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JUNE 2012 VOL 2 I NO 2

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Impact of a Pharmacist-Managed Oral Chemotherapy Program on Nonfulfillment Rates Kaylee Drenker, PharmD; April Sondag, PharmD; Robert Mancini, PharmD

ORIGINAL RESEARCH

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 ARTICLE

Current Treatment Options for the Management of Glioblastoma Multiforme Larry W. Buie, PharmD, BCPS, BCOP; John M. Valgus, PharmD, BCOP, CPP

From The Literature

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

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EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

REVIEW ARTICLES Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale New Haven Yale New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

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JUNE 2012

VOLUME 2, NUMBER 2

JOURNAL OF

PUBLISHING STAFF

HEMATOLOGY ONCOLOGY PHARMACY ™

Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com 732.992.1886 TM

THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TABLE OF CONTENTS

Editorial Director Dalia Buffery dalia@greenhillhc.com 732.992.1889 Associate Editor Lara J. Lorton

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

42 Impact of a Pharmacist-Managed Oral Chemotherapy Program on Nonfulfillment Rates Kaylee Drenker, PharmD; April Sondag, PharmD; Robert Mancini, PharmD

Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732.992.1536 Directors, Client Services Joe Chanley joe@greenhillhc.com 732.992.1524 Production Manager Stephanie Laudien

ORIGINAL RESEARCH

47 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 ARTICLE

57 Current Treatment Options for the Management of Glioblastoma Multiforme Larry W. Buie, PharmD, BCPS, BCOP; John M. Valgus, PharmD, BCOP, CPP

Quality Control Director Barbara Marino Business Manager Blanche Marchitto blanche@greenhillhc.com Editorial Contact: Telephone: 732.992.1536 Fax: 732.656.7938 E-mail: JHOP@greenhillhc.com

MISSION STATEMENT

From The Literature

64 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy Robert J. Ignoffo, PharmD, FASHP, FCSHP

The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with highquality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

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 of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

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PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Impact of a Pharmacist-Managed Oral Chemotherapy Program on Nonfulfillment Rates Kaylee 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.” Nonfulfillment 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 assistance 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 alternate therapy. Only 1% of patients overall were unable to obtain the medication because of financial reasons. Conclusion: Successful collaboration with patient financial advocates has allowed our pharJ Hematol Oncol Pharm. macist-managed OCP to reach low medication nonfulfillment rates. Maintaining and processing 2012;2(2):42-45. prescriptions within the health system (ie, MSTI) allowed controllable factors for nonfulfillment (ie, www.JHOPonline.com cost and loss to follow-up) to be kept at rates lower than those previously seen in other studies. Disclosures are at end of text This study did not address mail-order or closed-door pharmacies.

O

ral chemotherapy has an ever-increasing role in the treatment of patients with cancer. The number of oral agents available to treat cancer has more than doubled in the past 15 years, and up to 35% of the agents in development are likely to be oral formulations.1 Nonfulfillment, or primary nonadherence, is defined as failure to obtain a medication that has been prescribed.2 The causes of nonfulfillment are numerous, and they are not well described in the literature. Important factors influencing nonfulfillment include patient-perceived

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

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concerns about medications, lack of perceived need for medications, and medication affordability issues.3 Nonfulfillment rates have been shown to increase as medication costs increase, especially as it relates to direct patient costs.2,3 Based on average wholesale price (AWP), oral chemotherapy prescriptions can cost from a few hundred dollars per chemotherapy cycle to more than $10,000 per cycle. Therefore, based on cost alone, these medications are at high risk for nonfulfillment. To combat this risk, the financial barriers to patients obtaining these medications need to be addressed. Nonfulfillment rates vary greatly in the literature. A recent systemic analysis reported an overall mean nonfulfillment rate of 16.4% based on all the studies reviewed.3 Another study focusing on electronic pre-

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Impact of Pharmacist-Managed OCP on Nonfulfillment Rates

scribing reported a 24% nonfulfillment rate that varied by class of medication, formulary status, and other factors (oncology medications were not included as a class in this study).4 In a third study, which specifically focused on oral chemotherapy prescriptions, the nonfulfillment rate reported was 10%.5 This present article describes how a pharmacistmanaged oral chemotherapy program (OCP) at one institution has positively affected nonfulfillment rates by addressing barriers to obtaining the prescribed medication, especially lack of medication affordability. This article does not address mail-order or closeddoor pharmacies; this was not included in the current evaluation.

Methods St Luke’s Mountain States Tumor Institute (MSTI) is a National Cancer Institute Community Cancer Center Program with 5 sites that serve a broad geographic area, including southern Idaho, eastern Oregon, and northern Nevada. Prescriptions for oral chemotherapy from any of MSTI’s providers go through a dispensing process as described in Figure 1. The first step in the process is that the prescriptions are sent directly to the oral chemotherapy office. After a pharmacist conducts a clinical evaluation, the prescription is sent to the outpatient pharmacy for a benefits investigation. A multidisciplinary team, which includes pharmacists, patient financial advocates, and social workers, addresses any potential financial barriers to obtaining the medication. Patient assistance programs are utilized to provide financial aid for uninsured and underinsured patients. Every patient referred to the OCP is tracked from receipt of the first prescription through termination of the treatment. For this study, the nonfulfillment rate (ie, the number of prescriptions that had been sent to the oral chemotherapy office but never dispensed to the patient) was assessed. These abandoned prescriptions were then classified according to the following reasons for nonfulfillment: • Inability to obtain the medication, including insurmountable 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 are then available for consultation when needed. For this evaluation, the total amount of a free drug that was

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Figure 1 Oral Chemotherapy Dispensing Process

Oral chemotherapy office

Outpatient pharmacy

Benefits team

Dispensing

• Prescription received • Prescription assessed and patient educated

• Benefits investigation • Lack of insurance, underinsurance, high cost identified

• 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

MSTI indicates St Luke’s Mountain States Tumor Institute.

obtained was calculated for each patient, by multiplying the AWP of the medication acquired by the average number of chemotherapy cycles the medication was continued in our patient population.

Results A total of 702 patients have been served by the MSTI OCP from its initiation in August 2009 through October 2011 (Figure 2). During this period, the patient nonfulfillment rate was 9% (N = 63). Of the total number of patients served by the MSTI OCP, only 1% (N = 7) of nonfulfillment was attributable to the inability to obtain the medication or to a medication affordability issue. All other reasons contributing to the nonfulfillment rate are listed in Figure 3. As of October 2011, the MSTI OCP has obtained more than $1 million of free drug assistance (Table) and more than $250,000 of copayment assistance for our patients.

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PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Figure 2 Oral Chemotherapy Patient Distributiona

19%

51%

14%

7% 9%

Active Discontinued Never started Patient assistance Mail order

(N = 702) a

As of October 2011.

Figure 3 Patient Nonfulfillment Distributiona (N = 63, 9% overall) 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%

25

Patients, N

20 15 10 5 0

Nonfullfillment

a

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

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Discussion The MSTI OCP was described in detail in a previous article published in this journal.6 The goal of the present article is to analyze the impact of this program on medication nonfulfillment. As the literature consistently reports, the most significant barrier to filling an oral chemotherapy prescription is the patient medication cost. Our patients’ medication affordability issues were attributed to low income, insurance denials, high cost-sharing (copay) insurance, and ineligibility for patient financial or free drug assistance. At MSTI, patient financial advocates are utilized to help obtain free drug or copay assistance through available patient assistance programs. The Association of Community Cancer Centers and the Oncology Nursing Society have reimbursement resources that patient financial advocates at MSTI use to identify reimbursement/assistance resources.7,8 High-priced medications and brand-name medications are more likely to have patient medication assistance programs available. Our patient financial advocates have reported that it is easier to obtain patient assistance for medications that are frequently prescribed, for medications prescribed within their US Food and Drug Administration–approved indication, for patients whose income is low or who lack insurance, and for medications that have user-friendly patient assistance programs. Gadkari and McHorney identified important barriers that contribute to increased nonfulfillment rates, as noted earlier, including patient concerns about medications, patients being unsure of the need for medications, and medication affordability issues.3 At MSTI, patients’ concerns about oral chemotherapy are addressed up front and as therapy progresses by a multidisciplinary healthcare team, including physicians, nurses, and pharmacists. Patients are provided with education on oral chemotherapy for its benefits and for the potential risks to ensure that patients can make an informed medication treatment decision. Frequent physician follow-up, along with pharmacist initial fill and refill medication counseling, allow for emphasizing the importance of oral chemotherapy medications to MSTI’s patients. Improved communication between the healthcare team and the patient helps to decrease nonfulfillment rates for oral chemotherapy medications. At MSTI, our evaluation showed other major reasons for nonfulfillment of oral chemotherapy medications, including: • Choosing an alternative therapy • The patient declined treatment

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• The patient had complications or died before the initiation of treatment. Alternative therapy was most often chosen based on imaging and pathology results. Physicians send the OCP a “prior authorization only” prescription so the pharmacist can assess prescription insurance coverage, while the imaging and pathology results are pending. In addition, the choice may be made by either the patient or the physician to decline treatment for advanced cancers when the risks outweigh the benefits. Alternatively, the patient may choose comfort care or hospice. In our evaluation, minor reasons for nonfulfillment were medication formulation issues, treatment at another facility, and loss to follow-up. The minor reasons contributing to nonfulfillment were only observed in <1% of the total patients studied.

