journal of hematology oncology pharmacy - june 2012, vol 2, no 2

JOURNAL OF

HEMATOLOGYONCOLOGYPHARMACY™

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

JUNE 2012VOL 2 I NO 2

©2012 Green Hill Healthcare Communications, LLC

PRACTICAL ISSUES IN PHARMACY MANAGEMENTImpact of a Pharmacist-Managed Oral Chemotherapy Program on Nonfulfillment RatesKaylee Drenker, PharmD; April Sondag, PharmD; Robert Mancini, PharmD

ORIGINAL RESEARCHPredictors for Severe Tumor Lysis SyndromeScott M. Wirth, PharmD, BCOP; Douglas T. Steinke, PhD; Amber P. Lawson, PharmD; Stephanie D. Sutphin, PharmD; Michael D. Blechner, MD; Val R. Adams, PharmD

REVIEW ARTICLECurrent Treatment Options for the Management of Glioblastoma MultiformeLarry W. Buie, PharmD, BCPS, BCOP; John M. Valgus, PharmD, BCOP, CPP

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

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39www.JHOPonline.com l Journal of Hematology Oncology Pharmacy Vol 2, No 2 l June 2012

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 Cuellar, 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, BCOP, CPPHematology/Oncology Senior Clinical Pharmacy SpecialistUniversity 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

40 l Journal of Hematology Oncology Pharmacy l www.JHOPonline.com June 2012 l Vol 2, No 2

Senior Vice President, Sales & Marketing

Philip [email protected]

PublisherJohn W. Hennessy

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Editorial DirectorDalia Buffery

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Associate EditorLara J. Lorton

Editorial AssistantJennifer Brandt

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Directors, Client ServicesJoe Chanley

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Quality Control DirectorBarbara Marino

Business ManagerBlanche Marchitto

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TABLE OF CONTENTS

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 ©2012 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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PRACTICAL ISSUES IN PHARMACY MANAGEMENT42 Impact of a Pharmacist-Managed Oral Chemotherapy Program

on Nonfulfillment RatesKaylee Drenker, PharmD; April Sondag, PharmD; Robert Mancini, PharmD

ORIGINAL RESEARCH47 Predictors for Severe Tumor Lysis Syndrome

Scott M. Wirth, PharmD, BCOP; Douglas T. Steinke, PhD; Amber P. Lawson, PharmD; Stephanie D. Sutphin, PharmD; Michael D. Blechner, MD; Val R. Adams, PharmD

REVIEW ARTICLE57 Current Treatment Options for the Management of

Glioblastoma MultiformeLarry W. Buie, PharmD, BCPS, BCOP; John M. Valgus, PharmD, BCOP, CPP

From The Literature64 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.

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THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICETM

JUNE 2012 VOLUME 2, NUMBER 2

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PRACTICAL ISSUES IN PHARMACY MANAGEMENT


Oral chemotherapy has an ever-increasing role inthe treatment of patients with cancer. Thenumber of oral agents available to treat cancer

has more than doubled in the past 15 years, and up to35% of the agents in development are likely to be oralformulations.1 Nonfulfillment, or primary nonadher-ence, is defined as failure to obtain a medication that hasbeen prescribed.2

The causes of nonfulfillment are numerous, and theyare not well described in the literature. Important factorsinfluencing nonfulfillment include patient-perceived

concerns about medications, lack of perceived need formedications, and medication affordability issues.3Nonfulfillment rates have been shown to increase asmedication costs increase, especially as it relates to directpatient costs.2,3 Based on average wholesale price(AWP), oral chemotherapy prescriptions can cost from afew hundred dollars per chemotherapy cycle to morethan $10,000 per cycle. Therefore, based on cost alone,these medications are at high risk for nonfulfillment. Tocombat this risk, the financial barriers to patients obtain-ing these medications need to be addressed.

Nonfulfillment rates vary greatly in the literature. Arecent systemic analysis reported an overall mean non-fulfillment rate of 16.4% based on all the studiesreviewed.3 Another study focusing on electronic pre-

Dr Drenker and Dr Sondag are oncology pharmacy residentsand Dr Mancini is an oncology pharmacist at St Luke’sMountain States Tumor Institute, Boise, ID.

Impact of a Pharmacist-Managed Oral Chemotherapy Program onNonfulfillment RatesKaylee Drenker, PharmD; April Sondag, PharmD; Robert Mancini, PharmD

Background: Oral chemotherapy has an ever-increasing role in the treatment of patients with

cancer, but high cost increases the risk for primary nonadherence or “nonfulfillment.” Non -

fulfillment is defined as failure to obtain a prescribed medication. Proven methods to decrease

nonfulfillment rates for oral chemotherapy are lacking in the literature.

Objective: This article describes how our pharmacist-managed oral chemotherapy program

(OCP) has impacted nonfulfillment rates by addressing barriers to obtaining the medication,

especially medication lack of affordability.

Methods: This study evaluated the percentage of patients who never filled their medications (ie,

nonfulfillment) and explored the reasons for lack of initiation of treatment in patients presented to

the OCP at St Luke’s Mountain States Tumor Institute (MSTI) between August 2009 and October

2011. Every patient presenting to the program was evaluated for nonfulfillment and for potential

reasons for lack of initiation of treatment. In addition, every patient who received financial assis-

tance or a free drug was identified, and the total dollar amount that was saved was compiled.

For this evaluation, the total amount of free drugs that was obtained was calculated for each

patient by multiplying the average wholesale price of the medication acquired by the average

number of cycles the medication is continued in our patient population.

Results: Between August 2009 (the date when the program was initiated) and October 2011,

a total of 702 patients were served by MSTI’s OCP. The overall nonfulfillment rate for that period

was 9%, and the primary reason for nonfulfillment was patient or physician choice for an alter-

nate therapy. Only 1% of patients overall were unable to obtain the medication because of finan-

cial reasons.

Conclusion: Successful collaboration with patient financial advocates has allowed our phar-

macist-managed OCP to reach low medication nonfulfillment rates. Maintaining and processing

prescriptions within the health system (ie, MSTI) allowed controllable factors for nonfulfillment (ie,

cost and loss to follow-up) to be kept at rates lower than those previously seen in other studies.

This study did not address mail-order or closed-door pharmacies.

J Hematol Oncol Pharm.2012;2(2):42-45.www.JHOPonline.comDisclosures are at end of text

scribing reported a 24% nonfulfillment rate that variedby class of medication, formulary status, and other fac-tors (oncology medications were not included as a classin this study).4 In a third study, which specificallyfocused on oral chemotherapy prescriptions, the nonful-fillment rate reported was 10%.5

This present article describes how a pharmacist-managed oral chemotherapy program (OCP) at oneinstitution has positively affected nonfulfillment ratesby addressing barriers to obtaining the prescribedmedication, especially lack of medication affordabili-ty. This article does not address mail-order or closed-door pharmacies; this was not included in the currentevaluation.

MethodsSt Luke’s Mountain States Tumor Institute (MSTI) is a

National Cancer Institute Community Cancer CenterProgram with 5 sites that serve a broad geographic area,including southern Idaho, eastern Oregon, and northernNevada. Prescriptions for oral chemotherapy from any ofMSTI’s providers go through a dispensing process asdescribed in Figure 1.

The first step in the process is that the prescriptionsare sent directly to the oral chemotherapy office. Aftera pharmacist conducts a clinical evaluation, the pre-scription is sent to the outpatient pharmacy for a ben-efits investigation. A multidisciplinary team, whichincludes pharmacists, patient financial advocates, andsocial workers, addresses any potential financial barri-ers to obtaining the medication. Patient assistance pro-grams are utilized to provide financial aid for uninsuredand underinsured patients.

Every patient referred to the OCP is tracked fromreceipt of the first prescription through termination ofthe treatment. For this study, the nonfulfillment rate(ie, the number of prescriptions that had been sent tothe oral chemotherapy office but never dispensed tothe patient) was assessed. These abandoned prescrip-tions were then classified according to the followingreasons for nonfulfillment:

• Inability to obtain the medication, including insur-mountable financial issues

• Patient selection of alternate therapy• Prescriber selection of alternate therapy• Patient declination of treatment or treatment at a

different facility• Patient complications or death before initiation of

treatment.Once a patient obtains a free drug, the financial

advocates follow such a patient and pharmacists arethen available for consultation when needed. For thisevaluation, the total amount of a free drug that was

obtained was calculated for each patient, by multiply-ing the AWP of the medication acquired by the aver-age number of chemotherapy cycles the medicationwas continued in our patient population.

ResultsA total of 702 patients have been served by the

MSTI OCP from its initiation in August 2009 throughOctober 2011 (Figure 2). During this period, thepatient nonfulfillment rate was 9% (N = 63). Of thetotal number of patients served by the MSTI OCP, only1% (N = 7) of nonfulfillment was attributable to theinability to obtain the medication or to a medicationaffordability issue. All other reasons contributing to thenonfulfillment rate are listed in Figure 3.

As of October 2011, the MSTI OCP has obtainedmore than $1 million of free drug assistance (Table)and more than $250,000 of copayment assistance forour patients.

Impact of Pharmacist-Managed OCP on Nonfulfillment Rates

43www.JHOPonline.com l Journal of Hematology Oncology PharmacyVol 2, No 2 l June 2012

Figure 1 Oral Chemotherapy Dispensing Process

MSTI indicates St Luke’s Mountain States Tumor Institute.

Oral chemotherapy

office

• Prescription received• Prescription assessed and patient educated

Outpatient pharmacy

• Benefits investigation

• Lack of insurance, underinsurance, highcost identified

Benefits team

• Pharmacist, social worker, and patient financial advocates coordinate

• Copay assistance programs and free medication programs investigated

• Prior authorization completed as needed

• Prescription filled and sent to oral chemotherapy office

• Medication dispensed to patient at their preferred MSTI clinic

• Patient medication follow-up continues

Dispensing

DiscussionThe MSTI OCP was described in detail in a previous

article published in this journal.6 The goal of the presentarticle is to analyze the impact of this program on med-ication nonfulfillment.

As the literature consistently reports, the most sig-nificant barrier to filling an oral chemotherapy pre-scription is the patient medication cost. Our patients’medication affordability issues were attributed to lowincome, insurance denials, high cost-sharing (copay)insurance, and ineligibility for patient financial or freedrug assistance.

At MSTI, patient financial advocates are utilized tohelp obtain free drug or copay assistance through avail-able patient assistance programs. The Association ofCommunity Cancer Centers and the OncologyNursing Society have reimbursement resources thatpatient financial advocates at MSTI use to identify re -imbursement/assistance resources.7,8 High-priced med-ications and brand-name medications are more likelyto have patient medication assistance programs avail-able. Our patient financial advocates have reportedthat it is easier to obtain patient assistance for medica-tions that are frequently prescribed, for medicationsprescribed within their US Food and DrugAdministration–approved indication, for patientswhose income is low or who lack insurance, and formedications that have user-friendly patient assistanceprograms.

Gadkari and McHorney identified important barriersthat contribute to increased nonfulfillment rates, asnoted earlier, including patient concerns about med-ications, patients being unsure of the need for medica-tions, and medication affordability issues.3

At MSTI, patients’ concerns about oral chemother-apy are addressed up front and as therapy progresses bya multidisciplinary healthcare team, including physi-cians, nurses, and pharmacists. Patients are providedwith education on oral chemotherapy for its benefitsand for the potential risks to ensure that patients canmake an informed medication treatment decision.

