableAEs led to imatinib discontinuation in only 2.1% ofthe patients. The most common AEs consisted ofsuperficial edema, nausea, and muscle cramps.34In the IRIS (International Randomized Study of

Interferon Versus STI571) study, a phase 3, open-label,randomized, controlled trial, imatinib was compareddirectly with IFN-alpha plus cytarabine as frontline treat-ment for newly diagnosed CML.10 A total of 553 patientsreceived 400 mg imatinib daily; the IFN-alpha plus cytara-bine group (N = 553) received gradually escalating dosesof IFN-alpha, up to 5 million U/m2 of body surface areadaily. When the maximum tolerated dose was reached,subcutaneous low-dose cytarabine was added to the regi-men for 10 days monthly.10 The study design allowed patient crossover from IFN-

alpha plus cytarabine to imatinib if patients showed noresponse to treatment, lost response, or had an AE; amajority of the patients (57.5%) crossed over to the ima-tinib group, and more than one third (43%) who crossedover did so because of intolerance of IFN-alpha.10 The analyzed results did not account for outcomes in

patients who crossed over to alternative therapies. Theimatinib arm demonstrated greater complete hemato-logic response (95.3% vs 55.5%, respectively; P <.001),MCyR (85.2% vs 22.1%; P <.001), and CCyR (73.8%vs 8.5%; P <.001) compared with the IFN-alpha plus

cytarabine arm. At 12 months, progression-free sur-vival (PFS) was 96.6% for the imatinib group and79.9% for the IFN-alpha group (P <.001).10 The 5-yearfollow-up demonstrated an increase in CCyR to 82%and OS of 89%.35 Only 6% of the patients randomizedto imatinib progressed to accelerated-phase or blast-phase CML, and these progression events occurred pri-marily within the first 2 to 3 years of treatment.35Two important analyses performed in the 5 -year fol-

low-up of the IRIS study demonstrated the association ofresponse at 12 months with long-term disease outcomes.In the first analysis, 97% of 350 patients who achievedCCyR by 12 months of imatinib treatment had not pro-gressed to accelerated-phase or blast-phase CML duringthe 5-year follow-up.35 Of the 139 patients who achievedCCyR and a major molecular response (MMR)—definedas ≥3-log reduction in BCR-ABL transcripts—at 12months, 100% remained free of progression to acceleratedphase or blast phase at 5 years. AEs decreased over time,and their general profile did not change.35

The results at 8-year follow-up were presented in2009.36 The estimated event-free survival (81%) andOS (85% when all causes are considered, 93% consid-ering only CML-related deaths) continue to remainhigh and stable. No new toxicities were identified, andonly 1 patient had disease progression.36Some patients develop resistance to imatinib prima-

rily in response to the emergence of cells containingBCR-ABLmutations unresponsive to imatinib. Most ofthese mutations occur in the kinase domain of thefusion protein.37 In addition, for some patients, the AEsare not tolerable and preclude the use of imatinib.

The Post-Imatinib EraThe second-generation TKIs dasatinib and nilotinib

were initially studied as treatment alternatives forpatients with imatinib-resistant or -intolerant CML.Dasatinib and nilotinib are capable of inhibiting mostBCR-ABL mutations, with the exception of the T315Imutation, which is resistant to all currently availableTKIs.38,39 The safety and efficacy of nilotinib and dasa-tinib were first established in the second-line setting inpatients with imatinib-resistant or -intolerant CML.

The Evolution of Tyrosine Kinase Inhibitor Therapy


Some patients develop resistance toimatinib primarily in response to theemergence of cells containing BCR-ABLmutations unresponsive to imatinib. Mostof these mutations occur in the kinasedomain of the fusion protein.


REVIEW ARTICLE


NilotinibNilotinib (originally known as AMN107) was

rationally designed through close examination of thecrystal structure of the imatinib/BCR-ABL tyrosinekinase complex.40 Nilotinib binds to the closed-loopstructure of the BCR-ABL tyrosine kinase. However,additional interaction sites between the BCR-ABLtyrosine kinase and nilotinib allow the drug to bindwith a much greater affinity than imatinib. The poten-cy of nilotinib for inhibition of the wild-type BCR-ABL is 20 to 40 times greater than that of imatinib, andits potency for inhibition of many BCR-ABLmutationsis much greater than that of imatinib.41 Although nilotinib binds to the BCR-ABL tyrosine

kinase with high affinity, its binding to other tyrosinekinases is largely reduced and is generally not significantat clinical doses.42 Nilotinib’s greater selectivity versusimatinib is seen in its higher affinity for the BCR-ABLtyrosine kinase, its similar inhibition of platelet-derivedgrowth factor and c-KIT receptor tyrosine kinases, and itslack of activity against a wide range of other protein kinas-es, including the C-Src oncogene.40The efficacy and safety of nilotinib were initially

reported in an open-label, phase 2 study of patients withimatinib-resistant or -intolerant CML-CP.43 At 6 monthsof follow-up, 48% of the patients achieved MCyR and31% achieved CCyR. The estimated 1-year OS was 95%:nilotinib was well tolerated in these patients. In responseto these positive data, nilotinib received FDA approval in2007 for second-line treatment of CML-CP. At 24 months of follow-up, 46% of patients

achieved CCyR with nilotinib therapy, 56% of whomachieved an MMR.44 The estimated PFS rate was 64%,and OS was 87% at 24 months, with no changes in thesafety profile.44 The efficacy and safety of nilotinib in the frontline

setting were evaluated in a phase 2 trial of 51 patientswith newly diagnosed CML-CP.45 By 3 months, 90% ofthe patients achieved CCyR; by 6 months, that per-

centage increased to 96%. At 12 months, 81% of thepatients achieved an MMR. The estimated event-freesurvival at 24 months was 90%; transformation-freesurvival was 98%.45 The most common AEs were increased liver

transaminase activity or bilirubin levels, skin rash,fatigue, hyperglycemia, neutropenia, anemia, andthrombocytopenia.45 Most AEs were grade 1 or 2.Grade 3 and 4 AEs included elevation of bilirubin,lipase, or amylase levels. Cardiac events were rare; 2patients developed hypertension, and 2 developed aprolonged corrected QT (QTc) interval; none of theseAEs was grade 3 or 4.45 A second phase 2 trial was conducted by the

GIMEMA (Gruppo Italiano Malattie e Matologichedell’Adulto) CML Working Party to investigate nilotinibas a first-line therapy in 73 patients with newly diagnosedCML.46 All patients achieved complete hematologicresponse within 3 months. By 6 months, 96% achievedCCyR, and by 12 months 85% achieved an MMR. AEswere similar to those observed in the previous trial.45,46 Arecent 3-year analysis demonstrated the durability ofnilotinib responses in patients with newly diagnosedCML, without any new safety concerns.47Nilotinib has been compared with imatinib in the

