Journal of Hematology Oncology Pharmacy by The Oncology Pharmacist

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MARCH 2011

JOURNAL OF

VOL 1 I NO 1

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

FROM THE EDITORS Introducing the Journal of Hematology Oncology Pharmacy

Patrick J. Medina, PharmD, BCOP; Val R. Adams, PharmD, BCOP, FCCP PRACTICAL ISSUES IN PHARMACY MANAGEMENT Infrastructure Issues in the US Drug Supply: Where Did the Drugs Go?

Timothy G. Tyler, PharmD, FCSHP REVIEW ARTICLES Chemotherapy Administration Sequence: A Review of the Literature and Creation of a Sequencing Chart

Robert Mancini, PharmD; Jessie Modlin, PharmD From Chemotherapy to Targeted Therapies: Current Treatment of Carcinoid Tumors and Pancreatic Neuroendocrine Tumors

Steve Stricker, PharmD, MS, BCOP CASE REPORT Severe Acneiform Eruption following Trastuzumab Therapy

Sara S. Kim, BS, PharmD, BCOP; Kerin Adelson, MD DEPARTMENTS

From the Literature Clinical Practice

r ie m e e u Pr iss

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Nplate® (romiplostim) Brief Summary WARNINGS AND PRECAUTIONS Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis Nplate® administration increases the risk for development or progression of reticulin fiber deposition within the bone marrow. In clinical studies, Nplate® was discontinued in four of the 271 patients because of bone marrow reticulin deposition. Six additional patients had reticulin observed upon bone marrow biopsy. All 10 patients with bone marrow reticulin deposition had received Nplate® doses ≥ 5 mcg/kg and six received doses ≥ 10 mcg/kg. Progression to marrow fibrosis with cytopenias was not reported in the controlled clinical studies. In the extension study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate® therapy. Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias. Prior to initiation of Nplate®, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable Nplate® dose, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate® and consider a bone marrow biopsy, including staining for fibrosis [see Adverse Reactions (6.1)]. Worsened Thrombocytopenia After Cessation of Nplate® Discontinuation of Nplate® may result in thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia may increase the patient’s risk of bleeding, particularly if Nplate® is discontinued while the patient is on anticoagulants or antiplatelet agents. In clinical studies of patients with chronic ITP who had Nplate® discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate® therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Nplate®, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions (6.1)]. Thrombotic/Thromboembolic Complications Thrombotic/thromboembolic complications may result from excessive increases in platelet counts. Excessive doses of Nplate® or medication errors that result in excessive Nplate® doses may increase platelet counts to a level that produces thrombotic/ thromboembolic complications. In controlled clinical studies, the incidence of thrombotic/thromboembolic complications was similar between Nplate® and placebo. To minimize the risk for thrombotic/ thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines 9 to achieve and maintain a platelet count of ≥ 50 x 10 /L [see Dosage and Administration (2.1)]. Lack or Loss of Response to Nplate® Hyporesponsiveness or failure to maintain a platelet response with Nplate® should prompt a search for causative factors, including neutralizing antibodies to Nplate® or bone marrow fibrosis [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate® and thrombopoietin (TPO). Discontinue Nplate® if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg. Malignancies and Progression of Malignancies Nplate® stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. In controlled clinical studies among patients with chronic ITP, the incidence of hematologic malignancy was low and similar between Nplate® and placebo. In a separate single-arm clinical study of 44 patients with myelodysplastic syndrome (MDS), 11 patients were reported as having possible disease progression, among whom four patients had confirmation of acute myelogenous leukemia (AML) during follow-up. Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Laboratory Monitoring Monitor CBCs, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate® therapy. Prior to the initiation of Nplate®, examine the peripheral blood differential to establish the baseline extent of red and white blood cell abnormalities. Obtain CBCs, including platelet counts and peripheral blood smears, weekly during the dose adjustment phase of Nplate® therapy and then monthly following establishment of a stable Nplate® dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate® [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.2)]. Nplate® Distribution Program Nplate® is available only through a restricted distribution program called Nplate® NEXUS (Network of Experts Understanding and

Supporting Nplate® and Patients) Program. Under the Nplate® NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive Nplate®. This program provides educational materials and a mechanism for the proper use of Nplate®. To enroll in the Nplate® NEXUS Program, call 1-877-Nplate1 (1-877-675-2831). Prescribers and patients are required to understand the risks of Nplate® therapy. Prescribers are required to understand the information in the prescribing information and be able to: B Educate patients on the benefits and risks of treatment with Nplate®, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering Nplate®. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescriber’s direction. B Review the Nplate® NEXUS Program Healthcare Provider Enrollment Form, sign the form, and return the form according to Nplate® NEXUS Program instructions. B Review the Nplate® NEXUS Program Patient Enrollment Form, answer all questions, obtain the patient’s signature on the Nplate® NEXUS Program Patient Enrollment Form, place the original signed form in the patient’s medical record, send a copy according to Nplate® NEXUS Program instructions, and give a copy to the patient. B Report any serious adverse events associated with the use of Nplate® to the Nplate® NEXUS Program Call Center at 1-877-Nplate1 (1-877-675-2831) or to the FDA’s MedWatch Program at 1-800FDA-1088. B Report serious adverse events observed in patients receiving Nplate®, including events actively solicited at 6-month intervals. ADVERSE REACTIONS Clinical Studies Experience Serious adverse reactions associated with Nplate® in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation [see Warnings and Precautions (5.1, 5.2)]. The data described below reflect Nplate® exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Nplate® was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Nplate® over an extended period of time. Overall, Nplate® was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks. Because clinical studies 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 observed in practice. In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate® and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Nplate® versus placebo. The majority of these adverse drug reactions were mild to moderate in severity. Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies Preferred Term Nplate® Placebo (n = 84) (n = 41) Arthralgia 26% 20% Dizziness 17% 0% Insomnia 16% 7% Myalgia 14% 2% Pain in Extremity 13% 5% Abdominal Pain 11% 0% Shoulder Pain 8% 0% Dyspepsia 7% 0% Paresthesia 6% 0% Among 142 patients with chronic ITP who received Nplate® in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. Immunogenicity As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay. In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (17/225) and the incidence of binding antibody development during Nplate® treatment was 10% (23/225). The incidence of preexisting antibodies to endogenous TPO was 5% (12/225) and the incidence of binding antibody development to endogenous TPO during Nplate® treatment was 5% (12/225). Of the

patients with positive antibodies to romiplostim or to TPO, one (0.4%) patient had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS No formal drug interaction studies of Nplate® have been performed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Nplate® use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Nplate® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Pregnancy Registry: A pregnancy registry has been established to collect information about the effects of Nplate® use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Nplate® pregnancy registry by calling 1-877-Nplate1 (1-877-675-2831). In rat and rabbit developmental toxicity studies no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbit) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses. Nursing Mothers It is not known whether Nplate® is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nplate®, a decision should be made whether to discontinue nursing or to discontinue Nplate®, taking into account the importance of Nplate® to the mother and the known benefits of nursing. Pediatric Use The safety and effectiveness in pediatric patients (< 18 years) have not been established. Geriatric Use Of the 271 patients who received Nplate® in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment No clinical studies were conducted in patients with renal impairment. Use Nplate® with caution in this population. Hepatic Impairment No clinical studies were conducted in patients with hepatic impairment. Use Nplate® with caution in this population. OVERDOSAGE In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Nplate® and monitor platelet counts. Reinitiate treatment with Nplate® in accordance with dosing and administration recommendations [see Dosage and Administration (2.2)]. Rx Only. This brief summary is based on Nplate® prescribing information v. 1 Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,835,809 and 7,189,827, as well as other patents or patents pending. © 2008 Amgen Inc. All rights reserved. MC46933-A-1 www.Nplate.com <http://www.Nplate.com> 1-877-Nplate1 (1-877-675-2831) v1

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Live rep support. E-learning. Patient resources.

Visit www.NplateHCP.com/Bvisit

Outpacing platelet destruction. Sustained response over time. 1-3 Individual results will vary Nplate® is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Nplate® should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate® should not be used in an attempt to normalize platelet counts. IMPORTANT SAFETY INFORMATION ■ Serious adverse reactions associated with Nplate® in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate® discontinuation. Additional risks include Bone Marrow Fibrosis, Thrombotic/ Thromboembolic Complications, Lack or Loss of Response to Nplate®, Hematological Malignancies and Progression of Malignancy in Patients with a Pre-existing Hematological Malignancy or Myelodysplastic Syndrome (MDS). ■ Nplate® is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. ■ Monitor CBC’s, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate® therapy. ■ Nplate® is available only through a restricted distribution program called Nplate® NEXUS (Network of Experts Understanding and Supporting Nplate® and Patients) Program. ■ In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.

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EDITORIAL BOARD

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

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

SECTION EDITORS CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

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

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Desert Regional Medical Center Comprehensive Cancer Center Palm Springs, CA

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

ORIGINAL RESEARCH Gary C. Yee, PharmD, FCCP, BCOP Professor Dept of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, NE

EDITORS-AT-LARGE Sandra Cueller, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

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

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy, Touro University–California Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX Scott Soefje, PharmD, BCOP Director Pharmacy Operations University of Texas Health Science Center at San Antonio, TX

John M. Valgus, PharmD, BCOP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

Check out our user-friendly website Enhanced search capabilities • Full text & PDFs for all articles

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Journal of Hematology Oncology Pharmacy

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March 2011

Vol 1, No 1

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MARCH 2011

VOLUME 1, NUMBER 1

PUBLISHING STAFF Publisher

Philip Pawelko phil@greenhillhc.com Editorial Director

Dalia Buffery JHOP@greenhillhc.com Associate Editor

Dawn Lagrosa dawn@greenhillhc.com

TABLE OF CONTENTS

Director, Client Services

Joe Chanley joe@greenhillhc.com

FROM THE EDITORS

Introducing the Journal of Hematology Oncology Pharmacy Patrick J. Medina, PharmD, BCOP; Val R. Adams, PharmD, BCOP, FCCP

Stephanie Laudien Quality Control Director

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Production Manager

Infrastructure Issues in the US Drug Supply: Where Did the Drugs Go? Timothy G. Tyler, PharmD, FCSHP

Barbara Marino Business Manager

REVIEW ARTICLES

Blanche Marchitto blanche@greenhillhc.com

Executive Administrator

Chemotherapy Administration Sequence: A Review of the Literature and Creation of a Sequencing Chart Robert Mancini, PharmD; Jessie Modlin, PharmD From Chemotherapy to Targeted Therapies: Current Treatment of Carcinoid Tumors and Pancreatic Neuroendocrine Tumors Steve Stricker, PharmD, MS, BCOP

FROM THE LITERATURE

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

CASE REPORT

Severe Acneiform Eruption following Trastuzumab Therapy Sara S. Kim, BS, PharmD, BCOP; Kerin Adelson, MD

CLINICAL PRACTICE

New Compounds Hold Promise for Prostate Cancer

Oncology Pharmacists’ Perspective Brian G. Cochran, PharmD, BCOP; Christopher A. Fausel, PharmD, BCPS, BCOP

Andrea Boylston Circulation Department

circulation@greenhillhc.com Editorial Contact:

Telephone: 732-992-1891 Fax: 732-656-7938 E-mail: JHOP@greenhillhc.com

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

Journal of Hematology Oncology Pharmacy™, ISSN applied for (print); ISSN applied for (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2011 by Green Hill Healthcare Communications LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: JHOP@greenhillhc. com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

Journal of Hematology Oncology Pharmacy

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March 2011

Vol 1, No 1

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FROM THE EDITORS

Introducing the Journal of Hematology Oncology Pharmacy CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP1; Val R. Adams, PharmD, BCOP, FCCP2 1 Associate Professor, Dept of Pharmacy, University of Oklahoma College of Pharmacy, Oklahoma City; 2Associate Professor, Pharmacy, and Program Director, PGY2, Specialty Residency Hematology/Oncology, University of Kentucky College of Pharmacy, Lexington

The Journal of Hematology Oncology Pharmacy (JHOP) seeks to provide hematology and oncology pharmacy practitioners and other hematology oncology professionals with high-quality peerreviewed information to help them optimize drug therapy for patients. The journal will be split into four major sections. Patrick J. Medina Original Research will provide an outlet for translational and practice-based research, including case reports and case series. Our goal for this section is that these articles will answer the clinically relevant pharmacy questions that remain unaddressed. Many of which do not require a million-dollar extramural grant

Articles will answer the clinically relevant pharmacy questions that remain unaddressed. to answer, but that does not diminish the quality of the questions or the answers. Clinical Controversies will discuss common clinical issues for which the treatment is not clear. On a daily basis, clinicians face clinical situations where decisions are made by extrapolating data to fit their clinical situation. Depending on which data are used to extrapolate or the interpretation of the situation, different therapeutic approaches may be taken. This section will include “point, counterpoint,” “roundtable discussion,” and “how I treat explanations” articles to describe the available data and how they are extrapolated into a therapeutic decision. Review Articles will include manuscripts focusing not only on drugs and disease states but also on basic science reviews regarding the complex molecular biology of can-

Journal of Hematology Oncology Pharmacy

cer. Although there is a plethora of review articles available to clinicians, most do not have a pharmacy focus, and few if any focus on the molecular biology of cancer and the complex signaling pathways associated with malignancy. As new classes of drugs emerge (eg, BRAF inhibitors), discussion about the pathways and the drugs targeting Val R. Adams the pathways will help pharmacists understand the drug classes based on the pharmacology of these agents. Practical Issues in Pharmacy Management will focus on real-world issues involving logistics, economics, and other practice-influencing topics. The section arguably has the greatest potential to fulfill an unmet hematology oncology pharmacy need by providing manuscripts on practice-related issues (eg, USP <797>, standing orders for new medications, justifying more pharmacy clinicians). We are excited to publish the inaugural issue of JHOP. As pharmacy practice and research become integral both to improving the clinical care of cancer patients as well as to expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. We as the co-editors-in-chief hope that this journal will fill many unmet needs by providing another avenue for the publication of peer-reviewed, high-quality pharmacy literature that is focused for hematology oncology practitioners. We encourage you to submit manuscripts for consideration and to provide your feedback on what would enhance the value of this publication for you and your colleagues. Please send manuscripts and comments to JHOP@ greenhillhc.com. ■

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PRACTICAL ISSUES IN PHARMACY MANAGEMENT

Infrastructure Issues in the US Drug Supply: Where Did the Drugs Go? Timothy G. Tyler, PharmD, FCSHP, Section Editor

orth America is facing a shortage of certain drugs, and you do not have to be a pharmacist buyer tasked with procurement to realize our drug supply is under pressure. Governmental and professional groups—including the US Food and Drug Administration (FDA), American Society of Clinical Oncology (ASCO), Institute for Safe Medication Practices (ISMP), Association of Community Cancer Center, and American Pharmacists Association, among others—have been stating that this is a serious problem that may not be resolved anytime soon. Pharmacists and physicians are spending significant resources on managing the shortage instead of treating patients. “Whatever the cause, drug shortages have become a key patientsafety concern in health care today,” according to a report issued by the ISMP this past summer.1 Michael P. Link, MD, incoming ASCO president, has said, “We’ve heard a crescendo of complaints and concerns…it’s the worst shortage we’ve experienced in three decades. In terms of scope, it’s huge.”2 The drug supply infrastructure is weak or failing in several key areas, ranging from recalls of already manufactured items to shortages for supplier or manufacturing reasons to manufacturers exiting the marketplace due to lack of incentive. There are even suggestions that all reasons put forth to date do not fully account for what is happening. Regardless of the reason, sourcing drugs has become challenging in general, and acutely so with regard to parenterals used in a hematology/oncology practice. This article seeks to evaluate the known causes for the drug shortage and provide a clearer picture of the current state of the crisis.

Recalls Many drugs appear to be recalled as a preventive measure or on cautionary advice. There are also recalls for egregious reasons, such as misbranding, gross contamination, and adulteration. Those who remember the Tylenol scare of 1982 will probably be unable to find anything today that compares. At that time, the fear and apprehension generated by the recall were palpable; the Dr Tyler is Director of Pharmacy Services, Comprehensive Cancer Center Desert Regional Medical Center, Palm Springs, California.

Journal of Hematology Oncology Pharmacy

recall was on everyone’s mind, in daily conversations, and blanketed the nightly news. When Johnson & Johnson launched the recall, it affected as many as 21 million drug packages in circulation.3 North America had had few recalls of over-the-counter products or of any kind that received much attention. Johnson & Johnson’s reaction set the bar for the future. It spared no expense to protect the public from what turned out to be a small number of tainted products, which were intentionally adulterated and not the result of manufacturing error. Still, the scarcity of recalls made it seem grandiose.3 By contrast, recalls are commonplace today. In fact, in early 2011, Johnson & Johnson issued a large voluntary recall for a suite of Tylenol products for problems such as lax cleaning procedures and poor documentation. After further investigation, one product was found to have incorrect labeling.4 In 2008, a slightly different situation occurred when the sourcing of raw materials caused Baxter to recall its heparin, which was manufactured in China. In that case, the animal source (pig intestine) had been laced with oversulfated chondroitin, resulting in the manufacture of tainted heparin.5 Regardless of the reasons, if the final by-product harms patients or has great potential to harm patients, the recall system is designed to remove them, and the number of recalls is climbing. A cursory review of the FDA website and the drug tracking site managed by the University of Utah indicates that there were about 30 drug recalls in 2010.6 A recall is when a product is removed from the market or a correction is made to the product because it is defective or has the potential to cause untoward harm. The FDA is tasked with oversight of drug safety, as well as recalls. However, only some recalls stem from an FDA concern about the product. Others occur when a company discovers a problem on its own. Regardless of the cause, recalls should not be confused with a market withdrawal or a stock recovery.7 Although the current number of recalls is high, they account for only a small portion of the disruptions that clinicians and patients face. For example, of the approximately 3500 items published on a wholesaler (AmerisourceBergen) website as backordered from a top-three drug wholesaler, only 16 were unavailable because of an

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The US Drug Supply

Table 1 Top Reasons for Shortage Cited on Wholesalers’ Backorder Sheets Reason cited by manufacturer

Products on backorder, N

Backordered products (n = 3460), %

Product production problems Demand exceeds vendor supplies Market shortage item Vendor not currently producing Total

1757 657

50.8 19.0

334 222 2970

9.7 6.4 85.9

Source: Reference 8.

active recall.8 This equates to less than 0.5%. Still, at the time of publication, the number of items unavailable is large. That number, however, includes a few medical supplies and is not entirely (but mostly) comprised of medications.8 The recall of Procrit in late 2010 because of lamellae, glass flakes, or protein clusters in the glass vials had a dramatic impact on hospitals, clinics, and practices using that growth factor, and it affected a large number of patients. That recall led to a shortage of the medication, and that, in turn, strained the availability of Aranesp, the only other product approved for chemotherapyinduced anemia. When one agent is recalled, the ripple effects can impact the availability of other agents used as alternatives and replacements. In addition, stockpiling or hoarding mentality can take hold.