Frequent physician follow-up, along with pharmacistinitial fill and refill medication counseling, allow foremphasizing the importance of oral chemotherapymedications to MSTI’s patients. Improved communica-tion between the healthcare team and the patient helpsto decrease nonfulfillment rates for oral chemotherapymedications.

At MSTI, our evaluation showed other major rea-sons for nonfulfillment of oral chemotherapy medica-tions, including:

• Choosing an alternative therapy• The patient declined treatment

PRACTICAL ISSUES IN PHARMACY MANAGEMENT


25

20

15

10

5

0

Alternative therapy chosen, 3%Expired/complication, 1.3%Formulation issue, 0.1%Declined treatment, 2.4%

Lost to follow-up, 0.3%Insurance issue, 1%Treated elsewhere, 0.6%

Figure 3 Patient Nonfulfillment Distributiona

(N = 63, 9% overall)

aPercentages are based on total number of patients (N = 702)served by oral chemotherapy office.

Patie

nts,

N

Nonfullfillment

9%7%

Figure 2 Oral Chemotherapy Patient Distributiona

51%

19%

14%

ActiveDiscontinuedNever startedPatient assistanceMail order

aAs of October 2011.

(N = 702)

Impact of Pharmacist-Managed OCP on Nonfulfillment Rates


• The patient had complications or died before theinitiation of treatment.

Alternative therapy was most often chosen based onimaging and pathology results. Physicians send theOCP a “prior authorization only” prescription so thepharmacist can assess prescription insurance coverage,while the imaging and pathology results are pending.

In addition, the choice may be made by either thepatient or the physician to decline treatment foradvanced cancers when the risks outweigh the benefits.Alternatively, the patient may choose comfort care orhospice. In our evaluation, minor reasons for nonful-fillment were medication formulation issues, treatmentat another facility, and loss to follow-up. The minorreasons contributing to nonfulfillment were onlyobserved in <1% of the total patients studied.

The literature reveals little regarding additionalmethods to decrease nonfulfillment. Several articlesoffer recommendations for increasing adherence to oralchemotherapy medications,9,10 but they do not addressprimary nonadherence. Potential avenues for furtherimprovement of primary nonadherence include in -creased utilization of resources to decrease patient costfor these medications, and increased patient educationto address concerns about medications and to empha-size the need for medication adherence.

ConclusionsWith our current established prescription processes

in place, the MSTI OCP has been able to ensure prop-er prescription reimbursement. As a result, <1% of thetotal medication costs have been written off. Successfulcollaboration with the patient financial advocates hasallowed the pharmacist-managed OCP to reach lowmedication nonfulfillment rates. Maintaining prescrip-tion processing within the health system allowed con-trollable factors for nonfulfillment (ie, cost and loss to

follow-up) to be kept at rates lower than those seen inprevious studies. n

Author Disclosure StatementDr Drenker and Dr Sondag reported no conflicts of inter-

est. Dr Mancini is on the Speaker’s Bureau for MillenniumPharmaceuticals.

References1. DeCardenas R, Helfrich J. Oral therapies and safety issues for oncology prac-tices. Oncol Issues. 2010;March/April:40-42.2. Gellad WF, Grenard J, McGlynn EA. A review of barriers to medication adher-ence: a framework for driving policy options. Santa Monica, CA: RANDCorporation; 2009. www.rand.org/content/dam/rand/pubs/technical_reports/2009/RAND_TR765.pdf. Accessed June 14, 2012. 3. Gadkari AS, McHorney CA. Medication nonfulfillment rates and reasons: nar-rative systematic review. Curr Med Res Opin. 2010;26:683-705.4. Fischer MA, Choudhry NK, Brill G, et al. Trouble getting started: predictors ofprimary medication nonadherence. Am J Med. 2011;124:1081.e9-1081.e22.5. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan charac-teristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract.2011;7(3 suppl):46s-51s.6. Mancini R, Kaster L, Vu B, et al. Implementation of a pharmacist-managedinterdisciplinary oral chemotherapy program in a community cancer center. JHematol Oncol Pharm. 2011;1:23-30.7. Association of Community Cancer Centers. Reimbursement and patient assis-tance programs: a guide for community cancer centers. Oncology Issues.2011;January/February:S1-S58. 8. Moore S, Brandt ML. Adherence to Oral Therapies for Cancer: Helping YourPatients Stay on Course Toolkit. 2010. www.ons.org/ClinicalResources/OralTherapies/media/ons/docs/clinical/AdherenceToolkit/oraladherencetoolkit-print.pdf. Accessed June 14, 2012. 9. Partridge AH, Avorn J, Wang PS, Winder EP. Adherence to therapy with oralantineoplastic agents. J Natl Cancer Inst. 2002;94:652-661. 10. Schneider SM, Hess K, Gosselin T. Interventions to promote adherence withoral agents. Semin Oncol Nurs. 2011;27:133-141.

Table Free Drug Assistance through the MSTI OralChemotherapy Program

Free drug Patients, N Total cost-savings, $a

Sorafenib (Nexavar) 5 85,705

Lenalidomide (Revlimid) 4 153,903

Sunitinib (Sutent) 11 382,367

Erlotinib (Tarceva) 6 83,682

Temozolomide (Temodar) 5 78,783

Lapatinib (Tykerb) 2 31,919

Capecitabine (Xeloda) 8 73,447

Otherb 6 201,836

Total 47 1,091,642

aTotal cost-saving is based on average wholesale price andreflect cost-saving to the patient and the pharmacy.bOthers include cyclosporine, deferasirox (Exjade), imatinib(Gleevec), dasatinib (Sprycel), pazopanib (Votrient), and abiraterone (Zytiga).MSTI indicates St Luke’s Mountain States Tumor Institute.

The MSTI OCP has been able toensure proper prescriptionreimbursement. As a result, <1% ofthe total medication costs have beenwritten off. Successful collaborationwith the patient financial advocateshas allowed the pharmacist-managedOCP to reach low medicationnonfulfillment rates.

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ORIGINAL RESEARCH


Tumor lysis syndrome (TLS) is a complication ofcancer therapy that leads to multiple abnormallaboratory findings and clinical manifestations.

The overall incidence of TLS has been reported to be42% in adults with hematologic malignancies; however,the incidence of patients with clinical manifestationsmay be 5% to 10% or less, and may depend on the typeof cancer.1-3 TLS with severe clinical consequences (ie,requirement of dialysis or mortality) may occur even lessfrequently, although the incidence has not been fullyelucidated in a real-world setting.

TLS is caused by the acute release of cellular compo-nents into the blood after the rapid destruction of ma -lignant cells.4,5 The abrupt lysis of tumor cells causes

the release of electrolytes, particularly potassium andphosphorus, from intracellular compartments, causingsystemic hyperkalemia and hyperphosphatemia. Hypo -calcemia can also occur secondary to hyperphos-phatemia.5,6 In addition, release of purine nucleotidesthat are metabolized to uric acid can accumulate andcrystallize in renal tubules, which will overwhelm nor-mal glomerular filtration processes and lead to renalinsufficiency or renal failure.7,8 Renal failure further per-petuates electrolyte abnormalities, resulting in even larg-er increases in potassium and phosphorus. Collectively,the syndrome can lead to clinical manifestations thatinclude seizures, cardiac abnormalities, neuromuscularinstability, the need for dialysis, and even death.9

Dr Wirth is a Clinical Pharmacy Specialist, University of Pittsburgh Medical Cancer Centers, Pittsburgh, PA; Dr Steinke specializes inPharmacoepidemiology and Health Services, University of Kentucky College of Pharmacy, Department of Pharmacy Practice andStudy, Lexington; Dr Lawson is a Clinical Pharmacy Specialist, UK HealthCare, University of Kentucky, Lexington; Dr Sutphin is aClinical Pharmacy Specialist, Department of Oncology, UK HealthCare, University of Kentucky College of Pharmacy, Department ofPharmacy Practice and Science, Lexington; Dr Blechner is an Anatomic and Clinical Pathologist, UConn Health Center, ConnecticutInstitute for Clinical and Translational Science, Farmington; Dr Adams is a Clinical Pharmacy Specialist, UK HealthCare, Universityof Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, Lexington.

Predictors for Severe Tumor Lysis SyndromeScott M. Wirth, PharmD, BCOP; Douglas T. Steinke, PhD; Amber P. Lawson, PharmD; Stephanie D. Sutphin, PharmD; Michael D. Blechner, MD; Val R. Adams, PharmD

Background: The incidence of tumor lysis syndrome (TLS) has been reported in 42% of adults

with hematologic malignancies and can result in serious laboratory findings and clinical manifes-

tations. The clinical manifestations may be severe, leading to dialysis therapy and/or death. The

exact incidence of these severe outcomes has not been determined; however, strategies to

determine the risk for these complications have been proposed.

Objective: To evaluate current risk categories and strategies to determine their ability to pre-

dict the incidence of dialysis or mortality secondary to TLS.

Methods: A total of 1327 patients with cancer who were identified by an internal registry data-

base from the University of Pittsburgh Medical Cancer Centers were assessed for risk of TLS

based on current guidelines and were stratified into low-, intermediate-, or high-risk categories.

These categories were assessed to determine if there is a difference in the incidence of dialysis

and/or the incidence of mortality among the risk groups for TLS, and to determine if baseline

population characteristics or laboratory abnormalities can predict severe patient outcomes.

Results: Of the 1327 patients evaluated, 6 (0.5%) had clinically severe outcomes secondary to

TLS. Patients with high or intermediate risk were significantly more likely to have clinically severe

outcomes compared with low-risk patients (2.98% vs 0.09%; P = .001). Predictors for severe

events included male sex, age, diagnosis of Burkitt’s lymphoma, abnormal renal laboratory

parameters, and categorization into higher-risk groups.

Conclusion: The overall incidence of clinically severe outcomes associated with TLS is low.

However, higher-risk patients are at a significantly increased risk for dialysis or for mortality based

on the results of the present study. Multiple laboratory and demographic factors should be con-

sidered when creating future predictive models for the clinical manifestations of TLS.


ORIGINAL RESEARCH


TLS may be classified as either a laboratory disorder(laboratory TLS [LTLS]) or as a laboratory disorder withclinical manifestations (clinical TLS [CTLS]). The cur-rent criteria for TLS are shown in Table 1.10 Guidelineshave recently been proposed for the management of TLSin pediatric and adult patients for both laboratory andclinical manifestations.10 The guidelines support riskstratification among patients that is determined by can-cer type and extent of disease (Table 2), as well as pro-vide prophylaxis and treatment recommendations foreach risk category.10

Protecting the kidneys is the primary focus of man-agement, because the kidneys are essential to clearingthe dying tumor’s metabolic products and electrolytes,which can accumulate to life-threatening concentra-tions. Because uric acid is the primary renal toxic prod-uct, minimizing the concentration in the renal tubule isparamount. This can be accomplished with allopurinol,which decreases the formation of uric acid through inhi-bition of xanthane oxidase, an enzyme that convertshypoxanthine and xanthine to uric acid.11,12

Alternatively, or in combination with allopurinol, ras-buricase (recombinant urate oxidase) can be used, whichmetabolizes uric acid into the more water-soluble, non-renally toxic allantoin.11,13-15 Hyperhydration is also

Table 1 Adult Laboratory and Clinical Tumor Lysis Syndromea,b

Element Value Change from baseline

Uric acid ≥476 µmol/L or 8 mg/dL 25% increase

Potassium ≥6 mmol/L or 6 mg/dL 25% increase

Phosphorus ≥1.45 mmol/L 25% increase

Calcium ≤1.75 mmol/L 25% decrease

aLaboratory tumor lysis syndrome (LTLS) is defined as either a25% change from baseline or a level above or below normal limits (as defined above) for ≥2 values 3 days before or 7 daysafter chemotherapy.bClinical tumor lysis syndrome meets the criteria for LTLS inaddition to 1 of the following conditions: an increase in serumcreatinine (≥1.5 × upper limit of normal), cardiac arrhythmia/sudden death, or seizure (if not attributable to therapeuticagent).Reprinted with permission from Coiffier B, Altman A, Pui CH,et al. Guidelines for the management of pediatric and adulttumor lysis syndrome: an evidence-based review. J Clin Oncol.2008;26:2767-2778. © 2008 American Society of ClinicalOncology. All rights reserved.

