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APRIL 2010

www.TheOncologyPharmacist.com

VOL 3, NO 2

der a e L d The ews an in N eeting e M erag Cov DRUG THERAPY CANCER CENTER PROFILE

New Treatments for Chronic Idiopathic Thrombocytopenic Purpura. Part 1. Romiplostim

Desert Regional Comprehensive Cancer Center Provides Variety of Services Under By Michael S. Mathisen, PharmD; and Laura Boehnke Michaud, PharmD, BCOP, FASHP One Roof By Karen Rosenberg

Clinical Pharmacy Services, The University of Texas M. D. Anderson Cancer Center, Houston

A

lthough thrombocytopenia is a common problem in patients with cancer, idiopathic thrombocytopenic purpura (ITP) is relatively rare and is difficult to treat when duration exceeds 6 months. ITP can be either acute (duration ≤6 months) or chronic, can occur in both adults and children, and can be primary or secondary to another disorder, including the malignancy. Primary chronic ITP is an autoimmune

O

pened in 1989, the Comprehensive Cancer Center (CCC) at Desert Regional Medical Center was the first multidisciplinary outpatient cancer program in the Palm Springs, California, area. The CCC represents the collaboration of the multispecialty regional medical center with Aptium Oncology, a national provider of oncology management and consulting services. The CCC now employs 120 healthcare professionals and provides a full range of services, including screening, diagnosis, treatment, and follow-up care under one roof. The 60,000-square-foot center houses a medical oncology infusion center, physician offices and examination rooms, a radiation oncology treatment area, outpatient surgery facilities, a laboratory, a pharmacy, a research department, a comprehensive breast center, and a patient resource center. Continued on page 16

Y TAR EN M I L MP CO

CE Credit

condition occurring more frequently in adults, which results from antibody-mediated platelet destruction and is characterized by a depressed platelet count and mucocutaneous bleeding.1,2 Although the stimulus for these antiplatelet antibodies in primary chronic ITP remains largely unknown, the goals of therapy include maintaining a platelet count above 50,000/mm3 to avoid life-threatening hemorrhagic complications. Corticosteroids are a mainstay of ther-

apy and are generally used as first-line therapy. Response rates range from 50% to 75%, but continued remission ranges from only 5% to 30%.2 Other options available for the management of ITP include rituximab, intravenous immunoglobulin, danazol, cyclophosphamide, immunosuppressive agents (eg, azathioprine, cyclosporine), and splenectomy, which all elicit varying degrees of responsiveness and have significant adverse Continued on page 6

GASTROINTESTINAL CANCERS

ASCO GU

Novel Treatment with Microspheres Showing Chemotherapy May Significantly Promise for Patients Benefit Stage IV Prostate Cancer with Liver Cancer By John Schieszer Patients on AndrogenTAMPA, FLORIDA—A new interventional radiolodeprivation Therapy gy treatment that utilizes intra-arterial yttrium-90 (YThe following articles are based on presentations at the 2010 ASCO Genitourinary Cancers Symposium in San Francisco.

The findings, based on data from the Surveillance, Epidemiology and End Results (SEER) and Medicare databases, may help pharmacists better counsel their older male patients about the potential benefits from chemotherapy. The survival benefit,

90) microspheres may prolong the lives of many patients with hepatocellular carcinoma. New data presented at the Society of Interventional Radiology’s 35th annual scientific meeting showed this approach may extend life for the more than three fourths of hepatocellular carcinoma patients who are not eligible for surgery. “This is encouraging news for liver cancer patients, especially those who have blockage in the portal vein. While patients aren’t cured, their lives are being

Continued on page 12

Continued on page 11

By John Schieszer

C

hemotherapy appears to be associated with a statistically significant decrease in the relative risk of prostate cancer—specific mortality among older men with stage IV prostate cancer who are receiving androgen-deprivation therapy (ADT), according to a new study.

Inside Conference News

Breast Cancer

Aspirin therapy and survival in patients with colorectal cancer

Work-at-home pharmacist program confers multiple benefits Based on a presentation by Sam Calabrese, RPh, MBA

Trastuzumab best given along with chemotherapy Based on a presentation by Edith Perez, MD

page 14

page 8

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©2010 Green Hill Healthcare Communications, LLC

r fo ay E d To e C om r e Fre m.c t is ur oex g Re Yo ww.c w


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You prepare anthracyclines, but are you prepared for an anthracycline extravasation? NEW LOWER PRICE OPTION Now Available

Totect® (dexrazoxane for injection) is indicated for the treatment of extravasation resulting from IV anthracycline chemotherapy.

First and only FDA approved treatment for anthracycline extravasation. Supplied as a convenient and accessible complete three day emergency treatment kit, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation. Demonstrates 98% overall efficacy based on two biopsy-confirmed clinical trials1,2 in preventing the need for: o Surgical debridement, plastic surgery and related healthcare costs o Postponement of a patient’s chemotherapy treatments o Rehabilitation, follow-up and avoidance of long-term consequences

For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors: ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply (800) 746-6273 (866) 677-4844 (800) 482-6700 (800) 633-7555

1

Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. All images and captions are copyright © Photo Researchers, Inc. They may not be copied, reproduced or used in any way without permission from Photo Researchers, Inc. Use without permission is a breach of copyright under national and international laws.

©

TopoTarget USA. All rights reserved. TOT0075/3-09 Totect and its logo mark are registered trademarks of TopoTarget USA, Inc., Rockaway, NJ, USA.

US Oncology (888) 987-6679


TOP_April2010_TON 4/12/10 10:36 AM Page 1

Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent, supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Contraindications: None known. Warnings: Pregnancy Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/ m2 basis) and embryotoxic and teratogenic at 8 mg/kg when given daily during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg were embryotoxic and teratogenic. Terato-

www.totect.com

TOT0075/03-09 ©2009 TopoTarget USA

genic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Reversible elevations of liver enzymes may occur. Blood counts and liver enzymes should be monitored. Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation. Women who have the potential to become pregnant should be advised that Totect might cause fetal harm. There are no known drug interactions. No carcinogenicity studies have been done with Totect in animals. The carcinogenic potential of dexrazoxane has not been investigated. Long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Dexrazoxane is mu-

Rx only Totect® is a registered trademark of TopoTarget A/S US Patent No. 6,727,253B2

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146

NDC 38423-110-01

Hameln Pharmaceuticals GmbH 31789 Hameln Germany

tagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs. The effect of dexrazoxane on labor and delivery in humans has not been studied. It is not known whether dexrazoxane or its metabolites are 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 dexrazoxane, 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. The safety and effectiveness of Totect in pediatric patients have not been established. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients has been observed. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Adverse reactions: Adverse reactions of nausea/ vomiting, diarrhea, stomatitis, bone marrow suppression (neutropenia, thrombocytopenia), altered liver function (increased AST/ALT), and infusion site burning have been observed. These adverse reactions have been reversible.

Manufactured for: TopoTarget A/SSymbion Science Park Fruebjergvej 3 DK-2 100 Copenhagen Denmark

Marketed by: TopoTarget USA Inc. 100 Enterprise Drive Rockaway, New Jersey 07866 (866) 478-8274


TOP_April2010_TON 4/12/10 10:36 AM Page 2

Editorial Board CO-EDITOR-INCHIEF

Susan Goodin, PharmD, FCCP, BCOP Cancer Institute of New Jersey New Brunswick, NJ

CO-EDITOR-INCHIEF Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK

John F. Aforismo, BSc Pharm, RPh, FASCP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Steve Stricker, PharmD, MS, BCOP

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Samford University McWhorter School of Pharmacy Birmingham, AL

Beth Faiman, RN, MSN, APRN, BC, AOCN

Jim Koeller, MS

Timothy G. Tyler, PharmD, FCSHP

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Center Cleveland, OH

Desert Regional Medical Center Palm Springs, CA

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

John M. Valgus, PharmD, BCOP

Indiana University Simon Cancer Center Indianapolis, IN

Novant Health Winston-Salem, NC

University of North Carolina Hospitals and Clinics Chapel Hill, NC

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

Gary C. Yee, PharmD, FCCP, BCOP

David C. Gammon, BS Pharm

Laura Boehnke Michaud, PharmD, BCOP, FASHP

RJ Health Systems International, LLC Wethersfield, CT

University of Nebraska College of Pharmacy Omaha, NE

Marlo Blazer, RPh, PharmD Betty M. Chan, PharmD, BCOP USC/Norris Cancer Hospital Los Angeles, CA

University of Massachusetts Memorial Hospital Worcester, MA

The University of Texas M. D. Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP Maine Center for Cancer Medicine Scarborough, ME

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APril 2010 I VOl 3, NO 2

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

www.TheOncologyPharmacist.com


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FROM THE EDITORS PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Director, Client Services John W. Hennessy john@greenhillhc.com

Susan Goodin, PharmD, FCCP, BCOP

Production Manager Stephanie Laudien

T

Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

GH Green Hill Healthcare Communications

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EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@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 The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® 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. ISSN #1944-9607.

The Oncology Pharmacist® is published 8 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 ©2010 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Com munications, 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.

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APril 2010 I VOl 3, NO 2

he annual Hematology/Oncology Pharmacy Association (HOPA) conference is always a reminder of the energy and enthusiasm the new generation of oncology pharmacists bring to their work and how dynamic this field has become. The keynote address at this year’s meeting by Joseph Bailes on what healthcare reform will mean for oncology was particularly timely, coming just days after the President signed into law the long-awaited Patient Protection and Affordable Care Act. As one attendee pointed out, this may have been the first major medical meeting at which the implications for practitioners of newly enacted legislation were addressed. Bailes’ remarks and other reports from the meeting will be featured in the June issue. This issue includes reports of exciting new advances from several other recent meetings, including the recent American Society of Clinical Oncology’s Gastrointestinal Cancers and Genitourinary Cancers conferences, and the Society of Interventional Radiology as

CONTENTS FEATURE ARTICLES 8 Conference News: ASHP Midyear Clinical Meeting Work-at-home pharmacist program confers multiple benefits Pharmacists can play important role in overseas medical mission Chemotherapy-induced visual disturbances often ignored

12 Conference News: ASCO GU Adverse reactions to targeted therapies for metastatic renal cell carcinoma are reversible

14 Continuing Education Aspirin therapy and survival in patients with colorectal cancer

18 Clinical Pharmacy Review Optimizing dasatinib therapy for patients with chronic-phase CML

Patrick Medina, PharmD, BCOP well as continuing coverage of the annual mid-year meeting of the American Society of Health-System Pharmacists, the American Society of Hematology annual meeting, and the San Antonio Breast Cancer Symposium. Other articles provide a more in-depth look at new therapies for idiopathic thrombocytopenic purpura and chronic myeloid leukemia. With the requirement for Risk Evaluation and Mitigation Strategies for drugs commonly used in oncology, such as for the erythropoiesis-stimulating agents darbepoetin and epoetin alfa announced just prior to the HOPA meeting, pharmacists will have additional responsibilities for educating colleagues and patients about safe and effective use of these agents. In view of the increasing sophistication of oncology pharmacy and the involvement of pharmacists in clinical research and trials, we are planning the launch of a new peer-reviewed journal, which will feature original research by oncology pharmacists. We invite our readers to submit CVs for advisory board positions and manuscripts to editorial@greenhillhc.com. ●

APril 2010 • VOl 3, NO 2 22 Breast Cancer Trastuzumab best given along with chemotherapy To protect bone, denosumab outperforms zoledronic acid in breast cancer patients

24 Hematologic Cancers Strong responses seen with bortezomib-based therapy after relapse in multiple myeloma Bendamustine–rituximab combo an effective first-line therapy for CLL

32 Pharmacy Life Compounding in the kitchen What you need to know about your credit score

DEPARTMENTS 26 Oncology Drug Codes Lymphomas

33 International Oncology News

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Drug Therapy New Treatments for Chronic Idiopathic... Continued from cover effects limiting quality of life. Whereas splenectomy is regarded as the single best treatment approach for refractory patients, 30% to 40% of patients have platelet counts <50,000 ¥ 109/L after the procedure, necessitating new options for salvage treatment with the goal of maintaining hemostasis.2 Traditional therapies for ITP have aimed at inhibiting the production of antiplatelet antibodies; however, the majority of patients with chronic ITP also have impaired platelet production in the presence of normal thrombopoietin (TPO) levels.3 Therefore, secondgeneration thrombopoiesis-stimulating agents have focused on methods to stimulate the TPO receptor, with minimal immunogenicity and no structural similarities to endogenous TPO. Romiplostim is the first US Food and Drug Administration (FDA)-approved thrombopoiesis-stimulating agent and is indicated in patients who have had inadequate response to corticosteroids, immunoglobulins, or splenectomy.4 Rom iplostim is a recombinant protein that binds to the TPO receptor, stimulating platelet production. It bears no structural resemblance to endogenous TPO, thus escaping immune recognition. Supporting evidence Results of two prospective, multinational, double-blind, phase 3 studies were recently published in a single manuscript, and serve as the foundation for which the approval of romiplostim was granted.3 The trials were of similar design, and data were combined for analysis. Both trials compared the efficacy of romiplostim with placebo (random-

ized 2:1) in patients with ITP. One trial enrolled patients after splenectomy, and the other enrolled nonsplenectomized patients; otherwise the eligibility was identical and included a mean platelet count <30 ¥ 109/L, no active malignancy or history of stem-cell disorder, normal organ function, and a hemoglobin level >9 g/dL. Continuation of concurrent therapies for ITP was permitted at a constant dose and schedule, and other “rescue” medications were allowed at any point of the study if needed. The starting dose of romiplostim was 1 µg/kg administered subcutaneously once weekly and was titrated to maintain a platelet count of 50 ¥ 109/L to 200 ¥ 109/L. Platelet response was defined as a platelet count of ≥50 ¥ 109/L at a weekly study visit. The primary efficacy measure for the study was a durable response, defined as weekly platelet responses during 6 or more of the final 8 weeks of evaluation. At the end of 24 weeks, more patients randomized to romiplostim than to placebo experienced a durable response to therapy (splenectomized patients, 38% vs 0%, P = .0013; nonsplenectomized patients, 61% vs 4.8%, P <.0001; all patients, 49% vs 2%, P value not stated; respectively). Also, significantly more patients in the placebo group required rescue medications for persistent thrombocytopenia (59.5% vs 21.7%, P <.0001). In splenectomized and nonsplenectomized patients, the median dose of romiplostim during the study was 2 µg/kg (1 µg/kg-3 µg/kg) and 3 µg/kg (2 µg/kg-7 µg/kg), respectively. However, doses required to maintain platelet counts varied widely between patients in both studies.3

Dosage, administration, and toxicity It is recommended that the lowest possible dose of romiplostim be employed to maintain a platelet count of 50 ¥ 109/L; the agent should not be used to try to normalize a patient’s platelet count.4 The initial dose of romiplostim is 1 µg/kg based on actual body weight, administered subcutaneously once weekly. Monitoring parameters and strategies for dose modification can be found in the Table. Romiplostim is supplied as 250-µg or 500-µg single-use vials of powder for reconstitution. After it is adequately mixed with preservative-free sterile water, a clear, colorless solution containing 500 µg/mL romiplostim should result. Because the final volume for injection may be very small, only syringes with graduations to 0.01 mL should be used.4 The most common adverse events associated with romiplostim (occurring more frequently than placebo) were arthralgia (26% vs 20%), dizziness (17% vs 0%), insomnia (16% vs 7%), and myalgia (14% vs 2%).3,4 The most serious adverse event noted with romiplostim thus far is reticulin fiber deposition within the bone marrow. Of 271 patients, reticulin was observed on bone marrow biopsy in 10 patients. One patient treated for an extended period progressed to bone marrow fibrosis during therapy. The manufacturer advises that the peripheral blood smear should be closely scrutinized before starting romiplostim to establish a baseline level of cellular abnormality.4 Worsening thrombocytopenia after discontinuation of romiplostim has been documented, and in several cases, platelet counts have

Table. Monitoring and Dosing Romiplostim Therapy Monitoring parameters Laboratory values

Recommendation

Complete blood count (including platelet count), peripheral blood smear

Weekly until platelet count stabilizes (>50 ¥ 109/L for 4 consecutive weeks without adjusting the dose); monthly once stable

Dosing modifications Platelet count <50 x 109/L

Recommendation Increase dose by 1 µg/kg

>200 x 109/L for 2 consecutive weeks

Reduce dose by 1 µg/kg

>400 x 109/L

Hold dose, continue to assess platelet count weekly; when platelet count is <200 x 109/L, may resume at a reduced dose by 1 µg/kg

Insufficient response

If platelet count fails to increase to a level considered to avoid important bleeding after 4 weeks of the maximum recommended dose (10 µg/kg), discontinue therapy; monitor complete blood count for at least 2 weeks after stopping romiplostim

Source: Reference 4.