Shortages Backordered medications and shortages are becoming an almost daily occurrence in health-system pharmacies and physician offices. The scope is broad enough to be hitting all areas of patient care, but it is impacting the oncology marketplace at levels that are difficult to absorb, particularly with high-use medications, including emergency and pain medications, anesthetic agents, and oncologics.9 The FDA and the American Society of HealthSystem Pharmacists (ASHP) maintain lists of drugs in short supply or unavailable. At press time, the FDA was tracking 48 shortages10 and the ASHP listed 145 items that are either on shortage or backorder.6 The ASHP list can be characterized as a more comprehensive resource because the FDA lists only those shortages of medically necessary products that have a significant impact on public health and safety. By definition, a drug is considered medically necessary if it is used to treat/prevent a serious disease or condition, with no other source immediately available and no medically acceptable alternative. The increase of shortages, from a low of 58 in 2004 to a high of about 200 in 2010, has continued with an

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almost unbroken trajectory upward, according to a report by Erin Fox, PharmD, manager of drug information services for the University of Utah, at the Drug Shortages Summit in November 2010.11 Data from the FDA indicate that in 2010, injectables accounted for more than three-fourths of all shortages. In addition, two-fifths of all shortages were the direct result of quality issues, such as microbial contamination, impurities, or particulates.12 Regardless of the reasons (and they are many and multifactorial), the shortage situation is impacting patient care. According to drug wholesaler AmerisourceBergen, at the time of publication there remain 3460 items on backorder from the manufacturers. This information is provided by manufacturers to facilitate understanding regarding the nature of the problem. At present, more than 80% of the items fall into one of four categories (Table 1).8 Of the 15 categories used to explain why a drug is unavailable, 11 account for just more than 14%.8 Most drugs are unavailable because of production and demand issues,8 resulting in ongoing frustration among providers. And because there is no advance warning, crisis management in trying to source desperately needed agents perpetuates stress. Particularly acute in the oncologic arena is the knowledge that certain regimens can cure disease and withholding them in those settings could be a death sentence to patients. Recently, it was my unpleasant duty to explain to a patient with testicular cancer why no cancer center in the country would be able to provide bleomycin as part of his treatment regimen. Similar situations have occurred in the past year with mitomycin and doxorubicin. To label this as “distasteful” is a gross understatement. “We are clearly facing one of the worst drug shortages of the past 30 years, particularly of life-saving medications, including chemotherapy products,” said Mike Cunningham, PharmD, vice president and general manager, GPO & Information Services, McKesson Specialty Care Solutions (e-mail communication, January 17, 2011). “The current shortages are leading to shortages of

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alternative products, thus perpetuating the cycle. Through work with the Healthcare Distribution Management Association [HDMA], McKesson Specialty Care Solutions is actively engaged in a collaborative advocacy effort with other professional associations working closely with the FDA to discuss causes and trends of drug shortages, and explore possible strategies to manage and mitigate shortages.” The comments from the wholesaler community are echoed in the physician office practice setting. “The shortage of critical life-saving chemotherapy drugs during 2010, and continuing in 2011, is unprecedented and unacceptable. These shortages have created operational hardships for oncologists and other healthcare providers, but more importantly, have compromised appropriate levels and timing of critical patient treatments,” noted Roy Beveridge, MD, medical director, US Oncology, in a response to queries about how the crisis is impacting the largest oncology physician practice in North America (e-mail communication, January 17, 2011). “While we have collaborated with other professional colleagues, drug manufacturers, and professional organizations to obtain products, the routine supply of many agents is still in question, and sufficient supplies of several critical drugs cannot be assured. We believe that the FDA should engage in all efforts to assist US healthcare providers in their ability to provide curative treatments to cancer patients.”

Businesses have often discontinued older products that are not as profitable as newer ones. This challenge, however, is now coupled with a new one—the everincreasing complexity of modern-day drug manufacturing makes manufacture a more resource-intensive process than in the past. William Guss, PharmD, MBA, FCSHP, vice president of pharmacy services for Aptium Oncology, Inc, provided an even graver summary of the shortages (e-mail communication, January 14, 2011). “We have taken the drug supply chain for granted because it is so efficient, but that is changing. Aptium manages hospital-based cancer centers, and each has a pharmacy with a small staff dedicated to that site. Our pharmacists wear many hats, one of which is to manage purchasing and inventory. They keep inventory carrying cost low, while maintaining enough so that no patient is ever turned away, but their biggest value in being in the center is having the ability to focus

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on the clinical and safety aspects of treatment. However, recalls, shortages, backorders, and specialty distribution channels that require drop shipments for REMS [risk evaluation and mitigation strategies] multitudes of separate agents, and special programs like REMS are imposing greater time and administrative burdens on our staff. Just stocking more of everything as insurance is not the answer, nor even plausible. These issues raise cost and reduce efficiency, but of most concern, increase the potential risk to patients.” To address the shortage issues, professional societies (American Society of Anesthesiologists, ASCO, ASHP, and ISMP) joined with pharmaceutical manufacturers, wholesalers/distributors, and the regulatory community (including the FDA) and convened the Drug Shortages Summit.11 The summit’s summary report identifies common causes for the shortages, which include manufacturing difficulties, natural disasters, reductions in the supply of raw materials (80% of which derive from outside the United States), unanticipated surges in demand, increases in voluntary recalls, enforcement activity by the FDA, and artificial shortages due to stockpiling/hoarding and manufacturer business decisions.11 Businesses have often discontinued older products that are not as profitable as newer ones. This challenge, however, is now coupled with a new one—the ever-increasing complexity of modern-day drug manufacturing makes manufacture a more resource-intensive process than in the past. Older products with low profit margins take lower precedent in the production lineup. The free-market system ensures that, as their scarcity increases, the price clinicians are willing to pay also increases such that companies will shift resources back to the production of items that have increased profit margin. Today, drug manufacturers can no longer just move a few pieces of equipment and twirl a few valves for a quick production run. Manufacturing interruptions can lead to significant ripple effects, because each production line is often used for multiple drugs, and the drug runs are done in amounts that will just satisfy projected/forecasted needs. This means that the system has very minimal slack and, if problems arise or batches do not pass regulatory scrutiny, shortages are inevitable. In addition, in today’s high-tech manufacturing plants, production runs and their scheduling are coordinated with the care and scrutiny of a space launch. The lead time needed to make switches between products may be significant—time that is affecting patients’ access to medications. For their part, manufacturers want the freedom to make decisions that uphold their fiduciary responsibility to shareholders, but they also want to provide for their customers. Many manufac-

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Table 2 Drug Shortages of Medically Necessary Oncolytics Drug name

Manufacturer

Reason(s) for shortage

Bleomycin

APP Pharmaceuticals, Bedford Laboratories, Hospira, Teva Pharmaceutical Industries Bristol-Myers Squibb APP Pharmaceuticals, Bedford Laboratories, Teva Pharmaceutical Industries APP Pharmaceuticals, Hospira, Teva Pharmaceutical Industries APP Pharmaceuticals, Bedford Laboratories, Teva Pharmaceutical Industries APP Pharmaceuticals, Bedford Laboratories, Teva Pharmaceutical Industries APP Pharmaceuticals, Bedford Laboratories, Teva Pharmaceutical Industries Lundbeck Pharma Amphastar Pharmaceuticals, APP Pharmaceuticals, Baxter Healthcare

Manufacturing delays, increased demand

Carmustine Cisplatin Cytarabine Doxorubicin

Etoposide

Leucovorin

Mechlorethamine Morphine

Manufacturing delays Manufacturing delays, increased demand Manufacturing delays, raw material issues Manufacturing delays, increased demand

Manufacturing delays, increased demand

Manufacturing delays, time delay in startup

Transfer to new manufacturing plant Manufacturing delays, increased demand

Source: Reference 13.

turers are lobbying for the reduction, not the addition, of red tape. As stated earlier, the FDA tracks drugs that are in short supply and fall into what it deems medically necessary or urgent need. By mid-February 2011, the FDA was tracking just under 60 drug irregularities.13 Most of the drugs in short supply are injectables, including sedating agents such as propofol, heparin, and hard-hitting chemotherapy drugs (Table 2).13 The FDA approved only 21 new drugs in 2010—the fewest since 2007. The FDA has recently shown more of a willingness to delay or reject medicines with potential safety risks. There were 25 approvals in 2009 and 24 approvals in 2008, according to the FDA’s website.14 Only 19 new drugs were given the green light in 2007, the fewest approved in a single year for 24 years.15

Taking Action The FDA, an agency within the Department of Health and Human Services, is charged with protecting the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biologic products. In addition, it regulates medical devices, the US food supply, cosmetics, dietary supplements, and products that give off radiation.16 Some Americans are calling for more governmental control, including the power to dictate to companies

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what to produce and when. More bureaucracy, however, is hardly a prescription for success. A simpler solution may be for a manufacturer to send an early warning of its removal of a product from production or confidential notification of a production problem. This would help the FDA to fulfill its existing role of ensuring access to essential medications for patients. The FDA has, in this role, worked with industry to accelerate approvals and approve the extension of expiration dates where data can corroborate the validity of doing so. The FDA also has allowed drug importation outside of normal channels. One recent example was when it assisted California’s access to sodium thiopental for capital punishment.17 Ideally, this power would be used to facilitate pharmacists’ access to imported live-saving medications, not life-ending ones. The salient point is that, when needed, the FDA can streamline the bureaucratic red tape to respond to a crisis. Pharmacists are the ideal conduit to partner with the FDA in trying times like these. Pharmacists are the drug experts, and their profession is expected to handle drug shortages. This appears to be true outside of the United States as well. The Canadian Pharmacists Association (CPhA) released a report in December 2010 that surveyed their membership (in October 2010) about whether they were unable to fill any prescriptions during their most recent

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shifts.18 Of the 427 pharmacists who responded online, 81% had problems locating a drug during their most recent shift, and 93% could not find at least one drug in the previous week. Most (89%) pharmacists also said that drug shortages have greatly increased over the past 12 months, and 70% said the shortages were affecting their patients’ health, with 91% stating patients were inconvenienced.18

Of the 110 drug shortages existing in 2008, only 35% involved sterile injectables. In 2009, that proportion rose to 46% of 157 drug shortages. One positive thing to come out of the current drug crisis in Canada is reflected in a statement by CPhA Executive Director Jeff Poston, PhD. Dr Poston calls for governments to increase the scope of practice for pharmacists to better use their skills and training to help patients deal with a shortage when it arises.19 Valerie Jensen, RPh, Associate Director of the Center for Drug Evaluation and Research–Drug Shortage Program at the FDA, is quoted to have said that “fewer and fewer firms are making these [generics]. It’s a complex manufacturing process compared to oral drugs and other drugs. These are not products that are really profitable.”20 Although there is no single overarching reason for the shortages, the potential for customers clamoring for scarce agents and not being particularly price sensitive is sending a loud message to the generic pharmaceutical manufacturers. “[We] are taking steps to address the shortages and expect the situation will improve significantly over the coming weeks and months,” said Jim Keon, president of the Canadian Generic Pharmaceutical Association.21 The association listed shortages of active pharmaceutical ingredients, changes to regulations, production issues, and changes to processes and equipment as possible reasons for the shortages. There have been several shortages as a result of microbial contamination, such as in the Genzyme plant that produced Cerezyme and Fabrazyme. Despite being manufactured by three corporations, during the height of the shortage in the summer of 2010, propofol was only available from one corporation because of microbial contamination with one of the manufacturers and an exit from the marketplace by the other. Surgeries and procedures were being postponed or canceled, but the FDA was able to assist in the temporary importation of the drug from a European supplier.20 As reported by Jensen and Rappaport in August 2010,

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data demonstrate the rising acuity of the situation.22 Of the 110 drug shortages existing in 2008, only 35% involved sterile injectables. In 2009, that proportion rose to 46% of 157 drug shortages.22 Although many reasons have been discussed, these authors provide nuance. They suggest that even though generic formulations of many agents have been on the market for some time, only a limited number of companies can successfully produce them, because of the complex and long manufacturing lead times.22 In addition, because companies’ production lines often are used for several product lines, any interruption in manufacturing process can impact multiple drugs. Just-in-time manufacture also ups the risk for any sudden change in supply or demand causing significant consequences for patients and clinicians. Lack of available medically acceptable alternatives to drugs that are backordered or on shortage adds to the crisis. This problem can become compounded if the medically appropriate substitutes or alternatives are not reimbursed by insurance companies. Frustrations only grow when the efforts to source a product or alternative results in product procurement, but we are still unable to fully solve the problem due to financial constraints. In May 2009, the Hematology Oncology Pharmacy Association (HOPA) conducted a survey of its membership, and found that only four drug shortages were having significant impact on patient care.23 That number would assuredly be higher if it were repeated today. In fact, most HOPA members recommended that the association lobby the FDA for allowance of emergency importing of drugs to deal with unanticipated shortages.23 Resources

Drug Shortages Summit Summary Report American Society of Anesthesiologists, American Society of Clinical Oncology, American Society of Health-System Pharmacists, Institute for Safe Medication Practices www.ashp.org/drugshortages/summitreport Current Drug Shortage US Food and Drug Administration www.fda.gov/Drugs/DrugSafety/DrugShortages/ ucm050792.htm Drug Product Shortages Management Resource Center American Society of Health-System Pharmacists www.ashp.org/DrugShortages/Current/

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Changes to laws or regulations are now being evaluated. In February 2011, Senators Amy Klobuchar (DMinn) and Bob Casey (D-Penn) introduced legislation that would require drug manufacturers to notify the FDA when a drug shortage may occur because of certain incidents, such as manufacturing problems, trouble obtaining raw materials used to manufacture the product, or business decisions, including ceasing manufacture of a drug. The legislation would also require the FDA to provide up-to-date public notifications of a shortage, as well as the agency’s plans to address such a shortage.24 In the same vein, ASHP’s Bona Benjamin, director of Medication-Use Quality Improvement, posits the idea for a governmental incentive program similar to that incentivizing the adoptions of electronic health records or the inducements to develop orphan drugs.25

Conclusion Particulates, lamellae, source problems, toxic by-products, microbial contamination, failed quality checks, adulteration, manufacture scheduling problems, and falling profit margins—whatever it is, these interruptions in drug supply endanger the access of patients to medication in the United States and beyond. Whether you support the new healthcare law or not, there is clear and present danger to the drug supply in North America and, although no immediately obvious solutions are available, perhaps the one constant in all of this is the pharmacist. Will our pharmacy leaders stand up and take charge? Will we as a profession promote ourselves as the caring professionals that have been operating for some time under stressful and draining conditions, doing our utmost to ensure that patients get the best treatment we can provide? Because this crisis appears not to be waning but accelerating, we need to look at ourselves and become the pharmacists we were meant to be. ■ Disclosure Dr Tyler is on the Speakers’ Bureau of Bristol-Myers Squibb and Eisai Pharmaceuticals. References 1. Drug shortages: national survey reveals high level of frustration, low level of safety. ISMP Medication Safety Alert. 2010;15(19):1-4. www.ismp.org/Newsletters/acutecare/archives/Sep10.asp#23. 2. Phillips C. Continued shortage of chemotherapy drugs causing concern. NCI Cancer Bulletin. www.cancer.gov/ncicancerbulletin/011111/page2. Published January 11, 2011. Accessed February 3, 2011. 3. Campbell J, Allen A, McIntyre DA. The ten worst drug recalls in the history of the FDA. 24/7 Wall St. http://247wallst.com/2010/12/10/the-ten-worst-drug-recalls-in-thehistory-of-the-fda/. Published December 10, 2010. Accessed February 3, 2011.