Table 2 Tumor Lysis Syndrome Risk Stratification Recommended by Current Guidelines

Cancer type

Risk category

High Intermediate Low

ALL WBC ≥100,000a WBC 50,000-100,000 WBC ≤50,000

AML WBC ≥50,000 monoblastic WBC 10,000-50,000 WBC ≤10,000

CLL N/A WBC 10,000-100,000; treatment with fludarabine

WBC ≤10,000

CML, multiple myeloma, and other solid tumors (testicular, SCLC)

N/A Rapid proliferation with anexpected rapid response

to treatmentb

Remainder of patients

NHL Burkitt’s, lymphoblastic, B-ALL DLBCL Indolent NHL

aWhite blood cell value is in cells/mm3.bAll patients with CML, testicular solid tumors, and SCLC were included in the intermediate-risk category, because they areexpected to have a high response to treatment and a rapid proliferation rate.ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-ALL, Burkitt’s acute lymphoblastic leukemia;CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; N/A, notapplicable; NHL, non-Hodgkin lymphoma; SCLC, small-cell lung cancer; WBC, white blood count.Reprinted with permission from Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adulttumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778. © 2008 American Society of ClinicalOncology. All rights reserved.

Predictors for Severe Tumor Lysis Syndrome


often used; it provides benefit by diluting the concentra-tion of uric acid in the renal tubule.10 The guidelines rec-ommend that low-risk patients are monitored closely,intermediate-risk patients receive allopurinol and intra-venous (IV) hydration, and high-risk patients receiverecombinant urate oxidase and IV hydration. Selectintermediate-risk patients in which hyperuricemiadevelops despite prophylactic allopurinol should alsoreceive recombinant urate oxidase.10

Available evidence supports the risk stratification;however, the risk categories have not been adequatelyconfirmed in a real-world setting.11,14,15 Current riskstratification methods have not been proved to predictthe incidence of dialysis and mortality in patients at riskfor TLS. The ability to predict patients at risk for renalfailure and subsequent dialysis, for example, would bebeneficial; it can be one of the most influential and cost-ly manifestations of this disorder, because it increasesmortality rates and length of hospital stay.2

The purpose of our study was to evaluate risk strate-gies and their ability to predict the incidence of clini-cally severe outcomes (eg, dialysis and mortality) sec-ondary to TLS complications. This allowed us todetermine if patients expected to be at higher riskaccording to proposed guidelines are more likely to suf-fer severe clinical outcomes secondary to TLS, andwhether more aggressive and expensive pharmacologicmanagement with recombinant urate oxidase should beconsidered. As a secondary analysis, we determined ifselected pretreatment laboratory abnormalities trans-late into clinical outcomes and which factors are mostpredictive of clinically severe outcomes in patients atrisk for TLS.

Patients and MethodsThis study was designed as a retrospective review of

patients at risk for TLS between January 1, 2005, andDecember 2, 2008, at a university hospital. The studywas approved by the Institutional Review Board, and itadhered to appropriate policies and procedures. The pri-mary end point was to determine if there is a differencein the incidence of dialysis and/or mortality in patientsat low risk for developing TLS compared with those athigh or intermediate risk based on current publishedguidelines for TLS risk. Secondary objectives were todetermine if there is a difference in the incidence of dial-ysis and mortality between individual risk categories forTLS, and to determine if baseline population charac -teristics or laboratory abnormalities can predict thesesevere outcomes.

A total of 1327 patients with cancer were identifiedby an internal registry database and were risk stratifiedaccording to disease state and/or baseline white blood

cell counts based on current guidelines (Table 2). Onlythe first antineoplastic treatment episode was consideredfor each individual, because the risk for TLS would behighest during the first course of treatment.

Administrative claims databases were used to deter-mine if patients received dialysis or died after therapy.Medical charts, including inpatient and outpatient dial-ysis records, were analyzed for all database-identifiedpatients to determine if death occurred within 1 monthafter treatment (consistent with TLS complications), orif they received dialysis within 2 weeks of therapy. Thesecriteria were used to define a TLS-associated severe out-come. Patients were excluded only if they were aged ≤18years. All therapies for the prevention or treatment ofTLS were allowed in this study.

The incidence of severe clinical outcomes betweenthe combined intermediate- and high-risk group werecompared with those in the low-risk group, as well asbetween each individual risk group. When available,baseline laboratory and demographic data were collectedto assess individual predictors for risk of clinical out-comes secondary to TLS compared with patients with-out these outcomes. Laboratory values were collected for1 week before treatment, and the averages of the totalvalues were considered baseline characteristics of eachpatient in the analysis.

Statistical AnalysisDemographic data and other patient characteristics

were described using descriptive statistics. Differencesbetween the intermediate- or high-risk category andthe low-risk category were compared using a 2-tailedFisher’s exact test. For analysis of differences betweenindividual risk categories, a multivariate 2 × 3 Fisher’sexact test (2-tailed; 95% confidence interval) was per-formed, followed by a univariate analysis to detect dif-ferences between individual risk categories.

A logistic regression analysis was used to calculate thecrude odds of characteristic variables predicting signifi-cant outcomes. A multivariate logistic regression modelwas then used to compare significantly different variablesadjusted for the primary risk category to control for differ-ences between risk groups. Binary covariates were encod-ed as 0 and 1, and cutoff values for continuous variableswere not included. For all tests, P <.05 was considered sig-nificant. All statistical analyses were performed usingSTATA v10.1 (StataCorp; College Station, TX).

Only the first antineoplastic treatmentepisode was considered for each individual,because the risk for TLS would be highestduring the first course of treatment.

ORIGINAL RESEARCH


ResultsOf the 1327 patients who were included in the analy-

sis, 168 patients were in the intermediate- or high-riskgroups, and 1159 patients were in the low-risk group.Analysis of each individual risk group reveals that there

were 1159 (87.4%), 141 (10.6%), and 27 (2.0%) indi-viduals at low, intermediate, and high risk, respectively.Demographic information of the patients in the study isshown in Table 3.

The overall incidence of clinically severe outcomessecondary to TLS was found in 6 (0.5%) patients (Table 4). Of these patients, 3 (0.2%) received dialysisand 3 died secondary to TLS complications (Table 5).

Of the entire at-risk population, patients with inter-mediate or high risk were significantly more likely tohave clinically severe outcomes compared with low-riskpatients (0.09% vs 2.98%; P = .001). No patients hadconcomitant dialysis and mortality in the study.

With regard to secondary objectives, the incidence ofdialysis occurred in 7.4%, 0.7%, and 0.0% of patients inthe high-, intermediate-, and low-risk groups, respec-tively. Mortality occurred in 0.0%, 1.4%, and 0.09% ofpatients in the high-, intermediate-, and low-risk groups,respectively. Univariate analysis revealed that of thetotal population, the intermediate- and high-risk groupshad more severe outcomes compared with the low-riskgroup (P = .001 and P = .005, respectively). Individualoutcomes of dialysis and mortality also had statisticallysignificant differences in the higher-risk group.Mortality incidence was significantly higher in theintermediate-risk group compared with that of the low-risk group (P = .033), and the incidence of dialysis wassignificantly higher in the high-risk group comparedwith that of the low-risk group (P = .001).

Baseline parameters most predictive of clinically sig-nificant outcomes based on the univariate analysisincluded male sex, age, and patients classified in theintermediate-, high-, and in the combined intermediate-and high-risk groups. Patients with Burkitt’s lymphomawere most at risk compared with standard (ie, those withcolorectal cancer) patients in the low-risk category. Inaddition, laboratory parameters, such as serum creati-nine (SCr), blood urea nitrogen (BUN), magnesium,and phosphorus, were all significant predictors of clini-cally severe outcomes. When adjusting for the primaryrisk categories (intermediate-, high-, and low-riskgroups), only SCr and BUN were significant predictorsof severe TLS (Table 6).

DiscussionSince the initiation of our study, other risk stratifica-

tion and treatment guidelines for TLS have been pub-lished.13,16,17 To our knowledge, however, this is the onlystudy that has compared the risk for TLS with severeclinical outcomes according to current guidelines. Ourstudy shows an overall low incidence of dialysis or mor-tality, regardless of risk category. Of the total at-risk pop-ulation, only 0.2% of the patients received dialysis, and0.2% died from TLS. This is very similar to data report-ed by Annemans and colleagues, in which the overallincidence of dialysis secondary to TLS was 1.3%, and0.8% of the total population died from the consequences

Table 3 Patient Characteristics (N = 1327)

Risk category

Intermediate/high Low

Population, N 168 1159

Age, mean yr (SD) 55 (13.2) 52 (15.7)

Sex, N (%)Male 112 (66.7) 290 (25.0)Female 56 (33.3) 869 (75.0)

Cancer type, N (%)Burkitt’s ALL 9 (5.4) 0 (0)

AML 36 (21.4) 41 (3.5)ALL 3 (1.8) 18 (1.6)

CLL 11 (6.5) 3 (0.3)

Bladder 0 (0) 34 (2.9)

Ovary/cervical 0 (0) 268 (23.1)

Breast 0 (0) 352 (30.4)

Testicular 18 (10.7) 0 (0)

Lung NOS 0 (0) 172 (14.8)

NSCLC 0 (0) 102 (8.8)

SCLC 91 (54.1) 0 (0)

Colorectal 0 (0) 74 (6.4)

Pancreas 0 (0) 67 (5.7)

Other 0 (0) 28 (2.4)

ALL indicates acute lymphoblastic leukemia; AML, acutemyeloid leukemia; CLL, chronic lymphocytic leukemia; NOS,not otherwise specified; NSCLC, non–small-cell lung cancer;SCLC, small-cell lung cancer; SD, standard deviation.