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April 2010 I VOl 3, NO 2

fallen below baseline levels. Thrombotic complications and carcinogenesis are also potentially serious complications associated with romiplostim. As with all new drugs, the true incidence of these severe adverse events cannot be precisely quantified until more experience is gained with the agent. Restricted distribution program and medication guide To assure the appropriate use and safety of romiplostim, the agent is available only via the Network of Experts Understanding and Supporting Nplate and Patients (NEXUS) Program. NEXUS is considered a risk evaluation and mitigation strategy and was a condition that the manufacturer agreed to for the drug to gain FDA approval.5 Twice yearly, healthcare providers are contacted by a NEXUS specialist to verify the patient enrollment roster, collect safety information, and discuss whether it is appropriate for each enrolled patient to continue receiving romiplostim. Prescribers who are enrolled must complete enrollment and baseline data forms for each new patient prescribed romiplostim. The appropriate forms can be found on the NEXUS website.6 Healthcare institutions must enroll separately. The manufacturer of romiplostim, Amgen, has also incorporated a mandatory medication guide into the risk management program, which is to be distributed to patients along with proper counseling prior to each dose of romiplostim. The most updated medication guide can be downloaded from the NEXUS website.7 Serious adverse events resulting from romiplostim therapy should immediately be reported to Amgen (877-675-2831) or the FDA (800-FDA-1088). Conclusion Romiplostim is a novel, thrombopoiesis-stimulating agent that has demonstrated substantial efficacy in patients with refractory chronic ITP. Although the long-term safety of romiplostim has not been clearly established, this agent appears to be relatively welltolerated in the majority of patients, but serious complications do occur and careful monitoring is necessary. The NEXUS risk management program should be beneficial in facilitating consistent monitoring and establishing the romiplostim risk-benefit profile. Favorable results in patients with ITP have encouraged investigation of use of romiplostim in other forms of thrombocytopenia, in cluding thrombocytopenia secondary to myelodysplastic syndrome or chemotherapy.8 The safety of romiplostim must first be established in these groups of Continued on page 24

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STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapyyeir induced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6* Can be used with multiple-day chemotherapy regimens mens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information. REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL448-A 08/09

www.ALOXI.com


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Conference News ASHP MIDYEAR CLINICAL MEETING The following articles are based on presentations at the 44th American Society of Health-System Pharmacists Midyear Clinical Meeting in Las Vegas, Nevada.

Work-at-home Pharmacist Program Confers Multiple Benefits By Jill Stein

I

nvestigators are reporting favorable results with a program that allows a hospital pharmacy to employ phar-

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

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macists who are not able to work onsite in the hospital. “The program has been a ‘win-win’ General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

for all parties involved,” said Sam Calabrese, RPh, MBA, director of inpatient pharmacy services at the Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

Cleveland Clinic in Cleveland, Ohio. The program has decreased the need for on-site pharmacists to work overtime and allowed them to work on patient-care floors. It Sam Calabrese, has also increased the RPh, MBA amount of orders being processed. The program has also provided for the first time an opportunity for pharmacists to practice their profession even when they are unable to work on-site at the hospital. “Other hospitals offer the same opportunity to a much smaller degree, and there are companies that do remote order entry for those hospitals that don’t have third shifts. However, to my knowledge, we are the sole institution with an on-site pharmacy 24/7 that additionally employs pharmacists at home,” he said. “When we were examining our staffing patterns, we tried to determine how best to capture pharmacists in the workforce who were not able to work on-site in the hospital setting but who nonetheless had the skills required to safely verify and process pharmacy orders,” Calabrese pointed out. At the same time, the Cleveland Clinic was experiencing a “doubledigit” shortage in pharmacists. “The shortage was so acute that our pharmacists often had to work mandatory extra shifts,” he added. Pharmacists who wish to participate in the off-site program undergo on-site training that lasts about 3 months, after which they are required to complete all standard pharmacist competence assessments. Pharmacists who qualify for the program are provided with computers, cell phones, and reference materials. They typically communicate with on-site staff using instant messaging and the telephone. Order clarifications are processed electronically, using electronic signatures and assistance from on-site pharmacists. Calabrese said that work-at-home pharmacists are very satisfied with the program, and only one of 12 who signed up for the program has dropped out. Finally, he noted that the at-home pharmacist’s ability to track orders is one aspect of the program he would like to improve. “If a nurse calls and says a dose is missing and wants to know if the order is still being prepared in the IV room or is out on delivery, the at-home pharmacist can’t answer that question,” he said. He added that an Internet-based tracking system will soon be installed, which should be helpful. ●

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Conference News

Pharmacists Can Play Important Role in Overseas Medical Mission

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harmacists can make a significant contribution to an overseas medical mission. In fact, the participation of a pharmacist on a recent mission to rural Kenya led by a California-based hospital proved to be so invaluable that all future missions to that region plan to have a pharmacist onboard.

included physicians and registered nurses. However, the decision to include a dispensary as part of the services provided by the mission meant that a pharmacist was needed. “The dispensary serves as a laboratory, a clinic, and a pharmacy all rolled into one, and the first team visiting Kenya real-

She set up a complete formulary and worked alongside local pharmacists completing and dispensing prescriptions with assistance from Swahili interpreters. Bhavi Shah, PharmD, clinical pharmacist and pharmacy educator at Hoag Memorial Hospital Presbyterian in Newport Beach, said, “My pharmacy training allowed me to work as a clinician, educator, and dispenser.” For the past few years, the Hoag Hospital has been involved in an outreach program that provides medical resources to underserved communities both locally and internationally. The medical personnel initially participating in the rural Kenya program

ized that they couldn’t set up a dispensary properly without the expertise of a pharmacist,” Shah said. Her responsibilities during the 10-day program were highly varied. Following meetings with team members to assess medical supply needs and determine dispensary conditions, she set up a complete formulary and worked alongside local pharmacists completing and dispensing prescriptions with assistance from Swahili interpreters. She also helped develop lectures and

handouts on topics that had been identified during prior missions as needing pharmacy education. Her “students” were pharmacists, nurses, and “clinical officers,” who are the equivalent of physicians assistants. “Sometimes we had to teach them really simple things,” Shah noted. “For example, they would prescribe a baby aspirin for a child,” she said. “They didn’t understand that the ‘baby’ in ‘baby aspirin’ did not mean that the product is intended for a baby.” Medical personnel in rural Kenya also tended to overprescribe antibiotics and were unable to distinguish between viral and bacterial infections. Shah also noted that she occasionally found herself working as a clinician. “I felt that with my clinical background, I was more credentialed than some of the local clinical officers,” she said. She cited the case of a young girl whose eczema she diagnosed. “The local medical personnel had not been able to diagnose her and had kept throwing [sic] antibacterials and antibiotics at her when all she needed was hydrocortisone and a moisturizer,” she said.

Shah acknowledged that the program was fraught with some insurmountable challenges. For example, most of the Kenyans in the area where they were working could not read or write so they were unlikely to retain what was explained to them by medical personnel. “So this made it difficult to deliver quality care,” she said. Polygamy also led to potential problems, she observed. “Men had multiple wives who had multiple kids,” she said. “And when we give out antibiotics in varying doses to multiple family members who are all illiterate, it’s easy to see how problems may result,” she said. Another problem is that antibiotic and antimalarial medications are available over-the-counter, which has led to overuse and escalating resistance. Finally, Shah said that although her responsibilities included teaching, she also had the opportunity to learn firsthand about clinical problems she had never encountered, including brucellosis, typhoid fever, and malaria. ● —Jill Stein

Chemotherapy-induced Visual Disturbances Often Ignored

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esearchers are calling for increased awareness of the potential for chemotherapy-induced visual disturbances. “Although multiple chemotherapy agents can produce visual disturbances in cancer patients, such incidents are rarely reported,” said Bruce Wong, MS, RPh, assistant director of pharmacy for clinical services at Newton-Wellesley Hospital in Newton, Massachusetts. “As a result, patients who are visually impaired due to chemotherapy are often excluded from a variety of treatments and resources that are routinely available to patients who are visually impaired from other causes, such as primary eye tumors, ocular metastases, and age.” Wong and colleagues examined clinical trials, package inserts, and case reports in the medical literature to determine which chemotherapy agents can cause visual disturbances. Next, they reviewed their pharmacy database to determine which of the offending chemotherapy agents were on formulary at their hospital.

www.TheOncologyPharmacist.com

The investigators identiknown to cause visual probfied 42 chemotherapy agents lems) were 65 years of age or on formulary during the 12older, and this percentage is month study period that may expected to increase, Wong ob induce visual disturbances, served. “As the population 19 of which had been ages, many diseases affecting administered. Overall, 175 the elderly such as cancer will patients received one or increase,” he said. “In fact, more of the 19 chemotheracancer incidence exponentialpy agents. “These numbers ly increases with advancing Bruce Wong, demonstrate the need for age, and a surge in the number MS, RPh awareness, education, and of older cancer patients is vigilant tracking of these potential side expected,” he added. Currently, pereffects,” Wong said. sons 65 years of age and older account Some of the most commonly used for 60% of newly diagnosed malignanagents include anastrozole, bicalu- cies and 70% of all cancer deaths. tamide, methotrexate, and tamoxifen. Wong recommends that all healthAccording to the medical literature, care professionals be “keenly aware” visual disturbances caused by these of the potential for chemotherapyagents include cataracts, conjunctivi- induced visual disturbances and take a tis, dry eye, lacrimation, and blurred more active role in preventing them or, vision. Side effects may develop, de - at the very least, informing patients pending on the agent, immediately, about strategies that may improve their gradually, or even several years after quality of life. treatment. A comprehensive eye examination, for About 25% of patients receiving example, should be done in cancer pachemotherapy agents (including those tients before, during, and after chemo-

therapy, he said. Pharmacists, at least those who have contact with patients, may want to remind patients of the importance of such an examination. It may also be helpful to make all documents (including prescriptions) intended for patients on chemotherapy agents known to cause visual disturbances available in large print or on audiotapes. Finally, he said that pharmacists should also consider providing information on public services such as state-supported transportation at a reduced rate for handicapped people; computer software that facilitates larger font, character size, and speech capabilities; and home aids, such as talking watches and calculators. “About 12% of patients who undergo chemotherapy develop visual problems as a result,” Wong said. “It is important to educate our colleagues as a first step in improving the quality of life of affected patients.” ● —Jill Stein

APril 2010 I VOl 3, NO 2

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Gastrointestinal Cancers Novel Treatment with Microspheres... Continued from cover extended and their quality of life is improving with Y-90 microsphere treatment,” said study investigator Riad Salem, MD, MBA, who is director of interventional oncology at Northwestern Memorial Hospital, Chicago. “This is a unique interventional radiology treatment, which combines the radioactive isotope Y-90 into microspheres that deliver radiation directly to a tumor. It is a particularly elegant way to give patients a cancer treatment that doesn’t harm the healthy cells.

in the body to the radiation. Each microsphere is about the size of five red blood cells in width. These beads are injected through a catheter from the groin into the liver artery supplying the tumor. The beads become lodged within the tumor vessels, where they exert their local radiation, causing cell death. Y-90 radiates from within and, because it is administered via the hepatic artery, it can be viewed as “internal” radiation, Salem explained. Y-90 treatment is approved by the US Food and Drug

“While patients aren’t cured, their lives are being extended and their quality of life is improving with Y-90 microsphere treatment.” —Riad Salem, MD, MBA Patients don’t feel sick or have any of the side effects that happen with standard cancer treatments.” Combining the radioactive isotope Y-90 into microspheres to deliver radiation directly to a tumor allows for a higher, local dose of radiation to be used without subjecting healthy tissue

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Administration for the treatment of unresectable hepatocellular carcinoma. He presented data from a study involving 291 patients with hepatocellular carcinoma, all of whom were treated with intra-arterial Y-90 microspheres as part of a single-center prospective study. The researchers

administered 526 Y-90 treatments (average, 1.8 per patient). They reviewed 1250 scans to assess response and time to progression. Survival by stage also was assessed. Overall, time to progression was 7.9 months. Salem said that, in oncologic standards for this disease, these were extremely promising findings. The survival times differed by the cancer staging system used: ChildPugh A (17.2 months), Child-Pugh B (7.7 months), and Barcelona Clinic Liver Cancer staging (A, 26.9 months; B, 17.2 months). Toxicities included fatigue (57%), transient pain (23%), nausea/vomiting (20%), and bilirubin toxicity (5%). “We take the approach that this is definitive therapy,” said Salem in an interview with The Oncology Pharmacist. “The trend is to move away from external beam and move to this kind of therapy for the liver, given the significant advantages and the limitations of external beam.” He noted that liver cancer treatment options are limited. Although surgical removal of liver tumors offers the best cancer for a cure, it is not possible for more than three fourths of primary liver cancer patients. Liver tumors are often inoperable because the tumor may be

too large or may have grown into major blood vessels or other vital structures. Sometimes many small tumors are spread throughout the liver, making surgery too risky or impractical, Salem explained. Historically, chemotherapy drugs and external radiation therapy have been ineffective at curing inoperable liver cancer. “These are early promising results. This information can be used to design future Y-90 trials and to describe Y-90 as a potential treatment option to liver cancer patients,” Salem said. He noted that this approach adds to interventional radiology’s nonsurgical advances for liver cancer, which include delivering chemotherapy directly to the affected organ (chemoembolization), killing the tumor with heat (radiofrequency ablation), or freezing the tumor (cryoablation) to treat cancer locally. ●

Did You Know? Medicare covers only 56% of the costs of administering chemotherapy and providing infusion room services to elderly patients, according to a study of cancer care in community practices.