The MSTI OCP has been able to ensure proper prescription reimbursement. As a result, <1% of the total medication costs have been written off. Successful collaboration with the patient financial advocates has allowed the pharmacist-managed OCP to reach low medication nonfulfillment rates. The literature reveals little regarding additional methods to decrease nonfulfillment. Several articles offer recommendations for increasing adherence to oral chemotherapy medications,9,10 but they do not address primary nonadherence. Potential avenues for further improvement of primary nonadherence include increased utilization of resources to decrease patient cost for these medications, and increased patient education to address concerns about medications and to emphasize the need for medication adherence.

Conclusions With our current established prescription processes in place, the MSTI OCP has been able to ensure proper prescription reimbursement. As a result, <1% of the total medication costs have been written off. Successful collaboration with the patient financial advocates has allowed the pharmacist-managed OCP to reach low medication nonfulfillment rates. Maintaining prescription processing within the health system allowed controllable factors for nonfulfillment (ie, cost and loss to

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Table Free Drug Assistance through the MSTI Oral Chemotherapy Program Patients, N Total cost-savings, $a

Free drug 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

Other

6

201,836

Total

47

1,091,642

b

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

follow-up) to be kept at rates lower than those seen in previous studies. n Author Disclosure Statement Dr Drenker and Dr Sondag reported no conflicts of interest. Dr Mancini is on the Speaker’s Bureau for Millennium Pharmaceuticals.

References 1. DeCardenas R, Helfrich J. Oral therapies and safety issues for oncology practices. Oncol Issues. 2010;March/April:40-42. 2. Gellad WF, Grenard J, McGlynn EA. A review of barriers to medication adherence: a framework for driving policy options. Santa Monica, CA: RAND Corporation; 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: narrative systematic review. Curr Med Res Opin. 2010;26:683-705. 4. Fischer MA, Choudhry NK, Brill G, et al. Trouble getting started: predictors of primary medication nonadherence. Am J Med. 2011;124:1081.e9-1081.e22. 5. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics 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-managed interdisciplinary oral chemotherapy program in a community cancer center. J Hematol Oncol Pharm. 2011;1:23-30. 7. Association of Community Cancer Centers. Reimbursement and patient assistance 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 Your Patients Stay on Course Toolkit. 2010. www.ons.org/ClinicalResources/Oral Therapies/media/ons/docs/clinical/AdherenceToolkit/oraladherencetoolkitprint.pdf. Accessed June 14, 2012. 9. Partridge AH, Avorn J, Wang PS, Winder EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94:652-661. 10. Schneider SM, Hess K, Gosselin T. Interventions to promote adherence with oral agents. Semin Oncol Nurs. 2011;27:133-141.

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ORIGINAL RESEARCH

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 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 manifestations. 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 predict the incidence of dialysis or mortality secondary to TLS. Methods: A total of 1327 patients with cancer who were identified by an internal registry database 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 Burkittâ&#x20AC;&#x2122;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 considered when creating future predictive models for the clinical manifestations of TLS.

T

umor lysis syndrome (TLS) is a complication of cancer therapy that leads to multiple abnormal laboratory findings and clinical manifestations. The overall incidence of TLS has been reported to be 42% in adults with hematologic malignancies; however, the incidence of patients with clinical manifestations may be 5% to 10% or less, and may depend on the type of cancer.1-3 TLS with severe clinical consequences (ie, requirement of dialysis or mortality) may occur even less frequently, although the incidence has not been fully elucidated in a real-world setting. TLS is caused by the acute release of cellular components into the blood after the rapid destruction of malignant cells.4,5 The abrupt lysis of tumor cells causes

J Hematol Oncol Pharm. 2012;2(2):47-55. www.JHOPonline.com Disclosures are at end of text

the release of electrolytes, particularly potassium and phosphorus, from intracellular compartments, causing systemic hyperkalemia and hyperphosphatemia. Hypocalcemia can also occur secondary to hyperphosphatemia.5,6 In addition, release of purine nucleotides that are metabolized to uric acid can accumulate and crystallize in renal tubules, which will overwhelm normal glomerular filtration processes and lead to renal insufficiency or renal failure.7,8 Renal failure further perpetuates electrolyte abnormalities, resulting in even larger increases in potassium and phosphorus. Collectively, the syndrome can lead to clinical manifestations that include seizures, cardiac abnormalities, neuromuscular instability, 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 in Pharmacoepidemiology and Health Services, University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Study, Lexington; Dr Lawson is a Clinical Pharmacy Specialist, UK HealthCare, University of Kentucky, Lexington; Dr Sutphin is a Clinical Pharmacy Specialist, Department of Oncology, UK HealthCare, University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, Lexington; Dr Blechner is an Anatomic and Clinical Pathologist, UConn Health Center, Connecticut Institute for Clinical and Translational Science, Farmington; Dr Adams is a Clinical Pharmacy Specialist, UK HealthCare, University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, Lexington.

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ORIGINAL RESEARCH

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

≤1.75 mmol/L

25% decrease

Calcium

a Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change from baseline or a level above or below normal limits (as defined above) for ≥2 values 3 days before or 7 days after chemotherapy. b Clinical tumor lysis syndrome meets the criteria for LTLS in addition to 1 of the following conditions: an increase in serum creatinine (≥1.5 × upper limit of normal), cardiac arrhythmia/ sudden death, or seizure (if not attributable to therapeutic agent). Reprinted with permission from Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778. © 2008 American Society of Clinical Oncology. All rights reserved.

TLS may be classified as either a laboratory disorder (laboratory TLS [LTLS]) or as a laboratory disorder with clinical manifestations (clinical TLS [CTLS]). The current criteria for TLS are shown in Table 1.10 Guidelines have recently been proposed for the management of TLS in pediatric and adult patients for both laboratory and clinical manifestations.10 The guidelines support risk stratification among patients that is determined by cancer type and extent of disease (Table 2), as well as provide prophylaxis and treatment recommendations for each risk category.10 Protecting the kidneys is the primary focus of management, because the kidneys are essential to clearing the dying tumor’s metabolic products and electrolytes, which can accumulate to life-threatening concentrations. Because uric acid is the primary renal toxic product, minimizing the concentration in the renal tubule is paramount. This can be accomplished with allopurinol, which decreases the formation of uric acid through inhibition of xanthane oxidase, an enzyme that converts hypoxanthine and xanthine to uric acid.11,12 Alternatively, or in combination with allopurinol, rasburicase (recombinant urate oxidase) can be used, which metabolizes uric acid into the more water-soluble, nonrenally toxic allantoin.11,13-15 Hyperhydration is also

Table 2 Tumor Lysis Syndrome Risk Stratification Recommended by Current Guidelines 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 an expected rapid response to treatmentb

Remainder of patients

Burkitt’s, lymphoblastic, B-ALL

DLBCL

Indolent NHL

Cancer type

NHL a

White blood cell value is in cells/mm3. All patients with CML, testicular solid tumors, and SCLC were included in the intermediate-risk category, because they are expected 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, not applicable; 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 adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767-2778. © 2008 American Society of Clinical Oncology. All rights reserved.

b

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Predictors for Severe Tumor Lysis Syndrome

often used; it provides benefit by diluting the concentration of uric acid in the renal tubule.10 The guidelines recommend that low-risk patients are monitored closely, intermediate-risk patients receive allopurinol and intravenous (IV) hydration, and high-risk patients receive recombinant urate oxidase and IV hydration. Select intermediate-risk patients in which hyperuricemia develops despite prophylactic allopurinol should also receive recombinant urate oxidase.10 Available evidence supports the risk stratification; however, the risk categories have not been adequately confirmed in a real-world setting.11,14,15 Current risk stratification methods have not been proved to predict the incidence of dialysis and mortality in patients at risk for TLS. The ability to predict patients at risk for renal failure and subsequent dialysis, for example, would be beneficial; it can be one of the most influential and costly manifestations of this disorder, because it increases mortality rates and length of hospital stay.2 The purpose of our study was to evaluate risk strategies and their ability to predict the incidence of clinically severe outcomes (eg, dialysis and mortality) secondary to TLS complications. This allowed us to determine if patients expected to be at higher risk according to proposed guidelines are more likely to suffer severe clinical outcomes secondary to TLS, and whether more aggressive and expensive pharmacologic management with recombinant urate oxidase should be considered. As a secondary analysis, we determined if selected pretreatment laboratory abnormalities translate into clinical outcomes and which factors are most predictive of clinically severe outcomes in patients at risk for TLS.