Of the entire at-risk population, patientswith intermediate or high risk weresignificantly more likely to have clinicallysevere outcomes compared with low-risk patients.



of TLS.2 Multiple other studies have also shownoverall low rates of CTLS after treatment withchemotherapy, although most studies did not prima-rily assess clinically severe outcomes.1,3,18

Despite the overall low incidence of severe clini-cal outcomes in our study, it was confirmed thatthose most at risk (intermediate/high-risk group)had an increased incidence of clinically severe out-comes compared with those at low risk. Significantdifferences were found between these 2 groups fordialysis and for mortality. These findings supportcurrent recommendations for more aggressive pro-phylaxis (ie, recombinant urate oxidase) in higher-risk patients, despite increased costs associated withthe therapy.10

However, there are no randomized, controlled stud-ies that have fully analyzed the clinical benefit ofaggressive management for the prevention of clinicallysevere outcomes in the setting of TLS. Urate oxidasehas been shown to be safe and effective in reducingserum uric acid concentrations in various populationswith overall low incidence of dialysis or mortality, butthis has not been extensively compared with more con-ventional strategies, such as allopurinol or IV hydra-tion.14,15,19,20

Only 1 patient died in the low-risk group. This patienthad colorectal cancer and LTLS, with no other docu-mented source of mortality according to availablerecords. Despite this patient, analysis of the entire at-riskpopulation reveals that the low-risk group had an overalllower incidence of clinically severe outcomes comparedwith the higher-risk groups. This reached statistical sig-nificance with dialysis compared with high-risk individu-als and mortality with intermediate-risk individuals.

Predictive models for TLS are currently lacking. Ananalysis of patients with acute myeloid leukemia (AML),however, revealed that baseline lactate dehydrogenase,serum uric acid concentrations, and male sex were signif-icant predictive values for TLS in this specific patientpopulation.21 Montesinos and colleagues revealedincreased risks of LTLS and CTLS in patients with AMLwith elevated SCr, uric acid, and white blood cell counts.3

Our univariate analysis did not reproduce identicalresults, because lactate dehydrogenase, serum uric acid,and white blood cell counts were not positive predictorsof clinically severe TLS. However, male sex and SCr didpredict the incidence of severe outcomes. In addition,baseline BUN, magnesium, and phosphorus were all pos-itive predictors for clinically severe TLS.

With regard to cancer type, patients with Burkitt’slymphoma were at highest risk for significant outcomescompared with those at low risk. Using data from theunivariate analysis, our multivariate analysis revealedthat BUN and SCr were again predictors for clinically

Table 4 Characteristics of Patients with Severe Outcomes (N = 21)

Patient Outcome Cancer type Risk category

Laboratory values

SCra, mg/dLPhosphorusa,

mg/dLCalciumb,c,

mg/dLPotassiuma,mmol/L

Uric acida,mg/dL

1 Dialysis AML Intermediate 8.5 8.3 6.0 5.5 7.7

2 Dialysis Burkitt’s ALL High 5.1 9.6 7.7 4.6 9.0

3 Dialysis Burkitt’s ALL High 5.0 19.2 6.7 5.8d 39.5

4 Mortality ALL Intermediate 1.4 11.8 6.2 6.2 10.9

5 Mortality AML Intermediate 4.2 12.0 5.3 4.3 9.7

6 Mortality Colon Low 8.0 11.1 8.3 6.2 —

aHighest values obtained 3 days before or 7 days after chemotherapy.bLowest values obtained 3 days before or 7 days after chemotherapy.cCalcium value corrected for albumin.d≥25% increase from baseline value.ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; SCr, serum creatinine.

Table 5 Incidence of Dialysis and Mortality in Intermediate/High- versus Low-Risk Groups

Risk categoryP valueaLow Intermediate/high

Total population, N 1159 168 —

Dialysis, N (%) 0 (0) 3 (1.79) .002

Mortality, N (%) 1 (0.09) 2 (1.19) .044

Total clinically severe outcomes, N (%)

1 (0.09) 5 (2.98) .001

aP <.05 is considered significant using Fisher’s exact test.

ORIGINAL RESEARCH


significant TLS when adjusted for primary risk groups,suggesting that baseline renal dysfunction is an impor-tant factor in predicting severe clinical outcomes ofTLS. Future studies should consider these risk predictorsfor the creation of predictive models.

LimitationsThere are limitations to our study. Our review is ret-

rospective, and therefore prospective studies are encour-

aged to support validity of the data. In addition, collec-tion methods for our data may have missed patients whohave received dialysis at an outside institution.

Our results also showed a low number of patients withsevere outcomes, which limits our ability to appropriate-ly incorporate the regression analysis and enhances ourprobability of error.

In addition, our data do not assess the influence oftherapies on the incidence of TLS. Patients were notstratified by risk according to therapies received for TLSprevention and treatment, although allopurinol use inhigher-risk patients is the standard approach, and theoverall use of recombinant urate oxidase therapy is lowat our institution.

Finally, for a majority of the patients, our data did notinclude the possibility of concomitant nephrotoxicagents that might have been utilized before or during the

Table 6 Predictors for Clinically Severe Tumor Lysis Syndrome

Predictive measure Odds ratio (95% confidence interval) Adjusted odds ratio (95% confidence interval)a

Risk category 1Low Referent —Intermediate/high 35.52 (4.12-305.94) —

Sex 0.088 (0.010-0.754) 0.253 (0.2612-2.441)

Age 0.944 (0.889-1.002) —

Risk category 2Low Referent —

Intermediate 25.17 (2.600-243.65) —High 92.64 (8.13-1055.26) —

Cancer typebB-ALL 20.857 (1.674-259.894) —

Laboratory valueSerum creatinine 3.272 (1.889-5.669) 2.492 (1.337-4.650)

BUN 1.077 (1.042-1.114) 1.060 (1.021-1.101)Calcium 0.422 (0.122-1.458) —

Potassium 2.066 (0.952-4.483) —LDH 0.999 (0.999-1.001) —Magnesiumc 165.085 (5.912-4609.872) —

Phosphorusc 2.919 (1.272-6.698) —

Uric acid 1.251 (0.948-1.651) —WBC 1.003 (0.992-1.013) —

aAdjusted for primary risk groups (intermediate/high, low risk); includes significant groups from univariate analysis.bCompared with those with colorectal cancer (low-risk group); includes only significant groups.cIn the multivariate analysis, no values are available for those with significant outcomes in respective primary risk groups.B-ALL indicates Burkitt’s acute lymphoblastic leukemia; BUN, blood urea nitrogen; LDH, lactate dehydrogenase;WBC, white blood count.

These findings support currentrecommendations for more aggressiveprophylaxis (ie, recombinant urate oxidase)in higher-risk patients, despite increasedcosts associated with the therapy.



period of active tumor lysis. Patients found to have severeoutcomes, however, did not have any evidence of the useof medications that significantly affect renal function.

ConclusionDespite these limitations, our study provides evi-

dence that higher-risk populations truly are at higherrisk for severe CTLS. As a result, more aggressive ther-apies, such as recombinant urate oxidase, may need tobe prescribed to prevent these outcomes in selectintermediate- or high-risk populations as currentguidelines suggest. In addition, multiple laboratoryand demographic factors should be considered whencreating predictive models for CTLS. Based on ourfindings, we encourage future randomized, prospectivetrials to analyze current therapies and their abilities toprevent and treat severe clinical outcomes in the set-ting of high-risk TLS. n

Author Disclosure StatementDr Sutphin is on the advisory board of Amgen. Dr Wirth,

Dr Steinke, Dr Lawson, Dr Blechner, and Dr Adams havereported no conflicts of interest.

References1. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-gradenon-Hodgkin’s lymphoma. Am J Med. 1993;94:133-139.2. Annemans L, Moeremans K, Lamotte M, et al. Incidence, medical resource utilisa-tion and costs of hyperuricemia and tumour lysis syndrome in patients with acuteleukaemia and non-Hodgkin’s lymphoma in four European countries. Leuk Lymphoma.2003;44:77-83.3. Montesinos P, Lorenzo I, Martin G, et al. Tumor lysis syndrome in patients withacute myeloid leukemia: identification of risk factors and development of a predictivemodel. Haematologica. 2008;93:67-74.4. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classi-fication. Br J Haematol. 2004;127:3-11.

5. Fleming DR, Doukas MA. Acute tumor lysis syndrome in hematologic malignancies.Leuk Lymphoma. 1992;8:315-318.6. Jeha S. Tumor lysis syndrome. Semin Hematol. 2001;38(4 suppl 10):4-8.7. Wolf G, Hegewisch-Becker S, Hossfeld DK, Stahl RA. Hyperuricemia and renalinsufficiency associated with malignant disease: urate oxidase as an efficient therapy?Am J Kidney Dis. 1999;34:E20.8. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol. 1993;13:273-280.9. Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, andtreatment of tumor lysis syndrome. Am J Med. 2004;116:546-554.10. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatricand adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778.11. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparisonbetween rasburicase and allopurinol in children with lymphoma or leukemia at highrisk for tumor lysis. Blood. 2001;97:2998-3003.12. Hande KR, Hixson CV, Chabner BA. Postchemotherapy purine excretion in lym-phoma patients receiving allopurinol. Cancer Res. 1981;41:2273-2279.13. Pession A, Masetti R, Gaidano G, et al. Risk evaluation, prophylaxis, and treat-ment of tumor lysis syndrome: consensus of an Italian expert panel. Adv Ther.2011;28:684-697.14. Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the pro-phylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J ClinOncol. 2001;19:697-704.15. Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recom-binant urate oxidase) for the prevention and treatment of hyperuricemia during induc-tion chemotherapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1(Groupe d’Etude des Lymphomes de l’Adulte Trial on Rasburicase Activity in AdultLymphoma) study. J Clin Oncol. 2003;21:4402-4406.16. Tosi P, Barosi G, Lazzaro C, et al. Consensus conference on the management oftumor lysis syndrome. Haematologica. 2008;93:1877-1885.17. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation ofrisk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malig-nant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578-586.18. Cheson BD, Frame JN, Vena D, et al. Tumor lysis syndrome: an uncommon com-plication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol.1998;16:2313-2320.19.Teo WY, Loh TF, Tan AM. Avoiding dialysis in tumour lysis syndrome: is urate oxi-dase effective?—a case report and review of literature. Ann Acad Med Singapore.2007;36:679-683.20. Pui CH, Relling MV, Lascombes F, et al. Urate oxidase in prevention and treatmentof hyperuricemia associated with lymphoid malignancies. Leukemia. 1997;11:1813-1816.21. Mato AR, Riccio BE, Qin L, et al. A predictive model for the detection of tumorlysis syndrome during AML induction therapy. Leuk Lymphoma. 2006;47:877-883.

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VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

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Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE 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. VELCADE is contraindicated for intrathecal administration. 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. 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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 of VELCADE vs. dexamethasone, 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: Bortezomib is metabolized by liver enzymes. Bortezomib 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 (bortezomib) 1.3 mg/m2/dose administered intravenously 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 in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously 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%).In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.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, VELCADE 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 bortezomib 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 VELCADEHCP.com.