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Conference News ASCO GU

Chemotherapy May Significantly Benefit... Continued from cover however, applied to men with stage IV prostate cancer who had metastatic disease, but not to men with stage IV nonmetastatic disease. “Essentially what we found was that there was about a 20% reduction in mortality for the people receiving chemotherapy compared with those who did not receive chemotherapy. Furthermore, what we found was that this benefit was only apparent in the group that has metastatic disease. We found no such benefit in the group with nonmetastatic disease,” said lead study investigator Michael Grabner, PhD, a postdoctoral fellow in pharmaceutical health services research at the University of Maryland School of Pharmacy, Baltimore. He said recent clinical trials have demonstrated a survival benefit for chemotherapy in men with castrationresistant prostate cancer. However, this study is unique because of its design and sample size. In this study, all the patients were 66 years old or older and were diagnosed with prostate cancer between 2000 and 2005. All the subjects were followed until

death or the end of the study period (December 31, 2007). The investigators restricted the cohort to men with incident stage IV disease who had received ADT. They were able to overcome observable selection bias by balancing covariates across the treat-

ple size was 4905 men. The mean age of the men was 77 years, and 84% were white. This group included 1252 men with nonmetastatic disease (mean age, 73.7 years; 86.5% white) and 3653 men with metastatic disease (mean age, 78 years; 83.2% white). Of the

“Essentially what we found was that there was about a 20% reduction in mortality for the people receiving chemotherapy compared with those who did not receive chemotherapy.” —Michael Grabner, PhD ment and control groups using propensity-score matching. The analysis was conducted for the entire cohort as well as for two subsets (men with metastatic disease and men without metastatic disease). Grabner told The Oncology Phar macist that after applying inclusion and exclusion criteria, the total sam-

total cohort, 23.4% received chemotherapy (20.9% of those with nonmetastatic disease and 24.2 of those with metastatic disease). The researchers found that for the full unmatched sample, chemotherapy was associated with a 14% reduction in the hazard of prostate cancer–

specific mortality compared with no chemotherapy. “The take-home message for oncology pharmacists is that it is crucial to differentiate between men with stage IV prostate cancer who have metastatic disease from the men who don’t have metastatic disease,” Grabner said. “It appears that the ability of chemotherapy to benefit these patients may depend on that difference.” Study coinvestigator C. Daniel Mullins, PhD, a professor of pharmacology at the University of Maryland School of Pharmacy, said the study findings were somewhat surprising since no benefit was seen in the men with nonmetastatic disease. “Our study shows that choosing the right patient to treat is important,” he told The Oncology Pharmacist. “The pharmacist has always been the person who is in the best position to communicate with the patient about their medicine. The physician will diagnose the disease, but the responsibility of explaining to the patients why it is so important to take the prescribed medicines gets transferred to the pharmacist.” ●

Adverse Reactions to Targeted Therapies for Metastatic Renal Cell Carcinoma Are Reversible

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ost cases of severe treatmentrelated adverse reactions to the targeted therapies for kidney cancer appear to be reversible and resolve after dose reduction or treatment interruption, according to Thomas Hutson, DO, PharmD, director of genitourinary oncology at Baylor Sammons Cancer Center, Dallas, Texas. He said optimal treatment with these targeted agents requires proactive monitoring, early intervention, and appropriate management of adverse effects. Taking these steps can help avoid unnecessary dose reductions, dose interruptions, or even early treatment discontinuation. The rapid increase in agents for renal cell carcinoma has changed the treatment paradigm. Sunitinib, sora fenib, pazopanib, and bevacizumab (vascular endothelial growth factor [VEGF] targeted therapies) and temsirolimus and everolimus (mammalian target of rapamycin [mTOR] in hibitors) have dramatically improved outcomes for patients with advanced disease. Hutson pointed out, however, that these therapies are not curative and are associated with mild-to-moder-

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ate toxicity. In addition, they must be administered long-term. “We have two main classes of agents. We have VEGF inhibitors and we have the mTOR inhibitors, and each class has its own unique set of toxicities. The takehome message is that the toxicities are readily manageable, with supportive care

VEGF inhibitors. It usually occurs early in the course of treatment, often within the first 8 to 12 weeks. Therefore, blood pressure monitoring, and treatment when necessary are recommended. Skin changes associated with both the mTOR inhibitors and VEGF inhibitors are very common, with an incidence as

“We really need to try to maintain dose intensity, keep the dose as high as possible with managing toxicity to allow the best quality of life for patients.” —Thomas Hutson, DO, PharmD or medical treatment,” he said in an interview with The Oncology Pharmacist. “Some patients may have to have dose interruptions, dose holidays, or dose reductions. However, we can generally manage toxicities in most patients, allowing them to stay on therapy.” He said hypertension is the most recognized cardiovascular effect of the

high as 50% according to published studies. The most common problems are hand-foot syndrome (VEGF inhibitors), changes in hair color and skin depigmentation (most commonly reported with the VEGF inhibitors sunitinib and pazopanib), skin rashes, acral erythema, subungual splinter hemorrhages, and mucositis/functional stomatitis.

Changes in glucose and cholesterol metabolism are expected toxicities of mTOR inhibitors (temsirolimus and everolimus), and close monitoring of fasting blood glucose and hemoglobin A1C in patients treated with mTOR inhibitors is required, Hutson advised. “One of the concepts that has emerged from our pharmacokinetic studies of the drugs is the concept that more is better. We really need to try to maintain dose intensity, keep the dose as high as possible with managing toxicity to allow the best quality of life for patients,” Hutson said. Pharmacists need to play a key role in educating patients about the expected toxicities and making sure the patients are aware of the importance of early recognition of the toxicities. “This has been an explosive time for renal cell carcinoma, with a number of new drugs approved. We essentially have had six new drugs approved in a little over 3 years, and with that is a steep learning curve for physicians, pharmacists, nurses, and others involved in supportive care, Hutson noted. ● —John Schieszer

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CONTINUING EDUCATION EDITORIAL BOARD

PROGRAM TOP2 • RELEASE DATE: APRIL 15, 2010 • EXPIRATION DATE: APRIL 15, 2011

Andrew T. Chan, MD, MPH

ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Gastrointestinal Unit Massachusetts General Hospital 55 Fruit Street GRJ 724 Boston, MA 02114

Aspirin Therapy and Survival in Patients with Colorectal Cancer

Betty M. Chan, PharmD, BCOP Assistant Professor of Clinical Pharmacy and Pharmaceutical Economics & Policy University of Southern California

By Andrew T. Chan, MD, MPH Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts STATEMENT OF NEED

Because colorectal cancer (CRC) remains the third most frequently diagnosed cancer in both men and women and the third leading cause of cancer-related death for both sexes, there is great interest in reducing both the incidence and mortality associated with this disease. However, data regarding aspirin use and survival after a diagnosis of CRC are unknown. Therefore, the most recent data regarding aspirin and CRC are met with great interest. Oncology pharmacists should be aware of the most recent data in order to be able to discuss results with patients diagnosed with CRC.

Clinical Professor USC/Norris Comprehensive Cancer Center 1441 Eastlake Avenue Los Angeles, CA 90033

PLANNING COMMITTEE Gloria Mui Medical Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604

TARGET AUDIENCE

Registered pharmacists, and other interested healthcare professionals, especially those caring for cancer patients

Julie Ann Tagliareni CME Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604

LEARNING OBJECTIVES

After completing this activity, the reader should be better able to: • Explain the rationale for use of aspirin to protect against colorectal cancer

Anne L. Finger President Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Jill Stein 22 rue Malher Paris, France 75004

• Describe the effects of prediagnosis and postdiagnosis use of aspirin on survival in patients with diagnosed colorectal cancer • Discuss potential indications and contraindications for aspirin use in patients at risk for colorectal cancer

A

lthough aspirin is best known for its uses as an analgesic, antiinflammatory, or cardiovascular prophylactic, regular aspirin use also may prevent colorectal adenoma and colorectal cancer (CRC).1 Aspirin’s ability to inhibit colorec-

tal tumor growth is probably due, in part, to its inhibition of cyclooxygenase-2 (COX2).2,3 The COX-2 enzyme is overexpressed in most colorectal cancer, and is known to inhibit natural cell death, encourage growth of tumor blood vessels, and increase tumor invasiveness.4-6 Despite aspirin’s protective effect against colorectal neoplasia, it is not recommended as a CRC chemopreventive agent due to concern over its potential harmful effects, including an increased risk for hemorrhagic stroke and gastrointestinal bleeding. However, there may be a role for aspirin use in colorectal cancer prevention among those at extremely high risk of dying from the disease. One such subgroup is patients diagnosed with nonmetastatic colorectal cancer. Although their prognosis is generally more favorable compared with patients who present with metastatic disease, patients with, for example, stage III disease have as high as a 40% chance of recurrent cancer and death.7 Thus, if an inexpensive, widely used medication such as aspirin could improve survival when added to conventional surgery and chemotherapy, it would represent a significant advance in the treatment of CRC. CRC is the third most common type of cancer in men and women. It is also the second most common cause of cancer-related death in men and the third most common cause of cancer-related death in women. According to estimates from the National Cancer Institute, almost 50,000 patients will die of CRC in 2009.8 Study analyzes data from two large prospective cohorts Although a role for aspirin in reducing

CONTINUING PHARMACY EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT

Veritas Institute for Medical Education, Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program (UPN 0394-0000-10-003-H01-P) is acceptable for 1.0 Contact Hours. Initial release date: April 15, 2010. A statement of credit will be available online to participants who successfully complete the program, learning assessment (>70%), and program evaluation form. There is no registration or processing fees. METHOD OF PARTICIPATION

1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Click on “CE Credits” 4. Click on “Click here to complete the posttest and obtain a CE certificate online” 5. Register to participate 6. Enter program number TOP2 7. Complete and submit the CE posttest and CE Activity Evaluation and Request for Credit Form online 8. Print your statement of credit

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APril 2010 I VOl 3, NO 2

CRC incidence is well-established, it is not clear whether aspirin can influence prognosis in patients with confirmed CRC. To determine the effect of aspirin use after diagnosis of CRC on survival, my colleagues and I conducted a prospective cohort study of 1279 patients with nonmetastatic (stage I, II, and III) CRC.9 Our patients were drawn from two large, ongoing prospective studies—the Nurses’ Health Study and the Health Professionals Follow-up Study. At the time of enrollment in these two studies, no patient had been diagnosed with colorectal cancer. Of the 1279 patients, 560 used aspirin regularly before the diagnosis of CRC and 549 used it after the diagnosis. Because patients were asked to provide information on their use of aspirin every 2 years, we were able to determine the effect of prediagnosis and postdiagnosis aspirin use on survival in patients with established CRC. We also assessed whether the effect of aspirin varied according to levels of tumoral expression of COX-2. Results show reduced mortality with aspirin After a median follow-up of 11.8 years, there were 193 (35%) total deaths and 81 (15%) deaths due to CRC among the 549 patients who took aspirin regularly after being diagnosed with CRC. Among aspirin nonusers, there were 287 (39%) total deaths and 141(19%) deaths due to CRC. Overall 5-year survival for the entire cohort was 88% for aspirin users compared with 83% for nonusers; 10-year survival rates were 74% and 69%, respectively. Multivariate analysis showed that patients who

This activity is provided free of charge to participants. FINANCIAL DISCLOSURES

Veritas Institute for Medical Education, Inc. is required to disclose to the activity audience the relevant financial relationships of the planners and faculty involved in the development of CE content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CE activity content over which the individual has control. In addition, all faculty are expected to openly disclose any unlabeled/unapproved/investigational uses of drugs or devices discussed in this activity. Disclosures are as follows: • Andrew T. Chan, MD, MPH, has nothing to disclose. • Betty M. Chan, PharmD, BCOP, has received research/grant support from Merck & Co. The staff of Veritas Institute for Medical Education, Inc. and Green Hill Healthcare Communications, LLC have nothing to disclose. DISCLAIMER

The opinions expressed in this activity are those of the presenters and do not necessarily reflect the opinions or recommendation of Veritas Institute for Medical Education, Inc. Copyright © 2010 Veritas Institute for Medical Education, Inc. All rights reserved.

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www.TheOncologyPharmacist.com used aspirin regularly after being diagnosed with CRC had a 29% lower risk of death from CRC than those who did not take aspirin (multivariate hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.53-0.95) and a 21% lower risk of overall mortality (multivariate HR, 0.79; 95% CI, 0.65-0.97). Prediagnosis use of aspirin, in contrast, was not associated with either CRC-specific or overall mortality. Aspirin’s benefit was most pronounced in patients whose primary tumors overexpressed COX-2; these patients were 61% less likely to die of CRC if they took aspirin after their diagnosis than patients with similar COX-2 levels who did not take aspirin (multi-

variate HR, 39; 95%CI, 0.20-0.76). Patients with COX-2–positive tumors also had a 38% lower risk of overall mortality (multivariate HR, 0.62; 95% CI, 0.42-0.93). The findings, which are consistent with those of other human and experimental data, suggest that COX-2– positive tumors may be relatively sensitive to the effects of aspirin whereas COX-2–negative tumors may be relatively aspirin-resistant. Among study subjects who had not used aspirin regularly before diagnosis, the association between postdiagnosis aspirin use and survival was found to be modestly dose-responsive. Compared with subjects who used any aspirin, the multivariate-adjusted HR for CRC-spe-

cific mortality was 0.57 (95% CI, 0.320.99) for those who used 0.5 to 5 standard aspirin tablets and 0.49 (95% CI, 0.181.35) for those who used six or more tablets per week (P for trend = .04). Study strengths and limitations We believe that our study has several notable strengths. For example, we used prospective data on aspirin use, which allowed us to minimize the possibility that patients would be inaccurate in their recollection of their aspirin use. Also, we compiled data on aspirin use both before and after patients had been diagnosed with CRC, which enabled us to clearly distinguish the effect of aspirin use after diagnosis

from that of aspirin use before diagnosis. Notably, all study participants were health professionals, and health professionals are presumably more likely to provide an accurate report of aspirin use. Perhaps the key study limitation is its observational design. We examined aspirin use in individuals who had either decided on their own to take aspirin or in whom aspirin had been prescribed for some other condition. Observational studies are generally less reliable than placebo-controlled studies. Our results thus need to be confirmed in placebo-controlled trials of aspirin or associated agents as adjuncts to other standard CRC treatments. Continued on page 16

COMMENTARY

The Use of Aspirin for Chemoprevention or as Adjuvant Therapy for Colorectal Cancer: Where Are We Today? Betty M. Chan, PharmD, BCOP Assistant Professor of Clinical Pharmacy and Pharmaceutical Economics & Policy, University of Southern California, Los Angeles

M

uch is known about the use of aspirin as a cardioprotective agent for prevention and treatment of myocardial infarction and acute and transient ischemic stroke. Now studies are emerging regarding the potential use of aspirin as primary chemoprevention of colorectal adenomas1 and as adjuvant therapy for colorectal cancer.2 In a large cohort study conducted by Chan and colleagues,2 the users of aspirin had a 29% lower cancer-specific mortality (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.53-0.95) and a 21% lower overall mortality (HR, 0.79; 95% CI, 0.650.97) among patients with colorectal cancer (stages I-III) compared with nonusers. When aspirin was initiated in patients who were nonusers before their colorectal cancer diagnosis, cancer-specific mortality was 47% lower (HR, 0.53; 95% CI, 0.33-0.86) and the benefit was greatly observed in patients with colorectal cancer that overexpressed cyclooxygenase-2 (COX-2) enzyme. For the entire cohort, the study reported an overall 5-year survival rate of 88% for aspirin users compared with 83% for non users, and an overall 10-year survival rate of 74% for aspirin users compared with 69% for nonusers. The results from this study further pose the question of the potential role of aspirin as adjuvant therapy in colorec-