ENESTnd (Evaluating Nilotinib Efficacy and Safety inClinical Trials–Newly Diagnosed Patients) trial, aphase 3 open-label study (Table 1).48 A total of 846patients with newly diagnosed CML-CP were random-ized in a 1:1:1 ratio into 3 arms: nilotinib 300 mg twicedaily, nilotinib 400 mg twice daily, or imatinib 400 mgonce daily (the control arm). The primary end pointwas MMR at 12 months.48At data cutoff, the MMR rates for the 300-mg and

400-mg nilotinib arms were 57% and 54%, respective-ly, compared with 30% in the imatinib arm.48 Themedian time to MMR, as estimated by a Kaplan-Meieranalysis, was shorter for the 300-mg nilotinib (8.6months) and 400-mg nilotinib (11.0 months) groups

Table 1 Nilotinib versus Imatinib: Treatment Discontinuation and Adverse Events in the ENESTnd Study

Nilotinib 300 mg bid (N = 282)

Nilotinib 400 mgbid (N = 281)

Imatinib 400 mg/day(N = 283)

Median dose, mg/day (range) 592 (543-600) 779 (581-800) 400 (389-400)

Median duration of treatment, mo 14 14 14

Discontinuation, N (%) 46 (16) 51 (18) 59 (21)Adverse events leading to discontinuation, N (%) 13 (28) 26 (51) 21 (35.6)Other reason for discontinuation, N (%) 33 (72) 25 (49) 38 (64.4)

ENESTnd, indicates Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients.Source: Reference 48.

6-Greisl_Cover 12/19/11 2:09 PM

compared with the imatinib arm (median not yetreached).48Complete molecular response (defined as <0.0032% of

baseline transcripts on the International Standard) at thedata cutoff was 13% and 12%, respectively, for the nilo-tinib 300-mg and 400-mg arms and 4% for the imatinibarm.48 CCyR rates by 12 months were significantly greaterin the 2 nilotinib arms compared with the imatinib arm(80% with nilotinib 300 mg and 78% with 400 mg vs 65%with imatinib; P <.001 for both comparisons).48Progression to accelerated-phase or blast-phase

CML occurred in 11 patients (4%) receiving imatinibcompared with 3 patients (<1%) receiving nilotinib (2in the 300-mg arm and 1 in the 400-mg arm).48Although no patient who attained an MMR had pro-gressed, 3 patients receiving imatinib who hadachieved CCyR progressed. Nilotinib was superior toimatinib in terms of the time to progression (P = .01 forthe 300-mg group and P = .004 for the 400-mg groupcompared with the imatinib-treated group).48Overall, grade 3 or 4 nonhematologic AEs were

uncommon. The incidence of nausea, diarrhea, vomit-ing, muscle spasm, and edema were higher in the ima-tinib arm, whereas rash, headache, pruritus, and ele-vated liver enzymes were higher in the nilotinib arms.48No patient had a QTc longer than 500 milliseconds ora decreased left-ventricular ejection fraction. Grade 3or 4 hematologic abnormalities occurred within thefirst 2 months of therapy for both treatments.48Recently, results of a 24-month analysis were pre-

sented, demonstrating that the responses observed withnilotinib were durable; no new safety concerns emergedwith longer follow-up.49 In mid-2010, this trial led tothe approval of nilotinib for the treatment of newlydiagnosed CML-CP in treatment-naïve patients.

DasatinibDasatinib (originally known as BMS-354825) was

identified through a screening of a small-moleculelibrary for inhibitors of the C-Src kinase.50 The affinityof dasatinib for the BCR-ABL fusion gene is 325-foldhigher than that of imatinib.42 Dasatinib can bind toopen and closed conformations of the BCR-ABL tyro-sine kinase as well as to most BCR-ABL mutations. Inaddition, dasatinib has inhibitory activity against theC-Src kinase, c-KIT, and the platelet-derived growthfactor receptors.42,50 The efficacy and safety of dasatinib were demonstrated

in a phase 2 study involving patients with imatinib-resist-ant or -intolerant CML-CP.51 At 8 months of treatment,90% of the patients achieved complete hematologicresponse, 52% achieved an MCyR, and the PFS rate was92%. Dasatinib was well tolerated, and there was no cross-

intolerance with imatinib.51 Follow-up at 15 months indi-cated 91% of patients achieved complete hematologicresponse and 59% maintained or attained MCyR; PFSwas 90%, and OS was 96%.52A recently published phase 2 study established the

safety and efficacy of dasatinib in the frontline set-ting.53 A total of 62 patients were randomized toreceive 100 mg once daily or 50 mg twice daily untileither disease progression or an unacceptable AEoccurred. The primary end point was an MMR in<40% of the treatment group within 12 months (theaverage response rate for imatinib).53Efficacy was similar for the 2 dosages. At 3 months,

82% of the patients achieved a CCyR, and 24%achieved an MMR. By 12 months, 98% of the patientsachieved CCyR and 71% achieved an MMR.Complete molecular response was achieved by 7% ofthe patients; however, this was lost by 30 months.53

Muscle and joint pain, fatigue, rash, headache, anddiarrhea were the most common nonhematologic AEs.Grade 3 and 4 nonhematologic AEs consisted offatigue (6%), joint and muscle pain (6%), peripheralneuropathy (5%), dyspnea (5%), and memory impair-ment (5%). Pleural effusion occurred in 13% of thepatients; 2% of these events were grade 3 in severity.Hematologic toxicities included neutropenia (63%),anemia (81%), and thrombocytopenia (69%).53 The DASISION (Dasatinib versus Imatinib Study

in Treatment-Naïve CML Patients) trial examinedfrontline treatment with dasatinib in comparison withimatinib.54 A total of 519 patients with newly diag-nosed CML-CP were randomized to 1 of 2 arms: dasa-tinib 100 mg daily or imatinib 400 mg daily. The pri-mary end point was a confirmed CCyR by 12 months.Confirmation required 2 measures of CCyR, at least 28days apart.54 Of the patients receiving dasatinib, 77%achieved confirmed CCyR versus 66% of imatinib-treated patients (P = .007). The rate of MMR, a sec-ondary end point, was 46% versus 28%, respectively, at12 months of follow-up (P <.001).54



A recently published phase 2 studyestablished the safety and efficacy ofdasatinib in the frontline setting. At 3months, 82% of the patients achieved aCCyR, and 24% achieved an MMR. By 12months, 98% of the patients achieved CCyRand 71% achieved an MMR.