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 © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0095 6/12

REVIEW ARTICLE


Glioblastoma multiforme (GBM) is classified as agrade 4 central nervous system (CNS) tumor bythe World Health Organization and is the most

malignant of the glial tumors. GBM is characterized byrapid mitotic activity, infiltrative growth, and necrosis.Microvascular proliferation is often present in the tumorand suggestive of aggressive angiogenesis. Patients maypresent with a variety of neurologic symptoms, includingheadaches, seizures, confusion, memory loss, personalitychanges, and focal neurologic deficits. Magnetic resonanceimaging is usually confirmatory, showing an enhancingmass, peritumoral edema, and central areas of necrosis.Multi modality treatment of GBM typically includes sur-gery, radiation, and chemotherapy. The natural history ofthe disease is progression, and prognosis remains poor, witha survival rate of <15 months for a majority of patients.1

EpidemiologyAccording to the Central Brain Tumor Registry of the

United States, in 2010 there were 22,020 new diag-noses and 13,140 deaths attributed to primary malig-nant brain and CNS tumors.2 GBM comprises 60% to70% of all newly diagnosed glioma, occurs at a medianage of 64 years, and is more common in men than inwomen.1 GBM has been associated with rare familialsyndromes that introduce genomic instability; howev-er, the only proved environmental risk factor associat-ed with the development of GBM is exposure to high-dose radiation, although a history of chemotherapy hasalso been associated.3,4The most common chemotherapies associated with

the development of secondary GBM have beenantimetabolite therapies (methotrexate and 6-mercap-topurine) for the treatment of acute lymphoblasticleukemia.4 Genetic polymorphisms affecting detoxifica-tion, DNA repair, and cell cycle regulation have alsobeen implicated in tumorigenesis.5 The incidence ofGBM has been increasing over the past 2 decades, large-ly because of improvements in imaging, availability ofmedical care, and treatment options for elderly patientsand reclassification of brain tumors.5

Dr Buie is Clinical Specialist, Hematology/Oncology, Universityof North Carolina Health Care, and Clinical AssistantProfessor, University of North Carolina Eshelman School ofPharmacy, and Dr Valgus is Clinical Pharmacist Practitioner,Hematology/Oncology, University of North Carolina HealthCare, and Clinical Assistant Professor, University of NorthCarolina Eshelman School of Pharmacy.

Current Treatment Options for theManagement of GlioblastomaMultiformeLarry W. Buie, PharmD, BCPS, BCOP; John M. Valgus, PharmD, BCOP, CPP

Background: Glioblastoma multiforme (GBM) is a highly malignant glial tumor characterized by

rapid growth and angiogenesis. Current frontline therapy consists of surgical resection, radiation,

and chemotherapy; however, all patients will progress. Over the past decade, there have been

increases in the quality and quantity of clinical data regarding the treatment of patients with GBM.

Objective: The purpose of this review is to describe the pathways of tumorigenesis, review

relevant data in both the frontline and recurrent disease settings, and discuss the place in ther-

apy of novel treatment options for GBM.

Methods: Stupp and colleagues revolutionized the management of patients with GBM with

their 2005 landmark study that demonstrated the benefits of surgery and radiotherapy plus con-

comitant and adjuvant temozolomide. Other studies have shown that after disease progression,

the administration of bevacizumab alone and in combination with cytotoxic chemotherapy result-

ed in increased progression-free survival. Data also support the use of daily temozolomide in

recurrent disease, leading to similar results, although there are no comparative studies with beva-

cizumab and temozolomide.

Conclusion: Much progress has been made in the treatment of GBM. Despite these advances,

nearly all patients progress after frontline therapy and options remain limited.


REVIEW ARTICLE


Molecular PathogenesisGBM is described clinically based on tumorigenesis.

GBM is classified into 2 main subtypes based on biolog-ic and genetic differences, with malignant transforma-tion ultimately resulting from genetic abnormalities anddysregulation of cell-signaling pathways. Primary (denovo) GBM is now recognized to be a molecular pheno-type separate from the slower-growing secondary GBMthat evolves from lower-grade gliomas.Primary GBM is common in patients aged >50 years

and is characterized by epidermal growth factor receptor(EGFR) overexpression and mutation, including variantEGFR amplification, loss of heterozygosity of chromo-some 10q leading to the deletion of phosphatase andtensin homolog (PTEN), and p16 deletion.5,6

Secondary GBM is less common and arises fromtumors with p53 mutations. It is characterized by over-expression of the platelet-derived growth factor receptor(PDGFR), aberrations in p16 and retinoblastoma path-ways, and loss of heterozygosity of chromosome 10q.5,6Despite these differences, primary and secondary

tumors are morphologically identical and are treatedwith similar regimens, although there may be differencesin response in patients receiving targeted therapies.Growth factor receptor signaling involving EGFR andPDGFR result in the activation of pathways, such as theRas-MAP kinase pathway, involved in cell cycle pro-gression and cell proliferation, and the PI3K/Akt path-way, which results in inhibition of apoptosis and cellularproliferation.5,6

PTEN, which is located on chromosome 10 and is aregulator of the PI3K/Akt pathway, is inactivated inapproximately 50% of patients with GBM. Vascularendothelial growth factor (VEGF) and activation of theVEGF receptor (VEGFR) are also upregulated, leadingto angiogenesis and tumor survival. Finally, there is someevidence that neural stem cells can give rise to gliomas,thereby secreting VEGF and promoting angiogenesiswithin the tumor microenvironment.6,7

First-Line Treatment OptionsThe most effective first-line treatment of GBM to

date remains optimal surgical resection, followed by thecombination of concomitant daily temozolomide andpostoperative radiation, followed by 6 cycles of adjuvanttemozolomide (see Table for selected chemotherapy reg-imens and dosing information).8-17 When compared withpostoperative radiation alone, temozolomide-based ther-apy resulted in a survival increase of 2.5 months (12.1 vs14.6 months, respectively) or a 37% relative reductionin the risk of death, with a median follow-up of 28months.8 Although this represents a significant improve-ment, temozolomide-based therapy had a 2-year survivalrate of only 26.5%.7 With 5 years of follow-up, this sta-tistic is even more dismal at only 9.8%.9Significant room for improvement remains for first-

line treatment options. It is also important to considerusing prophylaxis for Pneumocystis carinii pneumoniawhen temozolomide is given in the concurrent phase,because of the increased risk for opportunistic infectionssecondary to potential severe lymphocytopenia.An important marker identified in the study by Hegi

and colleagues was MGMT (O6-methylguanine-DNAmethyltransferase).18 The MGMT gene encodes for aDNA repair protein, which removes alkyl groups from theO6 position of guanine; this is an important site for DNAalkylation. In tumor cells with high levels of MGMT,resistance can develop through blunting the effect of alky-lating agents, such as temozolomide and dacarbazine.MGMT silencing via promoter methylation results in aloss of MGMT function, leaving cells more susceptible toalkylating drugs. In fact, in this temozolomide trial,MGMT promoter methylation was an independent favor-able prognostic marker. In patients whose tumors hadMGMT promoter methylation and received temozolo-mide-based therapy, the median overall survival (OS) was21.7 months and the 2-year OS rate was 46%.18Although MGMT is clearly predictive of outcome in

patients with GBM who receive temozolomide-basedtherapy, the clinical benefit of this marker remains to bedetermined.19 This is mainly a result of the lack of effec-tive therapeutic alternatives in patients whose MGMTpromoter methylation status does not suggest a signifi-cant benefit from alkylating drug–based therapy. Severalinvestigators are searching for possible dosing alterationsthat may overcome this resistance mechanism.Clarke and colleagues evaluated the safety and effica-

cy of 2 alternative adjuvant temozolomide dosing sched-ules in the frontline management of 85 patients withGBM.10 The first strategy was metronomic or continuousdaily dosing of temozolomide. This method of deliverywas postulated to provide combined antitumor, as well asantiangiogenic, effects via damage to endothelial cells intumor vasculature. In addition, metronomic delivery ofcontinuous low-dose temozolomide results in inhibition

The most effective first-line treatment ofGBM to date remains optimal surgicalresection, followed by the combination ofconcomitant daily temozolomide andpostoperative radiation, followed by 6cycles of adjuvant temozolomide.

Current Treatment Options for Glioblastoma Multiforme


of MGMT that could possibly overcome this majorresistance pathway. The second delivery schedule wasdose-dense temozolomide, which is based on theNorton-Simon model of cell proliferation. This methodalso has the potential to inhibit MGMT. Both methodswere well tolerated, with no unexpected toxicities orrates of toxicities observed. Lymphopenia was commonbut did not result in any cases of P carinii pneumonia.Two-year survival in the dose-dense and metronomic

arms were 34.8% and 28%, respectively.10 Although thistrial was limited by the small sample size and lack ofdirect comparison to standard-dose temozolomide, thetolerable side-effect profile and impressive efficacy ofdose-dense and metronomic temozolomide warrant fur-ther investigation in randomized controlled trials.10Another strategy to overcome chemotherapy-resistant

mechanisms is the use of multidrug chemotherapy. Thedrug that has generated recent optimism for the treat-

Table Common Regimens in the Treatment of Glioblastoma Multiforme

Study Regimen/cycle length Dose

Stupp R, et al8,9 Standard temozolomide6 wks

Concomitant phase: temozolomide 75 mg/m2 daily whilereceiving radiation (6 wks)

Standard temozolomide28 days

Adjuvant phase: temozolomide 150-200 mg/m2 daily, for 5 days, repeated every 28 days for up to 6 cycles

Clarke JL, et al10 Dose-dense adjuvant temozolomide28 days

Temozolomide 150 mg/m2 daily on days 1-7 and days 15-21 every 28 days for 6 cycles

Metronomic adjuvant temozolomide28 days

Temozolomide 50 mg/m2 daily on days 1-28 for 6 cycles

Gállego Pérez-Larraya J, et al11 Standard temozolomide(elderly patients)28 days

Temozolomide 150-200 mg/m2 daily for 5 days, repeatedevery 28 days, for up to 12 cycles

Vredenburgh JJ, et al12 Bevacizumab plus irinotecan6 wks

Cohort 1: bevacizumab 10 mg/kg every 2 wks plus irinotecan 125 mg/m2 (no EIAEDs) every 2 wks, or irinotecan 340 mg/m2 (EIAEDs) every 2 wksCohort 2: bevacizumab 15 mg/kg every 3 wks plus irinotecan 125 mg/m2 weekly for 4 wks (no EIAEDs), oririnotecan 350 mg/m2 weekly for 4 wks (EIAEDs)

Friedman HS, et al13 Bevacizumab plus irinotecan6 wks

Bevacizumab 10 mg/kg every 2 wks plus irinotecan 125 mg/m2 (no EIAEDs) every 2 wks, or irinotecan340 mg/m2 (EIAEDs) every 2 wks

Bevacizumab alone (2-wk schedule) 6 wks

Bevacizumab 10 mg/kg every 2 wks

Raizer JJ, et al14 Bevacizumab alone (3-wk schedule) 6 wks

Bevacizumab 15 mg/kg every 3 wks

Batchelor TT, et al15 Cediranib28 days

45 mg by mouth daily

Perry JR, et al16 Metronomic temozolomide28 days

Temozolomide 50 mg/m2 by mouth daily

Yung WK, et al17 Erlotinib28 days

150 mg by mouth daily (no EIAEDs)300 mg daily (EIAEDs), with both groups allowed titration

EIAEDs indicates enzyme-inducing antiepileptic drugs.