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tal cancer patients who overexpress the COX-2 enzyme. About 80% to 85% of colorectal cancers overexpress the COX-2 enzyme, which promotes inflammation and cell proliferation. The overexpression of the COX-2 enzyme has been associated with a poorer prognosis among patients with colorectal cancers.3,4 Although celecoxib, a selective COX-2 enzyme inhibitor, is US Food and Drug Administration–approved for use to reduce the number of intestinal polyps in patients with familial adenomatous polyposis, its use has been associated with cardiovascular toxicity.5 Aspirin, like nonsteroidal antiinflammatory drugs, also has inhibition activity against both the COX-1 and COX2 enzymes; and although the use of aspirin is widely used as a cardioprotective agent, its use as primary chemoprevention of colorectal cancer is currently not recommended by clinical guidelines because of concern with adverse effects, primarily gastrointestinal irritation and bleeding and the potential need for long-term therapy.6 Although studies have demonstrated the use of aspirin as effective in reducing the incidence of colorectal adenoma and colorectal cancer, the potential adverse effects from long-term aspirin use remain a concern. Monitoring guidelines are needed. Coadministration of a proton pump inhibitor along with the use of aspirin has been pro-

posed as a treatment option and is currently being investigated in a clinical trial. Until more safety and efficacy data are available, screening is still the most important step people can take to protect themselves against colorectal cancer. Screening guidelines are available for patients and healthcare professionals from the National Comprehensive Cancer Network.7 In addition, new colorectal cancer screening recommendations were also published in 2008 from the US Preventive Services Task Force.8,9 Joint guidelines from the American Cancer Society, the US Multisociety Task Force on Colorectal Cancer, and the American College of Radiology are also available.10 All guidelines recommend screening to begin at age 50 for both men and women. Screening should start earlier in patients with: • Increased risk factors, such as a personal history of adenoma/polyps, colorectal cancer, or inflammatory bowel disease, or a positive family history of colorectal cancer • Presence of Lynch syndrome/hereditary nonpolyposis colorectal cancer or polyposis syndromes • Symptoms of colorectal cancer. References 1. Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst. 2009;101:256-266.

2. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649-659. 3. Eberhart CE, Coffey RJ, Radhika A, et al. Upregulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183-1188. 4. Ogino S, Kirkner GJ, Nosho K, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res. 2008;14:8221-8227. 5. Solomon SD, Wittes J, Finn PV, et al; for the Cross Trial Safety Assessment Group. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117:2104-2113. 6. Dubé C, Rostom A, Lewin G, et al; for the US Preventive Services Task Force. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146:365-375. 7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. V.1.2010. www. nccn.org/pro fessionals/physician_gls/PDF/colorectal_screen ing.pdf. Accessed January 27, 2010. 8. US Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2008;149:627-637. 9. Whitlock EP, Lin JS, Liles E, et al. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:638-658. 10. Levin B, Lieberman DA, McFarland B, et al; for the American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58:130-160.

APril 2010 I VOl 3, NO 2

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CONTINUING EDUCATION Continued from page 15

Aspirin Therapy... Summary and conclusion What we now know • Patients with CRC who take aspirin may reduce their risk of dying from the disease by nearly 30%. • Aspirin use after rather than before the development of stage I, II, or III cancer is associated with improved survival. • Aspirin appears to primarily benefit only those patients whose primary tumors test positive for the COX-2 enzyme. • Patients with stage III disease at the time of diagnosis derive as much benefit from aspirin use as patients who have stage I or II disease at diagnosis. • Former aspirin users obtain less benefit from subsequent aspirin use than former nonusers. • Our data suggest that aspirin may alter the biology of established colorectal tumors (ie, reduce the risk of recurrence among patients with cancer) in addition to preventing their occurrence (ie, reduce the risk of developing an initial cancer). At

this time, it is unclear exactly how aspirin interacts with the tumor to improve survival. • Our data demonstrate the potential for using COX-2 as a marker to tailor aspirin use in patients with newly diagnosed CRC. What we do not know • Because the study was observational, we were not able to determine what roles factors other than aspirin may have played in decreasing cancer deaths. • We do not know yet whether all patients with CRC will benefit from aspirin so we cannot make recommendations yet about who should take it and how often and at what dose. All these questions require additional research, including placebocontrolled trials of aspirin as adjuvant therapy for CRC. An ongoing study being conducted in Asia is comparing aspirin with placebo in patients with nonmetastatic CRC.10 At this time, we cannot make broad

recommendations about the use of aspirin in patients with CRC. Some patients may already be taking aspirin for other reasons, such as heart attack prevention. However, the risk of serious side effects with long-term exposure means that physicians should not prescribe aspirin to treat CRC until the evidence in favor of a significant benefit is definitive and until there is proof that its benefits outweigh its risks. For now, the best treatments for CRC are surgery, chemotherapy, and radiation therapy. References 1. Dubé C, Roston A, Lewin G, et al; for the U.S. Preventive Services Task Force. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146:365-375. 2. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007;356: 2131-2142. 3. Markowitz SD. Aspirin and colon cancer—targeting prevention? N Engl J Med. 2007;356: 2195-2198. 4. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol. 2005;23:2840-2855.

5. Eberhart CE, Coffey RJ, Radhika A, et al. Upregulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183-1188. 6. Soumaoro LT, Uetake H, Higuchi T, et al. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res. 2004;10:8465-8471. 7. Goldberg RM. Intensive surveillance after stage II or III colorectal cancer: is it worth it? J Clin Oncol. 2006;24:330-331. 8. Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: colon and rectum. Based on November 2008 SEER data submission, posted to the SEER website, 2009. http://seer.can cer.gov/statfacts/html/colorect.html. Accessed November 25, 2009. 9. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649-659. 10. National Cancer Institute. Clinical trials (PDQ): phase III randomized study of acetylsalicylic acid (aspirin) in patients with completely resected Dukes stage C colon or rectal cancer, Dukes stage B rectal cancer, or high-risk Dukes stage B colon cancer. January 30, 2009. http:// www.cancer.gov/search/viewclinicaltrials.aspx?c drid=577892&version=healthprof. Accessed November 25, 2009.

Jill Stein contributed to preparation of this manuscript.

CANCER CENTER PROFILE

Desert Regional Comprehensive Cancer Center... Continued from cover get a lot of support from Administration and the medical staff. It is a very collaborative practice here and definitely an enjoyable place to work.”

Multidisciplinary staff of Desert Regional Comprehensive Cancer Center.

The center employs a multidisciplinary team of physicians with expertise in all the major types of cancer and offers a variety of treatment options, including chemotherapy, radiation therapy, gene therapy, and surgery. Patients have access to on-site psychosocial, nutritional support, and financial counseling services. In addition, the CCC provides genetic testing for women at high risk for breast or ovarian cancer, a hospice program, a pain management program, support groups, and volunteer services. Because of its excellent reputation, patients come from far away to be treated at Desert Regional CCC, and social workers help arrange housing for patients and their families; translators are available to assist foreign visitors.

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April 2010 I VOl 3, NO 2

Pharmacist plays many roles Through its affiliation with Aptium Oncology–managed cancer centers throughout the country, the CCC offers patients the opportunity to participate in phase 1 to 4 clinical trials. Oncology pharmacist Craig Elg, PharmD, BCOP, coordinates clinical trials in addition to his other responsibilities. “At any given time, we have 40 to 50 clinical trials open and running,” he says. “One of my responsibilities is to make sure that the pharmacy portion of those trials is running smoothly and correctly. I go to the site initiation visits and meet with the monitors to make sure that the protocol is being followed properly, the drugs are being stored in the correct manner, destruction policies are being followed, and all the

paperwork is done. Since we implemented our electronic medical record (EMR), I’m also involved in building the protocols for all the new research trials. Once we sign on to do something, those order sets are put into the EMR so that the physicians have easy access to them.” In addition to their more traditional responsibilities for counseling patients and providing support to medical staff on a variety of supportive care issues, such as fatigue and pain management, Elg and his fellow pharmacists at the center have the ability through special California law to prescribe controlled substances to help manage patients with cancer pain. Desert Regional CCC provides an environment in which employees are encouraged to do new things and take on new responsibilities, Elg has found. “You

Nurse appreciates range of specialties Oncology nurse Kristin Rupp, RN, BSN, OCN, agrees, saying, “We feel as if we are a family here. Coming here as a transplant from Indiana, it has been very welcoming.” Rupp previously worked on the oncology floor of a local hospital in Indiana and in private oncology practices in Indiana and California. In her previous jobs, she says the nurses had to take on other responsibilities, such as mixing chemotherapy, in addition to their nursing duties. “We wore all hats. We were the nurse; we administered chemotherapy in our office; we ran the lab; we were the social worker; the dietitian, everything.” At the CCC, she says, “I can rely on all the different professions—the pharmacists, the dietitians, social workers, and others—to add their knowledge and expertise to taking care of the patient as a whole. This allows me to focus on my nursing role.” There are also advantages for patients. “We have everything here under one roof,” making it possible for patients to see different specialists in one visit, she notes. “The level of expertise that I am surrounded by every day makes care of the patient top notch.” ●

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TOP_April2010_TON 4/12/10 2:29 PM Page 18

Clinical Pharmacy Review

Optimizing Dasatinib Therapy for Patients with Chronic-phase CML By Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services, Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, California

C

hronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), which is formed by genetic exchange between chromosomes 9 and 22 and codes for the pathogenic tyrosine kinase BCR-ABL.1-3 Historically, therapeutic interventions for CML have included busulfan, hydroxyurea, interferon-a, and stem cell transplantation.4 These therapies vary greatly in tolerability, toxicity, and efficacy. Current treatment options primarily comprise the tyrosine kinase inhibitors that target BCR-ABL, which have revolutionized

the treatment of this disease. Imatinib was the first BCR-ABL inhibitor to be approved by the US Food and Drug Administration (FDA) for CML. It is currently the standard first-line treatment, although its use is limited by resistance and/or intolerance. In the International Randomized Interferon and STI-571 (IRIS) trial, 31% (171/553) of patients randomized to imatinib discontinued the study within 5 years of follow-up because of unsatisfactory therapeutic effect, adverse events (AEs), switching to alternative treatment, or other reasons.5 Subsequent BCR-ABLâ&#x20AC;&#x201C;targeted agents have been developed and approved: dasatinib and nilotinib. Preclinical studies have indicated that dasatinib was the

most potent inhibitor of native (unmutated) BCR-ABL. Indeed, both dasatinib and nilotinib were shown to be more potent than imatinib (dasatinib, ~325fold; nilotinib, ~20-fold).6 Dasatinib was initially approved in June 2006 based on data from the phase 2 SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib (START) study. START consisted of a series of multicenter, open-label studies of dasatinib 70 mg twice daily in chronic-phase (CP), accelerated-phase (AP), or myeloid or lymphoid blast crisis (BC) CML with resistance or intolerance to prior therapy, including imatinib.7-10 Results from a recent dose-optimization study (CA180-034) have led to a newly approved starting dose for dasatinib in

Table 1. Recommendations for Concomitant Administration of Dasatinib with CYP3A4 Inhibitors or Inducers CYP3A4 Inhibitors

CYP3A4 Inducers

Agents

Ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin

Dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital

Actions

Toxicity should be monitored closely and dasatinib dose reduction of 20 mg/day-40 mg/day should be considered

CYP3A4 inducers with less enzyme induction potential should be used if possible; dose increases of dasatinib in 20-mg increments is recommended

CYP3A4 indicates cytochrome P450 enzyme 3A4. Source: Reference 12.

patients with CP CML: 100 mg administered orally once daily in the morning or in the evening. For patients with AP CML, BC CML, or Ph+ acute lymphoblastic leukemia (ALL), the dose has also recently changed to a once daily schedule of 140 mg. Pharmacokinetic information Pharmacokinetic analysis demonstrated that dasatinib reaches maximum plasma concentration between 0.5 and 6 hours after oral administration. At a dose range of 15 mg/day to 240 mg/day, elimination is linear, and increase in area under the curve is proportional to the dose. The overall mean terminal half-life is 3 to 5 hours. These results were, in part, the rationale for twicedaily dosing. Once-daily dosing has proved to be at least as effective as twice-daily dosing, with an improved tolerability profile.11,12 Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence within the range of 100 ng/mL to 500 ng/mL.12 Dasatinib is metabolized primarily to its active metabolite by the cytochrome P450 enzyme 3A4 (CYP3A4). The active metabolite is unlikely to play a major role in the observed pharmacology of the drug, because it represents only 5% of the dasatinib area under the curve. In the human liver, dasatinib is a time-dependent inhibitor of CYP3A4 but does not induce human CYP enzymes. Elimination is primarily via the feces (85%) and urine (4%).12

Table 2. Adverse Reactions Reported in â&#x2030;Ľ20% of Patients in Dasatinib Clinical Studies of CML 100 mg once daily Chronic phase (n = 165)

140 mg once daily

Accelerated phase (n = 157)

Myeloid blast crisis (n = 74)

Lymphoid blast crisis (n = 33)

All grades

Grades 3/4

All grades

Grades 3/4

All grades

Grades 3/4

All grades

Grades 3/4

Fluid retention

34

4

35

8

34

7

21

6

Diarrhea

27

2

31

3

20

5

18

0

Headache

33

1

27

1

18

1

15

3

Skin rash

17

2

15

0

16

1

21

0

Nausea

18

1

19

1

23

1

21

3

Hemorrhage

11

1

26

8

19

9

24

9

Fatigue

24

2

19

2

20

1

9

3

Dyspnea

20

2

20

3

15

3

3

3

CML indicates chronic myeloid leukemia. Source: Reference 12.