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4. Berkrot B. J&J faults cleaning procedures in massive recalls. Reuters Newswire. www.reuters.com/article/2011/01/15/us-johnsonandjohnson-idUSTRE70D6RC 20110115. Published January 14, 2011. Accessed February 3, 2011. 5. US Food and Drug Administration. Recall of heparin sodium for injection. FDA Public Health Update. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInfo rmationforPatientsandProviders/ucm112665.htm. Published February 28, 2008. Accessed February 3, 2011. 6. American Society of Health-System Pharmacists. ASHP drug product shortages management resource center. www.ashp.org/DrugShortages/Current/. Accessed February 3, 2011. 7. US Food and Drug Administration. Recently posted recalls. FDA Recalls, Market Withdrawals, & Safety Alerts. www.fda.gov/Safety/Recalls/default.htm. Accessed February 3, 2011. 8. AmerisourceBergen. Manufacturer backorder information. January 11, 2011. 9. Salahi L. U.S. hospitals facing largest drug shortage in decades. MedPage Today. www.medpagetoday.com/PublicHealthPolicy/GeneralProfessionalIssues/24073. Published December 27, 2010. Accessed February 3, 2011. 10. US Food and Drug Administration. 2010 recalls, market withdrawals & safety alerts. www.fda.gov/Safety/Recalls/ArchiveRecalls/2010/default.htm. Published January 12, 2011. Accessed February 3, 2011. 11. American Society of Health-System Pharmacists. Drug Shortages Summit summary report. American Society of Anesthesiologists, American Society of Clinical Oncology, American Society of Health-System Pharmacists, Institute for Safe Medication Practices. www.ashp.org/drugshortages/summitreport. Published January 10, 2011. Accessed February 3, 2011. 12. Shaw G. Drug shortage puts cancer centers in crisis. Clinical Oncology News. www.clinicaloncology.com/ViewArticle.aspx?d=Solid%2bTumors&d_id=148&i= January%2b2011&i_id=698&a_id=16512. Published January 2011. Accessed February 3, 2011. 13. US Food and Drug Administration. Current drug shortages. www.fda.gov/ Drugs/DrugSafety/DrugShortages/ucm050792.htm. Published January 12, 2011. Accessed February 3, 2011. 14. US Food and Drug Administration. NME drug and new biologic approvals. 2008/2009. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/DrugandBiologicApprovalReports/NMEDrugandNewBio logicApprovals/default.htm. Accessed February 3, 2011. 15. Darcé K. 2010 drug approval extends frustrating trend for biotech companies. San Diego Union-Tribune. www.signonsandiego.com/news/2011/jan/11/2010-drugapproval-extends-frustrating-trend-biote/. Published January 11, 2011. Accessed February 11, 2011. 16. US Food and Drug Administration. FDA fundamentals. www.fda.gov/ AboutFDA/Transparency/Basics/ucm192695.htm. Published August 16, 2010. Accessed February 3, 2011. 17. Associated Press. FDA helps Ariz., Calif. get execution drug. Bloomberg Businessweek. www.businessweek.com/ap/financialnews/D9KM2L402.htm. Published January 11, 2011. Accessed February 3, 2011. 18. Canadian Pharmacists Association. Canadian Drug Shortages Survey: Final Report. December 2010. www.pharmacists.ca/content/About_CPHA/Whats_ Happening/CPhA_in_the_News/CPhADrugShortagesReport_Dec2010.pdf. Accessed February 3, 2011. 19. Canadian Pharmacists Association survey reveals drug shortages a serious concern [press release]. www.pharmacists.ca/content/about_cpha/whats_happening/ news_releases/release_detail.cfm?release_id=193. Published December 15, 2010. Accessed February 3, 2011. 20. Eggertson L. Continuing drug shortages affect North American patients. CMAJ. 2010;182:E811-E812. http://www.cmaj.ca/cgi/content/full/182/18/E811. Accessed December 15, 2010. 21. Statement from the Canadian Generic Pharmaceutical Association (CGPA) regarding shortages of prescription medicines [press release]. www.canadiangenerics.ca/ en/news/aug_17_10.asp. Published August 17, 2010. Accessed February 3, 2011. 22. Jensen V, Rappaport BA. The reality of drug shortages—the case of the injectable agent propofol. N Engl J Med. 2010;363:806-807. 23. Griffith N. HOPA Drug Shortage Survey, May 2009—results. Hematology/ Oncology Pharmacy Association Newsletter. Fall 2009:4-5. www.hoparx.org/docu ments/Fall2009Newsletter.pdf. Accessed February 3, 2011. 24. Klobuchar, Casey introduce bill to address unprecedented prescription drug shortages [press release]. http://klobuchar.senate.gov/newsreleases_detail.cfm?id =330941&. Published February 7, 2011. Accessed February 9, 2011. 25. Alazraki M. Drug shortages: a deadly problem with no cure in sight. Daily Finance. www.dailyfinance.com/story/drug-shortages-a-deadly-problem-with-nocure-in-sight/19783927/. Published January 11, 2011. Accessed February 15, 2011.

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Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Associate Professor of Hematology and Oncology Emory University School of Medicine

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University

Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health

Topics include: â&#x20AC;˘ Hodgkinâ&#x20AC;&#x2122;s Disease â&#x20AC;˘ Follicular Lymphoma â&#x20AC;˘ Mantle Cell Lymphoma â&#x20AC;˘ Waldenstromâ&#x20AC;&#x2122;s Macroglobulinemia â&#x20AC;˘ Diffuse Large B-Cell Lymphoma â&#x20AC;˘ T-Cell Lymphoma

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

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

Target Audience These activities were developed for physicians, nurses, and pharmacists.

Accreditation This activity has been approved for 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided. For complete learning objectives and accreditation information, please refer to each activity. This activity is jointly sponsored by Global Education Group and Medical Learning Institute, Inc. Coordination for this activity provided by Center of Excellence Media, LLC.

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or inquire@globaleducationgroup.com. COEAsize3211MM

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REVIEW ARTICLE

Chemotherapy Administration Sequence: A Review of the Literature and Creation of a Sequencing Chart Robert Mancini, PharmD; Jessie Modlin, PharmD

J Hematol Oncol Pharm. 2011;1(1):17-25.

Background: Oncology pharmacists receive numerous questions regarding the sequence of chemotherapy administration. Several chemotherapy agents (eg, doxorubicin, docetaxel, paclitaxel, etc) are extensively metabolized through the cytochrome P450 pathway, and many chemotherapy agents (eg, taxanes, platinum agents) have high degrees of protein binding. In addition, many chemotherapy agents have cell cycle–specific mechanisms of action that may increase the cytotoxicity or antagonize the mechanism of the second agent. We conducted a literature search for data supporting same-day chemotherapy administration sequences. This was achieved by searching PubMed using keyword searches, including any combination of the drug name with “administration,” “sequencing,” or “interactions.” Results: The literature search yielded 110 articles for evaluation. The original 110 articles provided evidence for 62 potential chemotherapy combination sequences. Based on the types of studies examined, 27 potential sequences remained clinically undefined because of a lack of clinical relevance of the studies that supported them, 21 combinations were justified with a particular sequence, and 14 combinations had evidence that sequence was irrelevant to outcomes. From these data, a chemotherapy administration sequence chart was created as a reference for nurses and pharmacists. Conclusion: From this literature search, we produced a chemotherapy sequencing chart that helps define recommended sequences of administration based on available published data. The sequence, if not clearly defined in the literature, should follow the sequence of administration published in that regimen’s original study.

n an effort to improve response rates to chemotherapy, agents often are combined to give a so-called twoprong attack against tumor cells. This is the basis for combining chemotherapy agents with different mechanisms of action. However, chemotherapy agents are subject to the rules of pharmacokinetics and thus have the potential for drug interactions. A common misconception is that because the agents have been tested as part of a chemotherapy regimen, they are safe and effective. The problem is that many phase 1 and 2 studies of a particular regimen do not give specifics about the order in which these agents were administered. Several chemotherapy agents (eg, doxorubicin, docetaxel, paclitaxel, and others) are extensively metabolized through the cytochrome P450 pathway, and many chemotherapy agents (eg, taxanes and platinum agents) have high degrees of protein binding. In addition, many chemotherapy agents have cell cycle–specific mecha-

Dr Mancini and Dr Modlin are oncology pharmacists, St. Luke’s Mountain States Tumor Institute, Boise, Idaho.

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nisms of action that may increase the cytotoxicity or antagonize the mechanism of the second agent.1 In some situations, the order of administration may dictate whether a particular effect or side effect is encountered based on the principles of pharmacokinetics and pharmacodynamics. Perhaps the most well known is the interaction between cisplatin and paclitaxel.2 When cisplatin precedes paclitaxel, profound and prolonged neutropenia may occur. This can delay the patient from receiving chemotherapy as prescribed. When the sequence is reversed (ie, paclitaxel before cisplatin), this detrimental side effect is diminished without negating efficacy.2 These concerns present real situations and lead to drug information questions that are often asked in a chemotherapy infusion center. Although there are extensive published data for some agents, like the taxanes, about drug interactions and sequencing, the data often can be hard to find, especially for less common or newer agents.1-5 In addition, drug information resources extrapolate published data from single agents to all agents in the same class, recommending a sequence that

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REVIEW ARTICLE

may not be proved clinically. An example is extrapolating the data on cisplatin and paclitaxel to imply the same interaction holds true between oxaliplatin and paclitaxel or carboplatin and docetaxel. We conducted a thorough review of the literature to examine the data that have been published supporting same-day chemotherapy administration sequences. From these data, we created a chemotherapy administration sequence chart to aid nurses and pharmacists in identifying whether there is a preferred sequence to be used only for agents given on the same day. We then superimposed this chart on a chemotherapy compatibility chart to make a new tool for use in our infusion centers.

were selected because those types of studies could not be extrapolated to in vivo results in humans. Studies were also excluded for final evaluation if the agents were not administered on the same day. This exclusion criterion was defined to apply these sequences to how chemotherapy is administered for same-day treatments at an infusion center. If there were conflicting data on a sequence after all studies were evaluated as clinically relevant, recommendations were made to err on the side of safety. In other words, if one study suggested a particular sequence was more toxic and a second study suggested there was no difference, we recommended the sequence that was less toxic rather than stating there was no difference.

Methods First, a list of all intravenous chemotherapy and monoclonal antibodies commonly used in combination regimens was created. Then, Micromedex Solutions’ IV Index with Trissle’s compatibility tool was used to assess whether medications were physically compatible via Ysite coinfusion. In addition, base solution compatibilities (lactated Ringers, normal saline, and dextrose 5% in water) for individual chemotherapy agents was evaluated. These steps were performed because they were easy to incorporate into the finalized chart, and it helped to combine existing compatibility charts with the sequencing chart into a single tool.

Results The literature search, conducted in October 2009, yielded 110 articles for evaluation. Of those studies, 29 were excluded for testing in vitro sequence only; 11 were excluded as they included only mice; nine were excluded because they did not compare results with the reverse sequence; and four were excluded for other reasons. (Three had trends toward pharmacokinetic changes but did not assess the clinical relevance of these changes, and one used oral agents.) Fifty-seven evaluable articles remained, 44 of which were clinical trials and 13 were literature reviews, typically for a single class of agents. The original 110 articles provided evidence for 62 potential chemotherapy combination sequences. Based on the types of studies examined, 27 potential sequences remained clinically undefined because of a lack of clinical relevance of the supporting studies (Table 1). This left 21 combinations with studies that justified a particular sequence (Table 2, page 22), and 14 combinations that provided evidence that sequence was irrelevant to outcomes (Table 3, page 23). The combinations with defined sequences or where literature supported no difference in outcomes or toxicity were superimposed onto a compatibility chart for use by our infusion centers (Figure, pages 20-21).

The combinations with defined sequences or where literature supported no difference in outcomes or toxicity were superimposed onto a compatibility chart for use by our infusion centers. For the sequencing chart, the administration sequence of the original studies on published regimens was evaluated. Any chemotherapy agent that is not traditionally given on the same day as another agent was excluded from the chart. Lexi-Comp and Micromedex were evaluated, as standards for drug information resources, for recommended sequence specifics in the administration and drug interaction sections. Finally, a thorough PubMed search was conducted using keyword searches including any combination of the drug name with “administration,” “sequencing,” or “interactions.” After the literature base had been established, studies were evaluated to determine whether they were clinically applicable. Studies were included if they were conducted in humans and evaluated both the forward and reverse sequence of administration. Review articles were also considered if they provided human clinical trial data. All other studies were excluded. These exclusion criteria

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Discussion The goal of this literature search was to create a user-friendly reference chart for pharmacists and nurses who work in outpatient infusion centers and on inpatient oncology floors. We have found that the chart we made has helped quickly define published literature for same-day administration. It must be stated, however, that this chart cannot be used for determining sequences of chemotherapy agents given over several days because that was not the original intent of the literature search. The literature search revealed that recommendations provided in commonly used drug information resources

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Chemotherapy Administration Sequence

Table 1 Suggested Chemotherapy Sequences that Lack Clinical Support Suggested sequence Suggested reason First agent Second agent 5-Fluorouracil Cisplatin Maximum synergistic activity; less toxicity 5-Fluorouracil Carboplatin Less overall toxicity Bleomycin Paclitaxel Synergistic effect Dacarbazine Gemcitabine Less accumulation of dacarbazine toxic metabolites Docetaxel 5-Fluorouracil Antagonistic in reverse sequence Docetaxel Oxaliplatin Lessens neutropenia

Etoposide Etoposide

Mitomycin Vincristine

Fludarabine

Cytarabine

Gemcitabine

Doxorubicin

Gemcitabine

Epirubicin

Gemcitabine

Fluorouracil

Gemcitabine

Docetaxel

Gemcitabine

Irinotecan

Gemcitabine

Oxaliplatin

Ifosfamide Irinotecan

Paclitaxel Bevacizumab

Irinotecan

Docetaxel

Oxaliplatin

5-Fluorouracil

Paclitaxel

Oxaliplatin

Paclitaxel Paclitaxel

5-Fluorouracil Irinotecan

Pemetrexed Pemetrexed Pralatrexate Topotecan Vinorelbine

Docetaxel Paclitaxel Gemcitabine Etoposide Gemcitabine

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Reason for exclusion In vitro only6-8; murine only9-12 In vitro and murine only13 In vitro14 Trend toward pharmacoknetic changes; no clinical relevance evaluated15 Murine only1 No literature found, reference in Lexi-Comp extrapolated from other taxane/platinum combinations

Antagonistic in reverse sequence Synergistic interaction, but not related to sequence Increases accumulation and augments metabolism of Ara-C in chronic lymphocytic leukemia cells leading to better efficacy Synergistic effect (antagonistic in opposite) Synergistic effect (antagonistic in opposite)

In vitro only16 Murine17

Gemcitabine increases fluorouracil area under the curve twofold when fluorouracil given first Synergistic effect (antagonistic in opposite) No sequence-related synergy, toxicity, or pharmacokinetic interactions in this sequence

Only studied one sequence, not reverse20

No pharmacokinetic interaction when given 24 hours apart Prevents profound cytopenias Bevacizumab does not affect irinotecan pharmacokinetics in this sequence Significant myelosuppression with this combination, but not related to sequence Synergistic effect (antagonistic in opposite) Lessens neutropenia; prevents decrease in oxaliplatin clearance Antagonistic in reverse sequence Less kinetic interactions; less hepatotoxicity Synergistic effect Synergistic effect Better therapeutic activity Synergistic effect Antagonistic in reverse sequence

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Primary analysis was in vitro; secondary analysis separated administration by >24 hours18 In vitro only19 In vitro only19

Only studied one sequence, not reverse21,22; no effect seen, small trial23 Single sequence6

Not same day (24-hour separation)24 Only studied one sequence, not reverse25 Single sequence26 Single sequence27

In vitro28 Murine only29; only studied one sequence, not reverse30 In vitro only1,31 Trend toward pharmacokinetic changes, no clinical relevance evaluated32; sequence had no effect33 In vitro only34 In vitro only35 In vitro and murine36 In vitro only37; oral etoposide used38 Single sequence39; pharmacokinetic only, no clinical relevance40 Journal of Hematology Oncology Pharmacy

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Figure Chemotherapy Sequencing Chart

Leucovorin

Ixabepilone

G1, C2 PD/T

C1, I2 PD

F1,C2 PD

ND Dox 1 T

Dox 1 T

LD1-D2 T

I1, D2 T

ND ND

LD1-D2 T

F1,C2 PD ND

I1, F2 PD/T

G1, C2 PD/T

I1, D2 T

C1, I2 PD

L1 P

I1, F2 PD/T

L1, F2 PD

* F1, M2 PD

M1, P

ND P1. C2 C1, P2 T T

D1, P2 PK/T

E1, P2 PK/T

P1. G2 PD/T

P1, G2 PD/T

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Leucovorin

Ixabepilone

Irinotecan

Ifosfamide

Idarubicin

Gemcitabine

Fluorouracil (5-FU)

Fludarabine

Etoposide

LD1-V2 T

Epirubicin

D1, V2 PK/T

Doxorubicin (Liposomal)

Doxorubicin

D1, T2 PK/T

Docetaxel

Daunorubicin

Dactinomycin

Cisplatin

Cetuximab

Carmustine

Carboplatin

Bleomycin

Bevacizumab

Bendamustine

Dacarbazine

T1, C2 T

Cytarabine

T1, C2 T

Second Chemotherapy Agent

Irinotecan

Ifosfamide

Idarubicin

Gemcitabine

Fluorouracil (5-FU)

Fludarabine

Etoposide

Epirubicin

Doxorubicin (Liposomal)

Doxorubicin

Docetaxel

Daunorubicin

Dactinomycin

Dacarbazine

Cytarabine

*Follow published guidelines SAME DRUG LINE THERAPEUTIC DUPLICATION Y-SITE COMPATIBLE Y-SITE INCOMPATIBLE NOT TESTED

Cyclophosphamide

Cisplatin

Cetuximab

Carmustine

Carboplatin

Bleomycin

Bevacizumab

Bendamustine Bevacizumab Bleomycin Carboplatin Carmustine Cetuximab Cisplatin Cyclophosphamide Cytarabine Dacarbazine Dactinomycin Daunorubicin Docetaxel Doxorubicin Doxorubicin (Liposomal) Epirubicin Etoposide Fludarabine Fluorouracil (5-FU) Gemcitabine Idarubicin Ifosfamide Irinotecan Ixabepilone Leucovorin Mechlorethamine Melphalan Mesna Methotrexate Mitomycin Mitoxantrone Oxaliplatin Paclitaxel Paclitaxel (Abraxane) Panitumumab Pemetrexed Pentostatin Rituximab Streptozocin Temsirolimus Topotecan Trastuzumab Vinblastine Vincristine Vinorelbine

Cyclophosphamide

First Chemotherapy Agent

Bendamustine

Second Chemotherapy Agent

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Chemotherapy Administration Sequence

D1, P2 PK/T

F1, M2 PD

Lactated Ringers

Dextrose 5% Water PVC

DHEP

D1, T2 PK/T

D1, V2 PK/T

Avoid

PVC

DHEP

LD1-V2 T

<0.4 mg/ml

P1. G2 PD/T

Avoid

PVC

DHEP

P1, G2 PD/T

* ND

M1, L2 PD For < 1hr

M1, L2 PD

Second Chemotherapy Agent

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Flush lines with D5W

DHEP

Avoid

PVC

DHEP

Lactated Ringers

PVC

Dextrose 5% Water

Avoid

Sodium Chloride

Vinorelbine

Vincristine

Vinblastine

Trastuzumab

Topotecan

Temsirolimus

Streptozocin

Rituximab

Pentostatin

Pemetrexed

Panitumumab

Paclitaxel (Abraxane)

Paclitaxel

Oxaliplatin

Mitoxantrone

Mitomycin

Methotrexate

Mesna

Melphalan

Mechlorethamine

Leucovorin

Ixabepilone

Flush lines with D5W

SEQUENCE LEGEND

PD= Pharmacodynamic/Efficacy PK= Pharmacokinetic T= Toxicity ND= No difference

First Chemotherapy Agent

Avoid T1, C2 T

E1, P2 PK/T

L1, F2 PD

Sodium Chloride

Vinorelbine

Vincristine

Vinblastine

Trastuzumab

T1, C2 T

P1. C2 T C1, P2 T

Topotecan

Temsirolimus

Base Solutions

Streptozocin

Rituximab

Pentostatin

Pemetrexed

Panitumumab

Paclitaxel (Abraxane)