REVIEW ARTICLE


ment of GBM is bevacizumab, an anti-VEGF mono-clonal antibody. This optimism has mostly been generat-ed from data with bevacizumab in the treatment of GBMrefractory to first-line temozolomide-based therapy.With its unique mechanism of action, as well as a man-ageable toxicity profile, bevacizumab is ideal to investi-gate with other antineoplastic drugs. In fact, a largeinternational, phase 3, multicenter, randomized trial iscurrently under way to evaluate standard temozolomide-based therapy, with or without the addition of beva-cizumab.20 The Radiation Therapy Oncology Group hasinitiated a multicenter, phase 3 trial investigating the useof bevacizumab as first-line therapy.21A preliminary safety report from a separate pilot phase

2 trial included bevacizumab, which was added to stan-dard, temozolomide-based therapy.22 Although relativelyhigh rates of fatigue, myelosuppression, wound break-down, and thrombosis were observed, the rates of thesetoxicities were deemed acceptable, and enrollment inthe trial continues. The use of the combination of temo-zolomide and bevacizumab should be limited to clinicaltrials until further results confirming the safety and effi-cacy of this combination are available.22

With so much focus on systemic therapy for GBM, itis easy to forget the benefits demonstrated with localtherapy with carmustine wafers. Placebo-controlled tri-als of carmustine wafers implanted at the time of initialsurgery demonstrated a significant survival benefit infavor of carmustine wafers. Patients were randomized toreceive either carmustine wafers plus radiotherapy oridentical-appearing placebo wafers plus radiotherapy.23A total of up to 8 wafers were implanted in each patient. Systemic therapy was prohibited for patients with GBM

unless recurrence was documented. Of the 240 patientsenrolled in the trial, 207 had GBM. The median survivalwas 13.5 months in the carmustine group and 11.4months in the placebo group, with 1-year survival rates of59.2% and 49.6%, respectively.23 This resulted in a 31%(95% confidence interval [CI], 3%-51%) risk reduction ofdeath in the carmustine-treated group compared with the

placebo-treated group, which was significant in the GBMsubgroup (P = .04). The time to Karnofsky performancestatus (KPS) and neuroperformance deterioration alsofavored the carmustine group. The adverse event profileswere similar for carmustine and placebo.23

Paucity of Data for the ElderlyA GBM population group not addressed in many clin-

ical trials is the elderly. For example, the landmark temo-zolomide trial excluded patients aged >70 years.8 Thepaucity of literature for elderly patients with GBM hasresulted in a lack of clear guidance on the best treatmentmodalities for this population.Radiation therapy offers benefit over supportive care

alone in elderly patients with a good performance status.In a randomized trial conducted by the Association ofFrench-Speaking Neuro-Oncologists, patients withGBM aged >70 years with a KPS >70 were randomizedto supportive care only or supportive care and radiother-apy (focal radiation in daily fractions of 1.8 Gy given 5days weekly, for a total dose of 50 Gy).24 A total of 85patients were enrolled at 10 institutions. The trial wasdiscontinued after the first interim analysis as a result ofsuperior survival rate in the radiotherapy arm. At amedian follow-up of 21 weeks, the hazard ratio for deathin the radiotherapy arm was 0.47 (95% CI, 0.29-0.76; P= .002), which yielded a median survival benefit of 12.2weeks. The median survival for patients receiving radio-therapy plus supportive care was 29.1 (95% CI, 25.4-34.9) weeks, and for those receiving supportive careonly, 16.9 (95% CI, 13.4-21.4) weeks. The KPS and cog-nition declined over time; however, there was no differ-ence between the 2 groups. No serious adverse eventswere reported with radiotherapy.24Although elderly patients were not included in the

trial by Stupp and colleagues,8,9 temozolomide has beenstudied in a phase 2 trial of patients with GBM aged ≥70years. In this nonrandomized trial, temozolomide 150 to200 mg/m2 daily for 5 days every 4 weeks was evaluated.11Radiotherapy was not administered in this trial. Of note,only patients with a poor performance status (KPS <70)were included in this trial.11A total of 70 patients from 8 institutions were

enrolled in the trial. Median treatment duration withtemozolomide was 2 cycles per patient (range, 0-13cycles). Dose delays and dose reductions occurred in20% and 24% of patients, respectively. The median OSwas 25 weeks (95% CI, 19-28 weeks). The 6-month and12-month OS rates were 44.3% (95% CI, 32.7%-55.9%)and 11.4% (95% CI, 3.9%-18.8%), respectively.Temozolomide was generally well tolerated. Grade 3 to 4neutropenia and thrombocytopenia occurred in 13%and 14% of patients, respectively.11

Radiation therapy offers benefit oversupportive care alone in elderly patientswith a good performance status. Arandomized trial conducted by theAssociation of French-Speaking Neuro-Oncologists was discontinued after the firstinterim analysis as a result of superiorsurvival rate in the radiotherapy arm.



Recurrent Disease TreatmentThe majority of patients with disease recurrence are

not eligible for further irradiation or surgical interven-tion. Median survival is 25 weeks, and survivorship at 1 year is estimated to be approximately 25%.25-27Progression-free survival (PFS) is correlated with OS inthis patient population, and the PFS at 6 months isbetween 9% and 15%.25-27 GBM is one of the most vas-cularized of all tumors, and angiogenesis is critical to dis-ease progression. Proangiogenic factors, such as VEGF,regulate vascularity, and VEGF is overexpressed in areasof necrosis, hypoxia, and endothelial proliferation.VEGF expression is correlated with tumor activity andaggressiveness, with GBM having the highest levels ofall gliomas.28,29High expression of VEGF is associated with microvas-

cular proliferation, accelerated tumor expansion, andpoor outcomes, but these tumors are also the most likelyto respond to antiangiogenic therapy. It is hypothesizedthat a higher VEGF ligand-to-receptor ratio may indi-cate more persistent VEGFR activation, and this ratiomay be increased with age.28,29Bevacizumab is a humanized immunoglobulin G1

monoclonal antibody that binds to and neutralizes cir-culating VEGF. Bevacizumab has been evaluated as asingle drug and in combination with cytotoxicchemotherapy in patients with recurrent GBM.Stark-Vance was the first to publish promising results

of bevacizumab in combination with irinotecan.30Previously, irinotecan had been used as single-drug ther-apy in patients with recurrent GBM because of goodCNS penetration; however, response rates were less than20%, with many patients not responding at all.31-33 Thetopoisomerase 1 inhibitor irinotecan works via a differ-ent mechanism of action than alkylation and is notaffected by MGMT, is not highly protein bound, andreadily crosses the blood–brain barrier, making it a logi-cal choice for combination with bevacizumab. Twenty-one patients with high-grade gliomas (53% GBM) weretreated with bevacizumab and irinotecan.30 In the earli-er study, 43% of patients had an objective response, andamong those not meeting criteria for response, most hadradiographic improvement consisting of reductions inperitumoral edema and contrast enhancement.30 Theseearly results indicated that bevacizumab may have a rolein the management of high-grade gliomas.30Vrendenburgh and colleagues verified the beneficial

results of bevacizumab in combination with irinotecanin 35 patients with histologically proven GBM that pro-gressed after external-beam radiation therapy and con-current temozolomide.12 The trial included 2 cohorts of patients receiving differing doses and schedules ofbevacizumab and irinotecan, with the irinotecan dose

dependent on the presence of enzyme-inducing anti -epileptic drugs.12Response to therapy was determined by magnetic res-

onance imaging (MacDonald Criteria) and clinicalexamination. Six-month PFS was 46% and median OSwas 42 weeks after 68 weeks of follow-up. A total of 57%of patients had at least a partial response to therapy, and7 patients completed 1 year of therapy. Thirteen patientsstopped therapy as a result of disease progression, and 11patients stopped therapy because of toxicity. Other rea-sons for discontinuation included venous thromboem-bolism (VTE), proteinuria, and CNS hemorrhage.12

Friedman and colleagues further established the role ofbevacizumab in a multicenter, phase 2, noncomparativetrial of bevacizumab alone and in combination withirinotecan.13 In the group that received bevacizumabalone versus the group that received irinotecan plus beva-cizumab, objective responses were 28.2% and 37.8%, PFSrates at 6 months were 42.6% and 50.3%, and medianOS rates were 9.2 months and 8.7 months, respectively.13The study did not achieve power to detect significant dif-ferences between these groups. Patients receiving beva-cizumab alone achieved overall response rates and PFSrates at 6 months that are greater than historical ratesachieved (which have been <20%) with cytotoxicchemotherapy alone. This demonstrates the value of theaddition of antiangiogenic therapy in recurrent GBM.This begs the question whether the additional benefits

of adding cytotoxic chemotherapy to bevacizumab areworth the risks when the response rates are similarbetween the 2 groups. Comparative studies of beva-cizumab alone and bevacizumab in combination withcytotoxic chemotherapy are needed to confirm the syn-ergy between the drugs in the recurrent setting.Toxicities common to bevacizumab (ie, hypertension,proteinuria, delayed wound healing, and hemorrhage)were similar between the groups. There were increasedincidences of VTE, diarrhea, and hematologic toxicityin the group receiving irinotecan.13Currently, bevacizumab is recommended to be dosed on

a schedule of every 2 weeks in patients with GBM. Aphase 2 evaluation of bevacizumab dosing every 3 weeksproduced 6-month PFS results that were more favorablethan historical controls14; however, no studies comparing

High expression of VEGF is associated withmicrovascular proliferation, acceleratedtumor expansion, and poor outcomes, butthese tumors are also the most likely torespond to antiangiogenic therapy.

REVIEW ARTICLE


dosing strategies of bevacizumab have been performed tomake formal recommendations on dose density.Cediranib is an oral pan-VEGFR tyrosine kinase

inhibitor (TKI) that also has activity against PDGF-βand c-Kit. Based on its mechanism of action and poten-tial molecular targets, cediranib should have activity inprimary and in secondary GBM. Preliminary studiesshowed that edema decreased and tumor vasculature wasnormalized after treatment with cediranib.15 Cediranibwas further evaluated in 31 patients with recurrent GBMin a single-center phase 2 study with a primary end pointof PFS at 6 months. All patients had undergone surgeryand radiation and most (29 of 31) had initial treatmentwith temozolomide. The 6-month PFS rate was 25.8%,median PFS was 117 days, and OS was 227 days. The useof cediranib also allowed decreased dexamethasonedoses. The most common toxicities were diarrhea,fatigue, and hypertension. There were no reports ofintracranial hemorrhage.15

Temozolomide has been the backbone of initial treat-ment of GBM. However, patients relapse and, for patientsreceiving chemotherapy, a resting period is required fornontumor cell recovery to occur. It is hypothesized thatduring this time DNA repair may take place, allowing fortumor regrowth. When compared with procarbazine,temozolomide in patients at first relapse resulted in animproved 6-month PFS rate (21% vs 8%; P = .008), andthis freedom from disease progression also was associatedwith maintained health-related quality of life.34 Con -tinuous low-dose or metronomic scheduling of temozolo-mide has been attempted to suppress MGMT activity,increase dose intensity, and increase the antiangiogeniceffects of other chemotherapies.16The RESCUE study tested this hypothesis and exam-

ined the effects of daily temozolomide when given topatients with high-grade glioma or GBM at first progres-sion after exposure to conventional dosing.16 Patientswith GBM were stratified into 3 groups according totheir previous duration of treatment with temozolomideand time of progression. All patients received temozolo-mide 50 mg/m2 daily continuously for up to 12 monthsor until disease progression. Overall 6-month PFS ratefor patients with GBM was 23.9%, with 7.4% progress-

ing while receiving extended adjuvant temozolomidebeyond 6 cycles but before completion of adjuvant treat-ment having the shortest time to progression (1.8months; P = .027) and 14.8% having the shortest sur-vival at 1 year. Best responses were in the early- or late-progression groups. Lymphopenia was the most commontoxicity, and there was no incidence of P carinii pneu-monia. The 6-month PFS rate and time to progressionwere similar between patients with methylated andunmethylated MGMT promoter status.16

Other Therapeutic OptionsEGFR has emerged as a potential target in patients

with malignant glioma, and overexpression of EGFR isassociated with a poor prognosis in GBM. Response ratesto small-molecule TKIs remain low and results are notuniform, although there is a subset of patients withEGFRvIII and PTEN expression that appear to benefitfrom TKI therapy.35Erlotinib has been evaluated in multiple phase 2 stud-

ies for high-grade glioma in patients receiving and notreceiving enzyme-inducing antiepileptic drugs. Bestresponses obtained to date have been 6-month PFS ratesof 20%, which are still higher than historical rates of 9%to 15%; however, none of the studies are controlled stud-ies. Because stable disease is the most common responsein patients receiving small-molecule therapy, it appearsthat erlotinib is cytostatic in GBM.17 Erlotinib has alsobeen evaluated in combination with bevacizumab in aphase 2 study of patients with recurrent malignantglioma; however, the 6-month PFS rate was lower(29.2%) among patients with GBM compared withother bevacizumab salvage regimens.36 The most com-mon side effects in studies with erlotinib were diarrheaand rash, which both correlate with increased PFS inGBM.17,36 Molecular stratification of patients with GBMmay identify those likely to respond to therapy.35Patients who do not have an intact PTEN may have

increased response to mTOR inhibitor and EGFR TKIcombinations. Some evidence of clinical response hasbeen seen in phase 1 investigations involving peptidevaccines37 and single drugs such as bortezomib38; howev-er, additional studies need to be performed to determinethe benefit of these drugs.