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April 2010 I VOl 3, NO 2

Drug interactions Because dasatinib is a CYP3A4 substrate, the use of CYP3A4 inhibitors may increase exposure to dasatinib and should be avoided. If CYP3A4 inhibitors must be used, toxicity should be monitored closely and dosages decreased as needed (Table 1). Caution is warranted any time azole antifungals, marcrolides, or antiretrovirals are used concurrently with dasatinib. Concurrent use of CYP3A4 inducers, such as rifampin, may decrease dasatinib plasma concentrations. Agents with less enzyme-induction potential would be preferable in patients who require CYP3A4 inducers; dasatinib dose escalation in 20-mg increments is recommended if it is necessary to use CYP3A4 Continued on page 20

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Clinical Pharmacy Review Optimizing Dasatinib Therapy... Continued from page 18 major cytogenetic response (MCyR) was achieved regardless of treatment schedule in this phase 1 study, even in patients CP CML (starting ANC <0.5 ¥ 109/L and/or platelets <50 ¥ 109/L 1. Stop dasatinib until ANC ≥1.0 ¥ 109/L and receiving the once-daily schedule who dose, 100 mg/day) platelets ≥50 ¥ 109/L achieved intermittent BCR-ABL inhibi2. Resume treatment at the original starting tion.18 The updated label for dasatinib includes results from a phase 3 dose-optidose mization study11 and from a phase 2 study 3. If platelets <25 ¥ 109/L and/or recurrence of of dasatinib versus high-dose imatinib.19 ANC <0.5 ¥ 109/L for >7 days, repeat step 1 Phase 2 study of dasatinib versus highand resume dasatinib at a reduced dose of dose imatinib in patients resistant to imatinib 80 mg/day (second episode) or discontinue 400 mg/day to 600 mg/day. High-dose (third episode) imatinib has commonly been used as a treatment option for patients who experiAP CML, BC CML, ANC <0.5 ¥ 109/L and/or platelets <10 ¥ 109/L 1. Check if cytopenia is related to leukemia ence resistance to standard doses (400 and Ph+ ALL (starting (bone marrow aspirate or biopsy) mg/day-600 mg/day) of imatinib in CML. dose, 140 mg twice daily) 2. If cytopenia is unrelated to leukemia, stop Previous studies have shown that escalatdasatinib until ANC ≥1.0 ¥ 109/L and platelets ing the dose of imatinib to 800 mg/day can induce responses in some of these ≥20 ¥ 109/L and resume at the original patients but that responses tend to be starting dose short in duration and increased drug 3. If recurrence of cytopenia, repeat step 1 and intolerance may be an issue.20-23 Hence, a resume dasatinib at a reduced dose of 100 phase 2 head-to-head randomized study mg once daily (second episode) or 80 mg of dasatinib versus high-dose imatinib once daily (third episode) (START-R) was undertaken.19 Dasatinib (70 mg twice daily) or high4. If cytopenia is related to leukemia, consider dose imatinib (800 mg/day) was adminisdose escalation to 180 mg once daily tered to patients with CP CML who were ALL indicates acute lymphoblastic leukemia; ANC, absolute neutrophil count; AP, accelerated phase; BC, blast crisis; CP, chronic phase; CML, chronic myeloid resistant to standard imatinib dosing. leukemia; Ph+, Philadelphia chromosome–positive. Crossover to the alternate treatment was Source: Reference 12. permitted after confirmed progression (ie, progression to AP or BC CML, loss of inducers. Use of St. John’s wort should be pnea or dry cough, should be evaluated tinib, with an incidence of 3% in 911 complete hematologic response [CHR] or avoided, because it may also decrease the by chest radiograph because early inter- patients reported in the prescribing MCyR, or increasing white blood cell dasatinib plasma concentrations. vention is desirable. Fluid-retention information.12 There is also in vitro evi- count), lack of MCyR at the week 12 Because the solubility of dasatinib is events can usually be managed by sup- dence of prolonged cardiac ventricular cytogenetic evaluation, or intolerance dependent on pH, concomitant adminis- portive care measures that include repolarization (QT interval) in patients (grade 3/4 nonhematologic toxicity or tration of dasatinib and antacids can diuretics or short courses of steroids. receiving dasatinib. In clinical studies, hematologic toxicity requiring multiple decrease the absorption of dasatinib; Severe pleural effusion (occurring in 2% these QTc interval changes from base- dose modifications). therefore, it is recommended that ant- of patients) may require thoracentesis line were 3 millisecond to 6 millisecond. With a 15-month follow-up, patients acids be taken at least 2 hours before or and oxygen therapy. Fluid retention Nine patients had QTc prolongation treated with dasatinib experienced signifafter dasatinib administration. Con- events were reported less frequently in reported as an AE, and three patients icantly increased response rates compared comitant use of proton pump inhibitors patients treated with 100 mg/day than in (<1%) experienced a QTc greater than with patients treated with high-dose imamay reduce bioavailability of dasatinib patients treated with 70 mg twice daily, 500 millisecond. Cardiotoxicity has also tinib (93% vs 82%, P = .034). Patients in and thus, ideally, should be avoided. thus providing more than just conven- been reported with imatinib15 and most the dasatinib arm also had significantly Antacids would be the preferred therapy ience or compliance as an incentive for recently with nilotinib, which has a black greater MCyR (52% vs 33%; P = .023) box warning included in the prescribing and complete cytogenetic response to use in place of proton pump inhibitors. the newly approved dosing schema. Although not studied, the use of H2 Treatment with dasatinib is also associ- information highlighting the risk of QT (CCyR; 40% vs 16%; P = .004) compared antagonists could also be a cause for con- ated with cytopenias. Nearly half the prolongation and sudden death.16 Al - with the high-dose imatinib arm. MCyR cern, because their mechanisms of action patients treated experienced neutropenia though the incidence of cardiotoxicity rates were higher with dasatinib comindirectly impact acid secretion in the and thrombocytopenia; 18% demonstrat- differs between agents, these AEs may be pared with the high-dose imatinib arm in gastrointestinal tract. ed anemia. With this in mind, complete related to BCR-ABL inhibition and, those who had no prior cytogenetic blood counts should be performed week- therefore, may be genuine class effects. response and those who received prior AEs and monitoring ly for the first 2 months then monthly Further research is needed to clarify the imatinib doses of 600 mg/day. Molecular In clinical studies, the most frequently thereafter (or as clinically indicated). mechanisms underlying these effects, and response rates were also significantly highreported adverse reactions to dasatinib Myelosuppression is generally reversible the use of tyrosine kinase inhibitors in er in the dasatinib arm versus the high(reported in ≥20% of patients) are pre- and usually managed by dose reductions general may benefit from closer monitor- dose imatinib arm (16% vs 4%; P = .038). sented in Table 2. The most frequently or interruptions (Table 3).12 Myeloid ing of cardiac function.17 Responses were generally achieved in reported serious adverse reactions with growth factors and/or platelet transfupatients with imatinib-resistant BCRclinical implications included pleural sions may help lessen the risks of compli- Clinical data supporting change to ABL kinase domain mutations. effusion (11%), pneumonia (3%), infec- cations associated with neutropenia and dasatinib prescribing information Dasatinib was also associated with a The dasatinib 70-mg twice-daily regi- significant prolongation in the time-totion (2%), febrile neutropenia (4%), gas- thrombocytopenia, respectively, and retrointestinal bleeding (4%), dyspnea duce the need for dose modification.13,14 men used in phase 2 studies and subse- treatment failure compared with high(3%), sepsis (1%), congestive heart fail- Similar to fluid-retention events, throm- quently FDA-approved was selected dose imatinib (hazard ratio [HR], 0.16; ure (2%), and pericardial effusion bocytopenia was reported less frequently based on phase 1 study data, which 95% confidence interval [CI], 0.10-0.26; (1%).12 Of these, the incidence of pleu- in patients treated with 100 mg/day than showed that BCR-ABL kinase inhibition P <.001).19 Rates of progression-free surral effusion is particularly concerning. with 70 mg twice daily. was more sustained across a 24-hour peri- vival showed a statistical difference in Patients who may develop symptoms of the dasatinib arm, with a Cardiotoxicity has been described od with the twice-daily schedule than corefavor suggestive of pleural effusion, such as dys- infrequently in patients receiving dasa- with the once-daily schedule.18 However, sponding risk reduction of 86% com-

Table 3. Dose Adjustments of Dasatinib for the Management of Neutropenia and Thrombocytopenia

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April 2010 I VOl 3, NO 2

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Clinical Pharmacy Review

pared with high-dose imatinib (HR, 0.14; 95% CI, 0.05-0.40; P <.001).19 These results suggest that when patients do not respond, or experience loss of response to imatinib, treatment with dasatinib is more effective than escalating the imatinib dose.19 Phase 3 dose-optimization study. A randomized, phase 3, open-label study was conducted to optimize the dose and schedule of dasatinib in patients with CP CML. Dasatinib was administered in once-daily and twice-daily schedules at two total daily doses (100 mg and 140 mg) in patients with CP CML after imatinib resistance or intolerance. The 100-mg daily dose was selected as the median total daily dose across the phase 2 program in CP CML.11 Similar, marked hematologic and cytogenetic efficacy was seen across all four treatment arms. Rates of CHR, MCyR, and CCyR were 90%, 59%, and 41% for patients receiving 100 mg/day and 87%, 55%, and 45% for patients receiving 70 mg twice daily.12 In this noninferiority trial design, the oncedaily schedule demonstrated comparable efficacy with the twice-daily schedule on the primary efficacy end point (difference in MCyR, 2.8%; 95% CI, 6.0-11.6). The main secondary end point of the study also showed comparable efficacy between the 100-mg total daily dose and the 140-mg total daily dose (difference in MCyR, –0.8%; 95% CI, 9.6-8.0). Because the minimum follow-up was only 6 months, too few progressions were available to estimate the duration of MCyR. Compared with the 70-mg twice-daily arm, 100 mg/day was associated with a reduced incidence of cytopenia and pleural effusions.11,12 Severe AEs (grades 3/4) included superficial localized edema (0%-1%), congestive heart failure (0%-2%), pericardial effusion (1%), pleural effusion (2%-3%), diarrhea (1%-4%), hemorrhage (1%-2%), and gastrointestinal bleeding (0%-2%).12 The incidence of all AEs (including grades 3/4) was lower in the 100-mg/day arm compared with the 70-mg twice-daily arm. The reduced rate of pleural effusions in the 100-mg/day arm is particularly encouraging. Grade 3/4 cytopenias occurred in all arms, but were less frequent in the 100-mg/day arm compared with the 70mg twice-daily arm. The 100-mg/day arm was associated with fewer treatment interruptions and discontinuations compared with the 70mg twice-daily arm. The rate of discontinuation for adverse reaction was 4% versus 12% in patients in the 70-mg twice-daily arm.12 Conclusions Dasatinib has become a treatment

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option for patients with all phases of CML or Ph+ ALL who have failed on or are intolerant to imatinib. The newly recommended dose of 100 mg once daily in patients with CP CML offers im proved safety and compliance profiles— as evidenced by fewer treatment delays and discontinuations—while maintaining efficacy compared with the previous 70-mg twice-daily dose. The 70-mg twice-daily dose remains the recommended regimen for patients with advanced CML and Ph+ ALL. New clinical data demonstrate greater efficacy with dasatinib compared with high-dose imatinib in CP CML patients resistant to standard-dose imatinib. From a practicing pharmacist’s standpoint, although clinical trial designs employ logical dosing choices, it is inevitable that these original “calculated guesses” (using preclinical and early clinical data) on dosing will, on occasion, require further investigation. Less than optimal dosing probably exists for multiple agents in cancer care, and is more likely with drugs whose clinical availability was accelerated because of unmet medical need. Clinicians wish to have the best available treatments for their patients, but all parties, including the pharmaceutical manufacturers, must be vigilant in the management of these new agents. It is desirable for new published data to be rapidly incorporated into labeling approval, as seen with the recent package change on dasatinib. Rapidly informing clinicians about dosage changes ultimately benefits patients, not only in improved safety and tolerability, but also potentially for improved clinical efficacy. ● Acknowledgments Writing and editorial support was provided by Kerrie Allen-O’Rourke, Johnathan Maher, and Josh Collis and was funded by Bristol-Myers Squibb. References 1. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079-1082. 2. Nowell PC, Hungerford DA. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst. 1961; 27: 1013-1035. 3. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature. 1973;243:290-293. 4. Savona M, Talpaz M. Chronic myeloid leukemia: changing the treatment paradigms. Oncology (Williston Park). 2006;20:707-711. 5. Druker BJ, Guilhot F, O’Brien SG, et al; for the IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417. 6. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants. Cancer Res. 2005;65:4500-4505.

7. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207-3213. 8. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143-4150. 9. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309. 10. Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110:2309-2315. 11. Hochhaus A, Kim DW, Rousselot P, et al. Dasatinib dose and schedule optimization in chronic-phase CML resistant or intolerant to imatinib: results from a randomized Phase-III trial (CA180034). Haematologica. 2007;92 (suppl 2):128. Abstract 0359. 12. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009. 13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V.3.2008. www.nccn.org/ professionals/physician_gls/PDF/cml.pdf. Accessed March 4, 2008. 14. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer. 2004;100:2592-2597.

15. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908-916. 16. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2007. 17. Xu Z, Cang Z, Yang T, Liu D. Cardiotoxicity of tyrosine kinase inhibitors in chronic myelogenous leukemia therapy. Haematol Revs. 2009;1(1):e4. 18. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541. 19. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143-5150. 20. Kantarjian H, Talpaz M, O’Brien S, et al. Highdose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004; 103:2873-2878. 21. Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473-475. 22. Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood. 2003;102:2702-2703. 23. Zonder JA, Pemberton P, Brandt H, et al. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res. 2003;9:2092-2097.

COMING SOON! JOURNAL OF

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Breast Cancer SABCS The following articles are based on presentations at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, Texas, December 9-13, 2009.

Trastuzumab Best Given Along with Chemotherapy By Caroline Helwick

F

or women with human epidermal growth factor receptor type 2 (HER2)-positive early breast cancer, delaying trastuzumab until chemotherapy is completed may impair outcomes, according to findings from the landmark N9831 trial. The findings were presented by Edith Perez, MD, director of the Breast Cancer Program at the Mayo Clinic, Jacksonville, Florida. The addition of 52 weeks of trastuzumab, either after standard chemotherapy with doxorubicin/cyclophosphamide followed by paclitaxel (AC-T) or concurrently with the paclitaxel, reduced the risk of breast cancer recurrence by 33% overall, but the benefit was significantly greater when trastuzumab was given concurrently with the paclitaxel portion of the chemotherapy, an approach that can now be recommended, Perez said. “Often, the research community con-

ducts studies that conclude with ‘that was interesting, but let’s do more research,’” she noted. “This is an important finding on how we can help prevent breast cancer recurrence and improve

ized to chemotherapy alone or chemotherapy followed by trastuzumab. The proportion of women remaining diseasefree increased from 72% with chemotherapy alone to 80% with the addition

“Based on a positive risk–benefit ratio, we recommend that adjuvant trastuzumab be incorporated in a concurrent fashion with taxane chemotherapy.” —Edith Perez, MD survival…. This will clearly inform physician decision-making.” The N9831 trial, by the North Central Cooperative Trials Group, consisted of two comparisons. The first comparison included 2448 women random-

of trastuzumab. The second comparison, which included 1903 women who were analyzed according to whether they received trastuzumab after chemotherapy (sequentially) or along with chemotherapy (concurrently with paclitaxel), con-

tinued for 52 weeks. The sequential use of trastuzumab reduced recurrences by 33% over chemotherapy alone. At a median follow-up time of 5.3 years, 80% of women receiving 52 weeks of trastuzumab after chemotherapy were alive and disease-free, compared with 72% not receiving trastuzumab. But by giving trastuzumab concurrently with the paclitaxel portion of chemotherapy, the risk of recurrence was reduced by an additional 25%, compared with the sequential delivery of the drug. With concurrent trastuzumab, 84% of women were alive and disease-free compared with 80% of women treated sequentially, Perez reported. “Based on a positive risk–benefit ratio, we recommend that adjuvant trastuzumab be incorporated in a concurrent fashion with taxane chemotherapy,” she said. ●

To Protect Bone, Denosumab Outperforms Zoledronic Acid in Breast Cancer Patients

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or the prevention of skeletal-related events (SREs) in breast cancer patients with bone metastasis, denosumab proved superior to zoledronic acid (ZA) in a head-to-head randomized comparison conducted in 2048 women. “Denosumab prevented more events, was better tolerated, and, as a subcutaneous [SC] injection, was more convenient for patients in this randomized double-blind trial against what has been the standard of care for treating bone metastasis,” said Alison Stopeck, MD, of the University of Arizona Cancer Center, Tucson, who described the study at a press briefing. She told reporters that should denosumab become US Food and Drug Administration (FDA)-approved, she will incorporate the drug “quickly” into her care of patients with bone metastases, “because subcutaneous administration is easy, you don’t need to monitor creatinine, and it is less toxic, assuming the price is not exorbitant.” Denosumab works by inhibiting RANK ligand, which regulates osteoclast activity and function. It is not yet FDA-approved for use in metastatic breast cancer. Patients with bone metastases not pre-

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April 2010 I VOl 3, NO 2

viously treated with intravenous (IV) bisphosphonates were randomized to treatment with SC denosumab 120 mg every 4 weeks and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. Patients also received supplemental calcium and vitamin D. During the 34-month study, 36.5% of patients treated with ZA developed SREs compared with 30.7% receiving denosumab, for a 6% absolute reduction in risk and a 16% relative risk reduction, Stopek announced.