Patients and Methods This study was designed as a retrospective review of patients at risk for TLS between January 1, 2005, and December 2, 2008, at a university hospital. The study was approved by the Institutional Review Board, and it adhered to appropriate policies and procedures. The primary end point was to determine if there is a difference in the incidence of dialysis and/or mortality in patients at low risk for developing TLS compared with those at high or intermediate risk based on current published guidelines for TLS risk. Secondary objectives were to determine if there is a difference in the incidence of dialysis and mortality between individual risk categories for TLS, and to determine if baseline population characteristics or laboratory abnormalities can predict these severe outcomes. A total of 1327 patients with cancer were identified by an internal registry database and were risk stratified according to disease state and/or baseline white blood

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cell counts based on current guidelines (Table 2). Only the first antineoplastic treatment episode was considered for each individual, because the risk for TLS would be highest during the first course of treatment. Administrative claims databases were used to determine if patients received dialysis or died after therapy. Medical charts, including inpatient and outpatient dialysis records, were analyzed for all database-identified patients to determine if death occurred within 1 month after treatment (consistent with TLS complications), or if they received dialysis within 2 weeks of therapy. These criteria were used to define a TLS-associated severe outcome. Patients were excluded only if they were aged ≤18 years. All therapies for the prevention or treatment of TLS were allowed in this study. The incidence of severe clinical outcomes between the combined intermediate- and high-risk group were compared with those in the low-risk group, as well as between each individual risk group. When available, baseline laboratory and demographic data were collected to assess individual predictors for risk of clinical outcomes secondary to TLS compared with patients without these outcomes. Laboratory values were collected for 1 week before treatment, and the averages of the total values were considered baseline characteristics of each patient in the analysis.

Only the first antineoplastic treatment episode was considered for each individual, because the risk for TLS would be highest during the first course of treatment. Statistical Analysis Demographic data and other patient characteristics were described using descriptive statistics. Differences between the intermediate- or high-risk category and the low-risk category were compared using a 2-tailed Fisher’s exact test. For analysis of differences between individual risk categories, a multivariate 2 × 3 Fisher’s exact test (2-tailed; 95% confidence interval) was performed, followed by a univariate analysis to detect differences between individual risk categories. A logistic regression analysis was used to calculate the crude odds of characteristic variables predicting significant outcomes. A multivariate logistic regression model was then used to compare significantly different variables adjusted for the primary risk category to control for differences between risk groups. Binary covariates were encoded as 0 and 1, and cutoff values for continuous variables were not included. For all tests, P <.05 was considered significant. All statistical analyses were performed using STATA v10.1 (StataCorp; College Station, TX).

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ORIGINAL RESEARCH

Table 3 Patient Characteristics (N = 1327) Risk category Intermediate/high

Low

168

1159

Age, mean yr (SD)

55 (13.2)

52 (15.7)

Sex, N (%) Male Female

112 (66.7) 56 (33.3)

290 (25.0) 869 (75.0)

9 (5.4)

0 (0)

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)

91 (54.1)

0 (0)

Colorectal

0 (0)

74 (6.4)

Pancreas

0 (0)

67 (5.7)

Other

0 (0)

28 (2.4)

Population, N

Cancer type, N (%) Burkittâ&#x20AC;&#x2122;s ALL AML

SCLC

ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; NOS, not otherwise specified; NSCLC, nonâ&#x20AC;&#x201C;small-cell lung cancer; SCLC, small-cell lung cancer; SD, standard deviation.

Results Of the 1327 patients who were included in the analysis, 168 patients were in the intermediate- or high-risk groups, and 1159 patients were in the low-risk group. Analysis of each individual risk group reveals that there

Of the entire at-risk population, patients with intermediate or high risk were significantly more likely to have clinically severe outcomes compared with low-risk patients. were 1159 (87.4%), 141 (10.6%), and 27 (2.0%) individuals at low, intermediate, and high risk, respectively. Demographic information of the patients in the study is shown in Table 3.

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The overall incidence of clinically severe outcomes secondary to TLS was found in 6 (0.5%) patients (Table 4). Of these patients, 3 (0.2%) received dialysis and 3 died secondary to TLS complications (Table 5). Of the entire at-risk population, patients with intermediate or high risk were significantly more likely to have clinically severe outcomes compared with low-risk patients (0.09% vs 2.98%; P = .001). No patients had concomitant dialysis and mortality in the study. With regard to secondary objectives, the incidence of dialysis occurred in 7.4%, 0.7%, and 0.0% of patients in the high-, intermediate-, and low-risk groups, respectively. Mortality occurred in 0.0%, 1.4%, and 0.09% of patients in the high-, intermediate-, and low-risk groups, respectively. Univariate analysis revealed that of the total population, the intermediate- and high-risk groups had more severe outcomes compared with the low-risk group (P = .001 and P = .005, respectively). Individual outcomes of dialysis and mortality also had statistically significant differences in the higher-risk group. Mortality incidence was significantly higher in the intermediate-risk group compared with that of the lowrisk group (P = .033), and the incidence of dialysis was significantly higher in the high-risk group compared with that of the low-risk group (P = .001). Baseline parameters most predictive of clinically significant outcomes based on the univariate analysis included male sex, age, and patients classified in the intermediate-, high-, and in the combined intermediateand high-risk groups. Patients with Burkittâ&#x20AC;&#x2122;s lymphoma were most at risk compared with standard (ie, those with colorectal cancer) patients in the low-risk category. In addition, laboratory parameters, such as serum creatinine (SCr), blood urea nitrogen (BUN), magnesium, and phosphorus, were all significant predictors of clinically severe outcomes. When adjusting for the primary risk categories (intermediate-, high-, and low-risk groups), only SCr and BUN were significant predictors of severe TLS (Table 6).

Discussion Since the initiation of our study, other risk stratification and treatment guidelines for TLS have been published.13,16,17 To our knowledge, however, this is the only study that has compared the risk for TLS with severe clinical outcomes according to current guidelines. Our study shows an overall low incidence of dialysis or mortality, regardless of risk category. Of the total at-risk population, only 0.2% of the patients received dialysis, and 0.2% died from TLS. This is very similar to data reported by Annemans and colleagues, in which the overall incidence of dialysis secondary to TLS was 1.3%, and 0.8% of the total population died from the consequences