ConclusionGBM is the most aggressive of the glial tumors. Much

progress has been made over the past decade in GBMresearch, and a new standard of care has emerged, withnearly all patients receiving radiotherapy plus concomi-tant and adjuvant temozolomide for newly diagnosedGBM. Despite these advancements, all patients willprogress eventually, and most patients are not eligible for

Temozolomide has been the backbone ofinitial treatment of GBM. However,patients relapse and, for patients receivingchemotherapy, a resting period is requiredfor nontumor cell recovery to occur.



additional radiation or for surgical resection of tumor on disease progression. Chemotherapy and biotherapyremain the standard of care for these patients.Because of the angiogenic potential of GBM, beva-

cizumab has emerged as a promising therapy for use in therecurrent disease setting. Six-month PFS, which trackswith OS, is a useful end point in this patient population,and treatment with bevacizumab alone and in combina-tion with cytotoxic chemotherapy have improved 6-month PFS over single-drug alkylator therapy.It is still unknown if the benefits of bevacizumab in

combination with cytotoxic chemotherapy outweighthe risks, and further comparative trials are needed to assess the value of this combination. Combinationsof bevacizumab and chemotherapy may result inimproved PFS, but these regimens are associated withincreased toxicities, including myelosuppression andthromboembolic events, which may limit their use insome patient populations.Data have emerged that temozolomide therapy can be

repeated for patients with relapsed disease, and that con-tinuous metronomic dosing may be beneficial, byextending PFS without further decreasing quality of lifewith increased toxicity.Questions still remain about the optimal timing for

bevacizumab therapy, and the best schedule for it.Based on the best data available, bevacizumab shouldstill be recommended to be given every 2 weeks topatients who have recurrent disease. This decade hasbrought much improvement and insight to the man-agement of GBM; however, there is still a lot to learnand much progress to be made. n

Author Disclosure StatementDr Buie and Dr Valgus have reported no conflicts of

interest.

References1. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492-507.2. Central Brain Tumor Registry of the United States. Fact sheet.www.cbtrus.org/factsheet/factsheet.html. Accessed February 1, 2012. 3. Edick MJ, Cheng C, Yang W, et al. Lymphoid gene expression as a predictor ofrisk of secondary brain tumors. Genes Chromosomes Cancer. 2005;42:107-116.4. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary braintumours after radiotherapy and antimetabolites. Lancet. 1999;354:34-39.5. Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molec-ular pathology of glioma. Nat Clin Pract Neurol. 2006;2:494-503.6. Nicholas MK, Lukas RV, Chmura S, et al. Molecular heterogeneity in glioblas-toma: therapeutic opportunities and challenges. Semin Oncol. 2011;38:243-253.7. Chi AS, Sorensen AG, Jain RK, Batchelor TT. Angiogenesis as a therapeutictarget in malignant gliomas. Oncologist. 2009;14:621-636.8. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitantand adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.9. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitantand adjuvant temozolomide versus radiotherapy alone on survival in glioblastomain a randomised phase III study: 5�year analysis of the EORTC�NCIC trial. LancetOncol. 2009;10:459-466.10. Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemother-

apy followed by either dose-dense or metronomic temozolomide for newly diag-nosed glioblastoma. J Clin Oncol. 2009;27:3861-3867.11. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderlypatients with newly diagnosed glioblastoma and poor performance status: an ANOCEFphase II trial. J Clin Oncol. 2011;29:3050-3055. 12. Vrendenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Bevacizumab plus irinote-can in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722-4729.13. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combinationwith irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-4740.14. Raizer JJ, Grimm S, Chamberlain MC, et al. A phase 2 trial of single-agent beva-cizumab given in an every-3-week schedule for patients with recurrent high-gradegliomas. Cancer. 2010;116:5297-5305.15. Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oralpan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patientswith recurrent glioblastoma. J Clin Oncol. 2010;28:2817-2823.16. Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intensetemozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol.2010;28:2051-2057.17. Yung WK, Vredenburgh JJ, Cloughesy TF, et al. Safety and efficacy of erlotinibin first-relapse glioblastoma: a phase II open-label study. Neuro Oncol. 2010;12:1061-1070.18. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit fromtemozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003.19. Weller M, Stupp R, Reifenberger G, et al. MGMT promoter methylation in malig-nant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6:39-51.20. A Study of Avastin (Bevacizumab) in Combination With Temozolomide andRadiotherapy in Patients With Newly Diagnosed Glioblastoma. http://clinical trials.gov/ct2/show/NCT00943826. Accessed July 1, 2011.21. Radiation Therapy Oncology Group. RTOG 0825 protocol information.www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0825. AccessedJuly 1, 2011.22. Lai A, Filka E, McGibbon B, et al. Phase II pilot study of bevacizumab in combi-nation with temozolomide and regional radiation therapy for up-front treatment ofpatients with newly diagnosed glioblastoma multiforme: interim analysis of safety andtolerability. Int J Radiat Oncol Biol Phys. 2008;71:1372-1380. 23. Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy withbiodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primarymalignant glioma. Neuro Oncol. 2003;5:79-88.24. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma inthe elderly. N Engl J Med. 2007;356:1527-1535.25. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors inrecurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17:2572-2578.26. Lamborn KR, Yung WK, Chang SM, et al. Progression-free survival: an importantend point in evaluating therapy for recurrent high grade gliomas. Neuro Oncol.2008;10:162-170.27. Ballman KV, Buckner JC, Brown PD, et al. The relationship between six-monthprogression-free survival and 12-month overall survival end points for phase II trials inpatients with glioblastoma multiforme. Neuro Oncol. 2007;9:29-38.28. Chamberlain MC. Emerging clinical principles on the use of bevacizumab for thetreatment of malignant gliomas. Cancer. 2010;116:3988-3999.29. Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. ClinMed Insights Oncol. 2011;5:117-129.30. Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignantglioma. Proc Soc Neuro-Oncol. 2005;7:369. Abstract 342.31. Prados MD, Lamborn K, Yung WK, et al. A phase 2 trial of irinotecan (CPT-11)in patients with recurrent malignant glioma: a North American Brain TumorConsortium study. Neuro Oncol. 2006;8:189-193.32. Cloughesy TH, Filka E, Kuhn J, et al. Two studies evaluating irinotecan treat-ment for recurrent malignant glioma using an every-3-week regimen. Cancer. 2003;97:2381-2386.33. Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent glioblastomamultiforme. J Neurooncol. 2002;56:183-188.34. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs pro-carbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer.2000;83:588-593.35.Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the responseof glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012-2024.36. Sathornsumetee S, Desjardins A, Vredenburgh, et al. Phase II trial of beva-cizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol.2010;12:1300-1310.37. Terasaki M, Shibui S, Narita Y, et al. Phase I trial of personalized peptide vaccinefor patients positive for human leukocyte antigen-A24 with recurrent or progressiveglioblastoma multiforme. J Clin Oncol. 2011;29:337-344.38. Phuphanich S, Supko JG, Carson KA, et al. Phase I clinical trial of bortezomibin adults with recurrent malignant glioma. J Neurooncol. 2010;100:95-103.

FROM THE LITERATURE


n Inotuzumab Ozogamicin Shows High ResponseRate in Refractory/Relapsed ALL

Background: Patients with refractory or relapsed acutelymphoblastic leukemia (ALL) have a poor prognosis.Inotuzumab ozogamicin is a monoclonal antibodyagainst CD22, which is highly expressed on the surfaceof leukemic cells in patients with ALL. Studies withother monoclonal antibodies against CD22 or othersurface antigens have shown encouraging activity inpatients with ALL.

Design: This phase 2 study conducted at M.D.Anderson Cancer Center investigated the use of ino-tuzumab ozogamicin in patients with relapsed or refrac-tory ALL. The study initially included adults only (aged>18 years) with refractory or relapsed ALL of B-cell ori-gin; after the safe use of ≥1 course of the study medica-tion in ≥10 adults, patients aged <16 years were also eli-gible to participate. The study enrolled 49 patients, 3 ofwhom were aged ≤16 years and the remainder wereadults. The primary end point was overall response.

Summary: A total of 49 patients were treated. Of thesepatients, 9 (18%) had a complete response (CR), 19(39%) had a marrow CR, 19 had resistant disease (39%),and 2 (4%) died within 4 weeks of treatment onset.Median number of courses was 2 (range, 1-5 courses), andmedian time between courses was 3 weeks (range, 3-6weeks). The overall response rate was 57%, and the medi-an overall survival (OS) was 5.1 months. The 57%response rate was much higher than the rates reported inprevious studies, but the study was of short duration.

The most frequent adverse events (AEs) in the firstcourse of treatment were fever (n = 29), hypotension (n = 13), increased bilirubin (n = 14), and increasedaminotransferase concentration (n = 28). These AEsdid not increase in frequency with subsequent treat-ment courses, and no additional events were seen withadditional courses.

Takeaway: Although this is only a phase 2 study, sin-gle-agent use of this monoclonal antibody producedimpressive results, including complete bone marrowresponses in more than 50% of the patients receiving

this drug, and median survival duration of 5.1 months.This drug warrants further study in refractory or relapsedALL in a phase 3 clinical trial. Furthermore, because ittargets another often-expressed surface marker—CD22—it should also be tested in combination withstandard first-line agents.

Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, ananti-CD22-calecheamicin conjugate, for refractory and relapsed acute lym-phocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403-411.

n Allogeneic Transplantation in Young Patients withALL Who Fail Induction Therapy

Background: Induction therapy failure is rare in chil-dren and adolescents with ALL, but it has been associ-ated with a poor outcome in this patient population.Treatment options after induction failure include allo-geneic hematopoietic stem-cell transplantation andchemotherapy.

Design: This large, retrospective, international studyincluded data from 14 cooperative groups, totaling44,017 patients aged 0 to 18 years with newly diagnosedALL. Induction failure was identified in a subgroup of1041 (2.4%) of these patients. Data were collected onclinical and biological characteristics, previous treat-ments used, early responses to treatment, and survivaloutcomes in this subgroup of patients.