“We also assessed whether staying on denosumab was beneficial, since patients who have an SRE are at risk for a second one,” she said. Again, the benefit of denosumab was clear, as time to first-andsubsequent on-study SRE was reduced by 23%, over ZA. At 30 months, 608 events occurred with ZA compared with just 474 events with denosumab, a highly significant difference. “Another encouraging observation was that the curves continue to separate,” she added. “We expect the data to

“We expect the data to continue to strengthen as patients are on the drug longer.” —Alison Stopeck, MD The study’s primary end point, time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression), was significantly shorter with ZA, at a median of 26.5 months, whereas half the denosumab-treated group has not yet experienced an SRE (ie, the end point has not been reached), Stopek reported.

continue to strengthen as patients are on the drug longer.” Denosumab was also more protective against hypercalcemia of malignancy, and was superior in an analysis of skeletal morbidity rate. “Most importantly for patients,” she said, denosumab was associated with a delay in the onset of moderate-to-severe

pain, from 64 days with ZA to 88 days. “What makes bone metastases so brutal is the pain, and patients on denosumab took longer to develop moderate-tosevere pain,” she reported. Adverse events were similar, although ZA was associated with higher incidence of acute-phase reactions (27.3% vs 10.4%). There was more renal toxicity with ZA but more hypercalcemia with denosumab. The occurrence of osteonecrosis of the jaw (ONJ) was rare and was not significantly different between the groups, occurring in 14 patients (1.4%) with ZA and 20 (2.0%) with denosumab. Importantly, 80% of subjects developing ONJ had risk factors for the condition, including dental extraction, poor dental hygiene, or dental appliances. Theresa Guise, MD, professor of medicine and Jerry W. and Peg S. Throgmartin professor of oncology at Indiana University School of Medicine, commented as moderator of the press briefing: “This study is very important. It shows that by inhibiting bone resorption in different ways we can get improved effects on preventing SREs.” ● —CH

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Metastatic Colorectal Cancer: Sound Strategies for Selecting First-Line Therapies

LOG ON TODAY TO PARTICIPATE www.coexm.com/ace01.asp FACULTY

Release Date: November 25, 2009 Expiration Date: November 24, 2010

Neal P. Christiansen, MD Assistant Professor of Medicine Medical University of South Carolina Division of Hematology/Oncology Charleston, South Carolina

TARGET AUDIENCE This activity is intended for hematologists, oncologists, oncology nurses, oncology/specialty pharmacists, and others who are involved with the care of patients with metastatic colorectal cancer (mCRC).

STATEMENT OF NEED Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the United States. Approximately 149,000 new cases are diagnosed each year. At the time of presentation, about 20% of patients with CRC will have metastatic disease. Cure at this stage is rarely possible, although some patients whose metastases are limited (especially if to the liver or lung) may be “cured” by surgical means. For most sufferers of mCRC, however, treatment is palliative, offering prolonged survival, improvement in symptoms, and enhanced quality of life.

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • Evaluate and assess current findings in the management of mCRC • Identify current first-line therapies, both chemotherapeutic and biologic agents, and practices in mCRC • Tailor a therapeutic regimen to meet the needs of the individual patient with mCRC • Employ select strategies to minimize exposure to ineffective therapies and their toxicities

INSTRUCTIONS To receive a statement of credit, you must: • Review the content of the activity • Successfully complete the post-test (70% or higher) • Complete the evaluation at the end of the activity Your statement of credit will be issued immediately upon successful completion of the post-test and submission of the evaluation

ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of California, Irvine School of Medicine (UCI) and Center of Excellence Media, LLC. The University of California, Irvine School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT The University of California, Irvine School of Medicine designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity is complimentary.

FACULTY INFORMATION AND DISCLOSURES Dr Christiansen has received consultancy fees from sanofi-aventis and Genentech. Off-label use of cetuximab (in patients in whom irinotecan has not failed) and bevacizumab (continuing after first-line therapy) will be discussed in this presentation. Conflict resolution: This presentation has been peer reviewed for evidence base and fair balance.

GENERAL DISCLOSURE STATEMENT It is the policy of the University of California, Irvine School of Medicine and the University of California CME Consortium to ensure balance, independence, objectivity, and scientific rigor in all CME activities. Full disclosure of conflict resolution will be made in writing via handout materials or syllabus. Bonnie Carroll, Director, CME, UC Irvine School of Medicine, has no financial or other relationship to products or devices with commercial interests related to the content of this CME/CE activity. Center of Excellence Media, LLC: The planners and managers have nothing to disclose related to the content of this activity. Erica Johansson, RN, Astute CE, LLC, has nothing to disclose related to the content of this activity. Dr. Randall F. Holcombe, University of California, Irvine School of Medicine, peer-reviewed the content for evidence base and fair balance. Dr Holcombe has no real or apparent conflicts of interest related to this activity. Conflict resolution: This presentation has been peer reviewed for evidence base and fair balance. This activity is in compliance with California Assembly Bill 1195, which requires continuing medical education components to include curriculum in the subjects of cultural and linguistic competency. For specific information regarding Bill 1195 and definitions of cultural and linguistic competency, please visit the CME web site at http://www.cme.uci.edu. This activity is supported by an educational grant from Genentech BioOncology.

In collaboration with


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Hematologic Cancers ASH The following articles are based on reports at the 51st Annual Meeting and Exposition of the American Society of Hematology (ASH), held in New Orleans, December 5-9, 2009.

Strong Responses Seen with Bortezomib-based Therapy after Relapse in Multiple Myeloma By Caroline Helwick

F

or patients with relapsed or refrac- director of the program for multiple tory multiple myeloma (MM), myeloma and related diseases at bortezomib-based therapy is effec- Princess Margaret Hospital, Toronto. tive after lenalidomide plus dex amOutcomes were analyzed for 49 ethasone (LD), according patients who received LD for to a Canadian study that recurrent MM (first- to fourthevaluated sequencing of line), followed by bortezomibnovel agents. based regimens for their next “The optimal sequencrelapse, without any interim thering of novel agents in apy. Thirty- nine (80%) patients MM is not certain. Due had also undergone autologous to limitations in provinstem-cell transplantation. Patients cial drug funding in received bortezomib alone (33%), Ontario, Canada, we had bortezomib plus steroids (47%), a unique opportunity to Donna Reece, MD bortezomib plus prednisone and evaluate the efficacy of cyclophosphamide (8%), bortebortezomib in patients who progressed zomib plus thalidomide and dexafter treatment with lenalidomide plus amethasone (4%), or bortezomib plus dexamethasone, provided through ex- another agent (8%). panded access programs and clinical triThe median treatment duration of als for relapsed or refractory disease,” LD was 5.3 months. For that regimen, said principal investigator Donna response included near-complete reReece, MD, associate professor and sponse (nCR) in 6%, very good partial response (VGPR) in 6%, partial response (PR) in 51%, minimal re-

sponse (MR) in 12%, stable disease (SD) in 19%, and progressive disease (PD) in 25%. After relapse, when patients began a bortezomib-based treatment, median follow-up was 6.5 months and the best responses to those regimens included complete response or nCR in 2%, VGPR in 16%, PR in 26%, MR in 14%, SD in 16%, and PD in 24%. Median progression-free survival (PFS) was 4.0 months, with a 12% median 1-year PFS rate. Median overall survival (OS) was 9.5 months, with a 31% median 1-year survival rate. Investigators assessed a number of factors for their prognostic effects on PFS and OS, including age at diagnosis, gender, subtype, duration of initial therapy, and response to LD, but only the patient’s response to the bortezomibbased therapy was significant (P <.0001 for PFS and P = .002 for OS). “The PFS and OS observed after bortezomib-based therapy is not de-

pendent on the response to lenalidomide plus dexamethasone,” Reece said. Patients who achieved at least a PR to bortezomib had a median PFS of 7.3 months, compared with 2.0 months for patients with MR or less. One-year PFS was 29% versus 13%, respectively. Similarly, for OS, a response of PR or better was associated with a median OS of 14.3 months, versus 3.9 months for a lesser response, and 1-year OS was observed in 12% and 14%, respectively. “We concluded that treatment of sequential multiple myeloma relapses with bortezomib-based therapy after progression on LD produces partial responses or better in 44% of patients, results in a median PFS similar to the 6.2 months seen with bortezomib in less heavily pretreated patients in the APEX trial [Richardson PG, et al. N Engl J Med. 2005;352(24):2487-2498], and demonstrates the effectiveness of bortezomib even after exposure to the potent LD combination,” Reece said. ●

DRUG THERAPY

New Treatments for Chronic Idiopathic... Continued from page 6

patients, however, before widespread use is advocated, and reimbursement for this novel agent will be limited to FDAapproved indications. ● References 1. Cines DB, Blanchette V. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995-1008. 2. Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2005; 106:2244-2251. 3. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395-403. 4. Nplate (romiplostim) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2008. 5. Thompson CA. FDA approves thrombopoiesisstimulating agent. Am J Health Syst Pharm. 2008;65:1788. 6. Enrollment. How do I enroll in the Nplate NEXUS program? www.nplatenexus.com/enroll ment.html. Accessed October 11, 2008. 7. Medication guide. Nplate (romiplostim). www. nplatenexus.com/pdfs/misc/nplate_mg.pdf. Accessed October 11, 2008. 8. Levy B, Arnason JE, Bussel JB. The use of secondgeneration thrombopoietic agents for chemotherapy-induced thrombocytopenia. Curr Opin Oncol. 2008;20:690-696.

Part 2 of this article on eltrombopag will appear in the June issue.

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April 2010 I VOl 3, NO 2

Bendamustine-Rituximab Combo an Effective First-line Therapy for CLL By Wayne Kuznar

O

ne third of patients with newly diagnosed, advanced chronic lymphocytic leukemia (CLL) who received the combination of bendamustine and rituximab achieved a complete response, according to researchers from the German CLL Study Group. Another 56% of the patients treated with this combination had partial responses, said principal investigator Kirsten Fischer, MD, Center of Integrated Oncology, University of Cologne, Germany, at the annual meeting and exposition of the American Society of Hematology. Bendamustine had already been shown to have considerable activity as monotherapy in CLL and many other lymphoid cancers, as well as in combination with rituximab in patients with relapsed or refractory CLL. This new study examined bendamustine in combination with rituximab as

first-line therapy in 117 patients, 48% of whom had Binet stage C disease and 41% of whom had Binet stage B. Rituximab was given as four 6-week cycles with two doses of bendamustine in each cycle. Some 72% of patients in the study were treated with all six cycles of therapy. The median observation time was 15.4 months, and the overall response rate was 90.9%. A complete response was observed in 32.7% and a partial response in 55.5%. All other patients (9.1%) had stable disease, and none of the patients had progressive disease. With up to 26 months of follow-up, 75.8% of the patients were still in remission, and median progression-free survival has not been reached. Objective response rates of approximately 90% were achieved among the different genetic subgroups, except for del(17p), a high-risk subgroup in which the partial response rate was 42.9%.

Complete responses occurred most often in patients with unmutated immunoglobulin variable region heavy chain. The overall response rate in this group was 88.9%. Hematologic toxicities were grade 3/4 anemia in 4.9%, grade 3/4 leukopenia in 14.6%, grade 3/4 neutropenia and thrombocytopenia in 6.5% and 6.1% of all given courses, respectively. Twenty-nine episodes of common toxicity criteria grade ≥3 infections were documented (5.1% of all courses). There were two treatment-related deaths during the study: one fatal pneumonia and one case of sepsis related to neutropenia. Based on these encouraging data, the group is now conducting a phase 3 trial in which the efficacy of bendamustine/ rituximab is being compared with that of fludarabine-based immunochemotherapy in the first-line treatment of CLL, said Fischer. ●

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

Medications Used for the Treatment of Lymphomas The following sections include: • Associated ICD-9-CM codes used for the classification of lymphomas • Drugs that have been FDA-approved in the treatment of lymphomas. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in lymphomas. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication

generic (Brand) name

HCPCS code: code description

alemtuzumab (Campath) asparaginase (Elspar) bendamustine (Treanda) betamethasone (Celestone Soluspan)

J9010: injection, alemtuzumab, 10 mg J9020: injection, asparaginase, 10,000 units J9033: injection, bendamustine HCl, 1 mg J0702: injection, betamethasone acetate, 3 mg and betamethasone sodium phosphate, 3 mg

Associated ICD-9-CM Codes Used for Lymphomas The following fifth-digit subclassification is for use with categories 200-202: 0 unspecified site, extranodal and solid organ sites 1 lymph nodes of head, face, and neck 2 intrathoracic lymph nodes 3 intra-abdominal lymph nodes 4 lymph nodes of axilla and upper limb 5 lymph nodes of inguinal region and lower limb 6 intrapelvic lymph nodes 7 spleen 8 lymph nodes of multiple sites 200 Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue 200.0 Reticulosarcoma 200.1 Lymphosarcoma 200.2 Burkitt’s tumor or lymphoma 200.3 Marginal zone lymphoma 200.4 Mantle cell lymphoma 200.5 Primary central nervous system lymphoma 200.6 Anaplastic large cell lymphoma 200.7 Large cell lymphoma 200.8 Other named variants Lymphoma (malignant): lymphoplasmacytoid type mixed lymphocytic-histiocytic (diffuse) Lymphosarcoma, mixed cell type (diffuse) Reticulolymphosarcoma (diffuse) 202 Other malignant neoplasms of lymphoid and histiocytic tissue 202.0 Nodular lymphoma 202.1 Mycosis fungoides 202.2 Sézary’s disease 202.3 Malignant histiocytosis 202.4 Leukemic reticuloendotheliosis 202.5 Letterer-Siwe disease 202.6 Malignant mast cell tumors 202.7 Peripheral T-cell lymphoma 202.8 Other lymphomas Lymphoma (malignant): not otherwise specified diffuse Excludes: benign lymphoma (229.0) 202.9 Other and unspecified malignant neoplasms of lymphoid and histiocytic tissue Follicular dendritic cell sarcoma Interdigitating dendritic cell sarcoma Langerhans cell sarcoma Malignant neoplasm of bone marrow not otherwise specified

FDAapproved for lymphomas

NCCN Drugs & Biologics Compendium off-label use for lymphomas

Current code price (AWP-based pricing), effective 4/1/10

Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10

CPT administration codes

$680.73

$578.01

96413, 96415

$70.42

$60.94

96401, 96413

$21.60

$18.47

96413

$6.85

$6.55

11900, 11901, 20600, 20605, 20610, 96372

Continued on page 28

26

April 2010 I VOl 3, NO 2

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TOP_April2010_TON 4/12/10 10:37 AM Page 27

NHL Mantle Cell Trial Now Recruiting Investigators and Enrolling Study Participants Celgene CC-5013-MCL-001

A Phase 2 Study for Patients With Relapsed/Refractory Mantle Cell Non-Hodgkin’s Lymphoma Primary Investigator André Goy, MD Primary Objective To determine the tumor response and duration of response of lenalidomide monotherapy in subjects with mantle cell lymphoma (MCL) who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib Key Eligibility Criteria* • Individuals with MCL previously treated with all of the following (alone or in combination): – Bortezomib† – An anthracycline or mitoxantrone – Rituximab – Cyclophosphamide • Individuals must have documented relapse after bortezomib treatment or be refractory to bortezomib • Excluding individuals who are candidates for high-dose chemotherapy/allogeneic stem cell transplant *Additional criteria apply. †Note: When the agent bortezomib is mentioned this also includes ANY BORTEZOMIB-CONTAINING REGIMEN.