Paclitaxel

Oxaliplatin

Mitoxantrone

Mitomycin

Methotrexate

Mesna

Melphalan

Mechlorethamine

Leucovorin

Ixabepilone

Second Chemotherapy Agent

Y-SITE COMPATIBLE Y-SITE INCOMPATIBLE VARIABLE NOT TESTED

Base Solutions

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Table 2 Chemotherapy Combinations with Data to Support a Specific Sequence Preferred sequence First agent Second agent Sequence benefit 5-Fluorouracil Methotrexate Better response and survival rates41,42 Cisplatin Irinotecan Better response rate; same toxicity43-45 Cyclophosphamide Paclitaxel Less cytopenias2,46,47 Docetaxel Vinorelbine Decreased neutropenia (proposed that polysorbate-80 in docetaxel blocks P-glycoproteinâ&#x20AC;&#x201C;mediated clearance of vinorelbine)48,49 Docetaxel Topotecan Decreased neutropenia. Reverse sequence causes a 50% reduction in docetaxel clearance50,51 Doxorubicin Paclitaxela Prevents increased maximum concentration and decreased clearance of doxorubicin; decreases severity of bone marrow suppression and mucositis2,4,5,52-54 Doxorubicin Docetaxel Less grade 4 neutropenia2,55 Epirubicin Paclitaxela Reverse sequence leads to increased maximum concentration and decreased clearance of epirubicin; decreases severity of bone marrow suppression and mucositis2,5,56 Fludarabine Cytarabine Enhances efficacy57 Gemcitabine Cisplatin Increases platinum-DNA adducts and lessens neutropenia; less toxic6,58,59 Ifosfamide Docetaxel Less myelosuppression60,61 Irinotecan 5-Fluorouracil Additive efficacy; less diarrhea and neutropenia6,62,63 Leucovorin 5-Fluorouracila Stabilizes thymidylate synthase to increase 5-fluorouracil cytotoxicity and efficacy64,65 Liposomal doxorubicin Docetaxel Less dose reductions and better tolerance of full dose in this sequence66 Liposomal doxorubicin Vinorelbine Decreased neutropenia and avoidance of increased vinorelbine area under the curve67,68 Methotrexate Leucovorina Leucovorin rescues cells after methotrexate administered to reduce toxicity; if leucovorin is given first, there is decreased efficacy of methotrexate69-73 Paclitaxel Cisplatina Less neutropenia74,75 Paclitaxel Gemcitabine Synergy; less risk of hepatotoxicity19,76,77 Pemetrexed Gemcitabine Most efficacious; least toxic78,79 Topotecan Carboplatin Less risk of neutropenia and thrombocytopenia80,81 Topotecan Cisplatin Less risk of neutropenia and thrombocytopenia82,83 a

Specific sequence recommended in Lexi-Comp Online.

were based on extrapolated data from drug classes but not studies directly comparing the two agents. An example of this is the taxanes and the platinum agents. We

The literature search revealed that recommendations provided in commonly used drug information resources were based on extrapolated data from drug classes but not studies directly comparing the two agents. were unable to find any data that directly examine the recommended sequence of docetaxel before oxaliplatin. In addition, the sequence of paclitaxel before carbo-

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platin has been extensively proved to be clinically irrelevant and yet this sequence remains recommended in drug information resources.2,85-92 These unreferenced recommendations, as one example, could potentially delay treatment, because an oxaliplatin dose could be administered first while docetaxel, which takes longer to reconstitute, is prepared. We found examples throughout the literature indicating that certain studies may not allow extrapolation to a given sequence. A review by Vaishampayan and colleagues, for instance, demonstrates that in vitro studies cannot be applied in clinical practice. The authors evaluated preclinical and clinical data to show that synergy is not always beneficial.2 When paclitaxel preceded doxorubicin in vitro, they found a threefold increase in cytotoxicity (a synergistic effect); in con-

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Chemotherapy Administration Sequence

trast, when this sequence was studied in humans, they found an increased frequency of mucositis, cardiotoxicity, and neutropenia. Synergistic antitumor activity does not necessarily, however, imply worse clinical toxicity. In a study by Zupi and colleagues, paclitaxel followed by gemcitabine was synergistic in vitro,19 and a study by Poole and colleagues showed that this sequence had less hepatotoxicity and neutropenia than the reverse.76 In studies where a given sequence may have toxicity or efficacy issues, we were unable to conclude that the reverse sequence would resolve the issue. This was demonstrated in a review by Smorenburg and colleagues.1 The authors examined data that suggested the sequence of methotrexate followed by docetaxel was antagonistic and thus had no efficacy, but the reverse sequence caused profound neutropenia, suggesting that this combination of agents should not be used in any sequence. Purely pharmacokinetic studies may not always be applied to their pharmacodynamic properties either. Combination studies of vinorelbine and gemcitabine are an example. In a pharmacokinetic study by Cattel and colleagues, there was an increase in gemcitabine area-under-thecurve and maximum concentration when vinorelbine was administered before gemcitabine.40 The reverse sequence, gemcitabine followed by vinorelbine, was found to be inactive in vivo.39 The comprehensive literature review also revealed several important clinical practice issues that must be evaluated on a consistent basis. One of the common questions encountered by pharmacists in our chemotherapy infusion centers is, “What drug should be administered first?” Pharmacists must use their resources in a timely manner to find the answer—a challenging task given the abundance of literature and resources available. This review has shown that we need solid head-to-head evidence comparing two sequences before we can draw any conclusion. It may not always be the best option to try to extrapolate data from other studies. This includes generalizing data from one agent to the entire therapeutic class, extrapolating data from preclinical studies, or automatically reversing a sequence when the reverse sequence was not directly compared.

Conclusion As this review has shown, there are several sequences that are well defined in the literature in terms of safety and efficacy. We can use these data, now in a more available format, to help answer some of the common questions regarding chemotherapy administration. At this point, the recommendation for sequence of administration of combination chemotherapy, if not clearly defined in the literature, should follow the sequence of administration published in that regimen’s original study. Further

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Table 3 Chemotherapy Combinations with Sequence Having No Effect on Efficacy or Toxicity Nanoparticle albumin-bound paclitaxel plus carboplatin84 Carboplatin plus paclitaxel2,85-92 Cisplatin plus 5-fluorouracil93,94 Docetaxel plus carboplatin95,a Docetaxel plus cisplatin2,96,97 Docetaxel plus epirubicin2-4,98,a Doxorubicin plus methotrexate/5-fluorouracil99 Etoposide plus topotecan100 Etoposide plus paclitaxel101-103 Gemcitabine plus carboplatin104,105 Gemcitabine plus docetaxel106,107 Gemcitabine plus irinotecan6,108 Irinotecan plus oxaliplatin109 Liposomal doxorubicin plus topotecan110 a

Specific sequence recommended in Lexi-Comp Online.

clinical studies will be conducted in the future that continue to elucidate the optimal sequence for all combination agents. We hope to evaluate the efficacy of the chart we devised to see whether it has helped increase efficiency and improve workflow for the pharmacists and nurses at our institution. ■

Disclosure Drs Mancini and Modlin did not report any potential financial conflicts of interest. References 1. Smorenburg CH, Sparreboom A, Bontebal M, et al. Combination chemotherapy of the taxanes and antimetabolites: its use and limitations. Eur J Cancer. 2001;37:2310-2323. 2. Vaishampayan U, Parchment RE, Jasti BR, et al. Taxanes: an overview of the pharmacokinetics and pharmacodynamics. Urology. 1999;54(6A suppl):22-29. 3. Airoldi M, Cattel L, Pedani F, et al. Clinical and pharmacokinetic data of a docetaxel-epirubicin combination in metastatic breast cancer. Breast Cancer Res Treat. 2001;70:185-195. 4. Holmes FA, Madden T, Newman RA, et al. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1996;14:2713-2721. 5. Danesi R, Conte PF, Del Tacca M. Pharmacokinetic optimisation of treatment schedules for anthracyclines and paclitaxel in patients with cancer. Clin Pharmacokinet. 1999;37:195-211. 6. Goel A, Grossbard ML, Malamud S, et al. Pooled efficacy analysis from a phase I-II study of biweekly irinotecan in combination with gemcitabine, 5-fluorouracil, leucovorin and cisplatin in patients with metastatic pancreatic cancer. Anticancer Drugs. 2007;18:263-271. 7. Esaki T, Nakano S, Tatsumoto T, et al. Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line. Cancer Res. 1992;52:6501-6506. 8. Cho H, Imada T, Oshima T, et al. In-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing of cisplatin treatment. Gastric Cancer. 2002;5:43-46. 9. Yu NY, Patawaran MB, Chen JY, et al. Influence of treatment sequence on efficacy of fluorouracil and cisplatin intratumoral drug delivery in vivo. Cancer J Sci Am. 1995;1:215-221.

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36. Toner LE, Vrhovac R, Smith EA, et al. The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkinâ&#x20AC;&#x2122;s lymphoma. Clin Cancer Res. 2006;12:924-932. 37. Bonner JA, Kozelsky TF. The significance of the sequence of administration of topotecan and etoposide. Cancer Chemother Pharmacol. 1996;39:109-112. 38. Miller AA, Niell HB. Phase I and pharmacologic study of sequential topotecan, carboplatin, and etoposide. Lung Cancer. 2001;33:241-248. 39. Juergens R, Brahmer J, Ettinger D. Gemcitabine and vinorelbine in recurrent advanced non-small cell lung cancer: sequence does matter. Cancer Chemother Pharmacol. 2007;59:621-629. 40. Cattel L, Airoldi M, Passera R, et al. Gemcitabine plus vinorelbine chemotherapy regimens: a pharmacokinetic study of alternate administration sequences. Pharm World Sci. 2004;26:238-241. 41. Mackintosh JF, Coates AS, Tattersall MH, et al. 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J Rheumatol. 1998;25:36-43. 71. Alarcon GS, Morgan SL. Folinic acid to prevent side effects of methotrexate in juvenile rheumatoid arthritis. J Rheumatol. 1996;23:2184-2185. 72. Joyce DA, Will RK, Hoffman DM, et al. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis. 1991;50:913-914. 73. Morgan SL, Oster RA, Lee JY, et al. The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum. 2004;50:3104-3011. 74. Milross CG, Peters LJ, Hunter NR. Sequence-dependent antitumor activity of paclitaxel (Taxol) and cisplatin in vivo. Int J Cancer. 1995;62:599-604. 75. Rowinsky EK, Gilbert MR, McGuire WP, et al. Sequences of Taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol. 1991;9:1692-1703. 76. Poole CJ, Perren T, Gawande S, et al. Optimized sequence of drug administration and schedule leads to improved dose delivery for gemcitabine and paclitaxel in combination: a phase 1 trial in patients with recurrent ovarian cancer. Int J Gynecol Cancer. 2006;16:507-514. 77. Oliveras-Ferraros C, Vazquez-Martin A, Colomer R, et al. Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: the importance of scheduling. Int J Oncol. 2008;32:113-120. 78. Adjei AA. Clinical studies of pemetrexed and gemcitabine combinations. Ann Oncol. 2006;15(supp 5):v29-v32. 79. Ma CX, Nair S, Thomas S, et al. Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:5929-5937. 80. Simpson AB, Calvert PM, Sludden JA, et al. Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules. Ann Oncol. 2002; 13:399-402. 81. Boss DS, Siegel-Lakhai WS, van Egmond-Schoemaker NE, et al. Phase 1 pharmacokinetic and pharmacodynamic study of carboplatin and topotecan administered intravenously every 28 days to patients with malignant solid tumors. Clin Cancer Res. 2009;15:4475-4483. 82. Rowinsky EK, Kaufmann SH, Baker SD, et al. Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol. 1996;14:3074-3084. 83. Raymond E, Burris HA, Rowinsky EK, et al. Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated nonsmall-cell lung carcinoma. Ann Oncol. 1997;8:1003-1008. 84. Stinchcombe TE, Socinski MA, Walko CM, et al. Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. Cancer Chemother Pharmacol. 2007;60:759-766. 85. DiPaola RS, Rubin E, Toppmeyer D, et al. Gemcitabine combined with sequential paclitaxel and carboplatin in patients with urothelial cancers and other advanced malignancies. Med Sci Monit. 2003;9:PI5-PI11. 86. Van Warmerdam LJ, Huizing MT, Giaccone G, et al. Clinical pharmacology of carboplatin administered in combination with paclitaxel. Semin Oncol. 1997;24 (suppl 2):97-104.

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87. Huizing MT, Giaccone G, van Warmerdam LJ, et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre. J Clin Oncol. 1997;15:317-329. 88. Giaccone G, Huizing M, Postmus PE, et al. Dose-finding and sequencing study of paclitaxel and carboplatin in non-small cell lung cancer. Semin Oncol. 1995;22(suppl 9):78-82. 89. Perez EA, Hartmann LC. Paclitaxel and carboplatin for advanced breast cancer. Semin Oncol. 1996;23(suppl 11):41-45. 90. Obasaju CK, Johnson SW, Rogatko A, et al. Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. Clin Cancer Res. 1996;2:549-552. 91. Belani CP, Kearns CM, Zuhowski EG, et al. Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol. 1999;17:676-684. 92. Markman M, Elson P, Kulp B, et al. Carboplatin plus paclitaxel combination chemotherapy: impact of sequence of drug administration on treatment-induced neutropenia. Gynecol Oncol. 2003;91:118-122. 93. Koizumi W, Kurihara M, Hasegawa K, et al. Sequence-dependence of cisplatin and 5-fluorouracil in advanced and recurrent gastric cancer. Oncol Rep. 2004; 12:557-561. 94. Falcone A, Allegrini G, Masi G, et al. 5-Fluorouracil administered as a 48-hour chronomodulated infusion in combination with leucovorin and cisplatin: a randomized phase II study in metastatic colorectal cancer. Oncology. 2001;61:28-35. 95. Ando M, Saka H, Ando Y, et al. Sequence effect of docetaxel and carboplatin on toxicity, tumor response and pharmacokinetics in non-small-cell lung cancer patients: a phase I study of two sequences. Cancer Chemother Pharmacol. 2005; 55:552-558. 96. Pronk LC, Schellens JH, Planting AS, et al. Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors. J Clin Oncol. 1997;15:1071-1079. 97. Royer I, Monsarrat B, Sonnier M, et al. Metabolism of docetaxel by human cytochromes P450: interactions with paclitaxel and other antineoplastic drugs. Cancer Res. 1996;56:58-65. 98. Lunardi G, Venturini M, Vannozzi MO, et al. Influence of alternate sequences of epirubicin and docetaxel on the pharmacokinetic behaviour of both drugs in advanced breast cancer. Ann Oncol. 2002;13:280-285. 99. Westermann AM, Taal BG, Swart M, et al. Sequence-dependent toxicity profile in modified FAMTX (fluorouracil-adriamycin-methotrexate) chemotherapy with lenograstim support for advanced gastric cancer: a feasibility study. Pharmacol Res. 2000;42:151-156. 100. Huisman C, Postmus PE, Giaccone G, et al. A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients. Ann Oncol. 2001;12:1567-1573. 101. Rosell R, Felip E, Massuti B, et al. A sequence-dependent paclitaxel/etoposide phase II trial in patients with non-small cell lung cancer. Semin Oncol. 1997;24(suppl 12):56-60. 102. Fleming GF, Roth BJ, Baker SD, et al. Phase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma: a Gynecologic Oncology Group Study. Am J Clin Oncol. 2000;23:609-613. 103. Felip E, Massuti B, Camps C, et al. Superiority of sequential versus concurrent administration of paclitaxel with etoposide in advanced non-small cell lung cancer: comparison of two phase II trials. Clin Cancer Res. 1998;4:2723-2728. 104. Edelman MJ, Quam H, Mullins B. Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell lines. Cancer Chemother Pharmacol. 2001;48:141-144. 105. Langer CJ, Calvert P, Ozols RF. Gemcitabine and carboplatin in combination: phase I and phase II studies. Semin Oncol. 1998;25(suppl 9):51-54. 106. Harita S, Watanabe Y, Kiura K, et al. Influence of altering administration sequence of docetaxel, gemcitabine and cisplatin in patients with advanced nonsmall cell lung cancer. Anticancer Res. 2006;26:1637-1641. 107. Rizvi NA, Spiridonidis CH, Davis TH, et al. Docetaxel and gemcitabine combinations in non-small cell lung cancer. Semin Oncol. 1999;26(suppl 16):27-31, 41-42. 108. Ramnath N, Yu J, Khushalani NI, et al. Scheduled administration of low dose irinotecan before gemcitabine in the second line therapy of non-small cell lung cancer: a phase II study. Anticancer Drugs. 2008;19:749-752. 109. Gil-Delgado MA, Bastian G, Guinet F, et al. Oxaliplatin plus irinotecan and FU-FOL combination and pharmacokinetic analysis in advanced colorectal cancer patients. Am J Clin Oncol. 2004;27:294-298. 110. Dupont J, Aghajanian C, Andrea G, et al. Topotecan and liposomal doxorubicin in recurrent ovarian cancer: is sequence important? Int J Gynecol Cancer. 2006;16(suppl 1):68-73.

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CALL FOR PAPERS The nation’s first peer-reviewed clinical journal for oncology pharmacists As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. The Journal of Hematology Oncology Pharmacy has been launched to provide another avenue for the publication of peer-reviewed, high-quality pharmacy literature to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients. Readers are invited to submit articles addressing research, clinical, and practice management issues in oncology pharmacy practice. All articles will undergo a blind peer-review process, and acceptance is based on that review.

The journal will be split into four main sections:

ORIGINAL RESEARCH

REVIEW ARTICLES

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

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

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

CLINICAL CONTROVERSIES

• Logistics • Economics • Practice-influencing issues

• Point, Counterpoint • Roundtable discussion • “How I treat”

Manuscripts should follow the Author Guidelines on pages 45-46 and available at www.JHOPonline.com. For more information, call 732-992-1890.

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ALOXI provides powerful CINV prevention that can’t be ignored. ®

ALOXI is the only IV 5-HT3 receptor antagonist specifically approved for the prevention of both acute and delayed CINV s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4

Eisai offers: s Contracting opportunities

Reimbursement resources

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults 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 s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. 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. 2. 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. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083C 08/10

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REVIEW ARTICLE

From Chemotherapy to Targeted Therapies: Current Treatment of Carcinoid Tumors and Pancreatic Neuroendocrine Tumors Steve Stricker, PharmD, MS, BCOP

J Hematol Oncol Pharm. 2011;1(1):29-36.