Summary: Conventional risk factors for children andadolescents with ALL, such as high leukocyte count(median, 42 × 109/L), age >6 years at diagnosis (median,8.1 years), Philadelphia chromosome, and T-cell pheno-type, were even more prevalent in this group and wereassociated with a worse prognosis. The study populationwas very heterogeneous; characteristics such as age ≥10years, T-cell leukemia, the presence of an 11q23rearrangement, and ≥25% blasts in the bone marrow atthe end of induction therapy were associated with a par-ticularly poor outcome. In contrast, high hyperdiploidy(a modal chromosome number >50) and age <6 yearswere associated with more favorable outcomes in patientswith precursor B-cell leukemia. Allogeneic stem-cell

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

FROM THE LITERATURE


transplantation was associated with better outcomes thanchemotherapy in patients with T-cell leukemia, but it didnot show benefit over chemotherapy in patients with pre-cursor B-cell ALL without other adverse genetic features.These patients fared better with chemotherapy.

Takeaway: This is the largest retrospective analysis ofoutcomes after treatment failure in childhood ALL.Clinical and biological factors were major determinantsin the outcomes observed in these patients. The best out-comes were seen in patients with precursor B-cell ALLwho were either aged <6 years or those who had highhyperdiploidy. These patients accounted for approxi-mately 25% of all patients with induction failure, andtheir outcomes were associated with a 10-year survivalrate of >50%. Patients with T-cell ALL who were aged <6years were best managed with allogeneic bone marrowtransplant therapy. In contrast, patients aged <6 years withprecursor B-cell ALL did better with chemotherapy thanwith transplantation. This study had several limitations,most notably the heterogeneity of the patient groups. Inaddition, the outcomes reported often preceded the use ofseveral new targeted agents, including tyrosine kinaseinhibitors. Clinicians should take the results of this studyand design trials that will further define the appropriatetreatment strategies in this patient population, especiallyin patient groups with the worst prognosis.

Schrappe M, Hunger SP, Pui C, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371-1381.

n Phased Ipilimumab Improves PFS and OS in NSCLC

Background: Ipilimumab, a fully human anticytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal anti-body, is approved in the United States for unresectable ormetastatic melanoma and is being studied alone or as partof a combination regimen in several other cancers.

Design: A double-blind, international, phase 2 studywas conducted to evaluate ipilimumab in combinationwith paclitaxel and carboplatin as first-line treatmentin advanced non–small-cell lung cancer (NSCLC).Because the sequence in which chemotherapy andimmunotherapy are given can have an impact on out-come, ipilimumab was given with the other agents in aconcurrent and in a phased regimen. To supplement eachchemotherapy administration, previously untreated adultpatients with NSCLC (stage IIIB/IV) were randomlyassigned 1:1:1 to a concurrent ipilimumab regimen (4 ipil-imumab doses followed by 2 placebo doses), a phased reg-imen (2 placebo doses followed by 4 ipilimumab doses), ora control regimen (up to 6 doses of placebo). Ipilimumab

or placebo, paclitaxel, and carboplatin were administeredintravenously once every 3 weeks for up to 18 weeks, fol-lowed by ipilim umab or placebo once every 12 weeks untilprogression, intolerance, or death. The primary end pointwas immune-related progression-free survival (PFS); PFSand duration of OS were key secondary end points.

Summary: A total of 204 patients were randomized tothe concurrent (n = 70), phased (n = 68), and control (n = 66) regimens. Phased ipilimumab improved immune-related PFS significantly compared with the control group(P = .05), whereas the concurrent regimen did not signif-icantly improve immune-related PFS (P = .13) versus thecontrol group. Phased ipilimumab also improved PFS (P = .02). For both immune-related PFS and PFS, differ-ences in favor of phased ipilimumab over the controlgroup appeared to be greater in patients with squamoushistology than those with nonsquamous histology. MedianOS durations were 9.7, 12.2, and 8.3 months for the con-current, phased, and control regimens, respectively.

Grade 3 and 4 immune-related AE rates were 20%,15%, and 6% for the concurrent, phased, and control reg-imens, respectively.

Takeaway: This randomized phase 2 study of ipilimu -mab has an interesting study design. It is designed toanswer 2 important questions: (1) does the addition ofipilimumab to standard paclitaxel/carboplatin therapyimprove PFS, immune-related PFS, or OS. And (2) doesthe scheduling of ipilimumab matter with regard to out-comes. The results confirm that the phased administra-tion method is preferred and improves immune-relatedPFS by 4 months (hazard ratio [HR], 0.71). In theaccompanying editorial published in the same issue, it isnoted that the concurrent administration method alsohad an HR of 0.81 (P = .15), which the author suggest-ed might have reached significance if the study size werelarger. Nevertheless, these results justify the study ofcombination chemotherapy plus ipilimumab versus astandard platinum doublet.

Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination withpaclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phaseII study. J Clin Oncol. 2012;30:2046-2054. Epub 2012 Apr 30.

n Immunotherapy with Ipilimumab and GVAXCombination Safe for Metastatic Castration-Resistant Prostate Cancer

Background: In 2011, prostate cancer represented11% of all cancer-related deaths in men. The granu-locyte-macrophage colony-stimulating factor (GM-CSF)-transduced allogeneic prostate cancer cells vac-cine (GVAX) has been studied in hormone-refractory

FROM THE LITERATURE


prostate cancer. When GM-CSF–secreting tumor-cellvaccines have been combined with the anti-CTLA-4monoclonal antibody ipilimumab in preclinical studies,these agents have acted synergistically. An open-label,phase 1 study in men with metastatic castration-resistantprostate cancer was undertaken to determine whetherimmunotherapy with these 2 agents can be combined safe-ly in the clinical setting.

Design: The dose-escalation study included 12 treat-ment-naïve patients with metastatic castration-resistantprostate cancer. A subsequent extension phase enrolled 16patients, for a total of 28 patients overall. All patientsreceived a priming GVAX intradermal dose. The patientsthen received additional doses every 2 weeks for 24 weeks,for a total of 13 injections. The patients received an esca-lating dose of ipilimumab 0.3, 1.0, 3.0, or 5.0 mg/kg every4 weeks, for a total of 6 infusions, each administered onthe same day as the GVAX vaccination. The primary endpoint was the safety of GVAX.

Summary: No severe immune-related AEs werereported with the lowest 2 doses. Other AEs includedhypophysitis in 3 patients with the 3.0-mg/kg dose and in2 patients with the 5.0-mg/kg dose. In addition, 1 patienthad grade 4 sarcoid alveolitis with the 5.0-mg/kg dose, adose-limiting effect. This led to the decision to expandthe patient enrollment for the 3.0-mg/kg dose ratherthan the 5.0-mg/kg dose. In addition, the findings includ-ed durable prostate-specific antigen (PSA) responses,

bone scan improvements, and tumor regression, indicat-ing that this immunotherapy has clinical activity in thistype of advanced prostate cancer. The most commonAEs were injection-site reactions, fatigue, and pyrexia.

Takeaway: The goal of this phase 1 trial was to estab-lish the safety of the anti-CTLA-4 antibody, ipilimumab,in combination with GM-CSF–secreting tumor-cell vac-cine (ie, GVAX) in patients with metastatic hormone-refractory prostate cancer. At the highest dose levelsattained, 3 and 5 mg/kg, immune-related reactionsoccurred, including hypophysitis and alveolitis (life-threatening). The additional study of the 3-mg/kg dosedemonstrated a manageable toxicity level. A total of 5 ofthe 28 patients had PSA responses. In addition, tumor-specific immune reactivity to GVAX (antibody responsesto filamin B and prostate-specific membrane antigen[PSMA]) were tested. Patients who developed a PSMA-specific antibody response had a median OS of 46.5months compared with 20.6 months in those without aPSMA-specific antibody response (P = .028). In addition,15 patients showed stabilization of disease on bone scan.These results indicate that this immune-based combina-tion therapy is worthy of further study. n

van den Eertwegh AJM, Versluis J, van den Berg HP, et al. Combinedimmunotherapy with granulocyte-macrophage colony-stimulating fac-tor-transduced allogeneic prostate cancer cells and ipilimumab inpatients with metastatic castration-resistant prostate cancer: a phase 1dose-escalation trial. Lancet Oncol. 2012;13:509-517.

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

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

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

See 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 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations 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)

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


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

Gemcitabine Injection For Intravenous Infusion Only.Must Be Diluted Before Use.Initial U.S. Approval: 1996

INDICATIONS AND USAGEGemcitabine is a nucleoside metabolic inhibitor indicated for:• Ovarian cancer in combination with carboplatin (1.1)

• Breast cancer in combination with paclitaxel (1.2)

• Non-small cell lung cancer in combination with cisplatin (1.3)

• Pancreatic cancer as a single-agent (1.4)

DOSAGE AND ADMINISTRATION

Gemcitabine Injection is for intravenous use only.

• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1)

• Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2)

• Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3)

• Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4)

• Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4)

DOSAGE FORMS AND STRENGTHS

• 200 mg/5.26 mL injection vial (3)

• 1 g/26.3 mL injection vial (3)

• 2 g/52.6 mL injection vial (3)

CONTRAINDICATIONS

Patients with a known hypersensitivity to gemcitabine (4)


• Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1)

• Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7)

• Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3)

• Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4)

• Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)

• Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

• Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

ADVERSE REACTIONS

The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1)

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

See 17 for PATIENT COUNSELING INFORMATION

Revised: 07/2011


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Topotecan Injection Must be diluted before intravenous infusionInitial U.S. Approval: 1996

WARNING: BONE MARROW SUPPRESSIONSee full prescribing information for complete boxed warning.

Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1)

CONTRAINDICATIONS

• History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4)

• Severe bone marrow depression (4)


• Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1)

• Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2)

• Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3)

• Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1)

ADVERSE REACTIONS

Small cell lung cancer:

• The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1)

• The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea,

alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1)

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.

Manufactured by:Hospira Australia Pty LtdMulgrave VIC 3170 Australia

Manufactured for:Hospira, Inc.Lake Forest, IL 60045 USAProduct of Australia

Manufactured and Distributed by:Hospira, Inc.Lake Forest, IL 60045 USA

Made in India

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia

Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India

Distributed by: Hospira, Inc., Lake Forest, IL 60045 USAGUJ DRUGS/G/28/1267

Reference: 1. Data on fi le. Hospira, Inc.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P11-3464-Nov., 11

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com.

ONEFOR ALL

As the complexity of healthcare evolves,

we’re doing our part to improve cost savings,

optimize workfl ow and enhance patient care.

With our generic oncology portfolio we provide

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR CLINICIANS—UNIQUE ONCO-TAIN™ VIALS REINFORCE SAFETY1

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST

HOSPIRA ONCOLOGY PORTFOLIO

160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

2 g/52.6 mL single-dose vial

1 g/26.3 mL single-dose vial

200 mg/5.26 mL single-dose vial

See Black Box Warning

DOCETAXEL INJECTION (10 mg/mL)

GEMCITABINE INJECTION(38 mg/mL)

1 PVC BOTTOM offers shatter resistance.

2 SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3 GLASS CLARITY allows for easy inspection of the vial as a fi nal safety check before administration.

4 PREWASHED VIALS reduce cytotoxic residue.

UNIQUE ONCO-TAIN SAFETY FEATURES

4 mg/4 mL single-dose vial

See Black Box Warning

TOPOTECAN INJECTION (1 mg/mL)

journal of hematology oncology pharmacy - june 2012, vol 2, no 2

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