REVIEW ARTICLE


An examination of the subpopulation of patients ineach arm who had achieved CCyR showed a greaterMMR rate with dasatinib than with imatinib (54% vs39%, respectively; P = .002).54 Progression to acceleratedphase or blast phase occurred in 5 patients (1.9%) in thedasatinib arm and in 9 patients (3.5%) in the imatinib

arm. At 12 months, the estimated rates of PFS were indis-tinguishable for the 2 groups (96% vs 97%, respectively).The OS was 97% for the dasatinib arm and 99% for theimatinib arm.54 AEs for the 2 treatment groups were primarily grade 1

and 2; however, the pattern of specific AEs was distinctfor the 2 treatments. Nausea, vomiting, muscle inflam-mation, rash, and fluid retention occurred more frequent-ly in the imatinib group.54 Pleural effusion, headache, andcytopenias were more frequent in the dasatinib group.Gastrointestinal or other bleeding events occurred in 5%of patients in the dasatinib and imatinib arms. Onepatient in each group had a QTc interval longer than 500milliseconds.54The recently reported 18-month DASISION results

showed that cytogenetic and molecular responsesremained higher in the dasatinib arm than in the ima-tinib arm and were associated with no new safety con-cerns (Table 2).55 Since 2006, dasatinib has been avail-able for the treatment of imatinib-resistant or -intolerantCML-CP, CML in blast phase, or CML in acceleratedphase. In October 2010, dasatinib received FDA approvalfor the treatment of newly diagnosed CML-CP. The 2011National Comprehensive Cancer Network guidelinesrecommend the use of imatinib, nilotinib, or dasatinib astreatment options for patients with newly diagnosedCML-CP.56Perhaps the most important differentiator between the

2 second-generation TKIs dasatinib and nilotinib is theirsafety profile. Compared with imatinib, nilotinib showeda relative increase in rash, headache, and pruritus, where-as dasatinib showed a relative increase in pleural effusion,headache, and cytopenia (Table 3).

Future TherapiesAurora kinase inhibitors, such as VX-68057 and

PHA-739358,58 inhibit the BCR-ABL T315I mutation,as well as other mutations. The investigational agentbosutinib has been evaluated in a phase 2 trial of 288patients with CML-CP who had been previously treat-ed with imatinib.59 After a median of 24.2 months offollow-up, 53% achieved an MCyR—the primary endpoint of the trial—and 41% achieved CCyR. Of the patients who achieved CCyR, 64% attained

an MMR. The drug was well tolerated, and the most frequently reported AE was gastrointestinal toxicity.Notably, bosutinib is not active against BCR-ABLmuta-tions with the T315I mutation.59 AP24534 (ponatinib)—a second investigational drug

that has activity in inhibiting BCR-ABL T315I—isbeing studied in a phase 2 trial of 320 patients withCML-CP, CML in accelerated phase, or CML in blastphase and Ph+ ALL.60 The study will include patients

Table 2 Dasatinib versus Imatinib: Treatment Discontinuation and Adverse Events in the DASISION Study

Dasatinib 100 mg once daily (N = 258)

Imatinib 400 mg once daily (N = 258)

Median dose, mg/day(range)

99 (21-136) 400 (125-657)

Median duration oftreatment, mo

14.0 14.3

Discontinuation, N (%)

40 (15.5) 48 (18.6)

Reason for discontinuationDrug-related AEs, N (%)

13 (5.0) 11 (4.3)

Hematologic AEs, N (%)

4 (1.6) 8 (3.1)

Treatment failure, N (%)

6 (2.3) 10 (3.9)

No CHR or CyR by6 mo, N (%) ± SD

2 (0.8) 4 (1.6)

PCyR at 12 mo, N (%)

3 (1.2) 6 (2.3)

No CCyR at 18 mo,N (%)

1 (0.4) 0

AE unrelated todrug, N (%)

3 (1.2) 1 (0.4)

Withdrew consent,N (%)

2 (0.8) 3 (1.2)

Became pregnant, N (%)

2 (0.8) 0

Did not adhere totherapy, N (%)

0 2 (0.8)

Lost to follow-up, N (%)

0 3 (1.2)

Request to discontinue, N (%)

2 (0.8) 1 (0.4)

Other reason, N (%) 1 (0.4) 3 (1.2)

AEs indicate adverse events; CCyR, complete cytogenetic response;CHR, complete hematologic response; CyR, cytogenetic response; DASISION, Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients; PCyR, partial cytogenetic response.Source: Reference 54.




with CML or ALL resistant to or intolerant of nilotinibor dasatinib or who have the T315I mutation. As these newer agents accumulate additional clini-

cal experience, the prospect for additional treatmentoptions for patients with CML refractory to first-linetreatment will be expanded.

ConclusionsThe improvement in outcomes with imatinib therapy

has ushered in a new era of CML management and pro-vided the impetus for the further development of targetedtherapies for cancer. The improved efficacy of nilotiniband dasatinib in achieving MMR and CCyR with earlyfollow-up suggests a potential change in the first-linetreatment of CML. There are no prospective head-to-head studies comparing the efficacy and safety of dasatiniband nilotinib in either the first-line or second-line treat-ment settings, making a direct comparison infeasible. The post-imatinib era for first-line treatment of CML

is emerging, but long-term follow-up is needed to confirmthe optimal therapy for newly diagnosed CML. Because ofthe relatively immature data in frontline therapy with sec-ond-generation TKIs, it is unknown whether an increasein the rates of CCyR and MMR translate into improve-ment in long-term freedom from disease progression andwhether the toxicities associated with nilotinib and dasa-tinib will decrease over time, as was observed in the IRISstudy with imatinib. Careful analysis is necessary to eluci-date the potential resistance profiles that may emerge fordasatinib and nilotinib. The emergence of second-generation TKIs for first-line

treatment of CML has raised the question of what theoptimal treatment standard is for second-line therapy. Theimpact of TKI therapy on the role of allogeneic SCT is

still being investigated. It is not yet known whether theadministration of TKIs after allogeneic SCT will improvelong-term disease control or treat relapsed Ph+ disease;however, work in this area is ongoing.61,62 ■

AcknowledgmentsFinancial support for medical editorial assistance

was provided by Novartis Pharmaceuticals. We thankRobert Scheinman, PhD, and Patricia Segarini, PhD,of Percolation Communications LLC, for their medicaleditorial assistance.

Author Disclosure Statement Dr Fausel is on the Speaker’s Bureau of Millennium Pharm -

aceuticals. Dr Greisl has reported no conflicts of interest.

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Table 3 Oral Dosages, Interactions, and Adverse Reactions of Tyrosine Kinase InhibitorsImatinib Dasatinib Nilotinib

Chronic-phase CML dose 400 mg/day 100 mg/day 300 mg bidAccelerated-phase or blast-crisis CML dose

600 mg/day or 400 mg bid

140 mg/day 400 mg bid

Metabolism CYP3A4 substrate/inhibitor CYP3A4 substrate CYP3A4 substrate CYP 2C8, 2C9, 2D6 and 3A4 inhibitor

Food intake with drug With food With/without food Without foodAdverse drug reactions Generalized edema

Periorbital edemaHeadacheRashNausea/vomitingMyelosuppression

EdemaHeadacheRashNausea/vomitingMyelosuppressionQTc prolongationPleural effusion

EdemaHeadacheRashNausea/vomitingMyelosuppressionQTc prolongation

CY indicates cytochrome; CML, chronic myeloid leukemia; QTc, corrected QT.