Study Design

Pretreatment Phase (4 Weeks)

N=133

• MCL diagnosis confirmed by local pathological review

Treatment Phasea (until disease progression)

• Lenalidomide starting dose 25 mg po once dailyb

Lenalidomide will be dosed po once daily on days 1-21 of each 28-day cycle. Subjects with creatinine clearance ≥30 mL/min but <60 mL/min will receive a lower starting dose of lenalidomide 10 mg po once daily. Dose may be escalated to 15 mg po once daily if no dose-limiting toxicities occur during the first 2 cycles.

a

b

Investigational use of lenalidomide. For more information contact Deborah Ingenito, Celgene Study Manager dingenito@celgene.com (908) 673-9581 www.clinicaltrials.gov (NCT00737529)

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


TOP_April2010_TON 4/12/10 10:37 AM Page 28

ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 26

generic (Brand) name

HCPCS code: code description

bexarotene (Targretin)

J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9040: injection, bleomycin sulfate, 15 units J9041: injection, bortezomib, 0.1 mg J9045: injection, carboplatin, 50 mg J9050: injection, carmustine, 100 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9060: cisplatin, powder or solution, per 10 mg J9062: cisplatin, 50 mg J9065: injection, cladribine, per 1 mg J8530: cyclophosphamide, oral, 25 mg

bleomycin (Blenoxane) bortezomib (Velcade) carboplatin (Paraplatin) carmustine (BiCNU) chlorambucil (Leukeran)

28

FDAapproved for lymphomas

NCCN Drugs & Biologics Compendium off-label use for lymphomas

Current code price (AWP-based pricing), effective 4/1/10

Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10

CPT administration codes

NDC level pricing $45.30

NDC level pricing $26.08

96401, 96409

$45.43

$38.24

96409

$48.55

$5.31

$205.69

$176.41

NDC level pricing $4.33

NDC level pricing $1.98

96409, 96413, 96415

$21.66

$9.91

96409, 96413, 96415

$58.20

$28.22

$2.09

$0.84

J9070: cyclophosphamide, 100 mg

$7.55

$4.35

96409, 96413, 96419

J9080: cyclophosphamide, 200 mg

$15.10

$8.69

96409, 96413, 96415

J9090: cyclophosphamide, 500 mg

$37.76

$21.73

96409, 96413, 96415

J9091: cyclophosphamide, 1.0 gram

$68.00

$43.46

96409, 96413, 96415

J9092: cyclophosphamide, 2.0 grams

$122.39

$86.92

96409, 96413, 96415

$2.31

$1.51

$22.21

$7.37

96409, 96413, 96415, 96450 96409, 96413

$25.20

$19.46

96409, 96413

$1,756.80

$1,494.82

96409, 96413, 96415

$0.15

$0.09

$0.09

$0.38

11900, 11901, 20600, 20605, 20610, 96372, 96374 N/A

$13.20

$3.04

96409

cisplatin (Platinol-AQ) cisplatin (Platinol-AQ) cladribine (Leustatin) cyclophosphamide, oral (Cytoxan) cyclophosphamide, injection (Cytoxan) cyclophosphamide, injection (Cytoxan) cyclophosphamide, injection (Cytoxan) cyclophosphamide, injection (Cytoxan) cyclophosphamide, injection (Cytoxan) cytarabine (Cytosar-U) dacarbazine (DTIC-Dome) daunorubicin (Cerubidine) denileukin diftitox (Ontak) dexamethasone (Decadron)

J9100: injection, cytarabine, 100 mg J9140: dacarbazine, 200 mg J9150: injection, daunorubicin, 10 mg J9160: injection, denileukin diftitox, 300 micrograms J1100: injection, dexamethasone sodium phosphate, 1 mg

dexamethasone (Decadron) doxorubicin HCl (Adriamycin)

J8540: dexamethasone, oral, 0.25 mg J9000: injection, doxorubicin hydrochloride, 10 mg

April 2010 I VOl 3, NO 2

✓ ✓ ✓

N/A

96409, 96413, 96415 96413, 96415 N/A

96413, 96415 N/A

www.TheOncologypharmacist.com


TOP_April2010_TON 4/12/10 10:37 AM Page 29

ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

generic (Brand) name

HCPCS code: code description

FDAapproved for lymphomas

doxorubicin liposome J9001: injection, doxorubicin (Doxil) hydrochloride, all lipid formulations, 10 mg etoposide J9181: injection, (Etopophos, Toposar) etoposide, 10 mg etoposide J8560: etoposide, (Vepesid) oral, 50 mg fludarabine J9185: injection, fludarabine phosphate phosphate, 50 mg (Fludara) gemcitabine J9201: injection, gemcitabine (Gemzar) hydrochloride, 200 mg hydrocortisone J1720: injection, hydrocortisone ✓ (Solu-Cortef) sodium succinate, up to 100 mg ✓ ibritumomab A9542: indium In-111 tiuxetan ibritumomab tiuxetan, diagnostic, (Zevalin) per study dose, up to 5 millicuries ibritumomab A9543: yttrium Y-90 ibritumomab ✓ tiuxetan tiuxetan, therapeutic, per (Zevalin) treatment dose, up to 40 millicuries ifosfamide J9208: injection, (Ifex) ifosfamide, 1 gram ✓ interferon J9214: injection, interferon, alfa-2b alfa-2b, recombinant, (Intron-A) 1 million units interferon gamma 1-b J9216: injection, interferon, (Actimmune) gamma 1-b, 3 million units isotretinoin J8499a: prescription drug, (Accutane) oral, non-chemotherapeutic, not otherwise specified lenalidomide J8999a: prescription drug, (Revlimid) oral, chemotherapeutic, not otherwise specified ✓ lomustine J8999a: prescription drug, (CeeNU) oral, chemotherapeutic, not otherwise specified ✓ lomustine S0178: lomustine, (CeeNu) oral, 10 mg mechlorethamine (Mustargen) melphalan (Alkeran) melphalan (Alkeran) mesna (Mesnex) mesna (Mesnex) methotrexate

J9230: injection, mechlorethamine hydrochloride (nitrogen mustard), 10 mg J8600: melphalan, oral, 2 mg J9245: injection, melphalan hydrochloride, 50 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9209: injection, mesna, 200 mg J8610: methotrexate, oral, 2.5 mg

NCCN Drugs & Biologics Compendium off-label use for lymphomas

Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10

CPT administration codes

$578.88

$472.01

$0.53

$0.49

$47.64

$28.26

N/A

$309.70

$205.81

96413

$173.83

$145.10

96413

$2.46

$3.14

96413

96413, 96415

$4,200.00

N/A

96365, 96366, 96372, 96374 96374

$37,800.00

N/A

79403

$56.40

$30.76

96413, 96415

$21.90

$15.84

96372, 96401

$517.89

$430.93

NDC level pricing NDC level pricing NDC level pricing $10.59

$178.71

96372

NDC level pricing NDC level pricing NDC level pricing S0178: not payable by Medicare $154.50

N/A

96409

N/A

N/A

N/A

N/A

$5.68

$4.83

$1,922.50

$1,500.32

NDC level pricing $10.44

NDC level pricing $4.26

96409

$3.61

$0.16

N/A

✓ ✓

Current code price (AWP-based pricing), effective 4/1/10

96409, 96413 N/A

Continued on page 30 www.TheOncologyPharmacist.com

APril 2010 I VOl 3, NO 2

29


TOP_April2010_TON 4/12/10 10:37 AM Page 30

ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 29

generic (Brand)

HCPCS code:

Continued from page 26

Current code price (AWP-based pricing), effective lymphomas

Medicare allowable (ASP + 6%), effective 4/1/10

CPT administration 4/1/10-6/30/10

methotrexate sodium

J9250: methotrexate sodium, 5 mg

$0.29

$0.21

96372, 96374, 96401, 96409, 96450

methotrexate sodium methoxsalen (Oxsoralen, 8-MOP, Oxsoralen Ultra) methylprednisolone (Depo-Medrol)

$2.86

$2.10

NDC level pricing $5.70

NDC level pricing $3.40

96372, 96374, 96401, 96409, 96450 N/A

$10.20

$6.64

11900, 11901, 20600, 20605, 20610, 96372

$2.36

$2.28

96365, 96366, 96372, 96374

$4.15

$3.06

96365, 96366, 96372, 96374

methylprednisolone (Medrol) mitoxantrone (Novantrone) nelarabine (Arranon) ofatumumab (Arzerra) ofatumumab (Arzerra):

J9260: methotrexate sodium, 50 mg J8499a: prescription drug, oral, non-chemotherapeutic, not otherwise specified J1030: injection, methylprednisolone acetate, 40 mg J1040: injection, methylprednisolone acetate, 80 mg J2920: injection, methylprednisolone sodium succinate, up to 40 mg J2930: injection, methylprednisolone sodium succinate, up to 125 mg J7509: methylprednisolone, oral, per 4 mg J9293: injection, mitoxantrone hydrochloride, per 5 mg J9261: injection, nelarabine, 50 mg C9260: injection, ofatumumab, 10 mg J9999a: not otherwise specified, antineoplastic drugs

$0.61

$0.08

$109.60

$45.27

96409, 96413

$123.19

$105.91

96413, 96415

$52.80

N/A

96413, 96415

J9263: injection, oxaliplatin, 0.5 mg J9268: injection, pentostatin, per 10 mg C9259: injection, pralatrexate, 1 mg J9999a: not otherwise classified, antineoplastic drugs

NDC level pricing $6.83

96413, 96415

oxaliplatin (Eloxatin) pentostatin (Nipent) pralatrexate (Folotyn) pralatrexate (Folotyn)

NDC level pricing $8.25

96413, 96415

$2,182.80

$1,246.38

96409, 96413

prednisolone (Millipred, Orapred, Veripred) prednisone

J7510: prednisolone, oral, per 5 mg

methylprednisolone (Depo-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Solu-Medrol)

✓ ✓

$187.50

11900, 11901, 20600, 20605, 20610, 96372

N/A

N/A

96409

NDC level pricing $0.02

96409

NDC level pricing $0.66

$0.05

$0.04

N/A

NDC level pricing $55.68

rituximab (Rituxan)

J9310: injection, rituximab, 100 mg

$664.32

NDC level pricing S0182: not payable by Medicare $578.40

N/A

procarbazine (Matulane)

J7506: prednisone, oral, per 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0182: procarbazine HCl, oral, 50 mg

procarbazine (Matulane)

30

name

FDAapproved for code description

NCCN Drugs & Biologics Compendium off-label use for lymphomas

April 2010 I VOl 3, NO 2

N/A

N/A

96413, 96415

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TOP_April2010_TON 4/12/10 10:37 AM Page 31

ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

generic (Brand) name

HCPCS code: code description

romidepsin (Istodax)

C9399a: unclassified drugs or biologicals (This code should only be used for new drugs and biologicals that are approved by the FDA on or after January 1, 2004) J9999a: not otherwise classified, antineoplastic drugs

romidepsin (Istodax) temozolomide, injection (Temodar) temozolomide, oral (Temodar) temsirolimus (Torisel) thalidomide (Thalomid) thiotepa (Thioplex) tositumomab (Bexxar) tretinoin (Vesanoid) vinBLAStine vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) vorinostat (Zolinza)

FDAapproved for lymphomas

J9328: injection, temozolomide, 1 mg (For billing prior to 1/1/10, use J9999 or C9253) J8700: temozolomide, oral, 5 mg J9330: injection, temsirolimus, 1 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9340: injection, thiotepa, 15 mg A9545: iodine I-131 tositumomab, therapeutic, per treatment dose J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9360: injection, vinblastine sulfate, 1 mg J9370: vincristine sulfate, 1 mg J9375: vincristine sulfate, 2 mg J9380: vincristine sulfate, 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified

NCCN Drugs & Biologics Compendium off-label use for lymphomas

Current code price (AWP-based pricing), effective 4/1/10 NDC level pricing

Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10

CPT administration codes

NDC level pricing

96413, 96415

NDC level pricing $4.90

96413, 96415

NDC level pricing $5.66

$10.65

$8.83

N/A

$58.72

$49.83

96413

NDC level pricing

N/A

NDC level pricing $138.00

$113.53 51720, 96409

$34,873.19

N/A

NDC level pricing $1.02

N/A

NDC level pricing $3.18

$8.12

$4.31

96409

$16.24

$8.62

96409

$40.60

$21.54

96409

NDC level pricing

NDC level pricing

N/A

96413, 96415

79403

96409

a

When billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J9999 for Folotyn) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement.