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

Outcome

Patient

Cancer type

Risk category Intermediate

1

Dialysis

AML

2

Dialysis

Burkitt’s ALL High

SCra, mg/dL

Phosphorus , mg/dL

Calciumb,c, mg/dL

Potassiuma, mmol/L

Uric acida, mg/dL

8.5

8.3

6.0

5.5

7.7

5.1

9.6

7.7

4.6

9.0

d

3

Dialysis

Burkitt’s ALL High

5.0

19.2

6.7

5.8

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

a

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

of TLS.2 Multiple other studies have also shown Table 5 Incidence of Dialysis and Mortality in Intermediate/Highoverall low rates of CTLS after treatment with versus Low-Risk Groups chemotherapy, although most studies did not primaRisk category rily assess clinically severe outcomes.1,3,18 a Despite the overall low incidence of severe cliniLow Intermediate/high P value cal outcomes in our study, it was confirmed that Total population, N 1159 168 — those most at risk (intermediate/high-risk group) 0 (0) 3 (1.79) .002 had an increased incidence of clinically severe out- Dialysis, N (%) comes compared with those at low risk. Significant Mortality, N (%) 1 (0.09) 2 (1.19) .044 differences were found between these 2 groups for Total clinically severe 1 (0.09) 5 (2.98) .001 dialysis and for mortality. These findings support outcomes, N (%) current recommendations for more aggressive prophylaxis (ie, recombinant urate oxidase) in higher- aP <.05 is considered significant using Fisher’s exact test. risk patients, despite increased costs associated with the therapy.10 Predictive models for TLS are currently lacking. An However, there are no randomized, controlled studanalysis of patients with acute myeloid leukemia (AML), ies that have fully analyzed the clinical benefit of however, revealed that baseline lactate dehydrogenase, aggressive management for the prevention of clinically serum uric acid concentrations, and male sex were signifsevere outcomes in the setting of TLS. Urate oxidase icant predictive values for TLS in this specific patient has been shown to be safe and effective in reducing population.21 Montesinos and colleagues revealed increased risks of LTLS and CTLS in patients with AML serum uric acid concentrations in various populations with elevated SCr, uric acid, and white blood cell counts.3 with overall low incidence of dialysis or mortality, but Our univariate analysis did not reproduce identical this has not been extensively compared with more conresults, because lactate dehydrogenase, serum uric acid, ventional strategies, such as allopurinol or IV hydraand white blood cell counts were not positive predictors tion.14,15,19,20 Only 1 patient died in the low-risk group. This patient of clinically severe TLS. However, male sex and SCr did predict the incidence of severe outcomes. In addition, had colorectal cancer and LTLS, with no other docubaseline BUN, magnesium, and phosphorus were all posmented source of mortality according to available itive predictors for clinically severe TLS. records. Despite this patient, analysis of the entire at-risk With regard to cancer type, patients with Burkitt’s population reveals that the low-risk group had an overall lymphoma were at highest risk for significant outcomes lower incidence of clinically severe outcomes compared compared with those at low risk. Using data from the with the higher-risk groups. This reached statistical sigunivariate analysis, our multivariate analysis revealed nificance with dialysis compared with high-risk individuthat BUN and SCr were again predictors for clinically als and mortality with intermediate-risk individuals.

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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 1 Low Intermediate/high

Referent 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 2 Low Intermediate High

Referent 25.17 (2.600-243.65) 92.64 (8.13-1055.26)

20.857 (1.674-259.894)

3.272 (1.889-5.669)

2.492 (1.337-4.650)

BUN Calcium

1.077 (1.042-1.114) 0.422 (0.122-1.458)

1.060 (1.021-1.101) —

Potassium

2.066 (0.952-4.483)

LDH Magnesiumc

0.999 (0.999-1.001) 165.085 (5.912-4609.872)

— —

Phosphorusc

2.919 (1.272-6.698)

Uric acid WBC

1.251 (0.948-1.651) 1.003 (0.992-1.013)

— —

Cancer typeb B-ALL Laboratory value Serum creatinine

— —

a

Adjusted for primary risk groups (intermediate/high, low risk); includes significant groups from univariate analysis. Compared with those with colorectal cancer (low-risk group); includes only significant groups. c In 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. b

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

These findings support current recommendations for more aggressive prophylaxis (ie, recombinant urate oxidase) in higher-risk patients, despite increased costs associated with the therapy. Limitations There are limitations to our study. Our review is retrospective, and therefore prospective studies are encour-

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aged to support validity of the data. In addition, collection methods for our data may have missed patients who have received dialysis at an outside institution. Our results also showed a low number of patients with severe outcomes, which limits our ability to appropriately incorporate the regression analysis and enhances our probability of error. In addition, our data do not assess the influence of therapies on the incidence of TLS. Patients were not stratified by risk according to therapies received for TLS prevention and treatment, although allopurinol use in higher-risk patients is the standard approach, and the overall use of recombinant urate oxidase therapy is low at our institution. Finally, for a majority of the patients, our data did not include the possibility of concomitant nephrotoxic agents that might have been utilized before or during the

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

Conclusion Despite these limitations, our study provides evidence that higher-risk populations truly are at higher risk for severe CTLS. As a result, more aggressive therapies, such as recombinant urate oxidase, may need to be prescribed to prevent these outcomes in select intermediate- or high-risk populations as current guidelines suggest. In addition, multiple laboratory and demographic factors should be considered when creating predictive models for CTLS. Based on our findings, we encourage future randomized, prospective trials to analyze current therapies and their abilities to prevent and treat severe clinical outcomes in the setting of high-risk TLS. n Author Disclosure Statement Dr Sutphin is on the advisory board of Amgen. Dr Wirth, Dr Steinke, Dr Lawson, Dr Blechner, and Dr Adams have reported no conflicts of interest. References 1. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med. 1993;94:133-139. 2. Annemans L, Moeremans K, Lamotte M, et al. Incidence, medical resource utilisation and costs of hyperuricemia and tumour lysis syndrome in patients with acute leukaemia 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 with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008;93:67-74. 4. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

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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 renal insufficiency 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, and treatment 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 pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:27672778. 11. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97:2998-3003. 12. Hande KR, Hixson CV, Chabner BA. Postchemotherapy purine excretion in lymphoma patients receiving allopurinol. Cancer Res. 1981;41:2273-2279. 13. Pession A, Masetti R, Gaidano G, et al. Risk evaluation, prophylaxis, and treatment 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 prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol. 2001;19:697-704. 15. Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1 (Groupe d’Etude des Lymphomes de l’Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol. 2003;21:4402-4406. 16. Tosi P, Barosi G, Lazzaro C, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93:1877-1885. 17. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 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 complication 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 oxidase 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 treatment of hyperuricemia associated with lymphoid malignancies. Leukemia. 1997;11:18131816. 21. Mato AR, Riccio BE, Qin L, et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma. 2006;47:877-883.

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ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.


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. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study 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

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Current Treatment Options for the Management of Glioblastoma Multiforme Larry 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 therapy 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 concomitant and adjuvant temozolomide. Other studies have shown that after disease progression, the administration of bevacizumab alone and in combination with cytotoxic chemotherapy resulted 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 bevacizumab 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.

G

lioblastoma multiforme (GBM) is classified as a grade 4 central nervous system (CNS) tumor by the World Health Organization and is the most malignant of the glial tumors. GBM is characterized by rapid mitotic activity, infiltrative growth, and necrosis. Microvascular proliferation is often present in the tumor and suggestive of aggressive angiogenesis. Patients may present with a variety of neurologic symptoms, including headaches, seizures, confusion, memory loss, personality changes, and focal neurologic deficits. Magnetic resonance imaging is usually confirmatory, showing an enhancing mass, peritumoral edema, and central areas of necrosis. Multimodality treatment of GBM typically includes surgery, radiation, and chemotherapy. The natural history of the disease is progression, and prognosis remains poor, with a survival rate of <15 months for a majority of patients.1

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

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J Hematol Oncol Pharm. 2012;2(2):57-63. www.JHOPonline.com Disclosures are at end of text

Epidemiology According to the Central Brain Tumor Registry of the United States, in 2010 there were 22,020 new diagnoses and 13,140 deaths attributed to primary malignant brain and CNS tumors.2 GBM comprises 60% to 70% of all newly diagnosed glioma, occurs at a median age of 64 years, and is more common in men than in women.1 GBM has been associated with rare familial syndromes that introduce genomic instability; however, the only proved environmental risk factor associated with the development of GBM is exposure to highdose radiation, although a history of chemotherapy has also been associated.3,4 The most common chemotherapies associated with the development of secondary GBM have been antimetabolite therapies (methotrexate and 6-mercaptopurine) for the treatment of acute lymphoblastic leukemia.4 Genetic polymorphisms affecting detoxification, DNA repair, and cell cycle regulation have also been implicated in tumorigenesis.5 The incidence of GBM has been increasing over the past 2 decades, largely because of improvements in imaging, availability of medical care, and treatment options for elderly patients and reclassification of brain tumors.5

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Molecular Pathogenesis GBM is described clinically based on tumorigenesis. GBM is classified into 2 main subtypes based on biologic and genetic differences, with malignant transformation ultimately resulting from genetic abnormalities and dysregulation of cell-signaling pathways. Primary (de novo) GBM is now recognized to be a molecular phenotype separate from the slower-growing secondary GBM that 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 variant EGFR amplification, loss of heterozygosity of chromosome 10q leading to the deletion of phosphatase and tensin homolog (PTEN), and p16 deletion.5,6