6-Greisl_Cover 12/19/11 1:17 PM

REVIEW ARTICLE


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Five-year fol-low-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med.2006;355:2408-2417.36. Deininger M, O’Brien SG, Guilhot F, et al. International Randomized Study ofInterferon vs STI571 (IRIS) 8-year follow-up: sustained survival and low risk for pro-gression or events in patients with newly diagnosed chronic myeloid leukemia inchronic phase (CML-CP) treated with imatinib. Blood. 2009;114:Abstract 1126. 37. Tauchi T, Ohyashiki K. Molecular mechanisms of resistance of leukemia toimatinib mesylate. Leuk Res. 2004;28(suppl 1):S39-S45.

38. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CMLand Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542-2551.39. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABLkinase inhibitor. Science. 2004;305:399-401.40. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, aselective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141.41. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidineinhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloidleukemia. Clin Cancer Res. 2005;11:4941-4947.42. Giles FJ, O’Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors inthe treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698-1707. Epub2009 May 28.43. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107),a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients withPhiladelphia chromosome-positive chronic myelogenous leukemia in chronicphase following imatinib resistance and intolerance. Blood. 2007;110:3540-3546.Epub 2007 Aug 22.44. Kantarjian HM, Giles FJ, Bhalla KN, et al. Update on imatinib-resistant chronicmyeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24months: clinical response, safety, and long-term outcomes. Blood. 2009;114:Abstract1129. 45. Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front-line treatment for patientswith chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392-397.Epub 2009 Dec 14.46. Rosti G, Palandri F, Castagnetti F, et al, for the GIMEMA CML Working Party.Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood.2009;114:4933-4938. Epub 2009 Oct 12.47. Rosti G, Castagnetti F, Gugliotta G, et al. 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Dasatinib induces notable hema-tologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after fail-ure of imatinib therapy. Blood. 2007;109:2303-2309. Epub 2006 Nov 30.52. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytoge-netic responses in patients with chronic myelogenous leukemia in chronic phase withresistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206. Epub 2008 Apr 10.53. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients withearly chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398-404. Epub2009 Dec 14. 54. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newlydiagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub 2010 Jun 5.55. Shah N, Kantarjian H, Hochhaus A, et al. Dasatinib versus imatinib in patientswith newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in theDASISION trial: 18-month follow-up. 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Brian G. Cochran, PharmD, BCOP

Michael B. Crockerham, MS, PharmD

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The Editors of the Journal of Hematology Oncology Pharmacy wish to extend aheartfelt Thank You to all those who participated in the peer-review processduring 2011. Your diligence and careful comments go a long way to ensure

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FROM THE LITERATURE


■ A Phase 3 Trial Comparing Axitinib and Sorafenibin Advanced Renal-Cell Cancer

Background: More than 170,000 people are diagnosedannually with renal carcinoma, resulting in 72,000deaths and a 30% relapse rate. Many patients are resis -tant to existing chemotherapy and cytokine treatments.However, the treatment of advanced renal-cell cancershas been changing through the use of drugs that inhibitangiogenesis by targeting the vascular endothelialgrowth factor receptors. This is the first phase 3 clinicaltrial to compare the effectiveness of 2 second-generationantiangiogenic agents—axitinib and sorafenib—in thetreatment of metastatic renal-cell cancer.

Design: This multicenter, randomized, unmasked,phase 3 clinical trial included 723 patients aged ≥18years from 175 sites, hospitals, and outpatient clinics in22 countries who had been diagnosed with renal-cell car-cinoma that had progressed despite first-line therapywith sunitinib, bevacizumab plus interferon-alfa, tem-sirolimus, or cytokines. From September 2008 to July2010, patients were randomized to axitinib 5 mg ini-tially, increased to 7 mg and then to 10 mg, twice daily(N = 361) or to sorafenib 400 mg twice daily (N = 362).Patients were randomized according to previous treat-ment type and Eastern Cooperative Oncology Group(ECOG) performance score. The primary end point wasprogression-free survival (PFS), assessed by a masked,independent radiology review of the intention-to-treat(ITT) population. Secondary end points were overallsurvival (OS), objective response rate, response dura-tion, and time to deterioration.

Summary: The median PFS was significantly (42%)longer with axitinib than with sorafenib (6.7 months vs4.7 months, respectively; hazard ratio [HR], 0.66; 95%confidence interval [CI], 0.54-0.81; 1-sided P <.001). Inpatients who previously received cytokines, the medianPFS was 12.1 months with axitinib and 6.5 months withsorafenib (HR, 0.46; 95% CI, 0.32-0.68; P <.001), andamong those who had received sunitinib, the medianPFS was 4.8 months and 3.4 months (HR, 0.74; 95% CI,0.57-0.96; P = .011). The objective response rate was19% with axitinib and 9% with sorafenib (P = .001), and

the median duration of response was 11 months and 10.6months, respectively. Treatment discontinuation fromtoxic effects was observed in 14 (4%) of the 359 patientswho received axitinib and 29 (8%) of the 355 patientswho received sorafenib. The most common adverseevents reported were diarrhea, hypertension, and fatiguein the axitinib group and diarrhea, palmar-plantar ery-throdysesthesia, and alopecia in the sorafenib group.

Takeaway: This new agent, axitinib, appears to be avery good second-line agent in the treatment ofadvanced renal-cell cancer. It appears to be as safe assorafenib, with a better objective response rate and alonger PFS. The maker of axitinib received a unanimous vote by

the US Food and Drug Administration (FDA) advisorycommittee favoring the use of this drug for patients withadvanced renal-cell cancer who have failed first-line sys-temic therapy. The FDA will be reviewing the product inthis setting early in 2012.

Rini BI, et al. Comparative effectiveness of axitinib versus sorafenib inadvanced renal-cell cancer. Lancet. 2011;378:1931-1939. Epub 2011 Nov 4.

■ Letrozole More Effective than Tamoxifen for Long-Term Mortality Reduction in PostmenopausalWomen with Breast Cancer

Background: Postmenopausal women with hormonereceptor–positive early invasive breast cancer are oftenmanaged with an aromatase inhibitor, such as letrozole.The aim of the Breast International Group (BIG) 1-98study was to compare tamoxifen and letrozole asmonotherapies and as sequential treatments. Because ofthe long-term risk of recurrence and death in thispatient population, an extended, 8.1-year median fol-low-up was conducted to assess patient outcomes afterthe treatment regimens ended in 2008.