Neuroendocrine tumors are rare, complex tumors arising from multiple anatomic sites. The accurate diagnosis, treatment, and monitoring of these diseases provide an excellent opportunity for multidisciplinary care. Clinical trials are varied, frequently underpowered, and difficult to compare because of the heterogeneous populations. For this reason, it is essential that practitioners gain a global understanding of treatment modalities involved in the management of patients with neuroendocrine tumors, including surgery, cytotoxic chemotherapy, biological therapies, and novel agents currently under investigation.

euroendocrine tumors (NETs) represent a spectrum of rare neoplasms derived from cells of the nervous and endocrine systems. Although these malignancies may arise from nearly any anatomic site, they most commonly are diagnosed in organs of the gastrointestinal tract and can be subdivided broadly according to their ability to produce and secrete hormonal products at supraphysiologic levels.1 The status of a NET as functional or nonfunctional is solely dependent on clinical manifestations resulting from excessive concentrations of peptide hormones, neuropeptides, and neurotransmitters leading to the characteristic carcinoid syndrome and is not determined by pathologic profiling.2 Carcinoid syndromeâ&#x20AC;&#x201D;defined as flushing, diarrhea, and abdominal painâ&#x20AC;&#x201D;can be disabling in some patients and commonly occurs in approximately half of all diagnosed patients, especially those with advanced disease that includes liver metastases.3-5 The specific patterns of hormone production, degree of aggressiveness, and response to therapy result in a heterogeneous class of rare tumors that make clinical trial design and standardization of therapy difficult. In 2000, the World Health Organization published guidelines to clarify the histopathologic categorization of NETs. This system divides these malignancies into three classifications: well-differentiated NETs, well-differentiated carcinomas, and poorly differentiated carcinomas.6 Well-differentiated NETs, including carcinoid tumors, are relatively indolent and may be benign, whereas wellDr Stricker is Assistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, Alabama.

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differentiated carcinomas imply malignant behavior with the possibility of metastasis. Poorly differentiated or high-grade carcinomas, including small-cell carcinomas, may be aggressive in pattern of growth and typically confer a poor prognosis.6-8 According to an analysis of the Surveillance, Epidemiology, and End Results database, NETs have an age-adjusted incidence of 5.25 cases per 100,000 people per year, representing approximately 1% to 2% of all malignant tumors.9 Although the rate of diagnosis of NETs has appeared to increase over the past 30 to 40 years (2.5% of all gastric neoplasms in the 1970s; 6% in 1999), improvements in the clinical management of these patients has lagged.10 This review summarizes clinical trials (Table) that have established the contemporary management of patients with carcinoid tumors and pancreatic NETs (PNETs) highlighting promising treatments that likely will affect patient care in the foreseeable future.

Surgery Surgery remains the preferred treatment modality and only curative option for patients with localized NETs. For patients with metastatic disease, consideration should be given to removal of the primary tumor, regional lymph nodes, and any isolated liver lesions.25 Debulking has been described to result in increased overall survival in a small subset of patients.26 Surgical management for patients with localized and metastatic carcinoid tumors and PNETs has been described extensively in the literature and, although beyond the scope of this review, should be the first consideration for any patient with a new diagnosis of NET.25,27-29

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Table Major Trials for Carcinoid Tumors and Pancreatic Neuroendocrine Tumors Author

Phase

Intervention

Response

Faiss et al3

Lanreotide, IFN alfa, or lanreotide + IFN alfa

PR: 4% lanreotide, 3.7% IFN alfa, 7.1% combination SD: 28% lanreotide, 25.9% IFN alfa, 17.9% combination

Kouvaraki et al11

5-FU + doxorubicin + streptozocin

ORR: 39% PFS (at 2 years): 41% OS (at 2 years): 74%

Kulke et al12

Thalidomide + temozolomide

ORR: 25% OS (at 1 year): 79% OS (at 2 years): 61%

Kulke et al13

107

Sunitinib

ORR: 16.7% PNETs, 2.4% carcinoid SD: 68% PNETs, 83% carcinoid TTP: 7.7 months PNETs, 10.2 months carcinoid OS (at 1 year): 81.8% PNETs, 83.4% carcinoid

Kvols et al14

Pasireotide

PR: 20% CR: 4.5%

Moertel et al15

105

Streptozocin + doxorubicin or streptozocin + 5-FU

TTP: 20 months streptozocin + doxorubicin, 6.9 months streptozocin + 5-FU OS: 2.2 years streptozocin + doxorubicin, 1.4 years streptozocin + 5-FU

Pavel et al16

Octreotide LAR + IFN alfa

PR: 12% SD: 65%

Ramanathan et al17

Dacarbazine

ORR: 33% OS: 19.3 months

Raymond et al18

171

Sunitinib or placebo

ORR: 9.3% sunitinib, 0% placebo PFS: 11.4 months sunitinib, 5.5 months placebo

Rinke et al19

Octreotide LAR or placebo

SD: 66.7% octreotide, 37.2% placebo TTP: 14.3 months octreotide, 6 months placebo

Sun et al20

2/3

249

5-FU + doxorubicin or 5-FU + streptozocin

ORR: 15.9% 5-FU + doxorubicin, 16% 5-FU + streptozocin OS: 15.7 months 5-FU + doxorubicin, 24.3 months 5-FU + streptozocin

Yao et al21

Octreotide LAR + everolimus

PR: 22% SD: 70% PFS: 60 weeks

Yao et al22

Stage I: Bevacizumab or pegylated IFN alfa-2b Stage II: Bevacizumab + pegylated IFN alfa-2b

PR: 18% bevacizumab, 0% pegylated IFN SD: 77% bevacizumab, 68% pegylated IFN PFS (at 18 weeks): 95% bevacizumab, 68% pegylated IFN

Yao et al23

115

Octreotide LAR + everolimus

PR: 9.6% SD: 67.8% PFS: 16.7 months

Yao et al24

410

Everolimus + best supportive care

PFS: 11 months everolimus, 4.6 months placebo PR: 5% everolimus, 2% placebo SD: 73% everolimus, 51% placebo

CR indicates complete response; NS, not specified; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PNETs, panrceatic neuroendocrine tumors; PR, partial response; SD, stable disease; TTP, time to progression.

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Chemotherapy Targeted Therapies

Somatostatin Analogs Somatostatin is an endogenous peptide secreted by neuroendocrine cells found throughout the central and peripheral nervous systems. It produces negative regulatory effects on digestive secretions and the release of hormones including serotonin, somatostatin, and vasoactive intestinal peptide, among others throughout the gastrointestinal system via exocrine, endocrine, paracrine, and autocrine activity. This results in symptomatic control of the hormonally mediated syndromes frequently observed in patients with metastatic carcinoid tumors and PNETs.30-32 Therapeutic interest in somatostatin lies in the knowledge that, to varying degrees, all NETs express the five somatostatin receptor subtypes (SSTR1 to SSTR5), each capable of regulating various biological effects via signal transduction pathways.33 Unfortunately, the therapeutic use of native human somatostatin is limited severely by a half-life of less than 3 minutes.34 For this reason, somatostatin analogs, such as octreotide and lanreotide, were first developed in the early 1980s as short-acting formulations, requiring multiple daily administrations. More recently, sustained-release formulations have been introduced extending the dosing interval to every 1 month or 3 months. These somatostatin analogs largely are believed to exert their biological activity via binding to SSTR2, with lower affinity to SSTR3 and SSTR5.33 More specifically, apoptotic effects of somatostatin analogs are mediated via SSTR2 and antiangiogenic effects via SSTR2 and SSTR3.35 Although somatostatin analogs have long been used in the management of carcinoid syndrome, as well as other hormonally mediated syndromes observed in patients with metastatic gastroenteropancreatic (GEP) NETs, until recently these compounds rarely had been documented to stabilize the growth of NETs or to result in the regression of these tumors because of their slowgrowing nature. The publication of the Placebo Controlled, DoubleBlind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine MiDgut Tumors (PROMID) represents a new era for the use of somatostatin analogs in the management of patients with carcinoid tumors.19 This trial conducted in Germany enrolled 85 treatment-naïve patients with a locally inoperable or metastatic NET of midgut origin who were assigned to treatment with octreotide LAR 30 mg intramuscularly (IM) monthly or to placebo. Patients were evaluated by computed tomography/magnetic resonance imaging until disease progression was documented. This study demonstrated a 67% reduction in risk of disease progression favoring octreotide LAR (26 progressions in the octreotide LAR group; 41 in the

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placebo group; P = .000015). In addition, median time to progression was superior for octreotide LAR compared with placebo (14.3 vs 6.0 months). Subgroup analyses demonstrated that the antiproliferative effects of octreotide LAR were most beneficial in newly diagnosed gastrointestinal NET patients with low hepatic tumor volume and resected primary tumors.19 Furthermore, octreotide LAR was well-tolerated, with diarrhea and flatulence reported as the most common adverse events. For practitioners, PROMID represents the first placebo-controlled trial to demonstrate inhibition of tumor growth with a somatostatin analog in this patient population. After publication of the PROMID study results, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for gastrointestinal NETs were updated to reflect the recommendation of octreotide therapy, 150 µg to 250 µg subcutaneously (SC) three times daily or 20 mg to 30 mg IM every 4 weeks, in patients with no symptoms of carcinoid syndrome and with unresectable tumors as an alternative to clinical trial or repeated imaging every 3 to 6 months until disease progression or symptomatic presentation.36 Other somatostatin analogs also have elicited interest in the management of carcinoid tumors. Faiss and colleagues conducted a randomized, open-label trial of lanreotide (1 mg SC three times daily) versus interferon (IFN) alfa (5 ¥ 106 units SC three times weekly) alone and in combination in 80 treatment-naïve patients with documented metastatic GEP NETs.3 After 12 months of follow-up, tumor progression had occurred in 14 of 25 patients receiving lanreotide, 15 of 27 patients receiving IFN, and 14 of 28 patients treated with the combination. The authors concluded that, although the response rate was lower than previously reported in nonrandomized studies, lanreotide was comparable in efficacy to IFN alfa, which was considered the standard of care at the time of study design. Although these results failed to establish lanreotide as first-line therapy in this patient population, it remains a somatostatin analog of interest. An ongoing phase 3 clinical trial (ClinicalTrials.gov Identification No. NCT00353496) is evaluating the activity of a new autogel formulation of lanreotide versus placebo in patients with pancreatic or intestinal NETs. Pasireotide is a novel somatostatin analog that binds to SSTR1, SSTR2, SSTR3, and SSTR5 better than octreotide. It has shown efficacy in controlling symptoms of carcinoid syndrome in a phase 2 clinical trial. Patients with pathologically confirmed metastatic carcinoid tumor with symptoms (flushing and diarrhea) refractory to management with octreotide LAR were treated with pasireotide titrated to a maximum daily

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REVIEW ARTICLE

dose of 1200 Âľg SC twice daily. Partial responses (PRs) were reported in nine of 44 patients (20%) and a complete response was observed in two patients (5%) with regard to symptom control.14 To date, pasireotide has not been evaluated for antiproliferative activity in patients with carcinoid tumors. Other strategies have evaluated the use of radiolabeled somatostatin analogs in the management of patients with carcinoid tumors and PNETs. Somatostatin scintigraphy has been used with clinical success since the early 1990s to localize previously undetected or metastatic lesions, and it remains an NCCN recommendation for visualization of these tumors.37 Because many NETs highly express somatostatin receptors, radiolabeled compounds intended for scintigraphy have been evaluated for therapeutic efficacy. The most promising of these compounds, 90Y-DOTA0,Tyr3 and 177Lu-DOTA0,Tyr3, have demonstrated overall response rates in clinical trials ranging from 24% to 33% for patients with GEP NETs.38 Adverse events included hematologic toxicity, nausea/vomiting, abdominal discomfort, and, less commonly, renal insufficiency.

Interferon Alfa IFN-based therapy has been an option in the management of carcinoid tumors since the publication of a pivotal study by Oberg and colleagues in 1983.39 This early research evaluated 3 million international units of leukocyte IFN daily for 1 month followed by 6 million international units daily for an additional 2 months in patients with midgut carcinoid tumors and carcinoid syndrome. Although this was a small study enrolling only nine patients, control of symptoms and reduction in urinary 5-hydroxyindoleacetic acid levels was achieved in six patients; however, no effect on tumor growth was reported. This trial stimulated an increase in research and development seeking a better understanding of the mechanism of action of IFNs and their role in NETs. It is now believed that IFNs have not only direct antiproliferative effects on malignant cells but also function within the cell cycle resulting in G1 and G0 arrest, affect cellular differentiation, and inhibit angiogenesis via interactions with tyrosine kinase 2 and Janus kinase 1, among other molecular targets.7,40,41 Having demonstrated efficacy with IFN in patients with metastatic GEP NETs in the German trial conducted by Faiss and colleagues alone and in combination with the somatostatin analog lanreotide as described previously, subsequent efforts have focused on improving the tolerability and clinical delivery of IFN-based therapy. These adverse events, which include fatigue, a flulike condition with constitutional symptoms (ie, fever, chills, malaise), myelosuppression, and elevations in hepatic

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enzymes, require diligent monitoring.3 In addition, patient adherence and discontinuation of IFN therapy are major challenges in ensuring sustained treatment of patients with carcinoid tumors.16 Drawing on experiences in the management of patients with chronic hepatitis C, where improvement in tolerability was noted, Pavel and colleagues evaluated pegylated IFN alfa in patients with GEP NETs. Patients progressing on octreotide LAR therapy were converted to pegylated IFN alfa-2b 50 Âľg to 100 Âľg weekly on the basis of body weight, laboratory analysis (including hepatic function and leukocyte count), and subjective reports of symptoms. Stable disease was noted in 13 of 17 patients, and symptomatic improvement was observed in seven of 10 patients. Tolerability of therapy was reported in 15 of 17 patients, with fatigue and weakness as the most common adverse events.16 Because more significant strides in tumor response and symptom management have been reported with other NET treatments, the most recent iteration of the NCCN clinical practice guidelines for NETs recommend use of IFN-based therapy only in patients with metastatic disease in whom no other treatment modalities are considered feasible.36

Mammalian Target of Rapamycin Inhibitors The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase responsible for the regulation of cellular growth, cell signaling, and metabolism. Cell proliferation mediated by mTOR has been described via the expression of the insulin-like growth factor (IGF)-1 and the IGF-1 receptor by low- to intermediate-grade NETs.42 Thus, inhibition of this pathway was speculated to be a viable mechanism for tumor control in patients with NETs and has resulted in suppression of growth of these malignancies.43 Everolimus is an oral rapamycin derivative originally developed in the 1990s as an immunosuppressant for patients having undergone transplantation. It subsequently has been approved for patients with renal cell carcinoma and is used in the unlabeled setting for patients with PNETs. The first clinical trial evaluating the efficacy of everolimus alone or in combination with octreotide LAR was conducted by Yao and colleagues at The M. D. Anderson Cancer Center. This open-label phase 2 trial treated patients with low-grade NETs (30 carcinoid; 30 islet cell) with octreotide LAR 30 mg every 28 days and everolimus 5 mg or 10 mg daily.21 The overall response rates, 17% for carcinoid and 27% for islet cell patients, and median progression-free survival (PFS), 63 weeks and 50 weeks, respectively, demonstrate efficacy for the combination of octreotide and everolimus.21 Although superior PFS was noted for the cohort of patients receiving 10 mg of everolimus, more

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Chemotherapy Targeted Therapies

grade 3/4 toxicities were reported in this group, requiring dose reductions including aphthous ulcers (9%), leukopenia (6%), thrombocytopenia (6%), hypophosphatemia (16%), and pneumonitis (3%).21 A confirmatory open-label phase 2 trial sought to further assess the efficacy of everolimus in patients with metastatic PNETs following failure of cytotoxic chemotherapy. Patients were randomized to receive everolimus 10 mg daily (n = 115) or everolimus 10 mg daily in combination with octreotide LAR 竕､30 mg monthly (n = 45). PR or disease stabilization occurred more frequently in patients receiving combination therapy. This was confirmed further by an extended PFS of 16.7 months in the combination arm compared with 9.7 months in the single-agent everolimus group.23 Adverse toxicities in both studies involving patients with NETs have been similar to those reported previously with everolimus. These include stomatitis, rash, diarrhea, fatigue, nausea, headache, and abdominal pain. 21,23 Grade 1/2 pneumonitis was observed in 6% of patients receiving everolimus and 13% of patients receiving everolimus and octreotide. All cases of pneumonitis were considered reversible and were treated by treatment interruption and subsequent dose reduction. Another phase 3 study of everolimus in patients with advanced low- to intermediate-grade PNETs was recently completed. The RADIANT-3 double-blind trial randomized patients to receive everolimus 10 mg daily (n = 207) or placebo (n = 203). The primary end point, PFS, was extended from 4.6 months to 11 months (P <.0001) in patients treated with everolimus.24,44 Although overall the response rate was low (5% PR for patients receiving everolimus, 2% PR for placebo), 73% of patients treated with everolimus achieved stable disease compared with 51% of patients receiving placebo.24 At the time of publication, median overall survival had not been met. However, 73% of patients initially randomized to the placebo arm have crossed over to receive everolimus, thus potentially complicating this analysis. Significant grade 3/4 adverse events in patients treated with everolimus included stomatitis (7%), anemia (6%), hyperglycemia (5%), and thrombocytopenia (4%). Currently, NCCN clinical practice guidelines consider everolimus a category 2B recommendation for patients with advanced PNETs.36 To date, the use of everolimus often has been limited to patients with advanced PNETs, frequently after failure of systemic chemotherapy. With the completion of the RADIANT-3 trial, everolimus may become the standard of care in patients with advanced PNETs, pending approval of this indication by the US Food and Drug Administration.