The most effective first-line treatment of GBM to date remains optimal surgical resection, followed by the combination of concomitant daily temozolomide and postoperative radiation, followed by 6 cycles of adjuvant temozolomide. Secondary GBM is less common and arises from tumors with p53 mutations. It is characterized by overexpression of the platelet-derived growth factor receptor (PDGFR), aberrations in p16 and retinoblastoma pathways, and loss of heterozygosity of chromosome 10q.5,6 Despite these differences, primary and secondary tumors are morphologically identical and are treated with similar regimens, although there may be differences in response in patients receiving targeted therapies. Growth factor receptor signaling involving EGFR and PDGFR result in the activation of pathways, such as the Ras-MAP kinase pathway, involved in cell cycle progression and cell proliferation, and the PI3K/Akt pathway, which results in inhibition of apoptosis and cellular proliferation.5,6 PTEN, which is located on chromosome 10 and is a regulator of the PI3K/Akt pathway, is inactivated in approximately 50% of patients with GBM. Vascular endothelial growth factor (VEGF) and activation of the VEGF receptor (VEGFR) are also upregulated, leading to angiogenesis and tumor survival. Finally, there is some evidence that neural stem cells can give rise to gliomas, thereby secreting VEGF and promoting angiogenesis within the tumor microenvironment.6,7

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

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date remains optimal surgical resection, followed by the combination of concomitant daily temozolomide and postoperative radiation, followed by 6 cycles of adjuvant temozolomide (see Table for selected chemotherapy regimens and dosing information).8-17 When compared with postoperative radiation alone, temozolomide-based therapy resulted in a survival increase of 2.5 months (12.1 vs 14.6 months, respectively) or a 37% relative reduction in the risk of death, with a median follow-up of 28 months.8 Although this represents a significant improvement, temozolomide-based therapy had a 2-year survival rate of only 26.5%.7 With 5 years of follow-up, this statistic is even more dismal at only 9.8%.9 Significant room for improvement remains for firstline treatment options. It is also important to consider using prophylaxis for Pneumocystis carinii pneumonia when temozolomide is given in the concurrent phase, because of the increased risk for opportunistic infections secondary to potential severe lymphocytopenia. An important marker identified in the study by Hegi and colleagues was MGMT (O6-methylguanine-DNA methyltransferase).18 The MGMT gene encodes for a DNA repair protein, which removes alkyl groups from the O6 position of guanine; this is an important site for DNA alkylation. In tumor cells with high levels of MGMT, resistance can develop through blunting the effect of alkylating agents, such as temozolomide and dacarbazine. MGMT silencing via promoter methylation results in a loss of MGMT function, leaving cells more susceptible to alkylating drugs. In fact, in this temozolomide trial, MGMT promoter methylation was an independent favorable prognostic marker. In patients whose tumors had MGMT promoter methylation and received temozolomide-based therapy, the median overall survival (OS) was 21.7 months and the 2-year OS rate was 46%.18 Although MGMT is clearly predictive of outcome in patients with GBM who receive temozolomide-based therapy, the clinical benefit of this marker remains to be determined.19 This is mainly a result of the lack of effective therapeutic alternatives in patients whose MGMT promoter methylation status does not suggest a significant benefit from alkylating drugâ&#x20AC;&#x201C;based therapy. Several investigators are searching for possible dosing alterations that may overcome this resistance mechanism. Clarke and colleagues evaluated the safety and efficacy of 2 alternative adjuvant temozolomide dosing schedules in the frontline management of 85 patients with GBM.10 The first strategy was metronomic or continuous daily dosing of temozolomide. This method of delivery was postulated to provide combined antitumor, as well as antiangiogenic, effects via damage to endothelial cells in tumor vasculature. In addition, metronomic delivery of continuous low-dose temozolomide results in inhibition

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Table Common Regimens in the Treatment of Glioblastoma Multiforme Study

Regimen/cycle length

Dose

Standard temozolomide 6 wks

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

Standard temozolomide 28 days

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

Dose-dense adjuvant temozolomide 28 days

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

Metronomic adjuvant temozolomide 28 days

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

GĂĄllego PĂŠrez-Larraya J, et al11

Standard temozolomide (elderly patients) 28 days

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

Vredenburgh JJ, et al12

Bevacizumab plus irinotecan Cohort 1: bevacizumab 10 mg/kg every 2 wks plus 6 wks irinotecan 125 mg/m2 (no EIAEDs) every 2 wks, or irinotecan 340 mg/m2 (EIAEDs) every 2 wks Cohort 2: bevacizumab 15 mg/kg every 3 wks plus irinotecan 125 mg/m2 weekly for 4 wks (no EIAEDs), or irinotecan 350 mg/m2 weekly for 4 wks (EIAEDs)

Friedman HS, et al13

Bevacizumab plus irinotecan Bevacizumab 10 mg/kg every 2 wks plus irinotecan 6 wks 125 mg/m2 (no EIAEDs) every 2 wks, or irinotecan 340 mg/m2 (EIAEDs) every 2 wks

8,9

Stupp R, et al

Clarke JL, et al10

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

Cediranib 28 days

45 mg by mouth daily

Perry JR, et al16

Metronomic temozolomide 28 days

Temozolomide 50 mg/m2 by mouth daily

Yung WK, et al17

Erlotinib 28 days

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

EIAEDs indicates enzyme-inducing antiepileptic drugs.

of MGMT that could possibly overcome this major resistance pathway. The second delivery schedule was dose-dense temozolomide, which is based on the Norton-Simon model of cell proliferation. This method also has the potential to inhibit MGMT. Both methods were well tolerated, with no unexpected toxicities or rates of toxicities observed. Lymphopenia was common but did not result in any cases of P carinii pneumonia. Two-year survival in the dose-dense and metronomic

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arms were 34.8% and 28%, respectively.10 Although this trial was limited by the small sample size and lack of direct comparison to standard-dose temozolomide, the tolerable side-effect profile and impressive efficacy of dose-dense and metronomic temozolomide warrant further investigation in randomized controlled trials.10 Another strategy to overcome chemotherapy-resistant mechanisms is the use of multidrug chemotherapy. The drug that has generated recent optimism for the treat-

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ment of GBM is bevacizumab, an anti-VEGF monoclonal antibody. This optimism has mostly been generated from data with bevacizumab in the treatment of GBM refractory to first-line temozolomide-based therapy. With its unique mechanism of action, as well as a manageable toxicity profile, bevacizumab is ideal to investigate with other antineoplastic drugs. In fact, a large international, phase 3, multicenter, randomized trial is currently under way to evaluate standard temozolomidebased therapy, with or without the addition of bevacizumab.20 The Radiation Therapy Oncology Group has initiated a multicenter, phase 3 trial investigating the use of bevacizumab as first-line therapy.21 A preliminary safety report from a separate pilot phase 2 trial included bevacizumab, which was added to standard, temozolomide-based therapy.22 Although relatively high rates of fatigue, myelosuppression, wound breakdown, and thrombosis were observed, the rates of these toxicities were deemed acceptable, and enrollment in the trial continues. The use of the combination of temozolomide and bevacizumab should be limited to clinical trials until further results confirming the safety and efficacy of this combination are available.22

Radiation therapy offers benefit over supportive care alone in elderly patients with a good performance status. A randomized trial conducted by the Association of French-Speaking NeuroOncologists was discontinued after the first interim analysis as a result of superior survival rate in the radiotherapy arm. With so much focus on systemic therapy for GBM, it is easy to forget the benefits demonstrated with local therapy with carmustine wafers. Placebo-controlled trials of carmustine wafers implanted at the time of initial surgery demonstrated a significant survival benefit in favor of carmustine wafers. Patients were randomized to receive either carmustine wafers plus radiotherapy or identical-appearing placebo wafers plus radiotherapy.23 A 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 patients enrolled in the trial, 207 had GBM. The median survival was 13.5 months in the carmustine group and 11.4 months in the placebo group, with 1-year survival rates of 59.2% and 49.6%, respectively.23 This resulted in a 31% (95% confidence interval [CI], 3%-51%) risk reduction of death in the carmustine-treated group compared with the

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placebo-treated group, which was significant in the GBM subgroup (P = .04). The time to Karnofsky performance status (KPS) and neuroperformance deterioration also favored the carmustine group. The adverse event profiles were similar for carmustine and placebo.23