Design: Currently in its twelfth year, BIG 1-98 is aninternational, randomized, phase 3, double-blind clini-cal trial with 8010 postmenopausal women (medianage, 61 years) from 148 hospitals in 27 countries whotested positive for estrogen-receptor or progesterone-

Concise Reviews of Studies Relevant toHematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section EditorClinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University—California, Mare Island Vallejo, CA

7-From theLit_Cover 12/19/11 1:18 PM

FROM THE LITERATURE


receptor cancer. Women who had evidence of metastaticdisease and previous or concurrent cancer other thanadequately treated noninvasive breast cancer, cervicalcancer, or carcinoma of the skin were excluded. Patientswere randomized to monotherapy with either letrozole2.5 mg orally once daily or tamoxifen 20 mg orally oncedaily for 5 years. They then were randomized to 1 of 4groups: monotherapy with tamoxifen or letrozole for 5years, sequential therapy with letrozole for 2 years fol-lowed by tamoxifen for 3 years, or tamoxifen for 2 yearsfollowed by letrozole for 3 years. After a significant dis-ease-free survival benefit with letrozole reported in 2005,the study protocol was amended to allow a crossover fromtamoxifen to letrozole. The final treatment phase endedin 2008. Efficacy comparisons were based on ITT analy-ses and on inverse probability of censoring weighted Coxmodels, which addressed the potential bias introducedfrom the selective crossover from tamoxifen to letrozole.The primary study end point was disease-free survival.Secondary end points included OS, distant recurrence-free interval (DRFI), and invasive breast cancer–freeinterval (BCFI).

Summary: After a median follow-up period of 8.1years, 2074 patients showed disease-free survival com-pared with 1569 patients showing disease-free survival bythe protocol-specified update in 2009. The additional 505events (a 32% increase) occurred between 2003 and2011, in the latter phases of the study. In addition, 5936(74%) of the patients were reported to be alive and with-out a disease-free survival event at their most recent fol-low-up. At a median follow-up of 8.7 years, letrozolemonotherapy was associated with significantly better dis-ease-free survival compared with tamoxifen therapy(HR, 0.82; 95% CI, 0.74-0.92; P = .002), OS (HR, 0.79;95% CI, 0.69-0.90; P = .006), DRFI (HR, 0.79; 95% CI,0.68-0.92; P = .003), and BCFI (HR, 0.80; 95% CI, 0.70-0.92; P = .002).

Takeaway: In early-stage hormone-responsive breastcancer, 5 years of letrozole monotherapy reduced bothrecurrence (HR, 0.79) and mortality (HR, 0.82) whencompared with 5 years of tamoxifen monotherapy.Sequential treatment with letrozole for 2 years, followedby 3 years of tamoxifen therapy or vice versa, was not dif-ferent from letrozole monotherapy in patients with BCFIor DRFI. With more than 8 years of follow-up, this study con-

firms that letrozole is more effective than tamoxifen in themanagement of early-stage postmenopausal breast cancer.

Regan MM, et al. Assessment of letrozole and tamoxifen alone and insequence for postmenopausal women with steroid hormone receptor-pos-itive breast cancer. Lancet Oncol. 2011;12:1101-1108.

■ Bortezomib plus Rituximab Superior to RituximabAlone in Relapsed Follicular Lymphoma

Background: Bortezomib and rituximab have demon-strated additive activity in preclinical models of lym-phoma. Both are active and usually well tolerated inpatients with follicular lymphoma (FL) and marginalzone lymphoma. A phase 3 study compared the effica-cy and safety of rituximab alone and in combinationwith bortezomib in patients who were rituximab-naiveor rituximab-sensitive and aged 18 years or older withrelapsed grade 1 or 2 disease.

Design: This unmasked, open-label, phase 3 trialincluded 676 rituximab-naïve and rituximab-sensitivepatients with relapsed grade 1 or 2 FL from 164 centersin 29 countries across Europe, the Americas, and Asiafrom April 2006 to August 2008. All patients had anECOG performance score of 0 to 2, no active centralnervous system lymphoma, and adequate hematologic,renal, and hepatic functions. Patients were excluded ifthey had grade 2 or higher peripheral neuropathy orneuropathic pain; clinical evidence of transformationto aggressive lymphoma; or treatment with antineo-plastics, investigational therapy, or radiation therapywithin 3 weeks of enrollment, nitrosoureas within 6weeks, radioimmunoconjugates or toxin immunoconju-gates within 10 weeks, stem-cell transplantation within6 months, or bortezomib at any time before randomiza-tion. Eligible patients were randomized to receive five35-day cycles of intravenous (IV) infusions of rituximab375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and on day1 of cycles 2 through 5, either alone (N = 340) or incombination with bortezomib 1.6 mg/m2 (N = 336),which was administered by IV injection on days 1, 8,15, and 22 in all treatment cycles. Randomization wasstratified by FL international prognostic index (FLIPI)score, previous use of rituximab, time since last therapy,and region. The primary end point was PFS, analyzed inthe ITT population. Secondary end points includedtime to progression, time to next treatment, and OS.

Summary: After a median follow-up of 34 months,the median PFS was 11.0 months (95% CI, 9.1-12.0) inthe rituximab group and 12.8 months (95% CI, 11.5-15.0) in the bortezomib plus rituximab group (HR,0.82; 95% CI, 0.68-0.99; P = .039). The estimated 2-year PFS rates were 23.5% and 31.2%, respectively. Ina subgroup analysis, bortezomib plus rituximab wasassociated with a longer PFS in patients with high-riskfeatures, including high FLIPI score (P = .013) andhigh tumor burden (P = .019). PFS was also signifi-cantly longer in patients aged ≤65 years (P = .005) butnot in older patients (P = .353). The combination ther-apy was also associated with a longer PFS than ritux-

7-From theLit_Cover 12/19/11 11:27 AM

FROM THE LITERATURE


imab alone in patients who received previous lines oftherapy, but the differences were not significant. Amongpatients who had received any previous rituximab thera-py, the median PFS was 9.2 months in the rituximabgroup versus 11.4 months in the bortezomib plus ritux-imab group (HR, 0.93; 95% CI, 0.70-1.24; P = .609). Ina post-hoc multivariate analysis for independent prog-nostic factors for PFS, treatment with bortezomib plusrituximab, time since last antilymphoma treatment >1year, female sex, absence of tumor burden, and stage I orII disease were associated with a longer PFS. Mostpatients in both groups who did not receive the 5-cyclemedian (range, 1-5) of treatment discontinued early inresponse to disease progression. The rate of adverseevents was higher with bortezomib plus rituximab (95%)than with rituximab alone (78%). The most commongrade 3 or higher adverse events were neutropenia, infec-tion, diarrhea, herpes zoster, nausea or vomiting, andthrombocytopenia. Drug-related adverse events leadingto death occurred in 3 (1%) patients who received bor -tezomib plus rituximab but in none of those whoreceived rituximab alone.