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Vascular Targeted Therapies NETs have been reported to be highly vascularized malignancies with common overexpression of vascular endothelial growth factor (VEGF), and VEGF receptors that may be linked to tumor growth and progression.45 For this reason, interest has focused on the potential use of angiogenesis inhibitors, such as sunitinib and bevacizumab, in the clinical management of these diseases. Sunitinib Sunitinib is an oral multitargeted tyrosine kinase inhibitor with activity against VEGF receptors type 1 and 2, platelet-derived growth factor receptors alpha and beta, stem-cell factor receptor, FMS-like tyrosine kinase-3, glial cell line窶電erived neurotrophic factor, and c-kit.46,47 A phase 2 study of sunitinib 50 mg daily for the first 4 weeks of a 6-week cycle (2 weeks off treatment) in 109 patients (41 carcinoid; 66 PNET) demonstrated a 16.7% objective response rate in patients with PNETs and 2.4% objective response rate in patients with carcinoid tumors. In addition, stable disease was observed in 68% of patients with PNETs and in 83% of patients with carcinoid tumors.13 Median time to progression was 7.7 months in PNET patients and 10.2 months in carcinoid patients. The most common grade 3 and 4 toxicities attributed to sunitinib were hematologic (primarily neutropenia), fatigue, hypertension, nausea/vomiting, and diarrhea. The clinical efficacy demonstrated by sunitinib in this study was evaluated further in a confirmatory phase 3 trial. The phase 3 comparison of sunitinib 37.5 mg daily versus placebo was conducted in 171 patients with advanced PNETs and was stopped by the independent data monitoring committee at the interim analysis after preliminary results indicated significant differences in efficacy as well as serious adverse events, including death, favoring patients randomized to sunitinib.18,48 Those patients receiving sunitinib achieved a median PFS of 11.4 months versus 5.5 months for those patients receiving placebo (P <.001). Two patients treated with sunitinib achieved a complete response and six additional patients had a PR (objective response rate: 9.3% sunitinib, 0% placebo; P = .007). A greater number of significant adverse events (grade 3 and 4) were experienced by patients treated with sunitinib, including neutropenia (12%), hypertension (10%), and hand-foot syndrome (6%).18,48 In addition, there were nine deaths in the sunitinib arm (1 study-related death, cardiac failure) and 21 deaths in the placebo arm (1 study-related, dehydration). However, because patients experiencing disease progression on placebo could cross over to sunitinib, median survival could not be calculated for either treatment arm.

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Overall, sunitinib has shown reasonable efficacy in the management of patients with advanced PNETs in the setting of clinical trials. It has been well-tolerated and, although grade 3/4 toxicities including hand-foot syndrome have not been significant in the clinical trials (1.9% to 6%), practitioner experience with sunitinib in other malignancies may be limiting its use in this patient population at this time.13,18,48

Bevacizumab Bevacizumab is a humanized anti-VEGF antibody that has been studied extensively in virtually all solid malignancies.49 A phase 2 study enrolling 44 patients with metastatic carcinoid tumors and currently managed with stable doses of octreotide LAR compared bevacizumab 15 mg/kg intravenously (IV) every 3 weeks to pegylated IFN alfa-2b (in combination with the prestudy dose of octreotide LAR) for 18 weeks or until disease progression.22 After this prespecified time point, patients were further treated with both bevacizumab and pegylated IFN until disease progression. Overall response rates (18% PR, 77% stable disease vs 0% PR, 68% stable disease) favored bevacizumab, and median PFS after 18 weeks of therapy was lengthened for patients treated with bevacizumab (95% vs 68%).22 Hypertension and fatigue were the most commonly reported grade 3/4 adverse events in patients receiving bevacizumab, whereas granulocytopenia and fatigue were reported in those patients treated with pegylated IFN.22 Ongoing phase 2/3 clinical trials are evaluating the role of bevacizumab in the management of patients with NETs in combination with octreotide and pegylated IFN (ClinicalTrials.gov Identification No. NCT00569127), temsirolimus (ClinicalTrials.gov Identification No. NCT01010126), pertuzumab (ClinicalTrials.gov Identifi cation No. NCT01121939), and everolimus and octreotide (ClinicalTrials.gov Identification No. NCT01229943). However, at this time, available data do not support the addition of bevacizumab to any treatment regimen for patients with NETs. Cytotoxic Chemotherapy Although NETs are frequently considered to be relatively resistant to chemotherapy, cytotoxic drug combinations have long been regarded as a cornerstone in the management of patients with these types of tumors.50 One of the most commonly used regimens, combining 5fluorouracil (5-FU) with streptozocin, resulted in a measurable increase in objective response rate (69% vs 45%; P = .05) and median overall survival (2.2 years vs 1.4 years; P = .004) when compared with the combination of streptozocin and the alkylating agent chlorozotocin in patients with PNETs.15 The impressive results obtained

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from this Eastern Cooperative Oncology Group (ECOG) study created hope that PNETs might be more chemotherapy-sensitive than previously believed. However, other trials attempting to verify the response rates and survival benefit of this chemotherapy combination have failed to validate these findings.51 A more contemporary phase 2/3 study conducted by ECOG did demonstrate a measurable increase in overall survival (24.3 vs 15.7 months; P = .0267) in 249 patients with metastatic carcinoid tumors treated with streptozocin and 5-FU in comparison with those receiving doxorubicin and 5-FU. This benefit is consistent with what had been previously reported. It is important to note that there were no differences between the regimens with regard to response rate (15.9% vs 16%) or PFS (4.5 vs 5.3 months).20 These observations led the authors to speculate that surrogate markers for tumor response, such as PFS and response rate, may be inadequate for the determination of activity in some neuroendocrine tumors, including those carcinoid tumor patients enrolled in this study.20 In addition, severe or life-threatening adverse events were reported in 70% of patients treated with streptozocin and 5-FU (hematologic toxicities, 20%; vomiting, 17%; diarrhea, 7%; renal failure, 2%) and 63% of patients receiving doxorubicin and 5FU (hematologic toxicities, 24%; skin, 6%; mucosal toxicity, 6%). With existing data in conflict regarding the potential benefit to patients with PNETs treated with doublet combinations of streptozocin, doxorubicin, and 5-FU, an additional trial combined these three drugs in patients with locally advanced and metastatic pancreatic endocrine carcinomas. The median response rate in the 84 patients treated was 39%. PFS at 2 years was 41% and overall survival at 2 years was 74%.11 Patients reasonably tolerated this regimen, with 22.6% experiencing grade 3/4 toxicities (leukopenia/neutropenia, 10.7%; mucositis, 4.7%; fatigue, 4.7%). A newer strategy of applying cytotoxic chemotherapy in the management of patients with metastatic NETs has used dacarbazine and temozolomide alone and in combination with other chemotherapy drugs. The ECOG E6282 study evaluating single-agent dacarbazine 850 mg/m2 IV every 28 days in 50 patients with unresectable PNETs reported a response rate of 33% of patients and a median survival rate of 19.3 months.17 These results demonstrated the potential efficacy of single-agent dacarbazine therapy for patients with advanced NETs. Temozolomide, an oral alkylating agent and alternative to dacarbazine, was evaluated in combination with thalidomide in 29 patients with metastatic NETs in a phase 2 study. Thalidomide was selected specifically for treatment in this setting because of its presumed antian-

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Chemotherapy Targeted Therapies

giogenic activity via inhibition of the VEGF and basic fibroblast growth factor pathways.12,52 This oral combination regimen (temozolomide 150 mg/m2 for 7 days every other week; thalidomide 50-400 mg daily) resulted in a 25% overall response rate among all patients. When evaluated separately, however, the response rate was 45% among patients with PNETs compared with 7% among patients with carcinoid tumors. Grade 3/4 toxicities occurred with less frequency than reported for other chemotherapy options used to treat NETs and included lymphopenia, diarrhea, and infection.12 Again, these studies appear to favor the chemotherapeutic sensitivity of PNETs as compared with carcinoid tumors. In addition to systemic treatment options, localized strategies should be considered for patients with liveronly metastasis. These therapies include transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), both of which are intended to gain locoregional control and improve patient outcomes. The goal of TACE is to disrupt the hepatic blood supply to cause tumor ischemia and necrosis, thus controlling growth. TACE procedures provide focused treatment using particulate embolization, often with polyvinyl alcohol particles, with or without the administration of local chemotherapy. If chemotherapy is used, many protocols combine cisplatin, doxorubicin, and mitomycin C and deliver this cytotoxic therapy via catheterization of the hepatic artery.53 These procedures are not without risk with patients subject to carcinoid crisis, liver abscess, biliary obstruction, hepatic artery dissection, and renal failure.53 However, for those patients who gain benefit, median PFS, in one case series, was 10 months with 33 months overall survival.54 In contrast, RFA administers high-frequency alternating electrical current to ablate or destroy small-volume metastases. This technique primarily is limited to patients with tumors smaller than 3 cm.55 Median survival in one study was 29 months with 94% of patients experiencing symptom improvement.55 Many cytotoxic therapies have been investigated as potential options in the management of NETs but have resulted in low response rates, poor overall survival, or unacceptable levels of toxicity. Because of these less than desirable outcomes, cytotoxic chemotherapy rarely should be considered as first-line management in treatment-naïve patients diagnosed with NETs. Rather, chemotherapy should be reserved for those patients who have failed previous therapies and in whom other treatment modalities are not feasible. Locoregional management, however, should be considered for any patient with unresectable liver metastases and otherwise overall good performance status and life expectancy.

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Conclusions Although surgical resection of primary tumors and isolated metastases remains the mainstay of treatment for patients with carcinoid tumors and PNETs, advances in biological and targeted therapies have increased interest in these rare tumors and has provided new options for the clinical management of these patients. The evidence for cytotoxic chemotherapy remains controversial with patients experiencing significant toxicities while achieving less than desirable responses, thus relegating the role of these therapeutic options to the palliative care setting. However, for as ineffective as the application of chemotherapy may be, the publication of the PROMID study has rejuvenated interest in the use of the somatostatin analogs, specifically octreotide LAR, in the routine management of patients with metastatic carcinoid tumors. In our practice, patients with metastatic carcinoid tumors are initiated on octreotide LAR 30 mg IM every 4 weeks, often within 1 month of tumor resection. Practitioners should ensure tolerance to octreotide therapy before converting patients to the LAR formulation. However, no specific protocol exists in the literature or from the manufacturer as to how patients should be converted. For this reason, we have adopted dosing octreotide immediate-release 50 µg SC twice daily for 2 weeks before a patient’s first LAR administration. For patients with metastatic PNETs, many patients in our practice are treated with streptozocin and fluorouracil following surgical resection and converted to everolimus upon disease progression. This strategy has been well-tolerated, and anecdotal observations suggest that patients have achieved a median overall survival comparable with that reported in the literature. Given the heterogeneity of carcinoid tumors and PNETs and the lack of standardization in choice of therapy, practitioner experience is very important in the management of these patients. Considerable interest, however, has existed in recent years in generating research to better understand these rare malignancies. More complete elucidation of the biochemical and molecular pathways involved in tumor growth and progression of these malignancies has allowed for the introduction of specific therapies to take advantage of these cellular processes. Recent studies of mTOR inhibitors, angiogenesis inhibitors, and other novel compounds have demonstrated increases in efficacy while minimizing toxicity to patients and have potentially unveiled the future management of NETs. ■ Disclosure Dr Stricker did not report any potential financial conflicts of interest. Continued

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References 1. Appetecchia M, Baldelli R. Somatostatin analogues in the treatment of gastro enteropancreatic neuroendocrine tumours, current aspects and new perspectives. J Exp Clin Cancer Res. 2010;29:19. 2. Klimstra D, Modlin I, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39:707-712. 3. Faiss S, Pape UF, Bohmig M, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—The International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003;21:2689-2696. 4. Eriksson B. New drugs in neuroendocrine tumors: rising of new therapeutic philosophies? Curr Opin Oncol. 2010;22:381-386. 5. Soga J, Yakuwa Y, Osaka M. Carcinoid syndrome: a statistical evaluation of 748 reported cases. J Exp Clin Cancer Res. 1999;18:133-141. 6. Solcia E, Kloppel G, Sobin L, et al. Histological Typing of Endocrine Tumours. 2nd ed. Berlin: Springer; 2000. 7. Oberg K. Diagnosis and treatment of carcinoid tumors. Expert Rev Anticancer Ther. 2003;3:863-877. 8. Scherubl H, Cadiot G, Jensen R, et al. Neuroendocrine tumors of the stomach (gastric carcinoids) are on the rise: small tumors, small problems? Endoscopy. 2010;42:664-671. 9. Yao J, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-3072. 10. Modlin I, Lye K, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934-959. 11. Kouvaraki M, Ajani J, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762-4771. 12. Kulke M, Stuart K, Enzinger P, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401-406. 13. Kulke M, Lenz HJ, Meropol N, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26:3403-3410. 14. Kvols L, Wiedenmann B, Oberg K, et al; for the SOM230 Carcinoid Study Group. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a phase II study. J Clin Oncol. 2006;24(18S):Abstract 4082. 15. Moertel C, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519-523. 16. Pavel M, Baum U, Hahn E, et al. Efficacy and tolerability of pegylated IFN-α in patients with neuroendocrine gastroenteropancreatic carcinomas. J Interferon Cytokine Res. 2006;26:8-13. 17. Ramanathan R, Cnaan A, Hahn R, et al. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol. 2001;12:1139-1143. 18. Raymond E, Dahan L, Raoul J, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-513. 19. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, doubleblind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656-4663. 20. Sun W, Lipsitz S, Catalano P, et al. Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol. 2005;23:4897-4904. 21. Yao J, Phan A, Chang D, et al. Efficacy of RAD001 (Everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26:4311-4318. 22. Yao J, Phan A, Hoff P, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:13161323. 23. Yao J, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69-76. 24. Yao J, Shah M, Ito T, et al; for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-523. 25. Hellman P, Lundstrom T, Ohrvall U, et al. Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg. 2002;26:991-997.

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26. Norton J. Surgical management of carcinoid tumors: role of debulking and surgery for patients with advanced disease. Digestion. 1994;55(supp 3):98-103. 27. Oberg K. Neuroendocrine gastrointestinal tumors—a condensed overview of diagnosis and treatment. Ann Oncol. 1999;10(suppl 2):S3-S8. 28. Caplin M, Buscombe J, Hilson A, et al. Carcinoid tumour. Lancet. 1998;352:799-805. 29. Kulke M, Mayer R. Carcinoid tumors. N Engl J Med. 1999;340:858-868. 30. Bousquet C, Puente E, Buscail L, et al. Antiproliferative effect of somatostatin analogs. Chemotherapy. 2001;47(suppl 2):30-39. 31. Kvols L, Moertel C, O’Connell M, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986;315:663-666. 32. Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2010;16:29632970. 33. Fazio N, Cinieri S, Lorizzo K, et al. Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas. Cancer Treat Rev. 2010;36(suppl 3):S87-S94. 34. Evers B, Parekh D, Townsend C Jr, Thompson J. Somatostatin and analogues in the treatment of cancer. Ann Surg. 1991;213:190-198. 35. Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer. 2008;15:701-720. 36. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Neuroendocrine Tumors. V.2.2010. www.nccn.org/professionals/physi cian_gls/pdf/neuroendocrine.pdf. Accessed February 25, 2011. 37. Lamberts S, Bakker W, Reubi J, Krenning E. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med. 1990;323:1246-1249. 38. Kwekkeboom D, Kam B, van Essen M, et al. Somatostatin receptor-based imagining and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17:R53-R73. 39. Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983;309:129-133. 40. Fazio N, de Braud F, Delle Fave G, Oberg K. Interferon-alpha and somatostatin analog in patients with gastroenteropancreatic neuroendocrine carcinoma: single agent or combination? Ann Oncol. 2007;18:13-19. 41. Pestka S, Langer J, Zoon K, Samuel C. Interferons and their actions. Annu Rev Biochem. 1987;56:727-777. 42. von Wichert G, Jehle P, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res. 2000;60:4573-4581. 43. Moreno A, Akcakanat A, Munsell M, et al. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer. 2008;15:257-266. 44. Yao J, Shah M, Ito T, et al. A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). Ann Oncol. 2010;21(suppl 8): Abstract LBA9. 45. La Rosa S, Uccella S, Finzi G, et al. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol. 2003;34:18-27. 46. Papaetis G, Syrigos K. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009;23:377-389. 47. Faivre S Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6:734-745. 48. Niccoli P, Raoul J, Bang Y, et al. Updated safety and efficacy results for the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of pancreatic neuroendocrine tumors (NET). J Clin Oncol. 2010;28(15S):Abstract 4000. 49. Bevacizumab. Anti-VEGF monoclonal antibody, Avastin, rhumab-VEGF. Drugs R D. 2002;3:28-30. 50. Turner N, Strauss S, Sarker D, et al. Chemotherapy with 5-fluorouracil, cisplatin, and streptozocin for neuroendocrine tumours. Br J Cancer. 2010;102:1106-1112. 51. Cheng P, Saltz L. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer. 1999;86:944-948. 52. D’Amato R, Loughnan M, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082-4085. 53. Kiely J, Rilling W, Touzios J, et al. Chemoembolization in patients at high risk: results and complications. J Vasc Interv Radiol. 2006;17:47-53. 54. Bloomston M, Al-Saif O, Klemanski D, et al. Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg. 2007;11:264-271. 55. Reddy S, Clary B. Neuroendocrine liver metastases. Surg Clin North Am. 2010;90:853-861.

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FROM THE LITERATURE

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

■ Bevacizumab-based Therapy Improves Outcomes in Elderly Patients with NSCLC Background: Efficacy and safety data of bevacizumab plus cisplatin/gemcitabine for elderly patients with non–small-cell lung cancer (NSCLC) could be extracted through subgroup analysis of patients in the AVAiL trial. Design: Using retrospective analysis of data from the placebo-controlled, phase 3 AVAiL trial, researchers evaluated data of the 304 study participants (aged ≥65 years). Most patients (83%) had adenocarcinoma. Patients in the AVAiL trial had received cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles plus 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, or placebo every 3 weeks until disease progression. Summary: Combining the patients in the two bevacizumab arms, 79% completed more than four cycles. In addition, patients in these two arms had improvement in progression-free survival (PFS) compared with those in the placebo arm (7.5 mg/kg bevacizumab: hazard ratio [HR], 0.71; P = .023; 15 mg/kg bevacizumab: HR, 0.84; P = .25). Objective response rates were 40% in the 7.5mg/kg bevacizumab group, 29% in the 15-mg/kg bevacizumab group, and 30% in the placebo group. Overall survival (OS) was similar for each bevacizumab arm versus placebo (7.5 mg/kg bevacizumab: HR, 0.84; P = .31; 15 mg/kg bevacizumab: HR, 0.88; P = .44). Takeaway: Several cytotoxic combination regimens are effective in patients with metastatic NSCLC. Because resistance is a common problem in NSCLC and mediated via both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), treatment may include VEGF or EGFR inhibitors. Bevacizumab combined with cisplatin was studied in the AVAiL trial and showed that when combined with cisplatin and gemcitabine, tumor response and OS were both improved using a bevacizumab dose of 7.5 mg/kg, but not the higher dose of 15 mg/kg. Based on this study, bevacizumab may be added to chemotherapy for initial therapy of advanced or recurrent NSCLC. Leighl NB, et al. J Thorac Oncol. 2010;5:1970-1976.