Paucity of Data for the Elderly A GBM population group not addressed in many clinical trials is the elderly. For example, the landmark temozolomide trial excluded patients aged >70 years.8 The paucity of literature for elderly patients with GBM has resulted in a lack of clear guidance on the best treatment modalities 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 of French-Speaking Neuro-Oncologists, patients with GBM aged >70 years with a KPS >70 were randomized to supportive care only or supportive care and radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days weekly, for a total dose of 50 Gy).24 A total of 85 patients were enrolled at 10 institutions. The trial was discontinued after the first interim analysis as a result of superior survival rate in the radiotherapy arm. At a median follow-up of 21 weeks, the hazard ratio for death in the radiotherapy arm was 0.47 (95% CI, 0.29-0.76; P = .002), which yielded a median survival benefit of 12.2 weeks. The median survival for patients receiving radiotherapy plus supportive care was 29.1 (95% CI, 25.434.9) weeks, and for those receiving supportive care only, 16.9 (95% CI, 13.4-21.4) weeks. The KPS and cognition declined over time; however, there was no difference between the 2 groups. No serious adverse events were reported with radiotherapy.24 Although elderly patients were not included in the trial by Stupp and colleagues,8,9 temozolomide has been studied in a phase 2 trial of patients with GBM aged â&#x2030;Ľ70 years. In this nonrandomized trial, temozolomide 150 to 200 mg/m2 daily for 5 days every 4 weeks was evaluated.11 Radiotherapy was not administered in this trial. Of note, only patients with a poor performance status (KPS <70) were included in this trial.11 A total of 70 patients from 8 institutions were enrolled in the trial. Median treatment duration with temozolomide was 2 cycles per patient (range, 0-13 cycles). Dose delays and dose reductions occurred in 20% and 24% of patients, respectively. The median OS was 25 weeks (95% CI, 19-28 weeks). The 6-month and 12-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 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively.11

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Recurrent Disease Treatment The majority of patients with disease recurrence are not eligible for further irradiation or surgical intervention. Median survival is 25 weeks, and survivorship at 1 year is estimated to be approximately 25%.25-27 Progression-free survival (PFS) is correlated with OS in this patient population, and the PFS at 6 months is between 9% and 15%.25-27 GBM is one of the most vascularized of all tumors, and angiogenesis is critical to disease progression. Proangiogenic factors, such as VEGF, regulate vascularity, and VEGF is overexpressed in areas of necrosis, hypoxia, and endothelial proliferation. VEGF expression is correlated with tumor activity and aggressiveness, with GBM having the highest levels of all gliomas.28,29 High expression of VEGF is associated with microvascular proliferation, accelerated tumor expansion, and poor outcomes, but these tumors are also the most likely to respond to antiangiogenic therapy. It is hypothesized that a higher VEGF ligand-to-receptor ratio may indicate more persistent VEGFR activation, and this ratio may be increased with age.28,29 Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody that binds to and neutralizes circulating VEGF. Bevacizumab has been evaluated as a single drug and in combination with cytotoxic chemotherapy in patients with recurrent GBM. Stark-Vance was the first to publish promising results of bevacizumab in combination with irinotecan.30 Previously, irinotecan had been used as single-drug therapy in patients with recurrent GBM because of good CNS penetration; however, response rates were less than 20%, with many patients not responding at all.31-33 The topoisomerase 1 inhibitor irinotecan works via a different mechanism of action than alkylation and is not affected by MGMT, is not highly protein bound, and readily crosses the bloodâ&#x20AC;&#x201C;brain barrier, making it a logical choice for combination with bevacizumab. Twentyone patients with high-grade gliomas (53% GBM) were treated with bevacizumab and irinotecan.30 In the earlier study, 43% of patients had an objective response, and among those not meeting criteria for response, most had radiographic improvement consisting of reductions in peritumoral edema and contrast enhancement.30 These early results indicated that bevacizumab may have a role in the management of high-grade gliomas.30 Vrendenburgh and colleagues verified the beneficial results of bevacizumab in combination with irinotecan in 35 patients with histologically proven GBM that progressed after external-beam radiation therapy and concurrent temozolomide.12 The trial included 2 cohorts of patients receiving differing doses and schedules of bevacizumab and irinotecan, with the irinotecan dose

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dependent on the presence of enzyme-inducing antiepileptic drugs.12 Response to therapy was determined by magnetic resonance imaging (MacDonald Criteria) and clinical examination. Six-month PFS was 46% and median OS was 42 weeks after 68 weeks of follow-up. A total of 57% of patients had at least a partial response to therapy, and 7 patients completed 1 year of therapy. Thirteen patients stopped therapy as a result of disease progression, and 11 patients stopped therapy because of toxicity. Other reasons for discontinuation included venous thromboembolism (VTE), proteinuria, and CNS hemorrhage.12

High expression of VEGF is associated with microvascular proliferation, accelerated tumor expansion, and poor outcomes, but these tumors are also the most likely to respond to antiangiogenic therapy. Friedman and colleagues further established the role of bevacizumab in a multicenter, phase 2, noncomparative trial of bevacizumab alone and in combination with irinotecan.13 In the group that received bevacizumab alone versus the group that received irinotecan plus bevacizumab, objective responses were 28.2% and 37.8%, PFS rates at 6 months were 42.6% and 50.3%, and median OS rates were 9.2 months and 8.7 months, respectively.13 The study did not achieve power to detect significant differences between these groups. Patients receiving bevacizumab alone achieved overall response rates and PFS rates at 6 months that are greater than historical rates achieved (which have been <20%) with cytotoxic chemotherapy alone. This demonstrates the value of the addition of antiangiogenic therapy in recurrent GBM. This begs the question whether the additional benefits of adding cytotoxic chemotherapy to bevacizumab are worth the risks when the response rates are similar between the 2 groups. Comparative studies of bevacizumab alone and bevacizumab in combination with cytotoxic chemotherapy are needed to confirm the synergy 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 increased incidences of VTE, diarrhea, and hematologic toxicity in the group receiving irinotecan.13 Currently, bevacizumab is recommended to be dosed on a schedule of every 2 weeks in patients with GBM. A phase 2 evaluation of bevacizumab dosing every 3 weeks produced 6-month PFS results that were more favorable than historical controls14; however, no studies comparing

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dosing strategies of bevacizumab have been performed to make formal recommendations on dose density. Cediranib is an oral pan-VEGFR tyrosine kinase inhibitor (TKI) that also has activity against PDGF-β and c-Kit. Based on its mechanism of action and potential molecular targets, cediranib should have activity in primary and in secondary GBM. Preliminary studies showed that edema decreased and tumor vasculature was normalized after treatment with cediranib.15 Cediranib was further evaluated in 31 patients with recurrent GBM in a single-center phase 2 study with a primary end point of PFS at 6 months. All patients had undergone surgery and radiation and most (29 of 31) had initial treatment with temozolomide. The 6-month PFS rate was 25.8%, median PFS was 117 days, and OS was 227 days. The use of cediranib also allowed decreased dexamethasone doses. The most common toxicities were diarrhea, fatigue, and hypertension. There were no reports of intracranial hemorrhage.15

Temozolomide has been the backbone of initial treatment of GBM. However, patients relapse and, for patients receiving chemotherapy, a resting period is required for nontumor cell recovery to occur. Temozolomide has been the backbone of initial treatment of GBM. However, patients relapse and, for patients receiving chemotherapy, a resting period is required for nontumor cell recovery to occur. It is hypothesized that during this time DNA repair may take place, allowing for tumor regrowth. When compared with procarbazine, temozolomide in patients at first relapse resulted in an improved 6-month PFS rate (21% vs 8%; P = .008), and this freedom from disease progression also was associated with maintained health-related quality of life.34 Continuous low-dose or metronomic scheduling of temozolomide has been attempted to suppress MGMT activity, increase dose intensity, and increase the antiangiogenic effects of other chemotherapies.16 The RESCUE study tested this hypothesis and examined the effects of daily temozolomide when given to patients with high-grade glioma or GBM at first progression after exposure to conventional dosing.16 Patients with GBM were stratified into 3 groups according to their previous duration of treatment with temozolomide and time of progression. All patients received temozolomide 50 mg/m2 daily continuously for up to 12 months or until disease progression. Overall 6-month PFS rate for patients with GBM was 23.9%, with 7.4% progress-

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ing while receiving extended adjuvant temozolomide beyond 6 cycles but before completion of adjuvant treatment having the shortest time to progression (1.8 months; P = .027) and 14.8% having the shortest survival at 1 year. Best responses were in the early- or lateprogression groups. Lymphopenia was the most common toxicity, and there was no incidence of P carinii pneumonia. The 6-month PFS rate and time to progression were similar between patients with methylated and unmethylated MGMT promoter status.16