Takeaway: This study shows that bortezomib com-bined with rituximab improved PFS in relapsed orrefractory FL. The greatest benefit for the combina-tion was observed in patients aged <65 years and inthose with poor prognostic factors. Significantimprovements were also noted in response rates, dura-bility of response, and time to next treatment for thecombination. Bortezomib plus rituximab produced ahigher rate of adverse events, including grade 3 toxic-ities such as diarrhea, neutropenia, and infections.This is the first phase 3 study to show the benefits ofrituximab alone or in combination in relapsed orrefractory FL.

Coiffier B, et al. Bortezomib plus rituximab versus rituximab alone inpatients with relapsed, rituximab-naive or rituximab-sensitive, follicularlymphoma. Lancet Oncol. 2011;12:773-784. Epub 2011 Jul 1.

■ Second-Generation TKIs Produce Faster Responsethan Imatinib in Newly Diagnosed CML Background: The second-generation tyrosine

kinase inhibitors (TKIs) dasatinib and nilotinib havea proven efficacy in the treatment of chronic myeloidleukemia (CML) in patients resistant to or intolerantof imatinib. However, it is unknown whether theEuropean LeukemiaNet (ELN) response definitions(ie, “optimal,” “suboptimal,” and “failure”) that werebased on imatinib treatment as front-line therapy are

relevant to the second-generation TKIs, because mostpatients who receive these more potent drugs achieveearly complete cytogenetic response (CCyR).

Design: In 2 simultaneous phase 2 trials, 167 patientswith newly diagnosed CML in the chronic phase wererandomized to nilotinib 400 mg twice daily (N = 81) orto dasatinib 100 mg once daily (N = 86). At 3, 6, 12,and 18 months of therapy, the incidence of optimal, sub-optimal, and failure responses (determined according toELN guidelines) was assessed in patients who were stillreceiving therapy and had demonstrated a hematologic,cytogenetic, and/or molecular response. Also evaluatedat these time points was event-free survival, defined bythe period from the start of treatment to the loss of com-plete hematologic response, the loss of CCyR or majorcytogenetic response, the discontinuation of therapybecause of toxicity or lack of efficacy, the progression ofCML to accelerated or blastic phases, or death. Survivalprobabilities were estimated by the Kaplan-Meiermethod and compared by the log-rank test.

Summary: Overall, 155 patients (93%) achieved aCCyR after a median follow-up period of 33 months,including 146 (87%) who achieved a major molecularresponse (MMR) and 46 (28%) who achieved com-plete molecular response (CMR). At 3 months, all 160evaluable patients demonstrated optimal response (ie,complete hematologic response). By 18 months, 99(84%) of 118 evaluable patients achieved an optimalresponse. At months 6, 12, and 18, the rates of subop-timal response (ie, less than MMR) were 2%, 1%, and12%, respectively. The failure response was not demon-strated until month 18, when it occurred in 5 (4%)patients. At each time point, disease-free survival didnot differ significantly between patients who achievedCCyR without an MMR or CMR and those whoachieved CCyR with an MMR or CMR.These results confirm that second-generation TKIs

used in the frontline setting are highly efficacious, withthe majority of responses occurring within the first 3months of therapy. In contrast, imatinib therapy pro-duces CCyR rates that peak around 12 to 18 months.Since the majority of patients (99%) achieved an opti-mal response within 3 months, the ELN definitions ofresponse are not applicable in patients being treatedwith second-generation TKIs.

Takeaway: This study shows that the second-genera-tion TKIs produce CCyRs after 3 months of treatment,a much faster rate than with imatinib (ie, 12-18 monthsfor maximum response). Furthermore, this study showsthat the standard response criteria established by theELN are not appropriate for use with these second-


FROM THE LITERATURE


generation agents. The authors also propose that forpatients receiving nilotinib or dasatinib, achieving aCCyR by 3 months is considered an optimal response,and that a partial cytogenetic response is suboptimal.

Jabbour E, et al. Front-line therapy with second-generation tyrosinekinase inhibitors in patients with early chronic phase chronic myeloidleukemia. J Clin Oncol. 2011;29:4260-4266.

■ High-Risk Myelodysplastic Syndrome Outcomesafter Azacitidine Treatment Failure

Background: Treatment with azacitidine is the currentstandard of care for high-risk myelodysplastic syndrome(MDS), despite frequent primary or secondary treat-ment failure in many patients. The absence of data onoutcomes after treatment failure limits the develop-ment of clinical trials and the interpretation of theirdata. An analysis of 4 clinical trial data sets aimed todescribe those outcomes.

Design: Outcomes data from 435 patients with high-risk MDS or acute myeloid leukemia (AML) with 20%to 30% blasts who demonstrated treatment failure afterreceiving azacitidine therapy between 2000 and 2009were compiled from 4 clinical trial cohorts: the JohnsHopkins University J9950 and J0443 trials; the AZ001trial; and the French azacitidine compassionate use pro-gram database. Therapy was administered for 8 weeks inthe J9950, J0443, and AZ001 trials and for 12 weeks inthe French azacitidine compassionate use program.Patients in all cohorts continued their azacitidine regi-men until their disease progressed or intolerance to ther-apy led them to discontinue it. OS rates were estimatedusing the Kaplan-Meier method, and prognostic factorsof OS were determined from univariate analyses.

Summary: A total of 302 (74%) patients receivedtherapy for MDS, and 133 (26%) received therapy forAML. The median follow-up after azacitidine failurewas 15 months. The median OS was 5.6 months, andthe 1-year and 2-year survival probability was 28.9%and 15.3%, respectively. Factors correlated with a

shorter OS included increasing age (P = .002), male sex(P = .04), high-risk cytogenetics (P = .002), higherbone marrow blast count before azacitidine treatment(P = .04), and the absence of previous hematologicresponse to azacitidine (P = .007). In addition, amonginitial responders to azacitidine, high-risk cytogeneticswere associated with a shorter OS after treatment fail-ure (P = .03). Post-failure treatment data were availablefor 270 patients. Among this group, the prognosis wasworst for patients who received unknown salvage (OS,3.6 months) or best supportive care (OS, 4.1 months)but was best for those who received investigationalagents (overall response rate [ORR], 11%; OS, 13.2months) or allogeneic stem-cell transplantation (ORR,68%; OS, 19.5 months). Poor outcomes were alsoobserved in patients who received low-dose chemother-apy (ORR, 0%; OS, 7.3 months) or intensive AML-like chemotherapy (ORR, 14%; OS, 8.9 months).

Takeaway: This study shows that there is no standardsecond-line chemotherapy treatment for high-risk MDSafter azacitidine failure. Best supportive care or cytotox-ic chemotherapy (ie, hydroxyurea, mercaptopurine,low-dose cytarabine, low-dose melphalan, or intenseAML-like chemotherapy) were not of any substantialbenefit to these patients. A variety of investigationalagents—DNA methyltransferase enzyme inhibitorsalone or in combination with histone deacetylaseinhibitors, thalidomide-derivative (ie, lenalidomide orthalidomide), treatments for patients in clinical trialsevaluating nonregistered drugs (including immunother-apy, bryostatin, triapine, farnesyl transferase inhibitors,and mammalian target of rapamycin inhibitors)—pro-duced better OS than best supportive care or cytotoxicchemotherapy. The best outcomes were observed inpatients receiving allogeneic bone marrow transplant.The authors suggest that the results of this study can beused as a basis for comparing new agents to be used inpalliative care in future trials. ■

Prébet T, et al. Outcome of high-risk myelodysplastic syndrome afterazacitidine treatment failure. J Clin Oncol. 2011;29:3322-3327.