■ Adding Sorafenib to Doxorubicin May Prolong Survival in Advanced Liver Cancer Background: Sorafenib combined with doxorubicin

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in patients with advanced hepatocellular carcinoma (HCC) had not yet been evaluated in a phase 2 or 3 trial. Previous trials found that sorafenib prolonged OS in patients with HCC and Child-Pugh A disease and that, in combination with doxorubicin, it was well tolerated by patients with solid tumors. Design: For this phase 2 study, researchers randomized patients with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, and ChildPugh A status who had not received prior systemic therapy. Patients were assigned to treatment with 60 mg/m2 of doxorubicin intravenously every 21 days plus either sorafenib 400 mg or placebo orally twice daily. The primary outcome measure was time to progression (TTP). Summary: The trial was halted early, based on analysis for efficacy. Of the 96 patients, 63 died: 25 in the doxorubicin-sorafenib group and 38 in the doxorubicin-placebo group. Median TTP was 6.4 months in the doxorubicin-sorafenib group compared with 2.8 months in the doxorubicin-placebo group (P = .02). The HR was 0.5 (95% confidence interval [CI], 0.30.9), representing a 50% reduction in the risk of progression in patients treated with doxorubicin plus sorafenib compared with reduction of risk progression in those treated with doxorubicin plus placebo (P = .02). Median OS was 13.7 months versus 6.5 months, respectively (P = .006), and PFS was 6.0 months and 2.7 months, respectively (P = .006). Adverse effects of the two agents were additive and similar to what would be expected with each agent alone. Takeaway: There is currently no standard treatment for patients with advanced HCC. Doxorubicin has been studied extensively in this disease, and has been shown to produce a small survival advantage compared with best supportive care alone (median survival, 10.6 vs 7.5 weeks). Other phase 2 studies have demonstrated a mean OS of 3 to 6 months. The disparity in results is probably related to patient selection. The current study produced promising results in TTP, median OS, and PFS for the combination of doxorubicin plus sorafenib. Furthermore, the addition of sorafenib to doxorubicin did not significantly increase toxicity over doxorubicin alone. Based on these results, a phase 3 trial of sorafenib plus doxorubicin versus sorafenib alone is being conducted. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160.

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FROM THE LITERATURE

■ Arsenic Immediately after Induction Improves Survival in APL Background: Although arsenic trioxide (As2O3) is used as an effective treatment for relapsed acute promyelocytic leukemia (APL), its benefit as consolidation treatment for patients in first remission has not been confirmed. Design: The North American Leukemia Intergroup Study Group randomized 481 patients to an induction regimen of tretinoin/cytarabine/daunorubicin, followed by two courses of the consolidation regimen of tretinoin/ daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to 1 year of maintenance therapy with either tretinoin alone or in combination with methotrexate/mercaptopurine. Summary: Of the 90% of patients on each arm who achieved remission, event-free survival was significantly improved for patients assigned to the As2O3 arm (80% vs 63% at 3 years; P <.0001). Survival was also better in the As2O3 arm (86% vs 81% at 3 years; P = .059), as was disease-free survival (90% vs 70% at 3 years; P <.0001). Takeaway: Standard consolidation has consisted of two cycles of an anthracycline (daunorubicin or idarubicin) plus all-trans retinoic acid (ATRA). Recent studies, however, have suggested an important role for As2O3. This study aimed to provide further data that consolidation with As2O3 is a reasonable approach for patients who have achieved complete remission. All end points of survival were improved with As2O3 when combined with ATRA and daunorubicin. Based on this data, As2O3 combination–based regimens have been added to the National Comprehensive Cancer Network guidelines as a standard consolidation regimen for APL. Powell BL, et al. Blood. 2010;116:3751-3757.

mg/m2; n = 539) or FAC (500 mg/m2, 50 mg/m2, 500 mg/m2; n = 521) every 3 weeks for six cycles beginning within 60 days of surgery. The primary end point, disease-free survival (DFS), was assessed at ≥5 years of follow-up. The secondary end point was OS. Summary: Of 1051 evaluable patients, 87.8% in the TAC group and 81.8% in the FAC group achieved DFS—a 32% reduction in the risk of disease recurrence (HR, 0.68; 95% CI, 0.49-0.93; P = .01) for the TAC group. OS was achieved by 95.2% of patients in the TAC group and 93.5% in the FAC group—a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.45-1.26; P = .29) for the TAC group. Subgroup analyses found no significant difference in DFS by hormone-receptor status, menopausal status, or number of high-risk factors. There was also no significant treatment interaction with HER2 status or hormone-receptor status. Grade 3 and 4 adverse events occurred in 28.2% of patients in the TAC group and 17.0% in the FAC group (P <.001). Most adverse events with TAC were remedied with granulocyte colony-stimulating factor. Takeaway: It is noteworthy that in this study, the rate of drug adherence was 94.5% and 97.7% for the TAC and FAC groups, respectively. The OS after 77 months of follow-up was not significantly different between treatment groups; however, the number of events was too small for analysis and will require longer follow-up. It is impressive that the risk of recurrence was significantly reduced by 32% with TAC therapy, which compares favorably with the BCIRG 001 trial’s use of the TAC and FAC regimens in node-positive patients (ie, a higher stage of disease) that produced a 28% risk reduction in the TAC group. Both the BCIRG study and this present study show that adjuvant TAC is effective in patients with node-positive and with node-negative, early-stage, high-risk breast cancer. Martin M, et al; for the GEICAM 9805 Investigators. N Engl J Med. 2010;363:2200-2210.

■ Adjuvant Docetaxel, Doxorubicin, Cyclophosphamide for Node-negative Breast Cancer Background: Among others, the Breast Cancer International Research Group (BCIRG) 001 trial showed that an adjuvant regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) reduced the risk for recurrence of breast cancer and for death over fluorouracil, doxorubicin, and cyclophosphamide (FAC). These results, however, have been in node-positive patients. Outcome data for patients with node-negative breast cancer have not yet been defined. Design: In this phase 3 open-label study, researchers randomized 1060 women with high-risk, node-negative breast cancer to receive TAC (75 mg/m2, 50 mg/m2, 500

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■ Long-term Benefit of Radiotherapy Confirmed, Tamoxifen for Ductal Carcinoma In Situ Background: Enhanced screening efforts have increased the number of patients diagnosed with ductal carcinoma in situ (DCIS). Of the treatment options available (surgery, radiotherapy, and hormonal therapy), radiotherapy has previously been shown effective in reducing recurrences of in situ or invasive ipsilateral disease. These long-term results of the UK, Australia, and New Zealand DCIS trial highlight the role of tamoxifen in this patient population. Design: Researchers randomized 1701 patients with

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FROM THE LITERATURE

locally excised DCIS into a 2 ¥ 2 factorial trial of radiotherapy, tamoxifen, or both. Each patient and surgeon team decided whether to enter into the 4-way randomization, or one of two 2-way randomizations. Researchers recommended a radiotherapy dose of 50 Gy in 25 fractions over 5 weeks (2 Gy/day on weekdays) and a tamoxifen dose of 20 mg daily for 5 years. Intention-to-treat analysis was performed on the primary end points of invasive ipsilateral new breast events for radiotherapy and any new breast event, including contralateral disease and DCIS, for tamoxifen. Summary: At a median follow-up of 12.7 (range, 10.9-14.7) years of 1694 patients eligible for analysis, 163 invasive (122 ipsilateral; 39 contralateral), 197 DCIS (174 ipsilateral; 17 contralateral), and 16 of unknown invasiveness or laterality was diagnosed. Incidence of all new breast events was reduced with radiotherapy (HR, 0.41; 95% CI, 0.30-0.56; P <.0001), as well as with tamoxifen (HR, 0.71; 95% CI, 0.58-0.88; P = .002), with radiotherapy reducing the incidence of ipsilateral invasive disease (HR, 0.32; 95% CI, .19-0.56; P <.0001) and ipsilateral DCIS (HR, 0.38; 95% CI,0.22-0.63; P <.0001), but having no effect on contralateral breast cancer (HR, 0.84; 95% CI, 0.45-1.58; P = .6). Tamoxifen reduced recurrent ipsilateral DCIS (HR, 0.70; 95% CI, 0.51-0.86; P = .03) and contralateral tumors (HR, 0.44; 95% CI, 0.25-0.77; P = .005), but had no effect on ipsilateral invasive disease. Takeaway: Several studies using adjuvant radiotherapy alone in DCIS have shown that it decreases local recurrence by 50% but not the occurrence of metastatic disease, and it does not reduce OS. This study confirms the results of previous studies that radiation therapy is the most effective treatment to prevent ipsilateral DCIS and all breast events. Tamoxifen has the added benefit of a systematic effect on reducing the risk of contralateral DCIS. Subgroup analysis showed that radiotherapy was most effective in women older than 50 years, whereas tamoxifen was most effective for women who had a low or an intermediate grade of disease. Therefore, both radiotherapy and tamoxifen should be used in the management of patients with DCIS. Cuzick J, et al. Lancet Oncol. 2011;12:21-29.

■ Systematic Review of Anti-EGFR Treatment and KRAS Mutation Status Background: KRAS, an oncogene that is frequently mutated in colorectal cancer (CRC), is a central signaling node that integrates signaling cascades in many EGFR pathways. It has been hypothesized, and many ret-

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rospective studies corroborate, that mutations in this gene could prevent benefit from anti-EGFR therapy. Taking it one step forward, researchers are conducting randomized controlled trials to evaluate the predictive ability of KRAS testing on survival outcomes with cetuximab or panitumumab treatment in patients with advanced CRC. Design: The investigators searched MEDLINE, PubMed, and the Human Genome Epidemiology Literature Finder for studies reporting on at least one of the following: overall mortality; recurrence, relapse, or disease progression; and treatment failure, which included time-to-event outcomes. The search was limited to those reported up through March 24, 2010, and stratified patients with CRC who had received cetuximab or panitumumab by KRAS status. Using undirected graphs, the investigators identified overlapping populations and excluded them from the meta-analysis. To summarize survival outcomes, they performed random-effects metaanalysis of HRs, relative HRs, and odds ratios (ORs) using the DerSimonian-Laird model. To summarize accuracy for predicting outcomes, they performed bivariate random-effects meta-analysis of sensitivity and specificity and calculated summary positive and negative likelihood ratios using corresponding CIs. Summary: The 45 publications that were eligible for analysis represent 24 nonoverlapping studies. Of these, 4 were re-analyses of randomized controlled trials of antiEGFR therapy versus best supportive care or chemotherapy alone, from which the investigators found no significant benefit in OS or PFS in patients with KRAS mutations (HR, 1.0). Their analysis of 22 studies with nonoverlapping populations found a summary specificity of 0.49 (CI, 0.43-0.55) and a summary sensitivity of 0.93 (CI, 0.87-0.97), which corresponds to a summary positive likelihood ratio of 7.35 (CI, 3.72-14.50) and a summary negative likelihood ratio of 0.55 (CI, 0.49-0.61). Takeaway: This meta-analysis study of KRAS mutation–positive or –negative CRC patients who were treated with anti-EGFR therapy shows that OS is almost 80% longer in those with wild-type KRAS. Furthermore, median PFS or TTP was shorter among patients with KRAS-positive tumors than with wild-type KRAS. The high positivity ratio suggests that KRAS mutations are a strong predictor of reduced survival, progression, and treatment failure. This study corroborates the warning on the US Food and Drug Administration–approved labeling that restricts the use of anti-EGFR antibody therapy to patients with CRC who test negative for KRAS mutations. ■ Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49.

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CASE REPORT

Severe Acneiform Eruption following Trastuzumab Therapy Sara S. Kim, BS, PharmD, BCOP1; Kerin Adelson, MD2 Department of Pharmacy; 2Division of Hematology/Oncology, The Mount Sinai Medical Center, New York

rastuzumab is a human epidermal growth factor receptor (HER)-2/neu inhibitor approved by the US Food and Drug Administration for the treatment of HER-2–positive breast cancer. Although acneiform rash, also known as papulopustular eruption, is a common cutaneous toxicity of epidermal growth factor receptor (EGFR) inhibitors,1 it has not been shown to be associated with trastuzumab therapy. In this article, we report on a patient who developed grade 3 acneiform rash (based on grading criteria by National Cancer Institute-Common Terminology Criteria for Adverse Events) after receiving trastuzumab therapy.

Case Report A 51-year-old woman with stage I estrogen receptor–weakly positive, progesterone receptor–negative, HER-2–positive breast cancer underwent a bilateral modified radical mastectomy, followed by a regimen of docetaxel/carboplatin/trastuzumab (TCH). At the time of treatment, she was not taking any other medications or herbal supplements. After receiving the first cycle of TCH, she presented with acneiform eruptions, predominantly on the face and scalp, which became more severe and extensive after the second cycle. Compared with the classic presentations of EGFR inhibitor–associated acneiform rash, the papules and pustules were larger in size (>0.5 to 1 cm; Figure). She was treated with oral minocycline and topical

Figure. Papulopustular eruption following trastuzumab therapy.

Journal of Hematology Oncology Pharmacy

mupirocin cream, both of which produced only a modest response. She was then given a local corticosteroid injection to the scalp lesions and showed a marked improvement. Despite the improvement of the skin lesions, however, she experienced three separate episodes of bacterial skin infections in the setting of nonneutropenia (leukocyte counts: range, 53007400/µL), all of which occurred at 3- to 4-week intervals (Table). The first infectious episode occurred 1.5 months after the initiation of chemotherapy at the left mastectomy site, followed by an infection at the port site, then a cellulitis of the right upper extremity. Despite the severe cutaneous complications, the patient has successfully completed all six cycles of TCH at full weight-based dose (Table), and is currently being treated with intravenous trastuzumab (6 mg/kg every 3 weeks) as single-agent therapy. She experienced complete resolution of acneiform eruption, but with residual facial hyperpigmentations.

Discussion Drug-induced acneiform rash and acne vulgaris share a close resemblance in appearance, but they differ pathologically and etiologically.2 Unlike acneiform rash, which is predominantly inflammatory papulopustular eruptions without the presence of comedones or any apparent infectious etiology, acne vulgaris is characterized by the presence of sebum and comedones.2-4 Like EGFR, HER-2 receptors have been shown to play a role in keratinocyte differentiations in the skin5; hence, the observed cutaneous toxicity in our patient could be associated with the deregulated process of keratinocyte differentiations, which is related to trastuzumab therapy. Although “acne” has been reported in 2% of trastuzumab-treated patients,6 clinical presentations of acne differ from the acneiform rash we observed in our patient. Likewise, although docetaxel has been associated with various types of cutaneous toxicities, this specific dermatologic toxicity—acneiform rash—has not yet been described with docetaxel therapy.7 Based on an objective causality assessment scale,8 trastuzumab is a possible cause of the cutaneous toxicity observed in our patient. The pattern of trastuzumabinduced acneiform eruption appears to resemble that of

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CASE REPORT

Table Timeline of TCH Therapy and the Occurrence of Cutaneous Complications Date (treatment day) Treatment cycle Cutaneous complication 05/26/09 (day 1)

First

06/15/09 (day 21)

Second

06/29/09 (day 35)

07/06/09 (day 42)

Third

07/27/09 (day 63)

Fourth

08/26/09 (day 93)

08/31/09 (day 98) 09/16/09 (day 114) 09/21/09 (day 119) 10/06/09 (day 134)

Supportive treatment

Mild to moderate papulopustular eruption noted on face/scalp

Started systemic minocycline therapy

Extensive and severe papulopustular eruption all over face/scalp Papulopustular eruption remained severe Mastectomy site infection

Started topical mupirocin to be applied on face/scalp Corticosteroid injected locally to the scalp Drained

Breast tissue expander removed Started systemic cephalexin therapy Fifth (therapy delayed by 2 weeks)

Started intranasal bactroban therapy Port site infection

Started systemic augmentin therapy

Cellulitis of right upper extremity

Admitted for observation and treated with intravenous antibiotics

Sixth

TCH indicates docetaxel, carboplatin, and trastuzumab.

EGFR inhibitors in that the eruption subsided with multiple exposure. Drug-induced pustules, in general, have been shown to be sterile. Nonetheless, the increased Staphylococcus carrier state and/or the impaired skin barriers in patients with severe papulopustular eruption have been suggested as the possible causes for developing secondary bacterial infections.1 In fact, a recent study showed that >50% of cases with drug-induced pustules were carriers for Staphylococcus.9 In our patient, bacterial cultures were not obtained at the time of acneiform eruption, thus the causal relationship could not be clearly established.

Conclusion Current management strategies for acneiform rash include alcohol-free topical emollient, oral antihistamine, topical clindamycin gel, and a tetracycline-derivative systemic antibiotic. Our patient responded well to local corticosteroid therapy, but the use of corticosteroids in acneiform rash remains controversial. Based on our experience, vigilant surveillance for infectious complications is warranted in patients who develop severe drug-induced acneiform rash. Further more, in light of documented cases of methicillin-resistant Staphylococcus aureus superinfection associated with acneiform rash,1 nasal sterilization has also been suggested as a preventive strategy against bacterial skin infection.1,9

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Therefore, in patients who develop severe druginduced acneiform eruption, it may be deemed appropriate to obtain bacterial cultures and prescribe a course of nasal mupirocin, at the time of eruption, to eradicate Staphylococcus colonization and minimize the risk of developing secondary bacterial infections. â&#x2013;

Disclosure Drs Kim and Adelson did not report any potential financial conflicts of interest. References 1. Agero AL, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657-670. 2. Shah NT, Kris MG, Pao W, et al. Practical management of patients with nonsmall-cell lung cancer treated with gefitinib. J Clin Oncol. 2005;23:165-174. 3. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol. 2001;144:1169-1176. 4. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6:803-812. 5. Maguire HC Jr, Jaworsky C, Cohen JA, et al. Distribution of neu (c-erbB-2) protein in human skin. J Invest Dermatol. 1989;92:786-790. 6. Herceptin (trastuzumab) [package insert]. San Francisco, CA: Genentech Inc; March 2009. 7. Taxotere (docetaxel) [package insert]. Bridgewater, NJ: sanofi-aventis; October 2010. 8. Naranjo CA, Busto U, Abel JG, Sellers EM. Empiric delineation of the probability spectrum of adverse drug reactions. Clin Pharmacol Ther. 1981;29:267-268. 9. Amitay-Laish I, David M, Stemmer SM. Staphylococcus coagulase-positive skin inflammation associated with epidermal growth factor receptor-targeted therapy: an early and a late phase of papulopustular eruptions. Oncologist. 2010;15:1002-1008.