Other Therapeutic Options EGFR has emerged as a potential target in patients with malignant glioma, and overexpression of EGFR is associated with a poor prognosis in GBM. Response rates to small-molecule TKIs remain low and results are not uniform, although there is a subset of patients with EGFRvIII and PTEN expression that appear to benefit from TKI therapy.35 Erlotinib has been evaluated in multiple phase 2 studies for high-grade glioma in patients receiving and not receiving enzyme-inducing antiepileptic drugs. Best responses obtained to date have been 6-month PFS rates of 20%, which are still higher than historical rates of 9% to 15%; however, none of the studies are controlled studies. Because stable disease is the most common response in patients receiving small-molecule therapy, it appears that erlotinib is cytostatic in GBM.17 Erlotinib has also been evaluated in combination with bevacizumab in a phase 2 study of patients with recurrent malignant glioma; however, the 6-month PFS rate was lower (29.2%) among patients with GBM compared with other bevacizumab salvage regimens.36 The most common side effects in studies with erlotinib were diarrhea and rash, which both correlate with increased PFS in GBM.17,36 Molecular stratification of patients with GBM may identify those likely to respond to therapy.35 Patients who do not have an intact PTEN may have increased response to mTOR inhibitor and EGFR TKI combinations. Some evidence of clinical response has been seen in phase 1 investigations involving peptide vaccines37 and single drugs such as bortezomib38; however, additional studies need to be performed to determine the benefit of these drugs. Conclusion GBM is the most aggressive of the glial tumors. Much progress has been made over the past decade in GBM research, and a new standard of care has emerged, with nearly all patients receiving radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed GBM. Despite these advancements, all patients will progress eventually, and most patients are not eligible for

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additional radiation or for surgical resection of tumor on disease progression. Chemotherapy and biotherapy remain the standard of care for these patients. Because of the angiogenic potential of GBM, bevacizumab has emerged as a promising therapy for use in the recurrent disease setting. Six-month PFS, which tracks with OS, is a useful end point in this patient population, and treatment with bevacizumab alone and in combination with cytotoxic chemotherapy have improved 6month PFS over single-drug alkylator therapy. It is still unknown if the benefits of bevacizumab in combination with cytotoxic chemotherapy outweigh the risks, and further comparative trials are needed to assess the value of this combination. Combinations of bevacizumab and chemotherapy may result in improved PFS, but these regimens are associated with increased toxicities, including myelosuppression and thromboembolic events, which may limit their use in some patient populations. Data have emerged that temozolomide therapy can be repeated for patients with relapsed disease, and that continuous metronomic dosing may be beneficial, by extending PFS without further decreasing quality of life with 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 should still be recommended to be given every 2 weeks to patients who have recurrent disease. This decade has brought much improvement and insight to the management of GBM; however, there is still a lot to learn and much progress to be made. n Author Disclosure Statement Dr Buie and Dr Valgus have reported no conflicts of interest.

References 1. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492507. 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 of risk of secondary brain tumors. Genes Chromosomes Cancer. 2005;42:107-116. 4. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354:34-39. 5. Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol. 2006;2:494-503. 6. Nicholas MK, Lukas RV, Chmura S, et al. Molecular heterogeneity in glioblastoma: therapeutic opportunities and challenges. Semin Oncol. 2011;38:243-253. 7. Chi AS, Sorensen AG, Jain RK, Batchelor TT. Angiogenesis as a therapeutic target in malignant gliomas. Oncologist. 2009;14:621-636. 8. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 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 concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5 year analysis of the EORTC NCIC trial. Lancet Oncol. 2009;10:459-466. 10. Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemother-

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apy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol. 2009;27:3861-3867. 11. Gállego Pérez-Larraya J, Ducray F, Chinot O, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol. 2011;29:3050-3055. 12. Vrendenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722-4729. 13. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with 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 bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer. 2010;116:5297-5305. 15. Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817-2823. 16. Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide 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 erlotinib in 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 from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003. 19. Weller M, Stupp R, Reifenberger G, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6:39-51. 20. A Study of Avastin (Bevacizumab) in Combination With Temozolomide and Radiotherapy 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. Accessed July 1, 2011. 22. Lai A, Filka E, McGibbon B, et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. 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 with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5:79-88. 24. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007;356:1527-1535. 25. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent 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 important end 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-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncol. 2007;9:29-38. 28. Chamberlain MC. Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas. Cancer. 2010;116:3988-3999. 29. Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. Clin Med Insights Oncol. 2011;5:117-129. 30. Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. 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 Tumor Consortium study. Neuro Oncol. 2006;8:189-193. 32. Cloughesy TH, Filka E, Kuhn J, et al. Two studies evaluating irinotecan treatment 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 glioblastoma multiforme. J Neurooncol. 2002;56:183-188. 34. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs procarbazine 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 response of 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 bevacizumab 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 vaccine for patients positive for human leukocyte antigen-A24 with recurrent or progressive glioblastoma multiforme. J Clin Oncol. 2011;29:337-344. 38. Phuphanich S, Supko JG, Carson KA, et al. Phase I clinical trial of bortezomib in adults with recurrent malignant glioma. J Neurooncol. 2010;100:95-103.

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Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy By Robert J. Ignoffo, PharmD, FASHP, FCSHP, Section Editor Clinical Professor Emeritus, University of California, San Francisco Professor of Pharmacy, College of Pharmacy, Touro University-California, Mare Island, Vallejo, CA

n Inotuzumab Ozogamicin Shows High Response Rate in Refractory/Relapsed ALL Background: Patients with refractory or relapsed acute lymphoblastic leukemia (ALL) have a poor prognosis. Inotuzumab ozogamicin is a monoclonal antibody against CD22, which is highly expressed on the surface of leukemic cells in patients with ALL. Studies with other monoclonal antibodies against CD22 or other surface antigens have shown encouraging activity in patients with ALL. Design: This phase 2 study conducted at M.D. Anderson Cancer Center investigated the use of inotuzumab ozogamicin in patients with relapsed or refractory ALL. The study initially included adults only (aged >18 years) with refractory or relapsed ALL of B-cell origin; after the safe use of ≥1 course of the study medication in ≥10 adults, patients aged <16 years were also eligible to participate. The study enrolled 49 patients, 3 of whom were aged ≤16 years and the remainder were adults. The primary end point was overall response. Summary: A total of 49 patients were treated. Of these patients, 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), and median time between courses was 3 weeks (range, 3-6 weeks). The overall response rate was 57%, and the median overall survival (OS) was 5.1 months. The 57% response rate was much higher than the rates reported in previous studies, but the study was of short duration. The most frequent adverse events (AEs) in the first course of treatment were fever (n = 29), hypotension (n = 13), increased bilirubin (n = 14), and increased aminotransferase concentration (n = 28). These AEs did not increase in frequency with subsequent treatment courses, and no additional events were seen with additional courses. Takeaway: Although this is only a phase 2 study, single-agent use of this monoclonal antibody produced impressive results, including complete bone marrow responses in more than 50% of the patients receiving

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this drug, and median survival duration of 5.1 months. This drug warrants further study in refractory or relapsed ALL in a phase 3 clinical trial. Furthermore, because it targets another often-expressed surface marker— CD22—it should also be tested in combination with standard first-line agents. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403-411.

n Allogeneic Transplantation in Young Patients with ALL Who Fail Induction Therapy Background: Induction therapy failure is rare in children and adolescents with ALL, but it has been associated with a poor outcome in this patient population. Treatment options after induction failure include allogeneic hematopoietic stem-cell transplantation and chemotherapy. Design: This large, retrospective, international study included data from 14 cooperative groups, totaling 44,017 patients aged 0 to 18 years with newly diagnosed ALL. Induction failure was identified in a subgroup of 1041 (2.4%) of these patients. Data were collected on clinical and biological characteristics, previous treatments used, early responses to treatment, and survival outcomes in this subgroup of patients. Summary: Conventional risk factors for children and adolescents 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 phenotype, were even more prevalent in this group and were associated with a worse prognosis. The study population was very heterogeneous; characteristics such as age ≥10 years, T-cell leukemia, the presence of an 11q23 rearrangement, and ≥25% blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. In contrast, high hyperdiploidy (a modal chromosome number >50) and age <6 years were associated with more favorable outcomes in patients with precursor B-cell leukemia. Allogeneic stem-cell