References • HCPCS Level II Expert 2010 • CPT 2010 • ICD-9-CM for Professionals Volumes 1 & 2; 2010 • The Drug Reimbursement Coding and Pricing Guide, Vol 7, No 2; RJ Health Systems International LLC; 2nd Quarter 2010 • FDA-approved indication (from products’ prescribing information) • NCCN Drugs & Biologics Compendium; 2010. National Comprehensive Cancer Network, Inc. Available at: www.nccn.org. Accessed February 15, 2010. To view the most recent and complete version of the NCCN compendium, go online to www.nccn.org • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 2nd Quarter 2010 (effective dates 4/1/10-6/30/10). Prices listed herein are effective as of April 1, 2010. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

This information was supplied by:

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

www.TheOncologyPharmacist.com

APril 2010 I VOl 3, NO 2

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TOP_April2010_TON 4/12/10 11:06 AM Page 32

Pharmacy Life

Compounding in the Kitchen By Jill Drury

F

rom an early point in my life, I have had two overriding passions: pharmacy and cooking. Pharmacy became my chosen career and intellectual outlet. Cooking is my hobby and ultimate stress reliever. Recently, I’ve been able to blend my two loves together. I am currently a full-time pharmacist at Rush University’s oncology/hematology clinic in Chicago. I also work parttime as a retail pharmacist for CVS Pharmacy. As a pharmacist, I regularly measure, compound, pour, and check a variety of drugs. In my positions, I am able to talk to and help people from all walks of life. The ability to help people with their medical needs is an immense

responsibility and continually provides me with honor and satisfaction in my job. But, I was still hungry for excitement, something outside my zone of comfort. Then, I realized that the professional skills I had honed as a pharmacist could be applied to my love of food—a delicious combination. My love of cooking started at an early age. I acquired my cooking gene from my mom and grandma, who are both great cooks. As the demands of school mounted, however, I found myself drifting away from the kitchen. Committed to getting my hobby back, I began collecting new cookbooks from my favorite chefs. I also updated my cooking utensils, buying as much that would fit in my kitchen and help me whip up tasty dish after tasty dish. I also dusted off family recipes from the “old” country. Then, I began to blend my two loves together. I persuaded my colleagues that we should apply the same skills we use behind the counter to the stovetops and ovens. I like to call our culinary method “compounding in the kitchen.” During the day, we measure, grind, and pour

chemicals for the benefit of our patients. We use those same skills to dazzle in the kitchen. The same patience and care necessary for pharmacy also are necessary for precision (and taste) in the kitchen. By applying the care we give to pharmaceutical compounding to any detailed recipe, we are able to ensure great dishes time and again. In addition, the checking and double-checking we devote to a final drug product can be used when cooking our favorite casserole or pastry. Cooking has become a natural outlet and extension of my job. What’s more, cooking brings my coworkers closer together and helps us create a better working environment. Making mistakes, sharing our successes, and tasting the results is rewarding for both us and our patients (who often get to sample our after-hour masterpieces). As much as I love my pharmacy career, I would like to take my cooking hobby to another level—catering to my patients in and out of the pharmacy. Ideally, I could take my dual skill set and embark on a career behind both the counter and the apron. ●

What You Need to Know About Your Credit Score By Eileen Koutnik-Fotopoulos

T

he current economic crisis is causing lenders and credit card issuers to err on the side of caution as more borrowers default on their loans and fall behind on credit card payments. The days when a good credit score was enough to qualify for the best mortgage, loan, and credit card rates are behind us. A few years ago, a credit score of 700 out of the maximum 850 ensured many people the most attractive mortgage and credit card rates. Now financial experts are telling potential borrowers they need a credit score of 720 or higher to qualify for the best rates. You have three credit scores: one each based on your credit reports from Equifax, Experian, and TransUnion. A good credit score is more than just paying your bills on time. Payment history only accounts for about one third of the formula that makes up your credit score. The credit-rating organization Fair Isaac Corporation breaks down a credit score into five variables: payment history, 35%; available credit used, 30%; length of credit history, 15%; types of credit used, 10%; new credit applications, 10%. Nationally recognized credit expert

32

April 2010 I VOl 3, NO 2

John Ulzheimer, president of consumer education for Credit.com, offers these tips on his website to help improve your score: • Keep credit card balances low. The percentage of available credit that a cardholder uses compromises about one third of a credit score. This variable is as important as paying bills on time. Keep your total balance at no more than 10% of your total credit limits. If you plan to submit a loan or credit application, pay off your credit cards completely and refrain from using them for 60 days before submitting the application. • Avoid too many applications for new credit. Applying for any type of credit can hurt your credit score. Almost 10% of your overall score is based on how many credit applications you have applied for in the past 12 months. If you do not have a good credit history, refrain from applying for credit cards you do not need. If you have a solid credit history, a couple of credit applications over the course of 1 year will not have a major impact on your score. Avoid filling out applications for anything that requires a credit

check until you have been approved for the loan you want. • Vary your credit. Nearly 10% of your total credit score is determined by your types of present and past credit. Lenders prefer borrowers with diversified credit including credit cards, retail cards, and student and auto loans. It is important to show you have had both major bank credit cards and installment debt, such as an auto loan. It does not matter if these accounts are active or have been paid off. Ulzheimer does not recommend you take out a loan or open a credit account to help your credit score. However, if you want to establish credit of a type that you have not previously used, such as an auto loan, you may want to consider a loan instead of paying cash. • Keep accounts open for a long time. Approximately 15% of your credit score is calculated by the age of your oldest accounts. The longer you have had the account the better. If you are just beginning to establish a credit history, ask a parent, spouse, or sibling to add you to their long-term credit account as an “authorized user.” ●

@Copyright iStockphotos.com/Larry Sherer

Jill’s Banana Pudding Ingredients 1 box vanilla wafers (reduced fat, optional) 7 bananas, sliced 2 cups milk (skim milk, optional) 1 (5-oz) box instant French vanilla pudding (sugar free, optional) 1 (8-oz) package cream cheese, softened (fat free, optional) 1 (14-oz) can sweetened condensed milk (fat free, optional) 1 (12-oz) container frozen whipped topping, thawed (fat free, optional)

Directions Line the bottom of a 13" ¥ 9" ¥ 2" dish with cookies, and layer bananas on top. In a bowl, combine the milk and pudding mix; blend well using a handheld electric mixer. Using another bowl, combine the cream cheese and condensed milk; mix until smooth. Fold the whipped topping into the cream cheese mixture. Add the cream cheese mixture to the pudding mixture and stir until well blended. Pour the mixture over the cookies and bananas; cover with the remaining cookies. Refrigerate until ready to serve.

How do you relieve stress after a busy day? Send your ideas and recipes to editorial@greenhillhc.com

©iStockphoto.com/Steven Aja

www.TheOncologypharmacist.com


TOP_April2010_TON 4/12/10 2:21 PM Page 33

International News

Reports from International Meetings and Researchers By Jill Stein

Zoledronic Acid Cuts Fracture Risk in Men with Advanced Prostate Cancer BARCELONA—Men with prostate cancer and malignant bone metastases who are treated with intravenous (IV) zoledronic acid are significantly less likely to sustain bone fractures than men not receiving an IV bisphosphonate, researchers announced at the 25th Anniversary European Association of Urology Congress. Henry Henk, PhD, with i3 Innovus in Eden Prairie, Minnesota, and colleagues presented data in 4976 men with prostate cancer and bone metastases. “Prostate cancer patients with malignant bone metastases frequently experience skeletal-related events, including pathologic fracture, spinal cord compression, and hypercalcemia of malignancy, which are associated with significant morbidity and mortality,” Henk said. Patients enrolled in the trial between January 1, 2001, and December 31, 2006, and remained in the study until they died or the study ended (December 31, 2007). Men treated with zoledronic acid developed fewer fractures (vertebral, nonvertebral hip, and nonvertebral nonhip) than men who did not. Overall, there were 5.9 fractures per 100 personyears in patients treated with zoledronic acid compared with 8.5 per 100 personyears in the placebo group (P = .0003). In addition, longer treatment with the bisphosphonate was associated with a lower fracture risk.

Disconnect Between Doctor and Patient Views on Breast Cancer Treatment Goals BARCELONA—Women with metastatic breast cancer and oncologists generally agree that overall survival is the most important end point when selecting a treatment, Canadian researchers announced at the 7th European Breast Cancer Conference. However, the groups disagree on how much improvement a treatment should provide before it should be included in the patient’s therapeutic strategy. Amir Sheik-Yousouf, MD, with the University of Toronto, and colleagues analyzed responses to surveys completed by 52 women with breast cancer and 28 oncologists. Their analysis revealed that over half of patients and oncologists alike considered overall survival to be the most important end point in “accepting” a therapy. Physicians, however, tended to consider much smaller improvements in overall survival as significant enough to adopt therapies. In fact, 48% of physicians thought that a minimum mean-

www.TheOncologyPharmacist.com

ingful incremental improvement in overall survival compared with first-line metastatic breast cancer therapy was 4 to 6 months, and 44% believed that 2 to 4 months was meaningful. Forty-six per-

cent of patients required a greater than 12-month improvement in overall survival to consider a treatment. Sheik-Yousouf said that although the findings are limited by the small number

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), patients who develop cytopenias. [See Adverse Reactions]. s The duration of cytopenias SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL caused by Rituxan can extend months beyond the treatment period. ADVERSE LEUKOENCEPHALOPATHY (PML) REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) Infusion Reactions: Rituxan administration can result in serious, including observed in clinical trials of patients with NHL were infusion reactions, fever, fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have lymphopenia, chills, infection, and asthenia. The most common adverse reactions of occurred. Approximately 80% of fatal infusion reactions occurred in Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion association with the first infusion. Carefully monitor patients during reactions and neutropenia. Clinical Trials Experience in Lymphoid Malignancies infusions. Discontinue Rituxan infusion and provide medical treatment for Because clinical trials are conducted under widely varying conditions, adverse reaction Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse rates observed in the clinical trials of a drug cannot be directly compared to rates in the Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring clinical trials of another drug and may not reflect the rates observed in practice. The data dialysis with instances of fatal outcome can occur in the setting of TLS described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan active-controlled trials (n = 356 and n = 1926). The population included 679 patients [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with Reactions: Severe, including fatal, mucocutaneous reactions can occur in CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as patients receiving Rituxan [see Warnings and Precautions, Adverse a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 Reactions]. s Progressive Multifocal Leukoencephalopathy (PML): JC virus doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 infection resulting in PML and death can occur in patients receiving Rituxan mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with [see Warnings and Precautions, Adverse Reactions]. s fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is Reactionss In the majority of patients with NHL, infusion reactions consisting of fever, indicated for the treatment of patients with: Relapsed or refractory, low-grade or chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after beginning the first infusion and resolved with slowing or interruption of the Rituxan first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. saline). The incidence of infusion reactions was highest during the first infusion (77%) Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in and decreased with each subsequent infusion. [See Boxed Warning, Warnings and combination with fludarabine and cyclophosphamide (FC), for the treatment of patients Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, with previously untreated and previously treated CD20-positive CLL. Limitations of use occurred in less than 5% of patients with NHL in the single-arm studies. The overall Rituxan is not recommended for use in patients with severe, active infections. incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan including fatal, infusion reactions. Severe reactions typically occurred during the first was administered following chemotherapy for the treatment of follicular or low-grade infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and NHL, the rate of infection was higher among patients who received Rituxan. In diffuse sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, large B-cell lymphoma patients, viral infections occurred more frequently in those who pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, received Rituxan. Cytopenias and hypogammaglobulinemiaa In patients with NHL ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in patients with an antihistamine and acetaminophen prior to dosing. Institute medical 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia reactions as needed. Depending on the severity of the infusion reaction and the required was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a A single occurrence of transient aplastic anemia (pure red cell aplasia) and two minimum 50% reduction in rate after symptoms have resolved. Closely monitor the occurrences of hemolytic anemia following Rituxan therapy occurred during the singlefollowing patients: those with pre-existing cardiac or pulmonary conditions, those who arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in experienced prior cardiopulmonary adverse reactions, and those with high numbers of 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure, occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses. with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden Table 1 confers a greater risk of TLS. Administer aggressive intravenous hydration and anti- Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Lowhyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b monitor renal function and fluid balance, and administer supportive care, including dialysis as All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous Any Adverse Events 99 57 Respiratory p y System y 38 4 reactions, some with fatal outcome, can occur in patients treated with Rituxan. These Bodyy as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid Chills 33 3 Bronchospasm 8 1 dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these Dyspnea 7 1 Infection 31 4 Asthenia 26 1 Sinusitis 6 0 reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan Headache 19 1 Metabolic and Nutritional in patients who experience a severe mucocutaneous reaction. The safety of Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 readministration of Rituxan to patients with severe mucocutaneous reactions has not Back Pain 10 1 Hyperglycemia 9 1 been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Throat Irritation 9 0 Peripheral Edema 8 0 5 0 LDH Increase 7 0 Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur HemeFlushing and Lymphatic y p System y 67 48 Digestive g System y 37 2 in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 The majority of patients with hematologic malignancies diagnosed with PML received Neutropenia 14 6 Vomiting 10 1 Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell Thrombocytopenia 12 2 Nervous System y 32 1 8 3 Dizziness 10 1 transplant. The patients with autoimmune diseases had prior or concurrent Skin Anemia and Appendages pp g 44 2 Anxiety 5 1 immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of Night Sweats 15 1 Musculoskeletal System y 26 3 Rash 15 1 Myalgia 10 1 their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting Arthralgia Pruritus 14 1 10 1 with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited Urticaria 8 1 Cardiovascular System y 25 3 Hypotension 10 1 to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan Hypertension 6 1 and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation by NCI-CTC criteria. with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was 6 months after Rituxan infusion. Previously Untreated Low-Grade NHLL In Study 4, approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory fungal, and new or reactivated viral infections can occur during and up to one year neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. following the completion of Rituxan-based therapy. New or reactivated viral infections 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical s the following adverse reactions, cardiac monitoring during and after all infusions of Rituxan for patients who develop Studies.] DLBCLL In Studies 6 and 7, [see Clinical Studies] clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed experience tumor lysis syndrome and in patients with NHL administered concomitant safety data collection in these studies was primarily limited to Grade 3 and 4 adverse cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7), institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLL The data below reflect Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 s The age range was Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies]. recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related

of participants, the data “highlight disparities between patients and oncologists in the relative ranking of defined therapeutic end points and in metastatic breast cancer treatment expectations.” ● adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicityy As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human antichimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic:: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/ Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary:: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. s Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertilityy No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy. Revised 02/2010 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010

APril 2010 I VOl 3, NO 2

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TOP_April2010_TON 4/12/10 2:21 PM Page Cov4

NOW IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

DRIVING BETTER OUTCOMES RITUXAN+FC improved median PFS in first-line and previously treated CLL1,2 In first-line CLL 1.7-year follow-up

39.8 months R-FC

vs

In relapsed/refractory* CLL 2.1-year follow-up

26.7 months

31.5 months

R-FC

FC

vs

21.7 months FC

8.3

5.0

month

month

improvement in median

improvement in median

PFS

PFS

CLL8 TRIAL (N=817)

REACH TRIAL (N=552) RITUXAN-NAIVE PATIENTS

In the CLL8 trial2 RITUXAN+FC more than doubled CR in first-line CLL compared with FC alone (36% vs 17%; p<0.0001)

In the REACH trial 2 Patients who responded to RITUXAN+FC (n=167) maintained their responses for nearly 2 years longer (48 months vs 27 months; p=0.0294) than those treated with FC alone (n=134)

Treatment considerations These trials were not designed or powered to detect a significant difference in PFS by age category. However, exploratory analyses defined by age suggest no observed benefit with the addition of RITUXAN to FC chemotherapy in previously untreated CLL patients 70 years of age or older and in previously treated CLL patients 65 years of age or older.1 *In the REACH trial, patients had received 1 prior therapy. Patients who had previously received RITUXAN or both fludarabine and cyclophosphamide, either sequentially or in combination, were excluded from the trial, as were fludarabine-refractory patients; alkylator-refractory patients were permitted.2 R=RITUXAN; FC=fludarabine and cyclophosphamide; PFS=progression-free survival; CR=complete response.

Indication RITUXAN® (Rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL. RITUXAN is not recommended for use in patients with severe, active infections.

BOXED WARNINGS and Additional Important Safety Information RITUXAN therapy can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia. In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment. For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc.

©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.

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February 2010

April 2010, Vol 3, No 2  

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