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CLINICAL PRACTICE

New Compounds Hold Promise for Prostate Cancer Oncology Pharmacists’ Perspective, page 44

By Caroline Helwick

irtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Docetaxel, the standard of care for these patients, provides a modest prolongation of survival, but there is an urgent need for novel treatment strategies. Recently, the biological and molecular mechanisms driving prostate cancer growth and progression have become better understood, and this has resulted in widespread clinical testing of numerous new targeted therapies. At least some of these may extend and ideally even save the lives of the 218,000 men who develop this disease annually, some 32,000 of whom will die of prostate cancer under current therapies.1

Immunotherapy Several forms of immunotherapy made news in 2010, most strikingly the antigen-specific product sipuleucel-T, which became US Food and Drug Administration (FDA)-approved on April 29, 2010, for metastatic castration-resistant prostate cancer (CRPC) based on survival benefits shown in phase 3 trials. Sipuleucel-T is an active cellular immunotherapy, that is, a type of therapeutic cancer vaccine. It is derived from autologous peripheral blood cells that are collected during leukapheresis to contain only antigen-presenting cells. This product is cultured ex vivo with a recombinant fusion protein containing prostatic acid phosphatase (a prostate antigen) and granulocytemacrophage colony-stimulating factor to produce the vaccine that is infused into the patient to boost T-cell response against prostate cancer cells. In the phase 3 IMPACT trial, patients receiving the vaccine had a median survival time of 25.8 months and 3-year survival of 32.1%, compared with 21.7 months and 23%, respectively, for patients receiving placebo.2 Although this amounted to a 22% relative reduction in risk of death, the vaccine did not delay disease progression, which occurred at approximately 14 weeks in each arm. Treating men with an immunotherapy when they have metastatic and castration-resistant disease is “an uphill battle that probably involves barriers that have not yet been defined,” according to Dan Longo, MD, of the National Institute on Aging, who wrote an accompanying editorial to the publication of the IMPACT

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results. He noted that a 22% reduction in mortality in this challenging group may bode well for use of the drug earlier in the disease, although he felt the lack of an effect on progression is concerning. Benefits to be gained from this drug may become clearer with the final results of the ongoing phase 2 ProACT trial.

Androgen Receptor Targeting Prostate cancer is a hormonally sensitive disease that can be controlled for long periods with androgen-deprivation therapy. The androgen receptor plays a critical role in maintaining the proliferation of prostate cancer cells, not only before androgen ablation but also after hormonal treatments fail. Novel therapeutic strategies aim to inhibit and destabilize the function of this receptor and its interaction with key proteins. Early success with these oral compounds is being observed. Abiraterone acetate is an orally administered small molecule that irreversibly and specifically inhibits cytochrome P17, a key enzyme in the generation of androgens and thus the production of testosterone. Testosterone levels in the testes and adrenals are thought to stimulate the growth of prostate cancer cells. Therefore, by selectively inhibiting the target enzyme, abiraterone consequently blocks testosterone production in both the adrenals and testes and suppresses cancer cell growth. Abiraterone has proven highly active in some men, with responses ranging from 45% in heavily pretreated patients to 75% in patients without extensive secondary hormonal therapy or chemotherapy.3 In a phase 2 trial reported this year by investigators from the United Kingdom, half of the 47 docetaxel-treated patients had ≥50% declines in prostate-specific antigen (PSA), and median time to PSA progression was 169 days.4 One fourth of the patients were still benefiting from the treatment after almost 1 year. Additional studies reported at the 2010 meeting of the American Society of Clinical Oncology showed durable responses (ie, median time to PSA progression of 71 weeks) in 58% of chemotherapy-naïve CRPC patients receiving abiraterone5 and prolonged remissions in patients with less than five circulating tumor cells after 1 month of abiraterone treatment.6 Also showing promise in this class of agents is

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New Compounds for Prostate Cancer

MDV3100. This small-molecule androgen receptor antagonist inhibits androgen receptor function by blocking nuclear translocation of the receptor and DNA binding. The drug’s researchers claim that MDV3100 differs from other antiandrogens in its robust affinity for the androgen receptor and its multifaceted approach to stifling androgen production and activity. It works by three complementary actions: blocking testosterone binding to the androgen receptor, impeding movement of the androgen receptor to the nucleus of prostate cancer cells, and inhibiting the binding to DNA. In a recent phase 1/2 trial, more than half the patients with CRPC had ≥50% reduction in PSA, and median time to progression was 47 weeks.7 In addition, 22% of patients had soft-tissue responses and 56% had stabilized bone disease. “We were encouraged to see antitumor activity in men whose disease had spread after either becoming resistant to previous hormone treatments or progressing following chemotherapy,” said the study’s lead author Howard Scher, MD, of Memorial Sloan-Kettering Cancer Center, in a press release. “These findings strengthen the drug’s potential to change the outlook for a group of patients who currently have limited effective treatment options.” MDV3100 is being further evaluated in the 1200-patient AFFIRM trial. Histone deacetylase inhibitors also target androgen receptor activity, and clinical trials are evaluating vorinostat and panobinostat within this class.

New Taxane The FDA recently granted approval to a promising new taxane, cabazitaxel, for the treatment of metastatic CRPC after docetaxel fails. Cabazitaxel works by disrupting the microtubular network that is essential for mitotic and interphase cellular functions and causes inhibition of cell division and cell death. Cabazitaxel showed a highly significant 30% reduction in mortality over mitoxantrone in the phase 3 TROPIC trial.8 In the final analysis of the study, median overall survival was improved from 12.7 months with mitoxantrone to 15.1 months with cabazitaxel.9 In a press statement, Richard Pazdur, MD, director of the Office of Oncology Drug Products at the FDA, commented on the potential value of cabazitaxel, “The FDA was able to review and approve the application for [cabazitaxel] in 11 weeks, expediting the availability of this drug to men with prostate cancer.” Future studies will evaluate the drug in less-advanced disease. Endothelial Receptor Antagonists Endothelins have been implicated in numerous

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physiologic and pathologic conditions. In prostate cancer, levels of endothelin-1 are increased, heightening the peptide’s ability to modulate mitogenesis and apoptosis upon binding to the endothelin-A receptor. Endothelin antagonism, therefore, may be useful in that it blocks the activation of endothelin-A and thereby inhibits tumor growth. The investigational oral endothelin receptor antagonists have shown some biologic activity but have not yet improved clinical outcomes in CRPC. In phase 3 trials of atrasentan, clinical efficacy was minimal although responses in PSA and other biomarkers were observed.10,11 The phase 3 SWOG S0421 trial is currently investigating docetaxel plus atrasentan. Similarly, zibotentan has been shown safe when coupled with docetaxel in preliminary studies, but clinical efficacy of zibotentan has not yet been established.12 Treatment with zibotentan plus docetaxel is being further evaluated in an ongoing phase 3 program that includes patients with nonmetastatic disease (ENTHUSE M0), asymptomatic metastatic CRPC (ENTHUSE M1), and symptomatic metastatic CRPC (ENTHUSE M1C). ■

References 1. National Institutes of Health. Prostate cancer. www.cancer.cancer.gov/cancertopics/ types/prostate. Accessed August 19, 2010. 2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 3. Ryan CJ, Rosenberg J, Lin A, et al. Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer. Presented at the 2007 American Society of Clinical Oncology Prostate Cancer Symposium. Abstract 278. 4. Reid AHM, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28: 1489-1495. 5. Ryan CJ, Smith MR, Logothetis C, et al. Median time to progression in chemotherapy-naïve patients with castration-resistant prostate cancer treated with abiraterone acetate and low-dose prednisone. Presented at the 2010 American Society of Clinical Oncology. Abstract 4671. 6. Danila DC, Anand A, Sung CC, et al. Molecular profiling of circulating tumor cells in patients with castrate metastatic prostate cancer receiving abiraterone acetate after failure of docetaxel-based chemotherapy. Presented at the 2010 American Society of Clinical Oncology. Abstract 4635. 7. Sher HI, Beer TM, Higano CS, et al. Antitumor activity of MDV3100 in castration-resistant prostate cancer: a phase I-II study. Lancet. 2010;375:1437-1446. 8. Sartor AO, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase 3 trial (TROPIC). Presented at the 2010 Genitourinary Cancers Symposium. Abstract 9. 9. De Bono JS, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology. Abstract 4508. 10. Michaelson MD, Kaufman DS, Kantoff P, et al. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer. 2006;107:530-535. 11. Nelson JB, Love W, Chin JL, et al. for the Atrasentran Phase 3 Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-1966. 12. Trump DL, Payne H, Miller K, et al. Phase I study of the specific endothelin A receptor antagonist zibotentan combined with docetaxel in patients with metastatic castration-resistant prostate cancer: assessment of efficacy, pain, and safety. Presented at the 2010 American Society of Clinical Oncology. Abstract 4664.

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CLINICAL PRACTICE

Oncology Pharmacistsâ&#x20AC;&#x2122; Perspective Brian G. Cochran, PharmD, BCOP1; Christopher A. Fausel, PharmD, BCPS, BCOP2 Oncology Clinical Pharmacist; 2Clinical Director, Oncology Pharmacy Services, Indiana University Simon Cancer Center, Indianapolis 1

herapy options for castration-resistant metastatic prostate cancer have expanded in 2010 with two new distinctly different modalities. Sipuleucel-T is a cellular immunotherapy consisting of activated antigen-presenting cells combined ex vivo with prostatic acid phosphatase and granuBrian G. Cochran locyte-macrophage colony-stimulating factor and immersed in autologous peripheral blood mononuclear cells. Sipuleucel-T was studied in 512 patients randomized 2:1 versus placebo in patients with castration-resistant metastatic prostate cancer that had a Gleason score less than 7, asymptomatic disease considered progressive on the basis of imaging studies or prostate-specific antigen measurements, and an expected survival of greater than 6 months.1 With a median follow-up of 34.1 months, the primary end point of the trial, overall survival, was 25.8 months for the sipuleucel-T cohort and 21.7 months for the placebo cohort. Toxicities attributed to the sipuleucel-T were mainly constitutional symptoms related to the infusion. Cabazitaxel is a tubulin-binding agent of the taxane class that has activity in paclitaxel- and docetaxel-resistant cancer cells lines. Prednisone 10 mg/day orally was combined with either cabazitaxel 25 mg/m2 intravenously every 21 days or mitoxantrone 12 mg/m2 intravenously every 21 days in a phase 3, open-label trial in castration-resistant metastatic prostate cancer patients who had disease progression following treatment with docetaxel.2 A total of 755 patients were equally randomized between the cabazitaxel and mitoxantrone arms to determine if there was a difference in the primary end point, overall survival. With a median follow-up of 12.8 months, the overall survival was 15.1 months for the cabazitaxel arm and 12.7 months for the mitoxantrone arm. Hematologic, gastrointestinal, and constitutional toxicities were the most commonly reported adverse events associated with cabazitaxel. Although these agents have proven efficacy, both showing an overall survival benefit of approximately

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3 to 4 months, each treatment carries considerable cost. Sipuleucel-T consists of three infusions totaling $93,000, and cabazitaxel costs $8000 per every 3-weekly infusion. The American Society of Clinical Oncology released a guidance statement in 2009 regarding the cost of cancer care, which Christopher A. Fausel emphasized the importance of physician and patient education on the cost of treatment.3 In addition, this statement recommended that patientâ&#x20AC;&#x201C;physician discussions regarding the cost of care be considered an important component of high-quality care and recognized the need for the creation of educational and support resources to effectively communicate costs with patients. Oncology pharmacists can take steps to educate and empower patients about treatment choices and costs. These include assisting in preparing educational tools regarding the cost of care for specific treatment protocols, educating physicians and nurses about treatment costs, and facilitating contacts for patients with social workers or care coordinators who can provide assistance with financial counseling. Oncology pharmacists can establish standard practices for supportive care specific to each of these newer high-cost agents to minimize the chance of toxicity and hospitalization, thus conserving further use of resources. Standard-of-care treatment in prostate cancer is now a very high-cost endeavor. Oncology pharmacists have the skill set to assure patients and caregivers that optimal patient care is being delivered while being mindful of judicious use of healthcare resources. â&#x2013;

References 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. deBono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154. 3. Meropol NJ, Schrag D, Smith TJ, et al. American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol. 2009;27:3868-3874.

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AUTHOR GUIDELINES MISSION STATEMENT—Journal of Hematology Oncology Pharmacy (JHOP) is an independent, peerreviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals in these fields with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients. GENERAL INFORMATION—Manuscripts submitted to JHOP must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP. The editors invite readers to submit a articles on a variety of points of view and approaches to meet the mission of the journal. Articles will be divided into four main categories, including (1) original research, to provide an outlet for translational and practice-based research, including case reports and case series; (2) review articles that focus on drug and disease state as well as on basic science regarding the complex molecular biology of cancer with a pharmacy focus; (3) clinical controversies that discuss common clinical issues for which treatment is unclear; this could include “point, counterpoint” and “how I treat” type of articles; (4) practical issues in pharmacy management will focus on real-world issues involving logistics, economics, and other practice-related topics. Manuscripts submitted must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by JHOP. All authors must sign an appropriate disclosure form and a copyright transfer/authorship form. PEER REVIEW/EDITING—All articles undergo an initial internal review for topic appropriateness and manuscript format. Manuscripts that are not submitted according to the guidelines in this document will be returned to the author. All manuscripts are subject to a strict, blinded peer review (by 2-4 reviewers), and acceptance is based entirely on that review. Reviewers look for the accuracy of the information and data presented, as well as the relevance to the objectives of JHOP. All authors’ identifying information is removed from the article for the purpose of the peer review, but any study

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funding information is provided to reviewers. Authors are notified as soon as possible regarding the initial decision of acceptance or rejection of the article. The majority of articles that are accepted for publication, however, will require revisions and resubmission. A second review is conducted when recommended by reviewers. Routine editorial changes are made on all articles to conform to house style, following the AMA Manual of Style, 10th ed.1 The edited manuscript is sent to the corresponding author for a final review and for any outstanding editorial queries. Time from submission to publication is generally 4 to 7 months, but could be longer, depending on the peer-review and editing processes. AUTHORSHIP/COPYRIGHT—Authors listed on the manuscript should only include those who have made a direct contribution to the content of the article, in accordance with the authorship criteria provided by the International Committee of Medical Journal Editors (ICMJE).2 Credit for authorship is based on a substantial contribution to (1) conception and design, or data analysis/interpretation, (2) drafting or revising the article critically for intellectual content, and (3) approval of the final version to be published. These 3 criteria must all be met.2 Those who have contributed to the article but do not meet these authorship criteria should be acknowledged at the end of the article. Provide authors’ highest academic degree and professional affiliations. Also provide the name, address, telephone number, e-mail, and fax number of the corresponding author. The corresponding author is responsible for securing signatures for all forms from all authors. All authors are required to sign an Authorship/Copyright Transfer Form, assigning all copyrights for the manuscript to Green Hill Healthcare Communications, LLC, publisher of JHOP. For an article to be considered for publication, authors must adhere to the manuscript format described in this document and follow the general ICMJE guidelines.2 DISCLOSURE STATEMENTS—All authors must disclose any relationship that could be viewed as a potential conflict of interest, based on ICMJE guidelines,2 including any financial interests, direct or indirect, and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript.

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Each author must sign the Financial Disclosure Form in accordance with the ICMJE guidelines.2 JHOP discloses all information regarding employment, consultancies, stock ownership, honoraria, grants, or other financial sources with potential conflict of interest in relation to a manuscript, or if authors discuss any products or services with such commercial interest. Any information regarding funding, grants, or other financial compensation must be listed on the title page of the manuscript. All published articles will include disclosure statements listing any relationships with real or potential conflict of interest for all authors and for the manuscript/research. PERMISSIONS—Authors must secure written permission to reuse or adapt any graphic elements (table, figure) from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. Authors are responsible for acknowledging all information that has been published previously. MANUSCRIPT FORMAT—Manuscripts that do not adhere to the format described in this document will be returned to the author.

Conclusion: The conclusion is not a summary of the article. Rather, it should add something new to the article, a point of view or comments related to the rationale for the article and what the article adds to the literature. Tables and figures: Cite all figures, tables, algorithms, and other graphics in the text, but place the graphic elements at the end of the article, after the references. Type all tables and all figure heads and captions in the Word document. Figures and other images must also be provided as individual graphic files, saved at high resolution (300 dpi), as jpg or pdf file. Attach an individual file for each image. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact JHOP@greenhillhc.com. References: Use most up-to-date, post-1990, primary sources only, cited consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Avoid automatic numbering or footnote/endnote features. Try to limit the number of references to 35. Use citation format according to the AMA Manual of Style.1 Examples:

Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author. List all funding sources for the study/article.

1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295: 676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news? pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008.

Abstract: Articles must include an abstract (200-300 words) that describes the main objectives of the article, why this article is important, and what it adds to the literature. The abstract must be divided into these categories: Background, Objectives, Methods (and Study Design, if relevant), Results, and Conclusion.

HOW TO SUBMIT MANUSCRIPTS—Articles that do not follow the guidelines described in this document will not be considered for publication.

An abstract for an article that does not represent research findings should include the following categories to suggest why the article is important and what its main objectives are: Background, Objectives, Discussion, Conclusion. Text: The entire text must be provided as a doublespaced Word file and all pages numbered consecutively. Cite any graphic elements (tables, figures, algorithms, appendix) consecutively in the text, but place actual tables/figures at the end of the article, after the references. Limit the length of the text to 3500 words (excluding references, tables, and figures).

Journal of Hematology Oncology Pharmacy

Save the manuscript as a Word file and attach individual files for each image or figure. Save images (figures) individually as an image file (jpg or pdf). Digital images must be saved at a high resolution (300 dpi). Submit the entire manuscript and cover letter stating the objectives of the article to JHOP@greenhillhc. com. For assistance call 732-992-1890. REPRINTS—Reprints may be ordered for a nominal fee by contacting JHOP@greenhillhc.com.

1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007. 2. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated April 2010. www.icmje.org/urm_full.pdf. Accessed June 1, 2010.

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THANK YOU FOR MAKING US In a recent survey, oncology pharmacists said that they read The Oncology Pharmacist 1.5 times more* than its closest competitor in the pharmacy market. Source: ÂŠ Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)

Read * 1 # e h T acy m r a h P y Oncolog blication u Tabloid P

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