These highly and moderately emetogenic chemotherapy regimens increase the risk of CINV.

Breast Cancer1,2

AC (doxorubicin + cyclophosphamide)TAC (docetaxel + doxorubicin + cyclophosphamide)TC (docetaxel + cyclophosphamide)CMF (cyclophosphamide + methotrexate + fluorouracil)TCH (docetaxel + carboplatin + trastuzumab)

Lymphoma1,5

ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) CHOP (cyclophosphamide + doxorubicin + vincristine +

prednisone) ± rituximabCVP (cyclophosphamide + vincristine + prednisone)

Lung Cancer1,3

Carbo-Tax (carboplatin + paclitaxel)Cisplatin + vinorelbineCisplatin + gemcitabineCisplatin + pemetrexed

Colorectal Cancer1,6,7

FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil)CapeOX (capecitabine + oxaliplatin)IrinotecanCisplatin-based regimens

Head and Neck Cancer1,4

Cisplatin-based regimensCarboplatin-based regimens

Ovarian Cancer1,8

Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin)Cisplatin

Help stop CINV before it starts, with a regimen including EMEND, a 5-HT3 antagonist, and a corticosteroid

EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.

Selected Important Safety InformationEMEND should be used with caution in patients receiv ing c o n c o m i t a n t m e d i c a t i o n s , i n c l u d i n g c h e m o t h e r a p y agents, that are pr imar i ly metabol ized through CYP3A4. Inhib i t ion of CYP3A4 by EMEND could result in e levated plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations couldbe elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine.In clinical studies, EMEND 125 mg /80 mg was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND 125 mg / 80 mg did not inf luence the pharmacokinetics of docetaxel or vinorelbine.Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.The efficacy of hormonal contraceptives may be reduced during coadministration with EMEND and for 28 days after the last

dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND.Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle.Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10%, in patients receiving highly emetogenic chemotherapy were asthenia /fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%).In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy in patients receiving moderately emetogenic chemotherapy were alopecia (12.4% EMEND vs 11.9% standard therapy) , dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia (5.8% vs 5.6%), asthenia (4.7% vs 4.6%), and stomatit is (3.1% vs 2.7%).In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2.2-fold; therefore, the dexamethasone dose administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. See PRECAUTIONS, Drug Interactions, in the Prescribing Information for EMEND for additional information on dosage adjustment for methylprednisolone when coadministered with EMEND.Please read the Brief Summary of the Prescribing Information for EMEND on the following pages.

References: 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: antiemesis—V.1.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: head and neck cancers—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Hodgkin lymphoma—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011.

Have you included

EMEND from Cycle 1?

CINV=chemotherapy-induced nausea and vomiting.

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. 21050812(2)(901)-EME emend.com

An antiemetic regimen including

9-Opinion_WallStrJourn_Cover 12/19/11 11:29 AM Page 41

Brief Summary of the Prescribing Information for INDICATIONS AND USAGEPrevention of Chemotherapy-Induced Nausea and Vomiting (CINV): EMEND, in combination with other antiemetic agents, is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin; and for prevention of nausea and vomiting associated with

initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative nausea and vomiting.

Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting.

Chronic continuous administration is not recommended.

CONTRAINDICATIONSEMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions].

WARNINGS AND PRECAUTIONSCYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications.

Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically signifi cant degree.

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased effi cacy of EMEND [see Drug Interactions].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically signifi cant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was coadministered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions].

Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of EMEND with warfarin may result in a clinically signifi cant decrease in international normalized ratio ( INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting [see Drug Interactions].

Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the effi cacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions].

Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients.

Chronic Continuous Use: Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profi le may change during chronic continuous use.

ADVERSE REACTIONSThe overall safety of aprepitant was evaluated in approximately 5300 individuals.

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

Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone.

In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively:

Body as a whole/Site unspecifi ed: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, 3.1

Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1

Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8

Hemic and lymphatic system: neutropenia: 3.1, 2.9

Metabolism and nutrition: anorexia: 10.1, 9.5

Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1

Respiratory system: hiccups: 10.8, 5.6

In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy.

In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profi le in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy (n=846), respectively:

Blood and lymphatic system disorders: neutropenia: 5.8, 5.6

Metabolism and nutrition disorders: anorexia: 6.2, 7.2

Psychiatric disorders: insomnia: 2.6, 3.7

Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4

Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7

Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9

EMEND® (aprepitant) capsules

General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6

In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar in the 2 treatment groups.

Highly and Moderately Emetogenic Chemotherapy: The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen in either HEC or MEC studies:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection

Neoplasms benign, malignant, and unspecifi ed (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinoma

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia

Psychiatric disorders: anxiety disorder, confusion, depression

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor

Eye disorders: conjunctivitis

Cardiac disorders: myocardial infarction, palpitations, tachycardia

Vascular disorders: deep venous thrombosis, fl ushing, hot fl ush, hypertension, hypotension

Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insuffi ciency, vocal disturbance

Gastrointestinal disorders: abdominal pain upper, acid refl ux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, fl atulence, obstipation, salivation increased

Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia

Renal and urinary disorders: dysuria, renal insuffi ciency

Reproductive system and breast disorders: pelvic pain

General disorders and administrative site conditions: edema, malaise, pain, rigors

Investigations: weight loss

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Laboratory Adverse Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively:

Proteinuria: 6.8, 5.3

ALT increased: 6.0, 4.3

Blood urea nitrogen increased: 4.7, 3.5

Serum creatinine increased: 3.7, 4.3

AST increased: 3.0, 1.3

The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.

The adverse-experience profi les in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV.

Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively:

Infections and infestations: urinary tract infection: 2.3, 3.2

Blood and lymphatic system disorders: anemia: 3.0, 4.3

Psychiatric disorders: insomnia: 2.1, 3.3

Nervous system disorders: headache: 5.0, 6.5

Cardiac disorders: bradycardia: 4.4, 3.9

Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2

Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; fl atulence: 4.1, 5.8; vomiting 2.5, 3.9

Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4

General disorders and general administration site conditions: pyrexia: 5.9, 10.6

The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant:

Infections and infestations: postoperative infection

Metabolism and nutrition disorders: hypokalemia, hypovolemia

Nervous system disorders: dizziness, hypoesthesia, syncope

Vascular disorders: hematoma

Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression

Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia

Skin and subcutaneous tissue disorders: urticaria

General disorders and administrative site conditions: hypothermia, pain

Investigations: blood pressure decreased

Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence

Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included:

Nervous system disorders: dysarthria, sensory disturbance

Eye disorders: miosis, visual acuity reduced

Respiratory, thoracic, and mediastinal disorders: wheezing

Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort

There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant.

Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).

Other Studies: In addition, 2 serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: 1 case of constipation, and 1 case of subileus.

CAPSULES


Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

Postmarketing Experience: The following adverse reactions have been identifi ed during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria

Immune system disorders: hypersensitivity reactions including anaphylactic reactions

DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically signifi cant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically signifi cant effect.

As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy-induced nausea and vomiting studies with EMEND refl ects an approximate 50% reduction of the dose of dexamethasone. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended.

Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically signifi cant degree. Therefore, no dose adjustment is recommended.

Chemotherapeutic agents: [see Warnings and Precautions] Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not infl uence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not infl uence the pharmacokinetics of vinorelbine to a clinically signifi cant degree.

CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce the metabolism of S(–) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as international normalized ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting.

Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15.

EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The coadministration of EMEND may reduce the effi cacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (eg, elderly patients) and degree of

monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy-induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).

Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfi navir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased effi cacy of EMEND.

Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased effi cacy of EMEND.

Additional Interactions: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.

Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once-daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.

USE IN SPECIFIC POPULATIONSPregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of EMEND in pediatric patients have not been established.

Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fi brosarcomas at 125 and 500 mg/kg/day doses in male mice.

Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test.

Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

PATIENT COUNSELING INFORMATION[See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.

Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their fi rst dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia.

Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause diffi culty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction.

EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting.

Administration of EMEND may reduce the effi cacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

For detailed information, please read the Prescribing Information.Rx only

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. 21050812(2)(901)-EME

EMEND® (aprepitant) capsules



MISSION STATEMENT—The Journal of HematologyOncology Pharmacy (JHOP) is an independent, peer-reviewed journal founded in 2011 to provide hema-tology and oncology pharmacy practitioners andother healthcare professionals in these fields withhigh-quality peer-reviewed information relevant tohematologic and oncologic conditions to help themoptimize drug therapy for patients.

GENERAL INFORMATION—Manuscripts submit-ted to JHOP must be original and must not have beenpublished previously, either in print or in electronicform. Manuscripts cannot be submitted elsewherewhile under consideration by JHOP.

The editors invite readers to submit articles on a vari-ety of points of view and approaches to meet the mis-sion of the journal. Articles will be divided into 4main categories, including (1) original research, to pro-vide an outlet for translational and practice-basedresearch, including case reports and case series; (2)review articles that focus on drug and disease state aswell as on basic science regarding the complex molec-ular biology of cancer with a pharmacy focus; (3) clin-ical controversies that discuss common clinical issuesfor which treatment is unclear, or “point, counter-point” and “how I treat” type of articles; (4) practicalissues in pharmacy management that will focus on real-world issues involving logistics, economics, and otherpractice-related topics.

PEER REVIEW—All articles undergo an initialinternal review for topic appropriateness and manu-script format. Manuscripts that are not submittedaccording to the guidelines in this document will bereturned to the author.

All manuscripts are subject to a strict, blinded peerreview (by 2-3 reviewers), and acceptance is deter-mined by the section editor based on that review.Reviewers look for accuracy of the information anddata presented, as well as relevance to the objectivesof JHOP.

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EDITING—Routine editorial changes are made onall articles to conform to house style, following theAMA Manual of Style, 10th ed.1 The edited manuscriptis sent to the corresponding author for a final reviewand for any outstanding editorial queries. Time fromsubmission to publication is generally 4 to 7 months,but could be longer, depending on the peer-review andrevision processes.

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Provide authors’ highest academic degree and profession-al affiliations. Also provide the name, address, telephonenumber, e-mail, and fax number of the correspondingauthor. The corresponding author is responsible for secur-ing signatures for all forms from all authors.

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in relation to a manuscript, or if authors discuss anyproducts or services with such commercial interest.Any information regarding funding, grants, or otherfinancial compensation must be listed on the title pageof the manuscript. All published articles will includedisclosure statements listing any relationships with realor potential conflict of interest for all authors and forthe manuscript/research.

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The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clini-cal journal for oncology pharmacists. As pharmacy practice and research become integral to improvingboth the clinical care of cancer patients as well as expanding the research literature in contemporaryoncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession.

Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publi-cation of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy prac-titioners and other hematology oncology professionals optimize drug therapy for patients with cancer.

Readers are invited to submit articles addressing new research, clinical, and practice management issuesin oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based onthat review.

ORIGINAL RESEARCH• Clinical • Basic science• Translational • Practice-based• Case reports• Case series

CLINICAL CONTROVERSIES• Point and counterpoint• Roundtable discussions• “How I treat”

COMMENTARIES

REVIEW ARTICLES• New drug classes• Disease states• Basic science• Pharmacology • Pathways and the drugs targeting them

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing informationfor Docetaxel.

Docetaxel Injection,For intravenous infusion only.Initial U.S. Approval: 1996

–––––––––––––––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS ––––––––––––––––––––––––––––––––––––––––––––––• Hypersensitivity to docetaxel or polysorbate 80 (4)• Neutrophil counts of <1500 cells/mm3 (4)

–––––––––––––––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS ––––––––––––––––––––––––––––––––––––––––––• Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or

myeloid leukemia (5.6)• Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin

toxicity may require dose adjustment (5.7)• Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose

adjustment or discontinuation if persistent. (5.8)• Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9)• Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to

become pregnant when receiving Docetaxel Injection (5.10, 8.1)

––––––––––––––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS –––––––––––––––––––––––––––––––––––––––––––––––Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity,thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea,vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONSee full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1)

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFTelevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6)

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone

premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy(5.4)

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) • Severe fluid retention may occur despite dexamethasone (5.5)

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, AustraliaManufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, IndiaDistributed by: Hospira, Inc., Lake Forest, IL 60045 USA Reference EN-2761

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Single Vial

Docetaxel Injection(10 mg/mL concentration)

• Larger 160 mg Multiple Dose Vial

• More convenient 80 mg Multiple Dose Vial

• Requires NO dilution with a diluent prior to adding to the infusion solution

Exclusive Onco-Tain™ packaging for safe handling1

Clarity of glass

Barrier sheath

PVC reinforced bottom

P11-3247-8.125x10.875-Apr., 11 � only

Docetaxel Injection is a microtubule inhibitor indicated for:

Breast Cancer (BC):single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC

Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

1. Data on fi le at Hospira

Indications and Usage Safety Information

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fl uid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

See brief Prescribing Information on reverse side.

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid RetentionSee full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80

• Severe fl uid retention may occur despite dexamethasone

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Download - Journal of Hematology Oncology Pharmacy - December 2011, VOL 1, NO 4

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