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transplantation was associated with better outcomes than chemotherapy in patients with T-cell leukemia, but it did not show benefit over chemotherapy in patients with precursor B-cell ALL without other adverse genetic features. These patients fared better with chemotherapy. Takeaway: This is the largest retrospective analysis of outcomes after treatment failure in childhood ALL. Clinical and biological factors were major determinants in the outcomes observed in these patients. The best outcomes were seen in patients with precursor B-cell ALL who were either aged <6 years or those who had high hyperdiploidy. These patients accounted for approximately 25% of all patients with induction failure, and their outcomes were associated with a 10-year survival rate of >50%. Patients with T-cell ALL who were aged <6 years were best managed with allogeneic bone marrow transplant therapy. In contrast, patients aged <6 years with precursor B-cell ALL did better with chemotherapy than with transplantation. This study had several limitations, most notably the heterogeneity of the patient groups. In addition, the outcomes reported often preceded the use of several new targeted agents, including tyrosine kinase inhibitors. Clinicians should take the results of this study and design trials that will further define the appropriate treatment strategies in this patient population, especially in 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 Tlymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody, is approved in the United States for unresectable or metastatic melanoma and is being studied alone or as part of a combination regimen in several other cancers. Design: A double-blind, international, phase 2 study was conducted to evaluate ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in advanced nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC). Because the sequence in which chemotherapy and immunotherapy are given can have an impact on outcome, ipilimumab was given with the other agents in a concurrent and in a phased regimen. To supplement each chemotherapy administration, previously untreated adult patients with NSCLC (stage IIIB/IV) were randomly assigned 1:1:1 to a concurrent ipilimumab regimen (4 ipilimumab doses followed by 2 placebo doses), a phased regimen (2 placebo doses followed by 4 ipilimumab doses), or a control regimen (up to 6 doses of placebo). Ipilimumab

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or placebo, paclitaxel, and carboplatin were administered intravenously once every 3 weeks for up to 18 weeks, followed by ipilimumab or placebo once every 12 weeks until progression, intolerance, or death. The primary end point was immune-related progression-free survival (PFS); PFS and duration of OS were key secondary end points. Summary: A total of 204 patients were randomized to the concurrent (n = 70), phased (n = 68), and control (n = 66) regimens. Phased ipilimumab improved immunerelated PFS significantly compared with the control group (P = .05), whereas the concurrent regimen did not significantly improve immune-related PFS (P = .13) versus the control group. Phased ipilimumab also improved PFS (P = .02). For both immune-related PFS and PFS, differences in favor of phased ipilimumab over the control group appeared to be greater in patients with squamous histology than those with nonsquamous histology. Median OS durations were 9.7, 12.2, and 8.3 months for the concurrent, phased, and control regimens, respectively. Grade 3 and 4 immune-related AE rates were 20%, 15%, and 6% for the concurrent, phased, and control regimens, respectively. Takeaway: This randomized phase 2 study of ipilimumab has an interesting study design. It is designed to answer 2 important questions: (1) does the addition of ipilimumab to standard paclitaxel/carboplatin therapy improve PFS, immune-related PFS, or OS. And (2) does the scheduling of ipilimumab matter with regard to outcomes. The results confirm that the phased administration method is preferred and improves immune-related PFS by 4 months (hazard ratio [HR], 0.71). In the accompanying editorial published in the same issue, it is noted that the concurrent administration method also had an HR of 0.81 (P = .15), which the author suggested might have reached significance if the study size were larger. Nevertheless, these results justify the study of combination chemotherapy plus ipilimumab versus a standard platinum doublet. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV nonâ&#x20AC;&#x201C;smallcell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-2054. Epub 2012 Apr 30.

n Immunotherapy with Ipilimumab and GVAX Combination Safe for Metastatic CastrationResistant Prostate Cancer Background: In 2011, prostate cancer represented 11% of all cancer-related deaths in men. The granulocyte-macrophage colony-stimulating factor (GMCSF)-transduced allogeneic prostate cancer cells vaccine (GVAX) has been studied in hormone-refractory

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prostate cancer. When GM-CSF–secreting tumor-cell vaccines have been combined with the anti-CTLA-4 monoclonal antibody ipilimumab in preclinical studies, these agents have acted synergistically. An open-label, phase 1 study in men with metastatic castration-resistant prostate cancer was undertaken to determine whether immunotherapy with these 2 agents can be combined safely in the clinical setting. Design: The dose-escalation study included 12 treatment-naïve patients with metastatic castration-resistant prostate cancer. A subsequent extension phase enrolled 16 patients, for a total of 28 patients overall. All patients received a priming GVAX intradermal dose. The patients then received additional doses every 2 weeks for 24 weeks, for a total of 13 injections. The patients received an escalating dose of ipilimumab 0.3, 1.0, 3.0, or 5.0 mg/kg every 4 weeks, for a total of 6 infusions, each administered on the same day as the GVAX vaccination. The primary end point was the safety of GVAX. Summary: No severe immune-related AEs were reported with the lowest 2 doses. Other AEs included hypophysitis in 3 patients with the 3.0-mg/kg dose and in 2 patients with the 5.0-mg/kg dose. In addition, 1 patient had grade 4 sarcoid alveolitis with the 5.0-mg/kg dose, a dose-limiting effect. This led to the decision to expand the patient enrollment for the 3.0-mg/kg dose rather than the 5.0-mg/kg dose. In addition, the findings included durable prostate-specific antigen (PSA) responses,

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bone scan improvements, and tumor regression, indicating that this immunotherapy has clinical activity in this type of advanced prostate cancer. The most common AEs were injection-site reactions, fatigue, and pyrexia. Takeaway: The goal of this phase 1 trial was to establish the safety of the anti-CTLA-4 antibody, ipilimumab, in combination with GM-CSF–secreting tumor-cell vaccine (ie, GVAX) in patients with metastatic hormonerefractory prostate cancer. At the highest dose levels attained, 3 and 5 mg/kg, immune-related reactions occurred, including hypophysitis and alveolitis (lifethreatening). The additional study of the 3-mg/kg dose demonstrated a manageable toxicity level. A total of 5 of the 28 patients had PSA responses. In addition, tumorspecific immune reactivity to GVAX (antibody responses to filamin B and prostate-specific membrane antigen [PSMA]) were tested. Patients who developed a PSMAspecific antibody response had a median OS of 46.5 months compared with 20.6 months in those without a PSMA-specific antibody response (P = .028). In addition, 15 patients showed stabilization of disease on bone scan. These results indicate that this immune-based combination therapy is worthy of further study. n van den Eertwegh AJM, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:509-517.

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

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

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

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

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

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

Must be diluted before intravenous infusion 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

INDICATIONS AND USAGE Gemcitabine 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)

WARNING: BONE MARROW SUPPRESSION See 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) WARNINGS AND PRECAUTIONS • 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)

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) WARNINGS AND PRECAUTIONS • 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)

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.

• 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 ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

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 USA GUJ DRUGS/G/28/1267

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

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


H OS P IR A ON C OL OG Y P O RT F O L IO

ONE FOR ALL D OCETAX EL IN JE C T ION ( 1 0 m g /mL )

160 mg/16 mL multiple-dose vial 80 mg/8 mL multiple-dose vial

As the complexity of healthcare evolves, we’re doing our part to improve cost savings, optimize workflow and enhance patient care. With our generic oncology portfolio we provide

20 mg/2 mL single-dose vial See Black Box Warning

ONE solution for ALL.

FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

FOR ADMINISTRATORS—MULTIPLE-DOSE VIALS LEAD TO LESS WASTE

FOR CLINICIANS—UNIQUE ONCO-TAIN ™ VIALS REINFORCE SAFETY 1

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

U N I Q U E O N C O - TA I N S A F E T Y F E AT U R E S 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 final safety check before administration.

4

PREWASHED VIALS reduce cytotoxic residue.

GEM CI TABI NE IN JE C T ION ( 3 8 m g /mL )

2 g/52.6 mL single-dose vial 1 g/26.3 mL single-dose vial 200 mg/5.26 mL single-dose vial

For more information, contact your

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

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

TOPOTECAN IN JE C T ION ( 1 m g /mL )

4 mg/4 mL single-dose vial See Black Box Warning

Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

P11-3464-Nov., 11

Profile for The Oncology Pharmacist

Journal of Hematology Oncology Pharmacy - June 2012, VOL 2, NO 2  

The Peer-Reviewed Forum for Oncology Pharmacy Practice

Journal of Hematology Oncology Pharmacy - June 2012, VOL 2, NO 2  

The Peer-Reviewed Forum for Oncology Pharmacy Practice

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